Cochrane Database of Systematic Reviews (Reviews) || Bendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia

Bendamustine for patients with indolent B cell lymphoid

malignancies including chronic lymphocytic leukaemia

(Review)

Vidal L Gafter-Gvili A Gurion R Raanani P Dreyling M Shpilberg O

This is a reprint of a Cochrane review prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2012 Issue 9

httpwwwthecochranelibrarycom

Bendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia (Review)

Copyright copy 2012 The Cochrane Collaboration Published by John Wiley amp Sons Ltd

T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

3SUMMARY OF FINDINGS FOR THE MAIN COMPARISON

4BACKGROUND

5OBJECTIVES

5METHODS

8RESULTS

Figure 1 9

Figure 2 11

Figure 3 12

Figure 4 13

Figure 5 13

14DISCUSSION

15AUTHORSrsquo CONCLUSIONS

15ACKNOWLEDGEMENTS

16REFERENCES

20CHARACTERISTICS OF STUDIES

32DATA AND ANALYSES

Analysis 11 Comparison 1 Bendamustine compared to other chemotherapy Outcome 1 Overall survival 33

Analysis 12 Comparison 1 Bendamustine compared to other chemotherapy Outcome 2 All-cause mortality 33

Analysis 13 Comparison 1 Bendamustine compared to other chemotherapy Outcome 3 All-cause mortality by type

lymphoid malignancy (fixed-effect) 34

Analysis 14 Comparison 1 Bendamustine compared to other chemotherapy Outcome 4 All-cause mortality by treatment

line (fixed-effect) 35

Analysis 15 Comparison 1 Bendamustine compared to other chemotherapy Outcome 5 All-cause mortality by type of

comparator (fixed-effect) 36

Analysis 16 Comparison 1 Bendamustine compared to other chemotherapy Outcome 6 All-cause mortality with or

without rituximab (fixed-effect) 37

Analysis 17 Comparison 1 Bendamustine compared to other chemotherapy Outcome 7 Progression-free survival 37

Analysis 18 Comparison 1 Bendamustine compared to other chemotherapy Outcome 8 Complete response 38

Analysis 19 Comparison 1 Bendamustine compared to other chemotherapy Outcome 9 Overall response rate (complete

and partial remission) 39

Analysis 110 Comparison 1 Bendamustine compared to other chemotherapy Outcome 10 Grade 3 to 4 adverse events 39

Analysis 111 Comparison 1 Bendamustine compared to other chemotherapy Outcome 11 Grade 3 to 4 adverse events

without CLL patients 40

40APPENDICES

43HISTORY

43CONTRIBUTIONS OF AUTHORS

43DECLARATIONS OF INTEREST

43DIFFERENCES BETWEEN PROTOCOL AND REVIEW

44INDEX TERMS

iBendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia (Review)


[Intervention Review]

Bendamustine for patients with indolent B cell lymphoidmalignancies including chronic lymphocytic leukaemia

Liat Vidal1 Anat Gafter-Gvili1 Ronit Gurion2 Pia Raanani2 Martin Dreyling3 Ofer Shpilberg2

1Department of Medicine E Beilinson Hospital Rabin Medical Center Petah Tikva Israel 2Institute of Hematology Davidoff

Center Beilinson Hospital Rabin Medical Center Petah Tikva Israel 3Medizinische Klinik III Klinikum der Universitaumlt Muumlnchen-

Groszlighadern Muumlnchen Germany

Contact address Liat Vidal Department of Medicine E Beilinson Hospital Rabin Medical Center 39 Jabotinski Street Petah Tikva

49100 Israel VidalL2clalitorgil vidallityahoocom

Editorial group Cochrane Haematological Malignancies Group

Publication status and date New published in Issue 9 2012

Review content assessed as up-to-date 30 May 2012

Citation Vidal L Gafter-Gvili A Gurion R Raanani P Dreyling M Shpilberg O Bendamustine for patients with indolent B cell

lymphoid malignancies including chronic lymphocytic leukaemia Cochrane Database of Systematic Reviews 2012 Issue 9 Art No

CD009045 DOI 10100214651858CD009045pub2


A B S T R A C T

Background

Indolent B cell lymphoid malignancies include follicular lymphoma small lymphocytic lymphoma mantle cell lymphoma lympho-

plasmacytic lymphoma and marginal zone lymphomas Chronic lymphocytic leukaemia (CLL) is a lymphoid malignancy similar to

small lymphocytic lymphoma (SLL) in its leukaemic phase

Indolent lymphoid malignancies including CLL are characterised by slow growth a high initial response rate and a relapsing and

progressive disease course Advanced-stage indolent B cell lymphoid malignancies are often incurable If symptoms or progressive disease

occur chemotherapy plus rituximab is indicated No chemotherapy regimen has been shown to improve overall survival compared to

a different regimen

Bendamustine is efficacious in the treatment of patients with indolent B cell lymphoid malignancies A number of randomised controlled

trials have examined the effect of bendamustine compared to other chemotherapy regimens in these patients Improved disease control

with no survival benefit is shown

Objectives

To evaluate the efficacy of bendamustine therapy for patients with indolent B cell lymphoid malignancies including CLL

Search methods

We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012 Issue 2)

MEDLINE (1966 to May 2012) EMBASE (1974 to November 2011) LILACS (1982 to May 2012) databases of ongoing trials

(accessed 30 April 2012) and relevant conference proceedings We searched references of identified trials and contacted the first author

of each included trial

Selection criteria

Randomised controlled trials that compared a bendamustine-containing regimen to other chemotherapy with or without immunother-

apy

1Bendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia (Review)


Data collection and analysis

Two authors independently appraised the quality of each trial and extracted data from included trials We estimated and pooled hazard

ratios (HR) and risk ratios (RR) with 95 confidence intervals (CI)

Main results

We included five trials randomising 1343 adult patients in the systematic review Allocation and blinding were unclear in three

trials and adequate in two Incomplete outcome data and selective reporting were adequate in all trials Trials varied in the type of

lymphoid malignancy bendamustine regimen and the comparator regimen In the three trials that included patients with follicular

lymphoma mantle cell lymphoma and other indolent lymphomas the comparator treatment was cyclophosphamide a combination of

cyclophosphamide vincristine doxorubicin and prednisone and fludarabine Two trials included only patients with CLL and compared

bendamustine to chlorambucil and to fludarabine We did not conduct a meta-analysis due to the clinical heterogeneity among trials

Bendamustine had no statistically significant effect on the overall survival of patients with indolent B cell lymphoid malignancies in any

of the included trials (trials of moderate quality) Progression-free survival was statistically significantly improved with bendamustine

treatment compared to other chemotherapy in three of the four trials that reported on it One trial demonstrated a non statistically

significant improvement of PFS The risk of grade 3 or 4 adverse events was similar when bendamustine was compared to CHOP and

fludarabine and higher when compared to chlorambucil Compared to chlorambucil quality of life was unaffected by bendamustine

treatment (one trial no meta-analysis)

Authorsrsquo conclusions

As none of the currently available chemotherapeutic protocols for induction therapy in indolent B cell lymphoid malignancies confer

a survival benefit and due to the improved progression-free survival in each of the included trials and a similar rate of grade 3 or 4

adverse events bendamustine may be considered for the treatment of patients with indolent B cell lymphoid malignancies However

the unclear effect on survival and the higher rate of adverse events compared to chlorambucil in patients with CLLSLL does not

support the use of bendamustine for these patients

The effect of bendamustine combined with rituximab should be evaluated in randomised clinical trials with more homogenous

populations and outcomes for specific subgroups of patients by type of lymphoma should be reported Any future trial should evaluate

the effect of bendamustine on quality of life

P L A I N L A N G U A G E S U M M A R Y

Bendamustine for patients with slow-growing lymphoma

Lymphoma is a cancer that originates from cells of the immune system in the lymph nodes called lymphocytes Slow-growing (indolent)

lymphoma is a group of lymphomas characterised by slow and continuous growth a high initial response rate to treatment that target

lymphoma cells (chemotherapy or rituximab) but a relapsing and progressive disease course It includes follicular lymphoma small

lymphocytic lymphoma and chronic lymphocytic leukaemia mantle cell lymphoma lymphoplasmacytic lymphoma and marginal zone

lymphoma With current therapy people with advanced-stage indolent lymphoma will experience relapse of their disease Bendamustine

is a type of chemotherapy that can be given to people with indolent lymphoma

We conducted a review of the effect of bendamustine for people with indolent B cell lymphoid malignancies After searching for all

relevant studies we found five studies with 1343 people

Our findings are summarised below

In people with indolent B cell lymphoma

- It is unclear whether bendamustine improves survival

- Bendamustine may prevent or delay progression of lymphoma

- Bendamustine may improve the response to treatment

- Bendamustine probably causes more serious side effects than certain chemotherapeutic drugs (as the combination of adriamycin

cyclophosphamide vincristine and prednisone or as fludarabine) and the same or less than other types of chemotherapy (chlorambucil)

- Only one study assessed quality of life and this study did not report different results for both treatment groups



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Bendamustinecomparedwithothertherapy

forBcelllymphoidmalignancy

PatientorpopulationpatientswithindolentBcelllymphoidmalignancy

Interventionbendamustine

Comparisonanytreatmentotherthanbendamustine(com

paratorintervention)

Outcomes

Assumed

risk

(control

group)(eventsper1000

patients)

Correspond-

ingrisk

(bendamustine


patients)

Relativeeffect

(95CI)

Noofparticipants

(studies)

Qualityoftheevidence

(GRADE)

Com

ments

Overallsurvival

Medianfollow-up35

to

44months

Asforall-causemortality


481patients(2studies)

oplusoplus

opluscopy

moderate

Moderatequality

dueto

serious

imprecision

a

wideconfidenceinterval

All-causemortality

Medianfollow-up28

to

44months

326per1000

277per1000

1202

patients(4studies)

oplusoplus

opluscopy

moderate

Reasonsandallocationof

losttofollow-uparenot

reported

in2trialsun-

clearriskofbias

GRADEWorkingGroupgradesofevidence

HighqualityFurtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect

ModeratequalityFurtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmaychangetheestimate

LowqualityFurtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate

VerylowqualityWeareveryuncertainabouttheestimate

CIconfidenceinterval

NNTnumberneededtotreat



B A C K G R O U N D

Description of the condition

The World Health Organization (WHO) classification published

in 2001 and updated in 2008 attempts to group lymphomas by

their corresponding normal cell (ie B cell T cell and natural killer

cell) using phenotypic molecular and cytogenetic characteristics

(Swerdlow 2008) The mature B cell lymphomas (also referred to as

non-Hodgkinrsquos lymphoma (NHL)) can be divided by their clinical

behaviour into aggressive (fast-growing) and indolent (slow-grow-

ing) the latter including up to 50 of NHL patients Indolent

lymphomas of mature B cell origin include follicular lymphoma

(FL) small lymphocytic lymphoma (SLL) mantle cell lymphoma

(MCL) lymphoplasmacytic lymphoma and marginal zone lym-

phomas (MZL) (Harris 1994 Swerdlow 2008) Chronic lympho-

cytic leukaemia (CLL) is a lymphoid neoplasm that is similar to

SLL in leukaemic phase (Rai 1975 Swerdlow 2008 Tsimberidou

2007) MCL has characteristics of aggressive as well indolent lym-

phoma

The Ann Arbor staging system originally developed for Hodgkinrsquos

lymphoma provides the basis for anatomic staging of NHL The

Ann Arbor stage depends on both the extent of disease (as lo-

cated with biopsy computerised tomography (CT) scanning and

positron emission tomography) and on systemic symptoms

The International Prognostic Index (IPI) is a prognostic score with

value in all of the NHL variants Specific prognostic scores have

been developed (follicular lymphoma IPI FLIPI and mantle cell

lymphoma IPI MIPI) (Hoster 2008 Hoster 2008b)

Indolent B cell lymphoid malignancies including CLL have many

common characteristics besides the common cell of origin (ma-

ture B cell) The watchful waiting strategy is acceptable in most

indolent B cell lymphoid malignancies including CLL (Ardeshna

2003 CLL trialist 1999 Young 1988) Indolent B cell lymphoid

malignancies as the name indicates are characterised by slow and

continuous growth a high initial response rate but a relapsing

and progressive disease course (Horning 1984) Advanced-stage

indolent NHL is often incurable Chemotherapy regimens for the

treatment of indolent B cell lymphoid malignancies include com-

binations of chlorambucil mitoxantrone cyclophosphamide vin-

cristine doxorubicin and prednisone and fludarabine-based reg-

imens In recent years immunotherapy has been used to improve

the clinical outcomes of patients with indolent NHL (Hallek 2010

Schulz 2007)

The course of indolent B cell lymphoid malignancies may be quite

variable depending on the histology as well as other variables Pa-

tients with localised (early-stage) lymphoma can be treated with

radiotherapy and may be cured (MacManus 1996 Wilder 2001)

For patients with advanced follicular lymphoma the average sur-

vival time is approximately 10 years A number of studies that

evaluated observation have compared treatment in patients with

advanced stage indolent B cell lymphoid malignancies (Ardeshna

2003 Young 1988) These trials have brought the acceptance of

the watchful waiting strategy and the development of indications

for treatment Despite major progress with the introduction of

monoclonal antibodies for the treatment of indolent lymphoid

neoplasms (Schulz 2007 Vidal 2009) the majority of patients can-

not be cured with the currently available therapies

The natural history of CLLSLL is extremely variable and survival

from initial diagnosis ranges from 2 to 20 years The first stag-

ing system for CLL was developed by Rai (Rai 1975) It is based

on the concept that in CLL there is a gradual and progressive

increase in the burden of leukaemic lymphocytes While median

survival of patients with CLL Rai stage 0 (lymphocytosis alone)

was 150 months median survival of patients with Rai stage III or

IV (anaemia or thrombocytopenia respectively) was 19 months

The Rai and the Binet staging system (which uses the number

of involved lymphoid sites anaemia andor thrombocytopenia to

define disease stage Binet 1981) are simple yet accurate predic-

tors of survival and are widely used by clinicians and researchers

Additional prognostic factors have been suggested including im-

munophenotypic and cytogenetic abnormalities such as ZAP70

and CD38 or deletion 17p and mutation status (Hamblin 1999

Kienle 2010)

Description of the intervention

Most patients with indolent B cell lymphoid malignancies present

with advanced disease ie stage III or IV Asymptomatic patients

can be observed (Ardeshna 2003 CLL trialist 1999 Young 1988)

About a third of patients with CLLSLL require repeated chemo-

therapy due to symptoms or advanced disease (Armitage 1998

Rai 1975) If treatment is required due to symptoms or progres-

sive disease immunotherapy-based treatment (ie chemotherapy

plus rituximab) is preferred as it improves response rate and pro-

longs progression-free survival (PFS) and overall survival (Hallek

2010 Schulz 2007) It is unknown which chemotherapy provides

the best results combined with immunotherapy Different che-

motherapy regimens without rituximab have been compared in-

cluding chlorambucil combinations of mitoxantrone chloram-

bucil prednisone (MCP) cyclophosphamide vincristine pred-

nisone (COP) cyclophosphamide doxorubicin vincristine pred-

nisone (CHOP) and fludarabine-based regimens None has been

shown to improve time to progression-free survival and overall sur-

vival (Glick 1981 Hagenbeek 2006 Klasa 2002 Nickenig 2006

Peterson 2003) Data from a large multicentre prospective co-

hort study in the United States the National LymphoCare Study

(NLCS) found that 55 of patients with follicular lymphoma

who require chemotherapy (regardless of disease stage) are treated

with a CHOP protocol 23 with a COP regimen and 155

using a fludarabine-based regimen (Friedberg 2009)

In order to improve survival new first-line treatments as well as

salvage regimens are being sought

Bendamustine 5-[Bis(2-chloroethyl)amino]-1-methyl-2-benzim-

idazolebutyric acid hydrochloride was developed and first studied



in the German Democratic Republic more than 30 years ago by

Ozegowski and Krebs (Ozegowski 1971) Its structure is charac-

terised by a nitrogen mustard derivative linked to a benzimida-

zole nucleus with a butanoic acid residue in position 2 this over-

all configuration is aimed at reducing the toxicity of the nitro-

gen mustard moiety It therefore has structural similarities to both

alkylating agents (nitrogen mustard derivative) and purine ana-

logues (benzimidazole ring) Only partial cross-resistance occurs

between bendamustine and other alkylators (Strumberg 1996)

Bendamustine can induce apoptosis of B cell chronic lymphocytic

leukaemia cell lines (Chow 2001) Synergistic effects on apoptosis

have been observed with combined rituximab and bendamustine

in lymphoma cell lines in vitro and in ex vivo cells from patients

with chronic lymphocytic leukaemia (Rummel 2002)

Based on its structure and its in vitro activity its clinical activity has

been assessed in the clinical setting to treat patients with indolent

B cell lymphoid malignancies including CLL

How the intervention might work

A number of phase III trials support the efficacy of bendamus-

tine for patients with indolent B cell lymphoid malignancies as

a single agent or in combination with other agents including

various chemotherapy protocols and anti-CD20 monoclonal an-

tibody (rituximab) (Friedberg 2008 Heider 2001 Kahl 2010

Koenigsmann 2004 Robinson 2008b Rummel 2005 Weide

2002 Weide 2004) Bendamustine has been combined with ritux-

imab in patients with relapsed CLL (Fischer 2008 Weide 2004)

The overall response rate was 77 with a 15 complete response

rate It was well tolerated grade 34 neutropenia and thrombo-

cytopenia occurred in 12 and 9 of all courses respectively

Grade 34 infection-related adverse events occurred in 5 of

courses with treatment-related deaths in 4 of patients (Fischer

2008) Bendamustine is well tolerated even in heavily pre-treated

lymphoma patients as monotherapy and in combination with

other chemotherapy its main adverse effects being leucopenia and

thrombocytopenia (Fischer 2008 Heider 2001 Kahl 2010)

Bendamustine has been recently approved by the US Food and

Drug Administration (FDA) for the treatment of CLL and ritux-

imab-refractory indolent B cell non-Hodgkin lymphoma

Why it is important to do this review

A number of randomised controlled trials have examined the ef-

fect of bendamustine in patients with indolent B cell lymphoid

malignancies Progression-free survival was similar or prolonged

with bendamustine compared to control and a survival benefit has

not been shown

O B J E C T I V E S

To evaluate the efficacy of bendamustine therapy for patients with

indolent B cell lymphoid malignancies including CLL

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised trials irrespective of publication status and language

Types of participants

Patients with histologically confirmed indolent B cell lymphoid

malignancies ie SLLCLL follicular lymphoma mantle cell

lymphoma lymphoplasmacytic lymphoma marginal zone lym-

phoma

We included both patients receiving bendamustine as first-line

therapy and patients with relapsed or refractory disease receiving

it as salvage therapy Patients might have received high-dose che-

motherapy following first-line or salvage therapy

We included patients of any age

Types of interventions

Investigational intervention

bull Bendamustine as a single agent or in combination with

chemotherapy and immunotherapy

Comparison interventions

bull Observation or steroids alone

bull Chemotherapy

bull Chemotherapy in combination with immunotherapy (ie

rituximab) or radio-immunotherapy

We included trials in which bendamustine was combined with

immunotherapy or radio-immunotherapy only if bendamustine

was compared to chemotherapy combined with the same im-

munotherapy or radio-immunotherapy

Chemotherapy includedmiddot

bull Adriamycin cyclophosphamide chlorambucil fludarabine

mitoxantrone vincristine

bull Steroids could be combined with any chemotherapeutic

regimen

Types of outcome measures

As defined in Cheson 2007 and Hallek 2008



Primary outcomes

bull Overall survival (OS)

bull All cause mortality This outcome was added post-hoc to

protocol due to the scarcity of OS data

Secondary outcomes

bull Progression-free survival (PFS)

bull Complete response (CR)

bull Overall response (partial and complete response)

bull Quality of life

bull Treatment-related mortality

bull Adverse events requiring discontinuation of therapy

bull Grade 34 adverse events

bull Infection-related adverse events

Search methods for identification of studies

Electronic searches

We searched the following databases

bull Cochrane Central Register of Controlled Trials

(CENTRAL) (The Cochrane Library 2012 Issue 2 see Appendix

1)

bull MEDLINE (1966 to May 2012) (through PubMed see

Appendix 2)

bull EMBASE (1974 to November 2011) see Appendix 3)

bull LILACS (1982 to May 2012) see Appendix 4)

bull clinical trials in haematological malignancies (

wwwhematology-studiesorg)

We used the terms rsquolymphomarsquo and similar OR rsquochronic lympho-

cytic leukaemiarsquo and similar with the term rsquobendamustinersquo and

similar

We combined the search terms with the highly sensitive search

strategy for identifying reports of randomised controlled trials (

Robinson 2002) in the MEDLINE search

Searching other resources

We searched the conference proceedings of the American Society

of Hematology (1995 to 2011) conference proceedings of the

American Society of Clinical Oncology Annual Meeting (1995 to

2011) and proceedings of the European Hematology Association

(2002 to 2011) for relevant abstracts

We searched databases of ongoing and unpublished trials (ac-

cessed 30 April 2012) httpwwwcontrolled-trialscom http

wwwclinicaltrialsgovct httpclinicaltrialsncinihgov

We contacted the first or corresponding author of each included

study and researchers active in the field for information regarding

unpublished trials or complementary information on their own

trial One author (Dr Merkle on behalf of Dr Knauf ) (Knauf

2009) replied and provided additional data Co-ordinators of two

ongoing clinical trials responded One clinical trial (Roche) is on-

going and analysis has not yet been performed Axel Hinke re-

sponded on behalf of Prof Niederle (Study chair) and provided

trial data (Niederle 2012)

We checked the citations of included trials and major reviews for

additional studies


Selection of studies

One review author (LV) inspected the title and when available

the abstract and applied the inclusion criteria Where relevant

articles were identified two review authors (LV AG) obtained and

inspected the full article independently and applied the inclusion

criteria In case of disagreement between the two review authors

a third author (RG) independently applied the inclusion criteria

We documented our justification for excluding studies

We included trials regardless of publication status date of publi-

cation and language

Data extraction and management

Two review authors (LV AG) independently extracted the data

from the included trials In case of disagreement between the two

review authors a third author (RG) independently extracted the

data We discussed the data extraction documented decisions and

where necessary contacted the authors of the studies for clarifica-

tion We collected all data on an intention-to-treat basis where

possible

We extracted checked and recorded the following data

1 Characteristics of trials

Publication status published published as abstract

unpublished

Year (defined as recruitment initiation year) and

country or countries of study

Trial sponsor (academic industrial)

Intention-to-treat analysis performed possible to

extract efficacy analysis

Design (method of allocation generation and

concealment blinding)

Unit of allocation (patient episodes cluster)

Duration of study follow-up

Response definition event definitions

Case definitions used (inclusion and exclusion criteria)

Assessment of mortality (primary outcome secondary

outcome safety)

2 Characteristics of patients

Number of participants in each group

Age (mean and standard deviation)



Type of disease (SLLCLL FL MCL

lymphoplasmacytic lymphoma MZL)

Disease status (untreated previously treated)

Number of patients with performance status le 2 gt 2

Number of patients with stage IIIIV disease

(according to Ann Arbor)

Number of patients with bulky disease

Number of patients with elevated lactate

dehydrogenase (LDH) levels

3 Characteristics of interventions

Treatment of control group (regimen dose number of

treatment days length of cycle and planned total duration of

therapy)

Experimental intervention

⋄ Dose number of treatment days length of cycle

and planned total duration of therapy

⋄ Regimen (monotherapy type of combination

therapy)

4 Characteristics of outcome measures (extracted for each

group and total events)

Overall survival

⋄ Number of deaths at 12 36 60 months end of

follow-up

⋄ Number of patients available for follow-up at the

time of evaluation of survival risk

⋄ Hazard ratio (HR) of OS and its standard error

(SE) confidence interval (CI) or P value

⋄ KM curve (yesno)

HR of EFS and its SE CI or P value

HR of PFS and its SE CI or P value

Number of patients who achieved complete response

(CR) at end of treatment

Number of patients who achieved partial response

(PR) at end of treatment

Quality of life (scale and score)

Adverse events (any grade 3 to 4 requiring

discontinuation of treatment infection-related)

Number of patients excluded from outcome

assessment after randomisation and the reasons for their

exclusion

Assessment of risk of bias in included studies

Two review authors (LV AG) independently assessed the trials

for methodological quality We described and assessed allocation

concealment sequence generation blinding incomplete outcome

data and selective outcome reporting individually and according

to The Cochrane Collaborationrsquos tool for assessing bias (Higgins

2011) We resolved any disagreement by discussion If disagree-

ment persisted a third review author (RG) extracted the data inde-

pendently We discussed the data extraction document disagree-

ments and their resolution and where necessary contacted the

authors of the studies for clarification If this was unsuccessful we

reported disagreements

Measures of treatment effect

We planned to estimate risk ratios (RR) for dichotomous data and

hazard ratios (HR) for time to event outcomes We planned to

estimate standardised mean difference (SMD) for quality of life

assessment

Unit of analysis issues

Cross-over trials

We did not expect trials with a cross-over design as the effect of the

chemotherapy in the first period is assumed to continue through

the second period

Multiple observations at different time points for the same

outcome

For time to event meta-analysis we used data at the longest follow-

up

For dichotomous data we analysed outcome data at 12 and 60

months separately We analysed adverse events at the end of che-

motherapy up to 12 months and if data were available at 60

months We analysed response rates only at the end of chemother-

apy up to 12 months

Events that may recur

Adverse events may occur more than once in the same individ-

ual mainly during different treatment cycles We extracted the

number of patients in each arm and the number of patients who

experienced at least one event We counted each patient once even

if repeated events occurred and analysed the data as dichotomous

data

Dealing with missing data

If possible we imputed missing data for patients who were lost to

follow-up after randomisation (dichotomous data) assuming poor

outcome (worse case scenario) for missing individuals

We planned to perform a sensitivity analysis of the primary out-

come excluding trials in which more than 20 of participants

were lost to follow-up

Assessment of heterogeneity

We assessed heterogeneity (the degree of difference between the

results of different trials) using the Chi2 test of heterogeneity and

the I2 statistic of inconsistency (Deeks 2011 Higgins 2003) We

defined a statistically significant heterogeneity as P value less than

01 or an I2 statistic greater than 50



Assessment of reporting biases

If at least 10 trials were included we would have inspected the fun-

nel plot of the treatment effect against the precision of trials (plots

of the log of the risk ratio for efficacy against the standard error) in

order to estimate potential asymmetry that may indicate selection

bias (the selective publication of trials with positive findings) or

methodological flaws in the small studies (Sterne 2011)

Data synthesis

Due to clinical heterogeneity no meta-analysis was done

If the HR and its SE (or CI) were not reported we estimated lsquoO -

Ersquo and lsquoVrsquo statistics indirectly using methods described by Parmar

1998

We planned to pool log HR for time to event outcomes using

an inverse variance method A HR less than 10 is in favour of

bendamustine treatment We planned to estimate risk ratios (RR)

and their CI for dichotomous data using the Mantel-Haenszel

method For response rate a RR more than 10 is in favour of

bendamustine treatment For analysis of adverse events a RR less

than 10 is in favour of bendamustine treatment We planned to

use a fixed-effect model and to repeat the primary analysis using

a random-effects model (DerSimonian and Laird method) in a

sensitivity analysis (Der Simonian 1997) We planned to estimate

SMD for continuous data (quality of life scales) using the inverse

variance method

Subgroup analysis and investigation of heterogeneity

We planned to explore potential sources of heterogeneity and po-

tentially important clinical characteristics through stratifying the

primary outcome by the patient subgroups given below

bull Age of patients (children adults)

bull Type of lymphoma (SLLCLL FL MCL


bull Treatment line (first-line salvage treatment)

bull Type of treatment protocol

With or without rituximab

Bendamustine alone or in combination with other

chemoimmunotherapy

bull Comparator treatment

No treatment or steroids

Chemoimmunotherapy

Alkylating agents based therapy

Purine analogues based therapy

We planned to formally assess differences between subgroups using

the Chi2 test for difference between subgroups (Deeks 2001)

We did not perform analysis of survival in children as no children

were included in the trials Overall survival data were not reported

according to the type of lymphoma thus we could not perform

such a subgroup analysis Due to the small number of included

trials we did not analyse overall survival by the treatment line or

by the type of treatment protocol

Bendamustine was not compared to placebo no treatment or

steroids in any of the included trials Therefore we did not carry

out analysis of bendamustine with these comparators

Sensitivity analysis

We planned to perform sensitivity analyses for the primary out-

come using the method of allocation concealment (Schulz 1995)

blinding (patients caregivers and assessors) allocation generation

incomplete outcome data (adequately inadequately addressed)

(Higgins 2011) the type of publication (full paper abstract un-

published) and the size of trials

Due to the small number of included trials we did not analyse

overall survival by allocation concealment blinding allocation

generation incomplete outcome data the type of publication and

the size of trials

R E S U L T S

Description of studies

See Characteristics of included studies Characteristics of excluded

studies Characteristics of ongoing studies

Results of the search

We screened 339 titles and abstracts Twenty-six of them were

relevant and we retrieved them for full details We excluded 14

studies An additional six ongoing trials were identified Of them

one provided us with the unpublished results (Niederle 2012)

Five trials (13 publications) fulfilled the inclusion criteria (Herold

2006 Knauf 2009 Niederle 2012 Rummel 2009 Rummel 2010)

(Figure 1)



Figure 1 Study flow diagram



Included studies

Two trials were published as abstracts (Rummel 2009 Rummel

2010) and two as full text (Herold 2006 Knauf 2009) The report

of one trial was accepted for publication (Niederle 2012) In these

trials 1343 adult patients were randomised between the years 1994

and 2006 Three trials did not analyse all randomised patients (for

details see Characteristics of included studies) 49 patients were not

included in meta-analyses thus 1294 were evaluated The median

follow-up ranged from 28 to 44 months

Type of patients

All five eligible trials included adult patients with indolent B

cell lymphoid malignancies requiring chemotherapy Three trials

(Herold 2006 Rummel 2009 Rummel 2010) included patients

with follicular lymphoma mantle cell lymphoma lymphoplasma-

cytic lymphoma and other indolent lymphomas The percentage

of patients with follicular lymphoma ranged from 40 to 52

and the percentage of patients with mantle cell lymphoma was

about 20 Two trials included only patients with CLL (Knauf

2009 Niederle 2012)

Three trials (Herold 2006 Knauf 2009 Rummel 2009) included

previously untreated patients and two trials included previously

treated patients (Niederle 2012 Rummel 2010)

A common inclusion criterion was good performance status (le

2 by Eastern Co-operative Oncology Group (ECOG) or World

Health Organization (WHO)) Common exclusion criteria in-

cluded with renal dysfunction hepatic dysfunction and active in-

fection Children were not included in any of the trials

Chemotherapy of comparator group

Bendamustine was compared to an alkylating agent-containing

protocol in three trials (Herold 2006 Knauf 2009 Rummel

2009) Bendamustine was compared to the combination of cyclo-

phosphamide doxorubicin vincristine and prednisone (CHOP)

(Rummel 2009) to cyclophosphamide (as part of the COP reg-

imen) (Herold 2006) and to chlorambucil (Knauf 2009) Ben-

damustine was compared to a purine analogue (fludarabine) in two

trials (Niederle 2012 Rummel 2010) The different comparators

may be responsible for the statistical heterogeneity in secondary

outcomes


steroids in any of the included trials

Chemotherapy protocol in the bendamustine group

The total dosage of bendamustine ranged from 180 mgm2 to

300 mgm2 body surface area (BSA) either divided into two days

of treatment (90 to 100 mgm2 BSA administered daily) and re-

peated every 28 days (Knauf 2009 Niederle 2012 Rummel 2009

Rummel 2010) or given over five days (60 mgm2 BSA each day)

and repeated every 21 days (Herold 2006)

In three trials (Niederle 2012 Rummel 2009 Rummel 2010)

rituximab was added to both treatment groups In one trial (Herold

2006) vincristine and prednisone were added to the two allocated

treatment groups (bendamustine versus cyclophosphamide)

Excluded studies

Fourtheen publications were not randomised controlled trials and

were excluded (Characteristics of excluded studies)

Risk of bias in included studies

See Figure 2 rsquoRisk of biasrsquo summary



Figure 2 rsquoRisk of biasrsquo summary review authorsrsquo judgements about each methodological quality item for

each included study



Two trials were of high quality (Knauf 2009 Niederle 2012) We

judged the quality of the other three trials as unclear as most of

the domains of methodological quality are not reported (Herold

2006 Rummel 2009 Rummel 2010)

Allocation

Allocation was adequately concealed in two trials (Knauf 2009

Niederle 2012) and was not reported in three trials (Herold 2006

Rummel 2009 Rummel 2010) Sequence was adequately gener-

ated in two trials (Knauf 2009 Niederle 2012) and the method

of random sequence generation was not reported in three trials

(Herold 2006 Rummel 2009 Rummel 2010)

We judged the quality of these trials as unclear risk of bias

Blinding

Patients and caregivers were not blinded to the allocated treatment

in all the included trials Outcome assessors were blinded to allo-

cated treatment group in one trial (Knauf 2009)


Incomplete outcome data

All randomised patients were included in the primary analysis of

one trial (Knauf 2009) In three trials 7 5 and 1 (Rummel

2009 Rummel 2010 Herold 2006 respectively) of randomised

patients were not analysed Two trials reported reasons for drop-

outs but did not report the number of excluded in each group

(Rummel 2009 Rummel 2010) Reasons for exclusions were spec-

ified in two reports (Rummel 2009 Rummel 2010) the allocation

of patients excluded after randomisation was not reported in three

(Herold 2006 Rummel 2009 Rummel 2010) The number of

randomised patients is unclear in Niederle 2012

We judged the quality of these trials as low risk of bias

Selective reporting

Four trials (Knauf 2009 Niederle 2012 Rummel 2009 Rummel

2010) addressed the outcomes specified in their protocol The

protocol of one trial (Herold 2006) was not available


Other potential sources of bias

Overall survival (or mortality) was a secondary outcome in all the

included trials

Four trials were supported by funding from pharmaceutical com-

panies (Herold 2006 Knauf 2009 Niederle2012 Rummel 2009)

As mentioned above two trials were reported as abstracts (Rummel

2009 Rummel 2010)


Effects of interventions

See Summary of findings for the main comparison

We amended the protocol and did not pool results due to the high

clinical heterogeneity as well as statistical heterogeneity of the pa-

tients in terms of disease (non-Hodgkinrsquos lymphoma CLL) and

disease status (untreated previously treated) interventions (dif-

ferent bendamustine-containing protocols) and the various com-

parator protocols

Overall survival

Three trials provided data on overall survival (Figure 3) All three

showed a non-statistically significant improvement in survival in

the bendamustine group as indirectly estimated (Parmar 1998)

Herold 2006 HR 093 (95 CI 061 to 144) Knauf 2009 HR

069 (95 CI 043 to 111) Niederle 2012 HR 082 (95 CI

047 to 142) Two trials (Rummel 2009 Rummel 2010) did not

provide any data on overall survival

Figure 3 Forest plot of comparison 1 Bendamustine compared to other chemotherapy outcome 11

Overall survival



Five trials reported on all-cause mortality (survival as dichotomous

data) Although not preplanned due to the scarcity of reported

data and the importance of mortality outcome we reported mor-

tality as a dichotomous data and estimated the RR of death in each

of the trials (Figure 4) Four trials showed a non-significant im-

provement in all cause mortality in the bendamustine group and

one trial showed no difference between groups (Rummel 2009)

Figure 4 Forest plot of comparison 1 Bendamustine compared to other chemotherapy outcome 12 All-

cause mortality

Survival analysis in subgroups of patients

No children were included in any of the trials

Data were not reported according to the type of lymphoma (SLL

CLL FL MCL lymphoplasmacytic lymphoma MZL) thus we

could not perform a subgroup analysis according to the type of

lymphoproliferative malignancy Two trials included only patients

with SLLCLL (Knauf 2009 Niederle 2012) (Analysis 13)

Moreover due to the small number of included trials we did not

analyse overall survival by the treatment line (Analysis 14) by

type of comparator (Analysis 15) or by the type of investigational

treatment protocol

We also present the results by the addition of rituximab to che-

motherapy regimen in both allocated groups (Analysis 17)




Progression-free survival (PFS)

(See Figure 5)


Progression-free survival



Three of the four trials (1132 patients) that reported on PFS of

patients with indolent B cell lymphoid malignancies demonstrated

an improved PFS with bendamustine compared to control (Knauf

2009 Rummel 2009 Rummel 2010) One trial (Niederle 2012)

demonstrated a non statistically significant improvement of PFS

with bendamustine No meta-analysis was done The estimated

hazard ratios (HR) of disease progression or death were HR 028

95 CI 019 to 042 (Knauf 2009 319 patients) HR 091 95

CI 050 to 164 (Niederle 2012 92 patients) HR 058 95 CI

043 to 077 (Rummel 2009 513 patients) HR 051 95 CI

037 to 071 (Rummel 2010 208 patients)

Complete and overall response

Four trials reported on CR rates (Herold 2006 Knauf 2009

Rummel 2009 Rummel 2010) We did not pool the results of

complete and overall response rate due to high statistical hetero-

geneity (I2 of heterogeneity = 88 and 97 respectively)

Bendamustine had no statistically significantly effect on CR rate as

compared to cyclophosphamide (RR 110 95 CI 060 to 200

Herold 2006 RR more than 1 is in favour of bendamustine) and

increased the RR of CR rate in three trials compared to chloram-

bucil (RR 1615 95 CI 514 to 5072 Knauf 2009) compared

to CHOP (RR 130 95 CI 102 to 164 Rummel 2009) com-

pared to fludarabine (RR 238 95 CI 144 to 396 Rummel

2010) Overall response rate was improved with bendamustine

when compared to chlorambucil (RR 222 95 CI 172 to 288

Knauf 2009) and fludarabine (RR 159 95 CI 129 to 195

Rummel 2010) and was not affected compared to cyclophospha-

mide (RR 086 95 CI 071 to 105 Herold 2006) and CHOP

(RR 100 95 CI 096 to 105 Rummel 2009) The high chance

of heterogeneity makes these results difficult to interpret and may

be explained by the intensity of the comparator chemotherapy

Quality of life

The effect of bendamustine on quality of life was reported in

one trial in which it was compared with chlorambucil (Knauf

2009) After completion of the study treatment no differences

were demonstrated with respect to physical social emotional and

cognitive functioning and self assessment of global health status

Adverse events

Treatment-related mortality was reported in one trial (Herold

2006) in two patients of 82 treated with bendamustine and none

of 80 patients in the comparator treatment group

Adverse events requiring discontinuation of therapy were reported

in one trial (Knauf 2009) Eighteen patients (11) discontinued

bendamustine therapy and five (3) discontinued chlorambucil

(P = 0005)

Data regarding grade 3 to 4 adverse events were reported in three

trials (Knauf 2009 Rummel 2009 Rummel 2010) Due to the

high statistical heterogeneity we did not pool the results of the

three trials Heterogeneity could be explained by the different

comparator chemotherapy while the risk of grade 3 or 4 adverse

events was increased when bendamustine was compared to chlo-

rambucil in patients with CLL (Knauf 2009) it was similar when

it was compared to fludarabine in patients with indolent B cell

lymphomas (Rummel 2010) and decreased compared to CHOP

(Rummel 2009) Excluding the trial that compared bendamustine

to chlorambucil (Knauf 2009) the pooled RR of grade 3 or 4 ad-

verse events was statistically significantly higher with CHOP or

fludarabine compared to bendamustine (RR 068 95 CI 051

to 089 I2 of heterogeneity = 0 fixed-effect model)

Two trials reported infection-related adverse events (Knauf 2009

Rummel 2009) In one trial (Knauf 2009) the rate of grade 3 or 4

infection was higher (8 13 of 161 patients) in the bendamus-

tine group compared to chlorambucil (3 5 of 151 patients) In

another trial that rate was decreased with bendamustine therapy

(95 of 260 patients) compared to CHOP (121 of 253 patients)

(Rummel 2009)

D I S C U S S I O N

Summary of main results

The previous reported evidence of bendamustine efficacy in the

treatment of patients with indolent B cell lymphoid malignancies

including CLL is mainly based of non-comparative reports which

were supportive of bendamustine therapy for patients with indo-

lent B cell lymphoid malignancies (Friedberg 2008 Heider 2001

Kahl 2010 Koenigsmann 2004 Robinson 2008b Rummel 2005

Weide 2002 Weide 2004) This systematic review summarises the

current data from randomised controlled trials No meta-analysis

was done

Bendamustine had no statistically significant effect on the overall

survival of patients with indolent B cell lymphoid malignancies

in any of the included trials Progression-free survival (PFS) was

statistically significantly improved with bendamustine treatment

in each of the trials that reported it No difference in the risk of

grade 3 or 4 adverse events was shown with the bendamustine-

containing protocol When bendamustine was compared to chlo-

rambucil quality of life was unaffected by the allocated treatment

Overall completeness and applicability ofevidence

Due to the clinical heterogeneity and the small number of trials

and patients it is impossible to draw clear conclusions based on

the results

Trials were diverse in the type of included patients the type of

lymphoma the treatment line the type of bendamustine-contain-

ing protocol and the type of comparator regimen No reports on



subgroups of patients according to type of lymphoma were avail-

able in the included trials The clinical heterogeneity and lack of

data might prevent us from recognising a subgroup of patients that

may gain an overall survival benefit with bendamustine

PFS was consistently better with bendamustine Although one

may argue that an improvement in quality of life may be translated

into fewer lymphoma-related symptoms and a longer time to the

next treatment this was not tested in the included trials The

clinical relevance of the improved PFS is unclear because patient-

important outcomes such as quality of life were evaluated in only

one trial (Knauf 2009)

In two of the included trials (Herold 2006 Knauf 2009) induction

treatment did not contain rituximab which has been shown to

have an important role in the treatment of patients with indolent

B cell lymphoid malignancies including CLLSLL

Quality of the evidence

Five trials were included in the review (Herold 2006 Knauf 2009

Niederle 2012 Rummel 2009 Rummel 2010) Three of them did

not report the methods of randomisation generation and alloca-

tion concealment (Herold 2006 Rummel 2009 Rummel 2010)

In none of the trials were the patients and caregivers blinded to

allocated treatment In one trial outcome assessors were blinded

to allocated treatment (Knauf 2009) but these data were not re-

ported in the other four trials In two trials incomplete data were

not adequately reported (Rummel 2009 Rummel 2010) Some

of the gaps in reporting measures of quality of trials and mor-

tality data might be because two trials were reported as abstracts

(Rummel 2009 Rummel 2010) and one as personal communi-

cation (Niederle 2012)

Despite clinical heterogeneity there is no statistical heterogeneity

in the analysis of overall survival

Agreements and disagreements with otherstudies or reviews

Current evidence does not support the use of any specific chemo-

therapy over the other in the treatment of patients with indolent

B cell lymphoid malignancies

Fludarabine was shown to improve the response rate of patients

with CLL who require therapy and is the standard of care for

fit patients (Catovsky 2007) Systematic reviews of the effect of

purine analogues on clinical outcomes in patients with CLL did

not show a survival benefit with fludarabine (Richards 2012

Steurer 2006 Zhu 2004) Other chemotherapy options in CLL are

chlorambucil cyclophosphamide (alone or in combination with

purine analogues) COP CHOP and alemtuzumab (Kimby 2001)

None of these options were found to be superior over the other

in terms of survival A systematic review examining the effect of

chlorambucil on disease control and overall survival is now in

progress (Vidal 2011)

The available chemotherapy regimens for indolent B cell lymphoid

malignancies include CHOP COP fludarabine-containing regi-

mens MCP and chlorambucil (Friedberg 2009) None of these

regimens was shown to improve survival A systematic review of

anthracycline-containing regimens for the treatment of follicular

lymphoma is now in progress A preliminary report of the meta-

analysis showed a progression-free survival benefit but no overall

survival benefit (Itchaki 2010)

The lack of clear superiority of any of the chemotherapeutic reg-

imens and the results of the included five randomised controlled

trials make bendamustine an optional treatment for patients with

indolent B cell lymphoid malignancies

A U T H O R S rsquo C O N C L U S I O N S

Implications for practice

Due to the improved progression-free survival in the primary trials

similar survival and a similar or lower rate of grade 3 or 4 adverse

events compared to CHOP and to fludarabine bendamustine may

be considered in the treatment of patients with indolent B cell

lymphoid malignancies For patients with refractory or relapsed

CLL bendamustine may be considered for patients eligible for

fludarabine treatment For patients with CLL who are candidates

only for chlorambucil treatment with bendamustine is associated

with a higher rate of adverse events and no survival benefit and is

therefore not recommended

Implications for research

The effect of bendamustine combined with rituximab should be

evaluated in randomised clinical trials with a more homogenous

population and the outcomes of subgroups of patients by the type

of lymphoma should be reported Future trials should put an em-

phasis on the effect of bendamustine on quality of life Quality

of life is one of the most important outcomes for patients with

indolent B cell lymphoid malignancies and as such this should be

evaluated and reported

Bendamustine should be compared with a fludarabine-containing

regimen as first-line treatment with rituximab for the treatment of

patients with small lymphocytic lymphomachronic lymphocytic

leukaemia

A C K N O W L E D G E M E N T S

We would like to thank Dr Nicole Skoetz Dr Kathrin Bauer and

Andrea Will of the Cochrane Haematological Malignancies Group

(CHMG) Editorial Base Ina Monsef for her help in constructing

the search strategy and running the search Dr Olaf Weingart and



Dr Sven Trelle (Editors) as well as Ceacuteline Fournier (Consumer

Editor) for their comments and review improvements

We would like to thank Drs Knauf and Merkle (Knauf 2009) and

Drs Hinke and Ibach (Niederle 2012) for their help and providing

complementary data

R E F E R E N C E S

References to studies included in this review

Herold 2006 published data only

Herold M Schulze A Niederwieser D Franke A Fricke

HJ Richter P et alfor the East German Study Group

Hematology and Oncology (OSHO) Bendamustine

vincristine and prednisone (BOP) versus cyclophosphamide

vincristine and prednisone (COP) in advanced indolent

non-Hodgkinrsquos lymphoma and mantle cell lymphoma

results of a randomised phase III trial (OSHO 19) Journal

of Cancer Research and Clinical Oncology 2006132(2)

105ndash12

Knauf 2009 published and unpublished data

Knauf U Lissichkov T Aldoud A Herbrecht R Liberati

A Loscertales J et alBendamustine versus chlorambucil

in treatment- naive patients with chronic lymphocytic

leukemia updated results of an international phase III

study Haematologica 2009 Vol 94 (Suppl 2)141

Abstract 0355

Knauf WU Lissichkov T Aldaoud A Herbrecht R

Liberati AM Loscertales J et alBendamustine versus

chlorambucil in treatment-Naive Patients with B-Cell

chronic lymphocytic leukemia (B-CLL) Results of an

International phase III study Blood 2007110(11)609alowast Knauf WU Lissichkov T Aldaoud A Liberati A

Loscertales J Herbrecht R et alPhase III randomized study

of bendamustine compared with chlorambucil in previously

untreated patients with chronic lymphocytic leukemia

Journal of Clinical Oncology 200927(26)4378ndash84

Knauf WU Lissitchkov T Aldaoud A Liberati A

Loscertales J Herbrecht R et alBendamustine versus

chlorambucil as first-line treatment in B cell chronic

lymphocytic leukemia an updated analysis from an

International phase III study Blood 2008 Vol 112728

Abstract No 2091

Knauf WU Lissitchkov T Herbrecht R Loscertales J

Aldaoud A Merkle K Bendamustine versus chlorambucil

in treatment-naive B-CLL patients Blood 2004 Vol 104

(11 Pt 2)287b

Knauf WU Lissitchkov T Raoul H Aldaoud A Merkle

KH Bendamustine versus chlorambucil in treatment-naive

B-CLL patients - results of a safety analysis Blood 2003

Vol 102 (11 Pt 2)357b

Niederle 2012 unpublished data onlylowast Hinke A Niederle N Bendamustine versus fludarabine in

chronic lymphocytic leukemia httpclinicaltrialsgovct2

showNCT01423032 [US NIH NCT01423032]

Rummel 2009 published data onlylowast Rummel JM Niederle N Maschmeyer G Banat A

von Gruenhagen U Losem C et alBendamustine plus

rituximab Is superior in respect of progression free survival

and CR rate when compared to CHOP plus rituximab as

first-line treatment of patients with advanced follicular

indolent and mantle cell lymphomas final results of

a randomized phase III study of the StiL (study group

indolent lymphomas Germany) Blood (ASH Annual

Meeting Abstracts) 2009114405

Rummel MJ von Gruenhagen U Niederle N Ballo

H Weidmann E Welslau M et alBendamustine plus

rituximab versus CHOP plus rituximab in the first-line

treatment of patients with follicular indolent and mantle

cell lymphomas results of a randomized phase III study of

the study group indolent lymphomas (StiL) Blood 2008

Vol 112(11)900 [Abstract No 2596]

Rummel MJ von Gruenhagen U Niederle N Rothmann F

Ballo H Weidmann E et alBendamustine plus rituximab

versus CHOP plus rituximab in the first line treatment of

patients with indolent and mantle cell lymphomas first

interim results of a randomized phase III study of the StiL

(study group indolent lymphomas Germany) Blood

2007 Vol 110(11)120a

Rummel 2010 published data only

Rummel JM Kaiser U Balser C Stauch BM Brugger

W Welslau M et alBendamustine plus rituximab versus

fludarabine plus rituximab In patients with relapsed

follicular indolent and mantle cell lymphomas - final results

of the randomized phase III study NHL 2-2003 on behalf

of the StiL (study group indolent lymphomas Germany)

Blood (ASH Annual Meeting Abstracts) 2010 Vol 116

856

References to studies excluded from this review

Catovsky 2011 published data only

Catovsky D Else M Richards S Chlorambucil--still not

bad a reappraisal Clinical lymphoma myeloma amp leukemia

201111(Suppl 1)S2ndash6

Cheson 2010 published data only

Cheson BD Friedberg JW Kahl BS Van der Jagt RH

Tremmel L Bendamustine produces durable responses with

an acceptable safety profile in patients with rituximab-

refractory indolent non-Hodgkin lymphoma Clinical

lymphoma myeloma amp leukemia 201010(6)452ndash7



DrsquoElia 2010 published data only

DrsquoElia GM De Angelis F Breccia M Annechini G Panfilio

S Danieli R et alEfficacy of bendamustine as salvage

treatment in an heavily pre-treated Hodgkin lymphoma

Leukemia Research 201034(11)e300ndash1

Ferrajoli 2005 published data only

Ferrajoli A Bendamustine in relapsed or refractory chronic

lymphocytic leukemia Haematologica 200590(10)1300A

Friedberg 2008 published data only

Friedberg JW Cohen P Chen L Robinson KS Forero-

Torres A La Casce AS et alBendamustine in patients

with rituximab-refractory indolent and transformed non-

Hodgkinrsquos lymphoma results from a phase II multicenter

single-agent study Journal of Clinical Oncology 200826(2)

204ndash10

Hesse 1972 published data only

Hesse P Anger G Fink R Initial experiences with a new

cytostatic agent (IMET 3106=1-methyl-2-(p-(bis-(beta-

chlorethyl)-amino)-phenyliminomethyl)-quinolinium

chloride) Archiv fur Geschwulstforschung 197240(1)40ndash3

Hesse 1972b published data only

Hesse P Jaschke E Anger G Clinical report on the cytostatic

agent cytostasan Deutsche Gesundheitswesen 197227(43)

2058ndash64

Kath 2001 published data only

Kath R Blumenstengel K Fricke HJ Hoffken K

Bendamustine monotherapy in advanced and refractory

chronic lymphocytic leukemia Journal of Cancer Research

and Clinical Oncology 2001127(1)48ndash54

Moosmann 2010 published data only

Moosmann P Heizmann M Kotrubczik N Wernli M

Bargetzi M Weekly treatment with a combination of

bortezomib and bendamustine in relapsed or refractory

indolent non-Hodgkin lymphoma Leukemia and

Lymphoma 201051(1)149ndash52

No authors listed published data only

No authors listed A new highly effective therapy of

indolent non-Hodgkin lymphomas with bendamustine

Onkologie 200326(1)92ndash3

No authors listed B published data only

No authors listed Bendamustine (Treanda) for CLL and

NHL Medical Letter on Drugs and Therapeutics 200850

(1299)91ndash2

Robinson 2008 published data only

Robinson KS Williams ME van der Jagt RH Cohen P

Herst JA Tulpule A et alPhase II multicenter study of

bendamustine plus rituximab in patients with relapsed

indolent B-cell and mantle cell non-Hodgkinrsquos lymphoma



Rummel MJ Gregory SA Bendamustinersquos emerging role

in the management of lymphoid malignancies Seminars in

Hematology 201148(Suppl 1)S24ndash36

Treon 2011 published data only

Treon SP Hanzis C Tripsas C Ioakimidis L Patterson CJ

Manning RJ et alBendamustine therapy in patients with

relapsed or refractory Waldenstromrsquos macroglobulinemia

Clinical Lymphoma Myeloma amp Leukemia 201111(1)

133ndash5

References to ongoing studies

Cephalon published data only

Study of bendamustine hydrochloride and rituximab

(BR) compared with R-CVP or R-CHOP in the first-

line treatment of patients with advanced indolent non-

Hodgkinrsquos lymphoma (NHL) or mantle cell lymphoma

(MCL) - referred to as the BRIGHT study Ongoing study

April 2009

Chen published data only

Bendamustine hydrochloride injection for initial treatment

of chronic lymphocytic leukemia Ongoing study March

2010

Eichhorst published data only

Fludarabine cyclophosphamide and rituximab or

bendamustine and rituximab in treating patients with

previously untreated B cell chronic lymphocytic leukaemia

Ongoing study September 2008

Mundipharma Research published data only

A trial to investigate the efficacy of bendamustine in patients

with indolent non-Hodgkinrsquos lymphoma (NHL) refractory

to rituximab Ongoing study February 2011

Roche published data only

A study of mabThera added to bendamustine or

chlorambucil in patients with chronic lymphocytic leukemia

(MaBLe) Ongoing study March 2010

Additional references

Ardeshna 2003

Ardeshna KM Smith P Norton A Hancock BW Hoskin

PJ MacLennan KA et alBritish National Lymphoma

Investigation Long-term effect of a watch and wait policy

versus immediate systemic treatment for asymptomatic

advanced-stage non-Hodgkin lymphoma a randomised

controlled trial Lancet 2003362(9383)516ndash22

Armitage 1998

Armitage JO Weisenburger DD New approach to

classifying non-Hodgkinrsquos lymphomas clinical features of

the major histologic subtypes Non-Hodgkinrsquos Lymphoma

Classification Project Journal of Clinical Oncology 199816

(8)2780ndash95

Binet 1981

Binet JL Auquier A Dighiero G Chastang C Piguet H

Goasguen J et alA new prognostic classification of chronic

lymphocytic leukemia derived from a multivariate survival

analysis Cancer 198148(1)198ndash206

Catovsky 2007

Catovsky D Richards S Matutes E Oscier D Dyer MJ

Bezares RF et alUK National Cancer Research Institute



(NCRI) Haematological Oncology Clinical Studies Group

NCRI Chronic Lymphocytic Leukaemia Working Group

Assessment of fludarabine plus cyclophosphamide for

patients with chronic lymphocytic leukaemia (the LRF

CLL4 Trial) a randomised controlled trial Lancet 200737

(9583)230ndash9

Cheson 2007

Cheson BD Pfistner B Juweid ME Gascoyne RD Specht

L Horning SJ et alRevised response criteria for malignant

lymphoma Journal of Clinical Oncology 200725(5)

579ndash86

Chow 2001

Chow KU Boehrer S Geduldig K Krapohl A Hoelzer

D Mitrou PS et alIn vitro induction of apoptosis of

neoplastic cells in low-grade non-Hodgkinrsquos lymphomas

using combinations of established cytotoxic drugs with

bendamustine Haematologica 200186(5)485ndash93

CLL trialist 1999

CLL Trialistsrsquo Collaborative Group Chemotherapeutic

options in chronic lymphocytic leukemia a meta-analysis

of the randomized trials Journal of the National Cancer

Institute 199991(10)861ndash8

Deeks 2001

Deeks JJ Altman DG Bradburn MJ Statistical methods

for examining heterogeneity and combining results from

several studies in meta-analysis In Egger M Davey Smith

G Altman DG editor(s) Systematic Reviews in Health Care

Meta-analysis in Context 2nd Edition London (UK) BMJ

Publication Group 2001

Deeks 2011

Deeks JJ Higgins JPT Altman DG (editors) Chapter 9

Analysing data and undertaking meta-analyses Higgins

JPT Green S (editors) Cochrane Handbook for Systematic

Reviews of Interventions Version 510 (updated March

2011) The Cochrane Collaboration 2011 Available from

wwwcochrane-handbookorg

Der Simonian 1997

DerSimonian R Laird N Meta-analysis in clinical trials

Controlled Clinical Trials 19867177ndash88

Fischer 2008

Fischer K Stilgenbauer S Schweighofer CD Busch R

Renschler J Kiehl M et alBendamustine in combination

with rituximab (BR) for patients with relapsed chronic

lymphocytic leukemia (CLL) a multicentre phase II trial

of the German CLL Study Group (GCLLSG) Blood (ASH

Annual Meeting Abstracts) 2008112330

Friedberg 2009

Friedberg JW Taylor MD Cerhan JR Flowers CR Dillon

H Farber CM et alFollicular Lymphoma in the United

States First Report of the National LymphoCare Study


Glick 1981

Glick JH Barnes JM Ezdinli EZ Berard CW Orlow

EL Bennett JM Nodular mixed lymphoma results of a

randomized trial failing to confirm prolonged disease-free

survival with COPP chemotherapy Blood 198158(5)

920ndash5

Hagenbeek 2006

Hagenbeek A Eghbali H Monfardini S Vitolo U Hoskin

PJ de Wolf-Peeters C et alPhase III intergroup study of

fludarabine phosphate compared with cyclophosphamide

vincristine and prednisone chemotherapy in newly

diagnosed patients with stage III and IV low-grade

malignant non-Hodgkinrsquos lymphoma Journal of Clinical

Oncology 200624(10)1590ndash6

Hallek 2008

Hallek M Cheson BD Catovsky D Caligaris-Cappio

F Dighiero G Dohner H et alInternational Workshop

on Chronic Lymphocytic Leukemia Guidelines for the

diagnosis and treatment of chronic lymphocytic leukemia

a report from the international workshop on chronic

lymphocytic leukemia updating the national cancer

institute-working group 1996 guidelines Blood 2008111

(12)5446ndash56

Hallek 2010

Hallek M Fischer K Fingerle-Rowson G Fink AM Busch

R Mayer J et alGerman Chronic Lymphocytic Leukaemia

Study Group Addition of rituximab to fludarabine and

cyclophosphamide in patients with chronic lymphocytic

leukaemia a randomised open-label phase 3 trial Lancet

2010376(9747)1164ndash74

Hamblin 1999

Hamblin TJ Davis Z Gardiner A Oscier DG Stevenson

FK Unmutated Ig V(H) genes are associated with a more

aggressive form of chronic lymphocytic leukemia Blood

1999941848

Harris 1994

Harris NL Jaffe ES Stein H Banks PM Chan JK Cleary

ML et alA revised European-American classification of

lymphoid neoplasms a proposal from the International

Lymphoma Study Group Blood 199484(5)1361ndash92

Heider 2001

Heider A Niederle N Efficacy and toxicity of bendamustine

in patients with relapsed low-grade non-Hodgkinrsquos

lymphomas Anticancer Drugs 200112(9)725ndash9

Higgins 2003

Higgins JPT Thompson SG Deeks JJ Altman DG

Measuring inconsistency in meta-analyses BMJ 2003327

557ndash60

Higgins 2011

Higgins JPT Altman DG Sterne JAC (editors) Chapter

8 Assessing risk of bias in included studies Higgins JPT

Green S (editors) Cochrane Handbook for Systematic




Horning 1984

Horning SJ Rosenberg SA The natural history of initially

untreated low-grade non-Hodgkinrsquos lymphomas New

England Journal of Medicine 1984311(23)1471ndash5



Hoster 2008

Hoster E Dreyling M Klapper W Gisselbrecht C van

Hoof A Kluin-Nelemans HC et alGerman Low Grade

Lymphoma Study Group (GLSG) European Mantle Cell

Lymphoma Network A new prognostic index (MIPI) for

patients with advanced-stage mantle cell lymphoma Blood

2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010

Itchaki G Gafter-Gvili A Lahav M Raanani P Vidal

L Paul M et alAnthracycline-containing regimens for

treatment of follicular lymphoma in adults systematic

review and meta-analysis Blood (ASH Annual Meeting

Abstracts) 2010 Vol 1162820

Kahl 2010

Kahl BS Bartlett NL Leonard JP Chen L Ganjoo K

Williams ME et alBendamustine is effective therapy in

patients with rituximab-refractory indolent B-cell non-

Hodgkin lymphoma results from a Multicenter Study

Cancer 2010116(1)106ndash14

Kienle 2010

Kienle D Benner A Laumlufle C Winkler D Schneider C

Buumlhler A et alGene expression factors as predictors of

genetic risk and survival in chronic lymphocytic leukemia

Haematologica 201095(1)102ndash9

Kimby 2001

Kimby E Brandt L Nygren P Glimelius B SBU-group

Swedish Council of Technology Assessment in Health Care

A systematic overview of chemotherapy effects in B-cell

chronic lymphocytic leukaemia Acta Oncologica 200140

(2-3)224ndash30

Klasa 2002

Klasa RJ Meyer RM Shustik C Sawka CA Smith A

Guevin R Randomized phase III study of fludarabine

phosphate versus cyclophosphamide vincristine and

prednisone in patients with recurrent low-grade non-

Hodgkinrsquos lymphoma previously treated with an alkylating

agent or alkylator-containing regimen Journal of Clinical


Koenigsmann 2004

Koenigsmann M Knauf W Fludarabine and bendamustine

in refractory and relapsed indolent lymphoma-a multicenter

phase III Trial of the East German Society of Hematology

and Oncology (OSHO) Leukemia and Lymphoma 200445

(9)1821ndash7

MacManus 1996

MacManus MP Hoppe RT Is radiotherapy curative for

stage I and II low-grade follicular lymphoma Results of a

long-term follow-up study of patients treated at Stanford

University Journal of Clinical Oncology 199614(4)

1282ndash90

Nickenig 2006

Nickenig C Dreyling M Hoster E Pfreundschuh M

Trumper L Reiser M et alCombined cyclophosphamide

vincristine doxorubicin and prednisone (CHOP) improves

response rates but not survival and has lower hematologic

toxicity compared with combined mitoxantrone

chlorambucil and prednisone (MCP) in follicular and

mantle cell lymphomas results of a prospective randomized

trial of the German Low Grade Lymphoma Study Group

Cancer 2006107(5)1014ndash22

Ozegowski 1971

Ozegowski W Krebs D IMET 3393 gamma-(1-methyl-

5-bis-(b-chloroethyl) amine-benzimidazolyl (2)-butyric

acid hydrochloride a new cytostatic agent from the

series of benzimidazole-Lost [IMET 3393 gammandash

(1ndashmethylndash5ndashbisndash(bndashchlor aumlthyl)ndashaminondashbenzimidazolyl

(2)ndashbuttersaumlurendashhydrochlorid ein neues Zytostatikum aus

der Reihe der BenzimidazolndashLoste] Zbl Pharm 1971110

1013ndash9

Parmar 1998

Parmar MK Torri V Stewart L Extracting summary

statistics to perform meta-analyses of the published

literature for survival endpoints Statistics in Medicine 1998

172815ndash34

Peterson 2003

Peterson BA Petroni GR Frizzera G Barcos M

Bloomfield CD Nissen NI et alProlonged single-agent

versus combination chemotherapy in indolent follicular

lymphomas a study of the cancer and leukemia group B


Rai 1975

Rai KR Sawitsky A Cronkite EP Chanana AD Levy RN

Pasternack BS Clinical staging of chronic lymphocytic

leukemia Blood 197546(2)219ndash34

RevMan 2011

The Nordic Cochrane Centre The Cochrane Collaboration

Review Manager (RevMan) 51 Copenhagen The Nordic

Cochrane Centre The Cochrane Collaboration 2011

Richards 2012

CLL Trialistsrsquo Collaborative Group (CLLTCG) Systematic

review of purine analogue treatment for chronic lymphocytic

leukemia lessons for future trials Haematologica 201297

(3)428ndash36

Robinson 2002

Robinson KA Dickersin K Development of a highly

sensitive search strategy for the retrieval of reports of

controlled trials using PubMed International Journal of

Epidemiology 200231(1)150ndash3

Robinson 2008b








Rummel 2002

Rummel MJ Chow KU Hoelzer D Mitrou PS Weidmann

E In vitro studies with bendamustine enhanced activity in

combination with rituximab Seminars in Oncology 200229

(4 Suppl 13)12ndash4

Rummel 2005

Rummel MJ Al-Batran SE Kim SZ Welslau M Hecker

R Kofahl-Krause D et alBendamustine plus rituximab is

effective and has a favorable toxicity profile in the treatment

of mantle cell and low-grade non-Hodgkinrsquos lymphoma


Schulz 1995

Schulz KF Chalmers I Hayes RJ Altman DG Empirical

evidence of bias Dimensions of methodological quality

associated with estimates of treatment effects in controlled

trials JAMA 1995273(5)408ndash12

Schulz 2007

Schulz H Bohlius J Skoetz N Trelle S Kober T Reiser M

et alChemotherapy plus rituximab versus chemotherapy

alone for B-cell non-Hodgkinrsquos lymphoma Cochrane

Database of Systematic Reviews 2007 Issue 4 [DOI

10100214651858CD003805pub2]

Sterne 2011

Sterne JAC Egger M Moher D (editors) Chapter 10

Addressing reporting biases In Higgins JPT Green S

(editors) Cochrane Handbook for Systematic Reviews

of Intervention Version 510 (updated March 2011)

The Cochrane Collaboration 2011 Available from


Steurer 2006

Steurer M Pall G Richards S Schwarzer G Bohlius J Greil

R Purine antagonists for chronic lymphocytic leukaemia

Cochrane Database of Systematic Reviews 2006 Issue 3

[DOI 10100214651858CD004270pub2]

Strumberg 1996

Strumberg D Harstrick A Doll K Hoffmann B

Bendamustine hydrochloride activity against doxorubicin-

resistant human breast carcinoma cell lines Anticancer

Drugs 19967(4)415ndash21

Swerdlow 2008

Swerdlow SH Campo E Harris NL Jaffe ES Pileri SA

Stein H et al(eds) World Health Organization Classification

of Tumours of Haematopoietic and Lymphoid Tissues Lyon

IARC Press 2008

Tsimberidou 2007

Tsimberidou AM Wen S OrsquoBrien S McLaughlin P Wierda

WG Ferrajoli A et alAssessment of chronic lymphocytic

leukemia and small lymphocytic lymphoma by absolute

lymphocyte counts in 2126 patients 20 years of experience

at the University of Texas MD Anderson Cancer Center


Vidal 2009

Vidal L Gafter-Gvili A Leibovici L Shpilberg O Rituximab

as maintenance therapy for patients with follicular

lymphoma Cochrane Database of Systematic Reviews 2009

Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011

Vidal L Gurion R Gafter-Gvili A Raanani P Robak T

Shpilberg O Chlorambucil for the treatment of patients

with chronic lymphocytic leukaemia or small lymphocytic


Issue 10 [DOI 10100214651858CD009341]

Weide 2002

Weide R Heymanns J Gores A Kuppler H Bendamustine

mitoxantrone and rituximab (BMR) a new effective

regimen for refractory or relapsed indolent lymphomas

Leukemia and Lymphoma 200243(2)327ndash31

Weide 2004

Weide R Pandorf A Heymanns J Kuppler H

Bendamustinemitoxantronerituximab (BMR) a very

effective well tolerated outpatient chemoimmunotherapy

for relapsed and refractory CD20-positive indolent

malignancies Final results of a pilot study Leukemia and


Wilder 2001

Wilder RB Jones D Tucker SL Fuller LM Ha CS

McLaughlin P et alLong-term results with radiotherapy for

stage I-II follicular lymphomas International Journal of

Radiation Oncology Biology Physics 200151(5)1219ndash27

Young 1988

Young RC Longo DL Glatstein E Ihde DC Jaffe ES

DeVita VT Jr The treatment of indolent lymphomas

watchful waiting vs aggressive combined modality

treatment Seminars in Hematology 19882511ndash6

Zhu 2004

Zhu Q Tan DC Samuel M Chan ES Linn YC

Fludarabine in comparison to alkylator-based regimen

as induction therapy for chronic lymphocytic leukemia

a systematic review and meta-analysis Leukemia and

Lymphoma 200445(11)2239ndash45lowast Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Herold 2006

Methods Allocation generation unclear

Allocation concealment unclear

Blinding no

ITT no

Number of dropouts 2164

Median follow-up 44 months

Participants 164 randomised 162 evaluable adult patients

Type of lymphoma follicular mantle cell lymphoplasmacytic lymphoma

Stage IIIIV

Previous treatment no

Mean age 58 years

WHO Performance status lt 2

Interventions Investigational intervention

Bendamustine 60 mgm2 on days 1 to 5 vincristine 2 mg on day 1 and prednisone 100

mgm2 on days 1 to 5 every 3 weeks for 8 cycles

Comparator intervention

Cyclophosphamide 400 mgm2 on days 1 to 5 vincristine 2 mg on day 1 and prednisone

100 mgm2 on days 1 to 5 every 3 weeks for 8 cycles

Outcomes Survival time was defined as time from the start of therapy until death

Time to progression was defined as the time from the start of therapy until progression

or disease-related death and was reported in responding patients

Time to treatment failure was defined as the time from the start of therapy until treatment

failure (objective progression change of randomised therapy intolerable toxicity or death

for any reason) Rates of treatment failure in each group are described but time to

treatment failure is reported only in responding patients

CR PR

Adverse events

Notes

Risk of bias

Bias Authorsrsquo judgement Support for judgement

Random sequence generation (selection

bias)

Unclear risk Not reported

Allocation concealment (selection bias) Unclear risk Not reported

Incomplete outcome data (attrition bias)

All outcomes

Unclear risk 2 patients (1) were not evaluable and not

included in the analysis Reasons and allo-

cation were not specified



Herold 2006 (Continued)

Selective reporting (reporting bias) Unclear risk The trialrsquos protocol was not available to

evaluate selective reporting

Time to progression and time to treatment

failure were reported only in responding

patients

Other bias Unclear risk Funded by Ribosepharm GmbH Clinical

Research Munich

Blinding of participants and personnel

(performance bias)

All outcomes

High risk Participants and personnel were not

blinded to allocated treatment

Blinding of outcome assessment (detection

bias)

All outcomes


Knauf 2009

Methods Allocation generation adequate

Allocation concealment adequate

Blinding no

ITT yes

Number of dropouts 0 (all patients were included in the analysis 7 patients did not

start allocated therapy)

Median follow-up 35 months (range 1 to 68)

Participants 319 randomised adult patients

Type of lymphoma CLLSLL

Stage Binet BC


Mean age 63 years median 63 and 66 years

WHO performance status 303311 patients lt 2 8311 patients = 2


IV bendamustine 100 mgm2 on days 1 to 2 every 4 weeks


Oral chlorambucil 08 mgkg on days 1 and 15 every 4 weeks

Outcomes Primary endpoints

Overall response rate CR or PR


Secondary endpoints

Time to progression

Duration of remission

Overall survival

Adverse events including infection rate



Knauf 2009 (Continued)

Notes

Risk of bias



bias)

Low risk Central randomisation

Allocation concealment (selection bias) Low risk The randomisation list (random number

table) was generated by an independent sta-

tistical institute Patients were randomised

in a 11 ratio consecutively in the order of

the CROrsquos notification of study entry per-

forming prospective stratification by centre

and Binet stage (Binet B or C) For the gen-

eration of blocks and stratification by cen-

tre and Binet stage a validated software pro-

gram RanCode (IDV-Gauting Germany)

was used


All outcomes

Low risk All patients were included in the analysis

of overall survival and progression-free sur-

vival 7 patients were not treated (1 allo-

cated to bendamustine 6 to chlorambucil)

Selective reporting (reporting bias) Low risk Analyses were done as stated in protocol

Other bias Unclear risk Supported by grants from Ribosepharm

GmbH Germany and Mundipharma In-

ternational United Kingdom


(performance bias)

All outcomes




bias)

All outcomes

Low risk ldquoFinal assessment of best response was per-

formed in a blinded fashion by an Indepen-

dent Committee for Response Assessment

(ICRA) and classified as based on the

National Cancer Institute Working Group

criteriardquo



Niederle 2012

Methods Allocation generation computer generated

Allocation concealment central

Blinding no

Number of dropouts 4 not eligible96


Participants 92 randomised adult patients with relapsed chronic lymphocytic leukaemia requiring

treatment after 1 previous systemic regimen


Stage Binet BC

Previous treatment 1 line (refractory or relapse)

Mean age 68 years


Interventions Investigational bendamustine 100 mgm2 iv day 1 + 2 q4w

Comparator fludarabine 25 mgm2 iv days 1 to 5 q4w

Outcomes (Non-inferior) progression-free survival

Overall survival

Notes Unpublished data provided by the investigators as individual patient data

Risk of bias



bias)

Low risk Computer-generated randomisation lists

created by a block randomisation method

with variable block size

Allocation concealment (selection bias) Low risk Central


All outcomes

Low risk 4 randomised patients were ineligible and

were not included in the analysis


Other bias Unclear risk Responsible party and sponsor WiSP Wis-

senschaftlicher Service Pharma GmbH


(performance bias)

All outcomes

High risk No blinding open label


bias)

All outcomes

High risk No blinding



Rummel 2009

Methods Allocation generation not reported

Allocation concealment not reported

Blinding no

ITT no




Type of lymphoma follicular lymphoma mantle cell lymphoma other indolent lym-

phoma

Stage 96 of patients stage IIIIV


Mean age 64 years (range 31 to 83 years)


Bendamustine 90 mgm2 on days 1 to 2 and rituximab 375 mgm2 on day 1 every 4

weeks up to 6 cycles


Standard CHOP and rituximab 375 mgm2 on day 1 every 3 weeks up to 6 cycles

Outcomes Progression-free survival

Overall survival

Event-free survival An event was defined by a response less than a partial response

disease progression relapse or death from any cause

Time to next treatment

Adverse events

Notes

Risk of bias



bias)




All outcomes

Unclear risk ldquoOf the 549 randomized patients 36 pa-

tients were not evaluable 10 did not receive

any study medication 9 due to withdrawal

of consent 13 due to incorrect diagnosis

and 4 for other reasonsrdquo Allocation of non-

evaluable patients is not reported


Other bias Unclear risk Research funding by Roche Pharma AG

Published as an abstract



Rummel 2009 (Continued)


(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no




Type of lymphoma follicular lymphoma mantle cell lymphoma lymphoplasmacytic

lymphoma other indolent lymphoma

Stage 93 of patients allocated to bendamustine and 86 allocated to fludarabine stage

IIIIV

Previous treatment yes






Fludarabine 25 mgm2 on days 1 to 3 and rituximab 375 mgm2 on day 1 every 4



Overall survival

Notes

Risk of bias



bias)







All outcomes

Unclear risk ldquo219 patients were randomized 11 pa-

tients were not evaluable due to protocol

violations and were not followed furtherrdquo

Allocation of non-evaluable patients is not

reported


Other bias Unclear risk Published as an abstract


(performance bias)

All outcomes




bias)

All outcomes


CHOP cyclophosphamide doxorubicin vincristine prednisone

CLL chronic lymphocytic leukaemia

CR complete response

ITT intention-to-treat

iv intravenous

PR partial response

SLL small lymphocytic lymphoma

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Catovsky 2011 No allocation to bendamustine treatment

Cheson 2010 Not a randomised controlled trial

DrsquoElia 2010 Not a randomised controlled trial (a case report of bendamustine for a patient with Hodgkinrsquos lymphoma)

Ferrajoli 2005 Not a randomised controlled trial

Friedberg 2008 Not a randomised controlled trial

Hesse 1972 Not a randomised controlled trial

Hesse 1972b Not a randomised controlled trial



(Continued)

Kath 2001 Not a randomised controlled trial

Moosmann 2010 Not a randomised controlled trial

No authors listed A review

No authors listed B A review

Robinson 2008 Not a randomised controlled trial

Rummel 2011 A review

Treon 2011 Not a randomised controlled trial

Characteristics of ongoing studies [ordered by study ID]

Cephalon

Trial name or title Study of bendamustine hydrochloride and rituximab (BR) compared with R-CVP or R-CHOP in the first-

line treatment of patients with advanced indolent non-Hodgkinrsquos lymphoma (NHL) or mantle cell lymphoma

(MCL) - referred to as the BRIGHT study

Methods The primary objective of the study is to compare the complete response (CR) rate of bendamustine and ritux-

imab (BR) with that of standard treatment regimens of either rituximab cyclophosphamide vincristine and

prednisone (R-CVP) or rituximab cyclophosphamide doxorubicin vincristine and prednisone (R-CHOP)

in patients with advanced indolent non-Hodgkinrsquos lymphoma (NHL) or mantle cell lymphoma (MCL)

An open-label randomised parallel group study of bendamustine hydrochloride and rituximab (BR) com-

pared with rituximab cyclophosphamide vincristine and prednisone (R-CVP) or rituximab cyclophospha-

mide doxorubicin vincristine and prednisone (R-CHOP) in the first-line treatment of patients with ad-

vanced indolent non-Hodgkinrsquos lymphoma (NHL) or mantle cell lymphoma (MCL)

Participants Previously untreated patients with advanced indolent non-Hodgkinrsquos lymphoma (NHL) or mantle cell lym-

phoma (MCL)

Interventions Bendamustine and rituximab

versus

R-CVP or R-CHOP

Outcomes Primary outcome measures

Complete response (CR) rate at end of treatment of bendamustine and rituximab (BR) with either R-CVP

or R-CHOP in the treatment of patients with advanced indolent non-Hodgkinrsquos lymphoma or mantle cell

lymphoma

Secondary outcome measures

Safety and tolerability of BR and R-CVP or R-CHOP

Overall response rate (ORR) = complete remission (CR) and partial remission (PR)


Quality of life as determined by the European Organisation for Research and Treatment of Cancer (EORTC)

30-item core quality of life questionnaire (QLQ-C30)



Cephalon (Continued)

Median durations of responses

Starting date April 2009

Contact information Cephalon

Notes NCT00877006

Chen

Trial name or title Bendamustine hydrochloride injection for initial treatment of chronic lymphocytic leukemia

Methods Allocation randomised

Endpoint classification safetyefficacy study

Intervention model parallel assignment

Masking open label

Primary purpose treatment

Participants Untreated chronic lymphocytic leukaemia patients

Interventions Bendamustine hydrochloride

d1-2 100 mgm2 28 days per cycle at most 6 cycles

versus

Chlorambucil

d1-d2 d15-d16 oral 04 mgkgday 28 days per cycle at most 6 cycles


Objective response rate

Secondary outcome measures progression-free survival


Overall survival

The incidence and severity of adverse events

Starting date March 2010

Contact information Dr Zhixiang Shen 86-021-64370045 ext 665251

Notes NCT01109264

Eichhorst

Trial name or title Fludarabine cyclophosphamide and rituximab or bendamustine and rituximab in treating patients with


Methods Phase III trial of combined immunochemotherapy with fludarabine cyclophosphamide and rituximab (FCR)

versus bendamustine and rituximab (BR) in patients with previously untreated chronic lymphocytic leukaemia



Eichhorst (Continued)

Participants Patients with previously untreated chronic lymphocytic leukaemia

Interventions Fludarabine cyclophosphamide and rituximab (FCR) versus bendamustine and rituximab (BR)

Outcomes Primary outcome measures progression-free survival rate after 24 months

Secondary outcome measures minimal residual disease complete response rates and partial response rates


Event-free survival

Overall survival

Overall response rate

Response rates in and survival times in biological subgroups

Toxicity rates

Quality of life

Standard safety analysis

Starting date September 2008

Contact information Barbara Eichhorst MD 49-221-478-4400

barbaraeichhorstuk-koelnde

Notes NCT00769522

Mundipharma Research

Trial name or title A trial to investigate the efficacy of bendamustine in patients with indolent non-Hodgkinrsquos lymphoma (NHL)

refractory to rituximab




Masking open label


Participants Patients with indolent B-cell non-Hodgkinrsquos lymphoma that did not respond (stable disease or progressive

disease) to rituximab or a rituximab-containing regimen during or within 6 months of the last rituximab

treatment

Interventions Bendamustine compared to treatment of physicianrsquos choice

Outcomes Primary outcome measures progression-free survival Defined as the interval between randomisation and

disease progression or death



Complete remission or partial remission

Duration of response

Overall survival

Safety and tolerability

Change in health-related quality of life measures (EORTC QLQ-C30)



Mundipharma Research (Continued)

Starting date February 2011

Contact information Margaret C Wilson and Jill Kiteley nfocontact-clinical-trialcom

Notes NCT01289223

Roche

Trial name or title A study of mabThera added to bendamustine or chlorambucil in patients with chronic lymphocytic leukemia

(MaBLe)




Masking open label

A randomised study to assess the effect on response rate of rituximab added to a standard chemotherapy

bendamustine or chlorambucil in patients with chronic lymphocytic leukaemia

Participants Patients with CLL with progressive Binet stage B or C ineligible for treatment with fludarabine For second-

line patients only pretreatment with rituximab andor chlorambucil is allowed

Interventions Rituximab 375 mgm2 iv day 1 of cycle 1 followed by 500 mgm2 iv every 4 weeks cycles 2 to 6 and

bendamustine 90 mgm2 (first-line) or 70 mgm2 (second-line) iv days 1 and 2 every 4 weeks cycles 1 to 6

versus

Rituximab (same schedule and dosage) and chlorambucil 10 mgm2 po days 1 to 7 every 4 weeks for up to

12 cycles

Outcomes Primary outcome measure

Complete response rate


Overall response rate complete response partial response stable disease progression-free survival disease-

free survival time to next leukaemia treatment duration of response overall survival molecular response

minimal residual disease

Adverse events laboratory parameters


Contact information genentechclinicaltrialsdruginfocom

Notes NCT01056510



D A T A A N D A N A L Y S E S

Comparison 1 Bendamustine compared to other chemotherapy

Outcome or subgroup titleNo of

studies

No of

participants Statistical method Effect size

1 Overall survival 3 Hazard Ratio (Fixed 95 CI) Totals not selected

2 All-cause mortality 5 Risk Ratio (M-H Fixed 95 CI) Totals not selected

3 All-cause mortality by type

lymphoid malignancy

(fixed-effect)

5 Risk Ratio (M-H Fixed 95 CI) Totals not selected

31 Lymphoma 3 Risk Ratio (M-H Fixed 95 CI) 00 [00 00]

32 CLL (excluding

lymphoma)

2 Risk Ratio (M-H Fixed 95 CI) 00 [00 00]

4 All-cause mortality by treatment

line (fixed-effect)

5 Risk Ratio (M-H Random 95 CI) Totals not selected

41 First-line treatment 3 Risk Ratio (M-H Random 95 CI) 00 [00 00]

42 Second-line treatment and

more

2 Risk Ratio (M-H Random 95 CI) 00 [00 00]

5 All-cause mortality by type of

comparator (fixed-effect)


51 Alkylating agents based

comparator


52 Purine analogues based

comparator


6 All-cause mortality with or

without rituximab (fixed-effect)


61 Chemotherapy-only

regimens


62 Rituximab chemotherapy

regimens


7 Progression-free survival 4 Hazard Ratio (Random 95 CI) Totals not selected

8 Complete response 4 Risk Ratio (M-H Random 95 CI) Totals not selected

9 Overall response rate (complete

and partial remission)


10 Grade 3 to 4 adverse events 3 Risk Ratio (M-H Random 95 CI) Totals not selected

11 Grade 3 to 4 adverse events

without CLL patients




Analysis 11 Comparison 1 Bendamustine compared to other chemotherapy Outcome 1 Overall survival

Review Bendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia


Outcome 1 Overall survival

Study or subgroup log [Hazard Ratio] Hazard Ratio Hazard Ratio

(SE) IVFixed95 CI IVFixed95 CI

Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10

Favours bendamustine Favours control

Analysis 12 Comparison 1 Bendamustine compared to other chemotherapy Outcome 2 All-cause

mortality



Outcome 2 All-cause mortality

Study or subgroup Favours experimental Control Risk Ratio Risk Ratio

nN nN M-HFixed95 CI M-HFixed95 CI

Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10

Favours experimental Favours control




mortality by type lymphoid malignancy (fixed-effect)



Outcome 3 All-cause mortality by type lymphoid malignancy (fixed-effect)

Study or subgroup Bendamustine Control Risk Ratio Risk Ratio


1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

2 CLL (excluding lymphoma)

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10





mortality by treatment line (fixed-effect)



Outcome 4 All-cause mortality by treatment line (fixed-effect)


nN nN

M-HRandom95

CI

M-HRandom95

CI

1 First-line treatment

Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

2 Second-line treatment and more

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10





mortality by type of comparator (fixed-effect)



Outcome 5 All-cause mortality by type of comparator (fixed-effect)



1 Alkylating agents based comparator

Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

2 Purine analogues based comparator

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10





mortality with or without rituximab (fixed-effect)



Outcome 6 All-cause mortality with or without rituximab (fixed-effect)


nN nN

M-HRandom95

CI

M-HRandom95

CI

1 Chemotherapy-only regimens

Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

2 Rituximab chemotherapy regimens

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10


Analysis 17 Comparison 1 Bendamustine compared to other chemotherapy Outcome 7 Progression-free

survival



Outcome 7 Progression-free survival


(SE) IVRandom95 CI IVRandom95 CI

Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10




Analysis 18 Comparison 1 Bendamustine compared to other chemotherapy Outcome 8 Complete

response



Outcome 8 Complete response

Study or subgroup Favours control Control Risk Ratio Risk Ratio

nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5

Favours control Favours bendamustine



Analysis 19 Comparison 1 Bendamustine compared to other chemotherapy Outcome 9 Overall response

rate (complete and partial remission)



Outcome 9 Overall response rate (complete and partial remission)


nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2


Analysis 110 Comparison 1 Bendamustine compared to other chemotherapy Outcome 10 Grade 3 to 4

adverse events



Outcome 10 Grade 3 to 4 adverse events


nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100





adverse events without CLL patients



Outcome 11 Grade 3 to 4 adverse events without CLL patients


nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S

Appendix 1 CENTRAL search strategy

ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)



Appendix 2 MEDLINE search strategy

Searches

1 bendamustin$twkfot

2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot

5 ldquoSDX-105rdquotwkfot

6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8

10 randomized controlled trialpt

11 controlled clinical trialpt

12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20



Appendix 3 EMBASE search strategy

Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw

6 ldquoSDX-105rdquotw

7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9

11 (random$ or placebo$)tiab

12 ((single$ or double$ or triple$ or treble$) and (blind$ or mask$))tiab

13 Controlled clinical trial$tiab

14 RETRACTED ARTICLE

15 Or11-14

16 (animal$ not human$)shhw

17 15 not 16

18 10 and 17



Appendix 4 LILACS search strategy

The following terms were searched

bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393

Appendix 5 Database of clinical trials in haematological malignancies search strategy

Bendamustine

H I S T O R Y

Protocol first published Issue 3 2011

Review first published Issue 9 2012

C O N T R I B U T I O N S O F A U T H O R S

LV is the co-ordinator of the review

LV is responsible for constructing the search strategy data collection writing to authors for additional information and organising

retrieval of papers

AG is responsible for undertaking searches in conference proceedings

AG LV RG and OS are responsible for screening search results abstracting data from papers screening retrieved papers against the

inclusion criteria and appraising quality of papers the latter review author was in charge in case of disagreement

LV is responsible for entering data into RevMan 5 (RevMan 2011)

AG LV RG PR and OS participated in preparing and reviewing the protocol

AG LV PR MD and OS participated in the analysis and interpretation of data

All review authors participated in writing the review

D E C L A R A T I O N S O F I N T E R E S T

M Dreyling received financial support for investigator-initiated trials (Celgene GSK Janssen Mundipharma Pfizer Roche Glycart)

and honoraria for scientific advisory boards (Calistoga Celgene Janssen Pfizer Pharmacyclics Roche) as well as educational presen-

tations (Janssen Mundipharma Pfizer Roche)

The other authors declare no conflict of interest



D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

Type of outcome measures

We added all-cause mortality assessed as dichotomous data as included published papers reported on mortality as dichotomous data

and there was not enough data to assess mortality (overall survival) as time to event outcome

We deleted partial response (PR) and added overall response rate (PR + complete response (CR))

Assessment of reporting bias

We conditioned inspection of the funnel plot on the inclusion of at least 10 trials

Subgroup analysis

Comparator treatment

bull Alkylating agents based therapy

bull Purine analogues based therapy

Data synthesis

For the primary outcomes we used a fixed-effect model and repeated the analysis using a random-effects model as described in the

protocol Due to the clinical heterogeneity we decided to pool all other outcomes using a random-effects model

We did not pool results of progression-free survival (PFS) overall response rate (ORR) and grade 3 or 4 adverse events due high

statistical heterogeneity

I N D E X T E R M S

Medical Subject Headings (MeSH)

Antineoplastic Agents Alkylating [lowasttherapeutic use] Antineoplastic Combined Chemotherapy Protocols [administration amp dosage

therapeutic use] Cyclophosphamide [administration amp dosage therapeutic use] Doxorubicin [administration amp dosage] Leukemia

Lymphocytic Chronic B-Cell [drug therapy mortality] Lymphoma B-Cell [lowastdrug therapy mortality] Lymphoma Follicular [drug

therapy mortality] Lymphoma Mantle-Cell [drug therapy mortality] Nitrogen Mustard Compounds [lowasttherapeutic use] Prednisone

[administration amp dosage] Recurrence Vincristine [administration amp dosage] Waldenstrom Macroglobulinemia [drug therapy mor-

tality]

MeSH check words

Adult Humans



T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

2PLAIN LANGUAGE SUMMARY

3SUMMARY OF FINDINGS FOR THE MAIN COMPARISON

4BACKGROUND

5OBJECTIVES

5METHODS

8RESULTS

Figure 1 9

Figure 2 11

Figure 3 12

Figure 4 13

Figure 5 13

14DISCUSSION

15AUTHORSrsquo CONCLUSIONS

15ACKNOWLEDGEMENTS

16REFERENCES

20CHARACTERISTICS OF STUDIES

32DATA AND ANALYSES

Analysis 11 Comparison 1 Bendamustine compared to other chemotherapy Outcome 1 Overall survival 33

Analysis 12 Comparison 1 Bendamustine compared to other chemotherapy Outcome 2 All-cause mortality 33

Analysis 13 Comparison 1 Bendamustine compared to other chemotherapy Outcome 3 All-cause mortality by type

lymphoid malignancy (fixed-effect) 34

Analysis 14 Comparison 1 Bendamustine compared to other chemotherapy Outcome 4 All-cause mortality by treatment

line (fixed-effect) 35

Analysis 15 Comparison 1 Bendamustine compared to other chemotherapy Outcome 5 All-cause mortality by type of

comparator (fixed-effect) 36

Analysis 16 Comparison 1 Bendamustine compared to other chemotherapy Outcome 6 All-cause mortality with or

without rituximab (fixed-effect) 37

Analysis 17 Comparison 1 Bendamustine compared to other chemotherapy Outcome 7 Progression-free survival 37

Analysis 18 Comparison 1 Bendamustine compared to other chemotherapy Outcome 8 Complete response 38

Analysis 19 Comparison 1 Bendamustine compared to other chemotherapy Outcome 9 Overall response rate (complete

and partial remission) 39

Analysis 110 Comparison 1 Bendamustine compared to other chemotherapy Outcome 10 Grade 3 to 4 adverse events 39

Analysis 111 Comparison 1 Bendamustine compared to other chemotherapy Outcome 11 Grade 3 to 4 adverse events

without CLL patients 40

40APPENDICES

43HISTORY

43CONTRIBUTIONS OF AUTHORS

43DECLARATIONS OF INTEREST

43DIFFERENCES BETWEEN PROTOCOL AND REVIEW

44INDEX TERMS

iBendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia (Review)















CD009045 DOI 10100214651858CD009045pub2


A B S T R A C T

Background







a different regimen




Objectives


Search methods





Selection criteria


apy






Main results










































Th

ere

wer

eli

mit

atio

ns

toth

ere

view

th

ed

emog

rap

hic

char

acte

rist

ics

ofp

eop

leth

atw

ere

invo

lved

inth

est

ud

ies

typ

eof

lym

ph

oma

and

the

typ

eof

trea

tmen

tsth

atw

ere

give

nva

ried

T

her

efor

eit

isd

iffi

cult

tod

raw

clea

rco

ncl

usi

ons

SU

MM

AR

YO

FF

IN

DI

NG

SF

OR

TH

EM

AI

NC

OM

PA

RI

SO

N[E

xpla

nati

on]







Outcomes

Assumed

risk

(control


patients)

Correspond-

ingrisk

(bendamustine


patients)

Relativeeffect

(95CI)

Noofparticipants

(studies)


(GRADE)

Com

ments

Overallsurvival

Medianfollow-up35

to

44months




oplusoplus

opluscopy

moderate

Moderatequality

dueto

serious

imprecision

a


All-causemortality

Medianfollow-up28

to

44months

326per1000

277per1000

1202

patients(4studies)

oplusoplus

opluscopy

moderate



reported

in2trialsun-

clearriskofbias










B A C K G R O U N D

















phoma
























Schulz 2007)






























Kienle 2010)











































































not been shown

O B J E C T I V E S



M E T H O D S


Types of studies






phoma












bull Chemotherapy











regimen





Primary outcomes




Secondary outcomes










Electronic searches




1)


Appendix 2)







similar























additional studies











cation and language








possible




unpublished













outcome safety)


















therapy)





therapy)



Overall survival


follow-up

















exclusion

















assessment


Cross-over trials



the second period


outcome


up





apy up to 12 months







data























Data synthesis




1998












variance method












chemoimmunotherapy



Chemoimmunotherapy
























the size of trials

R E S U L T S











(Figure 1)






Included studies









Type of patients









2009 Niederle 2012)



















outcomes














Excluded studies








each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans
















CD009045 DOI 10100214651858CD009045pub2


A B S T R A C T

Background







a different regimen




Objectives


Search methods





Selection criteria


apy






Main results










































Th

ere

wer

eli

mit

atio

ns

toth

ere

view

th

ed

emog

rap

hic

char

acte

rist

ics

ofp

eop

leth

atw

ere

invo

lved

inth

est

ud

ies

typ

eof

lym

ph

oma

and

the

typ

eof

trea

tmen

tsth

atw

ere

give

nva

ried

T

her

efor

eit

isd

iffi

cult

tod

raw

clea

rco

ncl

usi

ons

SU

MM

AR

YO

FF

IN

DI

NG

SF

OR

TH

EM

AI

NC

OM

PA

RI

SO

N[E

xpla

nati

on]







Outcomes

Assumed

risk

(control


patients)

Correspond-

ingrisk

(bendamustine


patients)

Relativeeffect

(95CI)

Noofparticipants

(studies)


(GRADE)

Com

ments

Overallsurvival

Medianfollow-up35

to

44months




oplusoplus

opluscopy

moderate

Moderatequality

dueto

serious

imprecision

a


All-causemortality

Medianfollow-up28

to

44months

326per1000

277per1000

1202

patients(4studies)

oplusoplus

opluscopy

moderate



reported

in2trialsun-

clearriskofbias










B A C K G R O U N D

















phoma
























Schulz 2007)






























Kienle 2010)











































































not been shown

O B J E C T I V E S



M E T H O D S


Types of studies






phoma












bull Chemotherapy











regimen





Primary outcomes




Secondary outcomes










Electronic searches




1)


Appendix 2)







similar























additional studies











cation and language








possible




unpublished













outcome safety)


















therapy)





therapy)



Overall survival


follow-up

















exclusion

















assessment


Cross-over trials



the second period


outcome


up





apy up to 12 months







data























Data synthesis




1998












variance method












chemoimmunotherapy



Chemoimmunotherapy
























the size of trials

R E S U L T S











(Figure 1)






Included studies









Type of patients









2009 Niederle 2012)



















outcomes














Excluded studies








each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans






Main results










































Th

ere

wer

eli

mit

atio

ns

toth

ere

view

th

ed

emog

rap

hic

char

acte

rist

ics

ofp

eop

leth

atw

ere

invo

lved

inth

est

ud

ies

typ

eof

lym

ph

oma

and

the

typ

eof

trea

tmen

tsth

atw

ere

give

nva

ried

T

her

efor

eit

isd

iffi

cult

tod

raw

clea

rco

ncl

usi

ons

SU

MM

AR

YO

FF

IN

DI

NG

SF

OR

TH

EM

AI

NC

OM

PA

RI

SO

N[E

xpla

nati

on]







Outcomes

Assumed

risk

(control


patients)

Correspond-

ingrisk

(bendamustine


patients)

Relativeeffect

(95CI)

Noofparticipants

(studies)


(GRADE)

Com

ments

Overallsurvival

Medianfollow-up35

to

44months




oplusoplus

opluscopy

moderate

Moderatequality

dueto

serious

imprecision

a


All-causemortality

Medianfollow-up28

to

44months

326per1000

277per1000

1202

patients(4studies)

oplusoplus

opluscopy

moderate



reported

in2trialsun-

clearriskofbias










B A C K G R O U N D

















phoma
























Schulz 2007)






























Kienle 2010)











































































not been shown

O B J E C T I V E S



M E T H O D S


Types of studies






phoma












bull Chemotherapy











regimen





Primary outcomes




Secondary outcomes










Electronic searches




1)


Appendix 2)







similar























additional studies











cation and language








possible




unpublished













outcome safety)


















therapy)





therapy)



Overall survival


follow-up

















exclusion

















assessment


Cross-over trials



the second period


outcome


up





apy up to 12 months







data























Data synthesis




1998












variance method












chemoimmunotherapy



Chemoimmunotherapy
























the size of trials

R E S U L T S











(Figure 1)






Included studies









Type of patients









2009 Niederle 2012)



















outcomes














Excluded studies








each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans



Th

ere

wer

eli

mit

atio

ns

toth

ere

view

th

ed

emog

rap

hic

char

acte

rist

ics

ofp

eop

leth

atw

ere

invo

lved

inth

est

ud

ies

typ

eof

lym

ph

oma

and

the

typ

eof

trea

tmen

tsth

atw

ere

give

nva

ried

T

her

efor

eit

isd

iffi

cult

tod

raw

clea

rco

ncl

usi

ons

SU

MM

AR

YO

FF

IN

DI

NG

SF

OR

TH

EM

AI

NC

OM

PA

RI

SO

N[E

xpla

nati

on]







Outcomes

Assumed

risk

(control


patients)

Correspond-

ingrisk

(bendamustine


patients)

Relativeeffect

(95CI)

Noofparticipants

(studies)


(GRADE)

Com

ments

Overallsurvival

Medianfollow-up35

to

44months




oplusoplus

opluscopy

moderate

Moderatequality

dueto

serious

imprecision

a


All-causemortality

Medianfollow-up28

to

44months

326per1000

277per1000

1202

patients(4studies)

oplusoplus

opluscopy

moderate



reported

in2trialsun-

clearriskofbias










B A C K G R O U N D

















phoma
























Schulz 2007)






























Kienle 2010)











































































not been shown

O B J E C T I V E S



M E T H O D S


Types of studies






phoma












bull Chemotherapy











regimen





Primary outcomes




Secondary outcomes










Electronic searches




1)


Appendix 2)







similar























additional studies











cation and language








possible




unpublished













outcome safety)


















therapy)





therapy)



Overall survival


follow-up

















exclusion

















assessment


Cross-over trials



the second period


outcome


up





apy up to 12 months







data























Data synthesis




1998












variance method












chemoimmunotherapy



Chemoimmunotherapy
























the size of trials

R E S U L T S











(Figure 1)






Included studies









Type of patients









2009 Niederle 2012)



















outcomes














Excluded studies








each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans



B A C K G R O U N D

















phoma
























Schulz 2007)






























Kienle 2010)











































































not been shown

O B J E C T I V E S



M E T H O D S


Types of studies






phoma












bull Chemotherapy











regimen





Primary outcomes




Secondary outcomes










Electronic searches




1)


Appendix 2)







similar























additional studies











cation and language








possible




unpublished













outcome safety)


















therapy)





therapy)



Overall survival


follow-up

















exclusion

















assessment


Cross-over trials



the second period


outcome


up





apy up to 12 months







data























Data synthesis




1998












variance method












chemoimmunotherapy



Chemoimmunotherapy
























the size of trials

R E S U L T S











(Figure 1)






Included studies









Type of patients









2009 Niederle 2012)



















outcomes














Excluded studies








each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans














































not been shown

O B J E C T I V E S



M E T H O D S


Types of studies






phoma












bull Chemotherapy











regimen





Primary outcomes




Secondary outcomes










Electronic searches




1)


Appendix 2)







similar























additional studies











cation and language








possible




unpublished













outcome safety)


















therapy)





therapy)



Overall survival


follow-up

















exclusion

















assessment


Cross-over trials



the second period


outcome


up





apy up to 12 months







data























Data synthesis




1998












variance method












chemoimmunotherapy



Chemoimmunotherapy
























the size of trials

R E S U L T S











(Figure 1)






Included studies









Type of patients









2009 Niederle 2012)



















outcomes














Excluded studies








each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans



Primary outcomes




Secondary outcomes










Electronic searches




1)


Appendix 2)







similar























additional studies











cation and language








possible




unpublished













outcome safety)


















therapy)





therapy)



Overall survival


follow-up

















exclusion

















assessment


Cross-over trials



the second period


outcome


up





apy up to 12 months







data























Data synthesis




1998












variance method












chemoimmunotherapy



Chemoimmunotherapy
























the size of trials

R E S U L T S











(Figure 1)






Included studies









Type of patients









2009 Niederle 2012)



















outcomes














Excluded studies








each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans















therapy)





therapy)



Overall survival


follow-up

















exclusion

















assessment


Cross-over trials



the second period


outcome


up





apy up to 12 months







data























Data synthesis




1998












variance method












chemoimmunotherapy



Chemoimmunotherapy
























the size of trials

R E S U L T S











(Figure 1)






Included studies









Type of patients









2009 Niederle 2012)



















outcomes














Excluded studies








each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans










Data synthesis




1998












variance method












chemoimmunotherapy



Chemoimmunotherapy
























the size of trials

R E S U L T S











(Figure 1)






Included studies









Type of patients









2009 Niederle 2012)



















outcomes














Excluded studies








each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans






Included studies









Type of patients









2009 Niederle 2012)



















outcomes














Excluded studies








each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans



Included studies









Type of patients









2009 Niederle 2012)



















outcomes














Excluded studies








each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans




each included study







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans







Allocation








Blinding

















Selective reporting







included trials




2009 Rummel 2010)









parator protocols

Overall survival









Overall survival











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans











cause mortality











treatment protocol







(See Figure 5)




































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans


































Quality of life






Adverse events







(P = 0005)





















(Rummel 2009)

D I S C U S S I O N










was done












the results

























































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans






















































































leukaemia












complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans







complementary data

R E F E R E N C E S











105ndash12







Abstract 0355















Abstract No 2091




(11 Pt 2)287b




Vol 102 (11 Pt 2)357b



















Vol 112(11)900 [Abstract No 2596]







2007 Vol 110(11)120a









856




























204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans

















204ndash10









2058ndash64



















(1299)91ndash2
















133ndash5








April 2009




2010















Ardeshna 2003







Armitage 1998





(8)2780ndash95

Binet 1981





Catovsky 2007










(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans








(9583)230ndash9

Cheson 2007




579ndash86

Chow 2001






CLL trialist 1999





Deeks 2001







Deeks 2011







Der Simonian 1997



Fischer 2008







Friedberg 2009





Glick 1981





920ndash5

Hagenbeek 2006








Hallek 2008








(12)5446ndash56

Hallek 2010






2010376(9747)1164ndash74

Hamblin 1999




1999941848

Harris 1994





Heider 2001




Higgins 2003



557ndash60

Higgins 2011







Horning 1984






Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans



Hoster 2008






2008111(2)558ndash65

Hoster 2008b






2008111(2)558ndash65

Itchaki 2010






Kahl 2010






Kienle 2010





Kimby 2001





(2-3)224ndash30

Klasa 2002








Koenigsmann 2004





(9)1821ndash7

MacManus 1996





1282ndash90

Nickenig 2006









Cancer 2006107(5)1014ndash22

Ozegowski 1971








1013ndash9

Parmar 1998




172815ndash34

Peterson 2003






Rai 1975




RevMan 2011




Richards 2012




(3)428ndash36

Robinson 2002





Robinson 2008b








Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans



Rummel 2002





Rummel 2005






Schulz 1995





Schulz 2007





10100214651858CD003805pub2]

Sterne 2011







Steurer 2006




[DOI 10100214651858CD004270pub2]

Strumberg 1996





Swerdlow 2008




IARC Press 2008

Tsimberidou 2007







Vidal 2009




Issue 2 [DOI 10100214651858CD006552pub2]

Vidal 2011





Issue 10 [DOI 10100214651858CD009341]

Weide 2002





Weide 2004







Wilder 2001





Young 1988





Zhu 2004










Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans





Herold 2006



Blinding no

ITT no





Stage IIIIV


Mean age 58 years















CR PR

Adverse events

Notes

Risk of bias



bias)




All outcomes











patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans








patients


Research Munich


(performance bias)

All outcomes




bias)

All outcomes


Knauf 2009



Blinding no

ITT yes






Stage Binet BC











Secondary endpoints

Time to progression


Overall survival





Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans




Notes

Risk of bias



bias)












was used


All outcomes










(performance bias)

All outcomes




bias)

All outcomes






criteriardquo



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans



Niederle 2012



Blinding no






Stage Binet BC


Mean age 68 years





Overall survival


Risk of bias



bias)






All outcomes







(performance bias)

All outcomes



bias)

All outcomes




Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans



Rummel 2009



Blinding no

ITT no





phoma










Overall survival




Adverse events

Notes

Risk of bias



bias)




All outcomes














(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans





(performance bias)

All outcomes




bias)

All outcomes


Rummel 2010



Blinding no

ITT no







IIIIV










Overall survival

Notes

Risk of bias



bias)







All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans





All outcomes





reported




(performance bias)

All outcomes




bias)

All outcomes






iv intravenous

PR partial response













(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans



(Continued)









Cephalon













phoma (MCL)


versus

R-CVP or R-CHOP




lymphoma













Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans







Notes NCT00877006

Chen





Masking open label





versus

Chlorambucil






Overall survival




Notes NCT01109264

Eichhorst













Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans









Event-free survival

Overall survival



Toxicity rates

Quality of life





Notes NCT00769522







Masking open label




treatment








Overall survival








Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans






Notes NCT01289223

Roche


(MaBLe)




Masking open label







versus


12 cycles










Notes NCT01056510






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans






studies

No of





lymphoid malignancy

(fixed-effect)



32 CLL (excluding

lymphoma)



line (fixed-effect)




more






comparator



comparator






regimens



regimens



















Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans









Herold 2006 -007 (022) 093 [ 061 144 ]

Knauf 2009 -037 (024) 069 [ 043 111 ]

Niederle 2012 -02 (028) 082 [ 047 142 ]

01 02 05 1 2 5 10



mortality






Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10











1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans










1 Lymphoma

Herold 2006 3282 4380 073 [ 052 102 ]

Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]


Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans









nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10












Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans











Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Rummel 2009 34260 33253 100 [ 064 157 ]


Niederle 2012 2449 2643 081 [ 056 118 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10










nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans









nN nN

M-HRandom95

CI

M-HRandom95

CI


Herold 2006 3282 4380 073 [ 052 102 ]

Knauf 2009 62162 70157 086 [ 066 112 ]

Niederle 2012 2449 2643 081 [ 056 118 ]


Rummel 2009 34260 33253 100 [ 064 157 ]

Rummel 2010 42109 4699 083 [ 060 114 ]

01 02 05 1 2 5 10



survival






Knauf 2009 -126 (02) 028 [ 019 042 ]

Niederle 2012 -01 (03) 090 [ 050 163 ]

Rummel 2009 -055 (015) 058 [ 043 077 ]

Rummel 2010 -067 (017) 051 [ 037 071 ]

01 02 05 1 2 5 10





response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans




response





nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 1882 1680 110 [ 060 200 ]

Knauf 2009 50162 3157 1615 [ 514 5072 ]

Rummel 2009 104260 78253 130 [ 102 164 ]

Rummel 2010 42109 1699 238 [ 144 396 ]

02 05 1 2 5










nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans









nN nN

M-HRandom95

CI

M-HRandom95

CI

Herold 2006 5482 6180 086 [ 071 105 ]

Knauf 2009 110162 48157 222 [ 172 288 ]

Rummel 2009 244260 237253 100 [ 096 105 ]

Rummel 2010 91109 5299 159 [ 129 195 ]

05 07 1 15 2



adverse events





nN nN

M-HRandom95

CI

M-HRandom95

CI

Knauf 2009 93161 30151 291 [ 206 411 ]

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100










nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans









nN nN

M-HRandom95

CI

M-HRandom95

CI

Rummel 2009 49260 74253 064 [ 047 088 ]

Rummel 2010 19109 2299 078 [ 045 136 ]

001 01 1 10 100


A P P E N D I C E S


ID Search

1 bendamustin

2 ribomustin

3 treand

4 levact

5 SDX

6 cytostasan

7 Zimet

8 Imet

9 (1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7 OR 8)




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans




Searches


2 ribomustin$twkfot

3 treand$twkfot

4 levact$twkfot


6 cytostasan$twkfot

7 zimet$twkfotnm

8 imet$twkfotnm

9 or1-8



12 randomizedab

13 placeboab

14 drug therapyfs

15 randomlyab

16 trialab

17 groupsab

18 or10-17

19 humanssh

20 18 and 19

21 9 and 20




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans




Searches

1 Bendamustine

2 bendamustin$tw

3 ribomustin$tw

4 treand$tw

5 levact$tw


7 cytostasan$tw

8 zimet$tw

9 imet$tw

10 Or1-9





15 Or11-14


17 15 not 16

18 10 and 17





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans





bendamustine

bendamustin

cytostasan

Treanda

Ribomustin

Zimet 3393

IMET 3393


Bendamustine

H I S T O R Y






retrieval of papers






















Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans










Subgroup analysis




Data synthesis





I N D E X T E R M S







tality]

MeSH check words

Adult Humans



Documents

Cochrane Database of Systematic Reviews (Reviews) || Bendamustine for patients with indolent B cell lymphoid malignancies including chronic lymphocytic leukaemia