Prof. Sergio Storti Università Cattolica Sacro Cuore Campobasso … · 2019. 6. 7. · R-BENDA Frail, Sergio Storti, Campobasso -Italy Deaths: n=23 Progression 15 (65%) Second cancer

19.11.2015

1

BENDAMUSTINE COMBINED WITH RITUXIMAB (R-B)

IN ELDERLY FRAIL PATIENTS

WITH NEWLY DIAGNOSED DLBCL:

A PHASE II STUDY OF THE FONDAZIONE ITALIANA LINFOMI (FIL).

Prof. Sergio Storti

Università Cattolica Sacro Cuore

Campobasso (Italy)

R-BENDA Frail: Background

� The incidence of NHL increases with age: over one third of NHL

cases involves elderly patients >70 years of age

� Rituximab (R) in combination with cyclophosphamide, doxorubicin,

vincristine, and prednisone (R-CHOP) is currently the most widely

used first-line therapy for Diffuse Large B-cell Lymphomas (DLBCL)

� However, many patients, including elderly and/or frail patients, may

not tolerate the toxicities associated with this regimen.

� Recent data suggested that bendamustine plus rituximab (BR) was

superior in effectiveness and tolerability compared to R-CHOP in

the treatment of indolent and mantle cell lymphomas.

� Here we report the safe and effective use of BR in these patients.

R-BENDA Frail, Sergio Storti, Campobasso -Italy

19.11.2015

2

Comprehensive Geriatric Assessment

in FIL Studies

Modified score originally proposed by Balducci (*)

Validation in a small population of elderly DLBCL (**, ***)

“FIL Version” of CGA

ADL IADL CIRS-G

Age

(*) Balducci L et al, The Oncologist, 2000

(**) Tucci A et al, Cancer, 2009

(***) Merli F et al, Leuk Lymph, 2013

The FIL StrategyChronological age does not fully explain complexity of elderly patients.

Comorbidities and functional, social, and biological behaviours are other dimensions of

elderly patients.

19.11.2015

3

Patient Registration and CGA

FIL WEBSITE (www.filinf.it)

ELDERLY PROJECT

Score and Profile

Select

Clinical

Study� FIT protocol

� UNFIT protocol

� FRAIL protocol

19.11.2015

4

R-BENDA Frail: ObjectivesPrimary end-points

� To evaluate the activity of R-B combination in terms of complete response rate (CRR).

� To evaluate the safety and tolerability of R-B combination in terms of rate of adverse

events occurrence.

Secondary end-points

� To evaluate progression free survival (PFS)

� To evaluate overall survival (OS)

R-BENDA Frail: Study Design� Phase II open-label, non-randomized, study

� Planned enrollement: 49 patients according to a Simon two-stages design

Stage 1

Stage 2

Analysis

19 3 12

25 10 20

44 11 19

unaccetable

toxicity

ineffective

regimen

Evaluable

Patients

Complete

RemissionToxicity


� Histologically proven CD20 positive diffuse large B-cell non-Hodgkin’s lymphoma

� Age > 70 years

� No previous treatment

� FRAIL patients defined as follows (see Appendices B-E):

� Age > 80 years with UNFIT profile

� ADL > 5 residual functions

� IADL > 6 residual functions

� CIRS 5-8 co-morbidities of grade 2

� or Age < 80 years with

� ADL < 4 residual functions, or

� IADL < 5 residual functions, or

� CIRS : 1 co-morbidity of grade 3-4, or > 8 co-morbidities of grade 2

� Life expectancy > 6 months

� Written informed consent

� Accessibility of patient for treatment and follow up

R-BENDA Frail: Inclusion Criteria

19.11.2015

5

� History of other malignancies within 5 years prior to study entry except for adequately

treated carcinoma in situ of the cervix or basal or squamous cell skin cancer

� Previous exposure to cytotoxic agents

� Suspect or clinical evidence of CNS involvement by lymphoma

� HBsAg, HCV or HIV positivity; HBcAb positivity is accepted only with concomitant

treatment with Lamivudine

AST /ALT > twice upper the normal range; bilirubin > twice upper the normal range; serum

creatinine > 2.5 mg /dl

Evidence of any severe active acute or chronic infection

� Concurrent co-morbid medical condition which might exclude administration of full dose

chemotherapy

� Senile dementia

� Any other co-existing medical or psychological condition that would preclude participation

in the study or compromise ability to give informed consen

R-BENDA Frail: Exclusion Criteria

R-BENDA Frail: Treatment Plan

nr of courses radiotherapybest

supportive care

IPI=0 and Stage I-II (non bulky) 4 R-B + 2 R according to

clinical

practice

according to medical

judgementAll others 6 R-B + 2 R


R-BENDA (R-B)

� Rituximab: 375 mg/m2 - intravenously - day 1*

� Bendamustine: 90 mg/m2 - intravenously - days 2 and 3**

Treatment will be administered on a 28-day cycle basis.

*Administration of rituximab during cycle 1 is postponed to day 8, thereafter

on day 1.

** After the first cycle, bendamustine can be administered on days 1-2 or days

2-3 according to Institutional/patient/physician choice.

19.11.2015

6

Patient

characteristics

N (%)

Age (years)

Median 82

Range 72-89

≥ 80 38 (83%)

Gender

Male 29 (59%)

ECOG PS

2-3 18 (37%)

Stage

III-IV 29 (59%)

LDH

Elevated 19 (40%)

R-BENDA Frail: Patients

� 49 pts enrolled from from Feb 2012 to Feb 2014

by 24 Italian centers

� AA IPI 0=11; 1=14; 2=16; 3= 6; NV= 2

� Age ≥ 80 years: 83%

� Unfavourable Criteria at CGA evaluation:

� n.3 (68%, 26)

� n.2 (26%, 10)

� n.1 (5%, 2)

� Most frequent comorbidities:

� cardiovascular (37%)

� metabolic (11%)

� respiratory diseases (7%)R-BENDA Frail, Sergio Storti, Campobasso -Italy

R-BENDA Frail: Treatment Discontinuation

24

I (n.4)

II (n.5)

III (n.7)

V (n.7)

VII (n.1)

AE n.2

PD n.2

AE n.2

PD n.3

AE n.3

PD n.4

AE n.5

PD n.2

PD n.1

Discontinued

patients

Cycle completed

(n.pts dicontinued)Cause

� 24/49 patients discontinued:

� 10 progressions of disease

� 8 adverse events

� 6 death

� 2 for lymphoma progression

� 1 cardiac failure

� 1 pneumonia

� 1 worsening BPCO

� 1 toxicity (not specified)

The adverse events that led to

treatment discontinuation were:

� persistent cytopenia (3)

� worsening general condition (2)

� coronary acute syndrome (1)

� second tumor (1)

� febrile neurtropenia with

infection (1)

19.11.2015

7

R-BENDA Frail: Treatment Discontinuation

CyclePts who completed the

cyclePts in PD

Pts who discontinued

for AE

Pts who discontinued for

deathTOT

I 49 49

II 45 1 1 2 49

III 40 3 2 4 49

IV 33 7 3 6 49

V 33 7 3 6 49

VI 26 9 8 6 49

VII 26 9 8 6 49

VII 25 10 8 6 49

CR

PR

PD

NV

27

1

5

1

12

6

22

3

CR

PD-SD15

6

uncompleted

treatment

completed

treatment

R-BENDA Frail: Response (n=49)

Response N (%)

CR 27 (55%)

PR 1 (2%)

SD 1 (2%)

PD 14 (29%)

NV 6 (12%)

tot 49 (100%)

24 25


19.11.2015

8

Grade III/IV toxicities were documented in 24 patients (53%)

R-BENDA Frail: Toxicity


0

.25

.5

.75

1

0 3 6 9 12 15 18 21 24 27 30 33 36

49 36 30 26 23 19 19 15 8 6 4 3 2N pts

PFS

0

.25

.5

.75

1

0 3 6 9 12 15 18 21 24 27 30 33 36

49 41 36 30 28 25 25 20 11 7 5 5 4N pts

OS

Cu

mu

lative

pro

ba

bili

ty

Follow-up, months

# events 23

OS% at 24 months: 49 (CI95 33-63)

Median OS: 23 months (CI95 10- .)

Median FU: 24 months (range 1-39)# events 31

PFS% at 24 months: 38 (CI95 24-52)

Median PFS: 13 months (CI95 4-31)

R-BENDA Frail: Outcome

2-years OS: 49%2-years PFS: 38%

19.11.2015

9

0.00

0.25

0.50

0.75

1.00

Cu

mu

lative

pro

ba

bili

ty

49 40 35 30 28 25 25 20 11 6 5 5 4OS49 36 30 26 23 19 19 15 8 6 4 3 2PFS

0 3 6 9 12 15 18 21 24 27 30 33 36

Follow-up, months

PFS OS

Median follow-up: 23 months (range 1-39)

R-BENDA Frail: Outcome

Median OS : 23 months

Median PFS : 13 months

2-years OS: 49%

2-years PFS: 38%


R-BENDA Frail: Relapses

• Complete Remission: 27/49 (55%)

• Relapses: 8/27 (30%)

• Duration of Response (median): 12,4 months (range 3,6 -32,1)

Second Line Therapy:

• No therapy-Palliation: 4

• Radiotherapy 1

• CHT regimen (R-COMP): 3 UNFIT profile, FRAIL due to age ≥ 80 yrs

(ADL=6, IADL=6, CIRS g3=0, CIRS g2=1)

FRAIL profile due to ADL and IADL impaired


FRAIL due to ADL and IADL impairment

and severe comorbidities



19.11.2015

10

R-BENDA Frail: Cause of Death


� Deaths: n=23

� Progression 15 (65%)

� Second cancer 2 (9%)

� Gastric carcinoma (pts in CR for lymphoma)

� Liver carcinoma (pts in CR for lymphoma)

� Cardiopathy 2 (9%)

� Toxicity (not specified) 1 (4%)

� Pneumonia 1 (4%)

� Worsening BPCO 1 (4%)

� Cachexia 1 (4%)

R-BENDA Frail: Conclusions


� Combination therapy with BR demonstrates low

toxicity profile in this high risk population.

� The promising results on activity can encourage

clinicians to considered BR for the treatment of FRAIL

elderly patients with DLBCL not eligible for R-CHOP.

19.11.2015

11

FIL Centres

FIL Data Centre

FIL Elderly Committee

All the patients

Documents

Prof. Sergio Storti Università Cattolica Sacro Cuore Campobasso … · 2019. 6. 7. · R-BENDA Frail, Sergio Storti, Campobasso -Italy Deaths: n=23 Progression 15 (65%) Second cancer