Rituximab in aggressive NHL: why combination therapy should not be delayed

Rituximab in aggressive NHL: why combination therapy should not be

delayed

Bertrand Coiffier

Pathologie des Cellules LymphoïdesEA 3737 – Université Claude Bernard

Groupe d’Étude des Lymphomes de l’Adulte

Service d’HématologieHospices Civils de Lyon

The benefits of monoclonal antibodies

Combining rituximab and chemotherapy– increases CR rates – prolongs survival

Rituximab plus CHOP (R-CHOP) is the gold standard

No sufficient data for other antibodies

CHOP = cyclophosphamide, doxorubicin, vincristine, predrisoneCR = complete response

Major randomised studies

R-CHOP as the standard

DLBCLAge 60–80 yearsNo prior treatment PS 0–2 Stage II–IV

RANDOMISATION

LNH 98.5 study: design

CHOP every

3 weeks x 8

R-CHOPevery

3 weeks x 8

Coiffier B, et al. N Engl J Med 2002;346:235

Rituximab: 375mg/m2 on day 1Cyclophosphamide: 750mg/m2 on day 1Doxorubicin: 50mg/m2 on day 1Vincristine: 1.4mg/m2 (up to 2mg/m2) on day 1Prednisolone: 40mg/m2/day days 1–5

Rituximab: 375mg/m2 on day 1Cyclophosphamide: 750mg/m2 on day 1Doxorubicin: 50mg/m2 on day 1Vincristine: 1.4mg/m2 (up to 2mg/m2) on day 1Prednisolone: 40mg/m2/day days 1–5

DLBCL = diffuse large B-cell lymphomaPS = performance status

LNH 98.5 study: treatment responses

p=0.005

Coiffier B, et al. N Engl J Med 2002;346:235PR = partial response

6

31

63

CHOP (n=197)

CR PR No response

718

75

R-CHOP (n=202)

Median follow-up 7 yearsPFS

OS

Coiffier B, et al. J Clin Oncol2007;25(Suppl. 18):443s (Abstract 8009)

EFS = event-free survival; PFS = progression-free survivalDFS = disease-free survival; OS = overall survival

EFS1.0

0.8

0.6

0.4

0.2

0Su

rviv

al p

rob

abil

ity CHOP

R-CHOP

p<0.0001

0 1 2 3 4 5 6 7 8 9

DFS1.0

0.8

0.6

0.4

0.2

0Su

rviv

al p

rob

abil

ity

CHOPR-CHOP

p=0.0001

CHOPR-CHOP

1.0

0.8

0.6

0.4

0.2

0Su

rviv

al p

rob

abil

ity

1.0

0.8

0.6

0.4

0.2

0Su

rviv

al p

rob

abil

ity

Years

CHOPR-CHOP

p<0.0001

p=0.0004

0 1 2 3 4 5 6 7 8 9Years

0 1 2 3 4 5 6 7 8 9Years

0 1 2 3 4 5 6 7 8 9Years

Results according to aaIPIPFS: high risk

OS: high risk

PFS: low risk

OS: low risk

aaIPI = age adjusted International Prognostic Index

1.0

0.8

0.6

0.4

0.2

0Su

rviv

al p

rob

abil

ity

CHOPR-CHOP

1.0

0.8

0.6

0.4

0.2

0Su

rviv

al p

rob

abil

ity

1.0

0.8

0.6

0.4

0.2

0Su

rviv

al p

rob

abil

ity

1.0

0.8

0.6

0.4

0.2

0Su

rviv

al p

rob

abil

ity

CHOPR-CHOP

CHOPR-CHOP

CHOPR-CHOP

p=0.0051

p=0.0030

p=0.0022

p=0.0213

0 1 2 3 4 5 6 7 8 9Years

0 1 2 3 4 5 6 7 8 9Years

0 1 2 3 4 5 6 7 8 9Years

0 1 2 3 4 5 6 7 8 9Years

Coiffier B, et al. J Clin Oncol2007;25(Suppl. 18):443s (Abstract 8009)

p=0.000000007

R-chemotherapy

Chemotherapy

1.0

0.8

0.6

0.4

0.2

0

Months

Pro

ba

bil

ity

MInT study1

TT

F

Years0 1 2 3 4 5

ECOG study3

Maintenance

ObservationCHOPR-CHOP

R-CHOP-14

p=0.000025

FF

S

0 5 10 15 20 25 30 35 40 45Months

RiCOVER study4

CHOP-14

British Columbia2

Years

Su

rviv

al Post-rituximab

Pre-rituximab

p=0.0001

1Pfreundschuh M, et al. Lancet Oncol 2006;7:379–912Sehn LH, et al. J Clin Oncol 2005;23:5027–33

3Habermann T, et al. J Clin Oncol 2006;24:3121–74Pfreundschuh M, et al. Lancet Oncol 2008;Jan 14:Epub ahead of print

MInT = MabThera International TrialECOG = Eastern Cooperative Oncology GroupTTF = time-to-treatment failureFFS = failure-free survival

R-CHOP: a consistent clinical benefit1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 20 25 30 35 40 45 50 0 1 2 3 4

1.0

0.8

0.6

0.4

0.2

0

YearsFeugier P, et al. J Clin Oncol 2005 23:4117–26

Su

rviv

alGELA R-CHOP study

0 1 2 3 4 5 6

R-CHOP

CHOP

P=0.007

Standard CHOP Rituximab 375mg/m2

1 2 3 4 5 6 7 8

R R

No further treatment

Rituximabfour infusionsevery 6 monthsfor 2 years

SDPRCR

Intergroup study of CHOP or R-CHOP rituximab as maintenance therapy

Habermann T, et al. J Clin Oncol 2006;24:3121–7SD = stable disease

Induction therapy: TTFP

rob

abil

ity

HR=0.78p=0.04

R-CHOP ( rituximab maintenance)

CHOP ( maintenance)

1.0

0.8

0.6

0.4

0.2

0

Years from study entry

Habermann T, et al. J Clin Oncol 2006;24:3121–7Evaluable patients n=546

0 1 2 3 4 5

ECOG 4494: effect of rituximab maintenance on FFS according to induction regimen

Years

R-CHOP inductionCHOP induction

0 1 2 3 4 5

p=0.81

Rituximab maintenance

Observation

p=0.0004

Pro

bab

ility

1.0

0.8

0.6

0.4

0.2

0

Rituximab maintenance

Observation

Years

Pro

bab

ility

0 1 2 3 4 5

1.0

0.8

0.6

0.4

0.2

0

Habermann T, et al. J Clin Oncol 2006;24:3121–7

CD20+ DLBCL18–60 years

IPI 0, 1stages II–IV,I with bulk

6 x CHOP-like+ 30–40 Gy (Bulk, E)

6 x CHOP-like+ rituximab

+ 30–40 Gy (Bulk, E)

MInT: trial design

Pfreundschuh M, et al. Lancet Oncol 2006;7:379–91

CHOP-21 (n=396)CHOEP-21 (n=362)MACOP-B (n=33)PMitCEBO (n=32)

Randomisation

MInT studyEFSEFS PFSPFS OSOS

Pfreundschuh M, et al. Lancet Oncol 2006;7:379–91

N at risk

R-chemotherapy 413 296 256 156 37 0 Chemotherapy 410 229 194 101 28 1

EF

S (

%)

100

80

60

40

20

0

413 313 266 151 37 0 413 364 318 184 51 2

410 253 205 104 27 1 410 349 283 150 44 1

Months0 12 24 36 48 60

Months Months

PF

S (

%)

OS

(%

)

R-chemotherapy

Chemotherapy

Log-rank p<0.0001 Log-rank p<0.0001 Log-rank p=0.0001

100

80

60

40

20

0

100

80

60

40

20

00 12 24 36 48 60 0 12 24 36 48 60

Chemotherapy

Chemotherapy

R-chemotherapyR-chemotherapy

CD20+ DLBCL

stages I–IV

61–80 years

RiCOVER-60: trial design

6 x CHOP-14+ 36 Gy (Bulk, E)

8 x CHOP-14+ 36 Gy (Bulk, E)

6 x CHOP-14+ 36 Gy (Bulk, E)+ 8 x rituximab

8 x CHOP-14+ 36 Gy (Bulk, E)+ 8 x rituximab

Eight doses of rituximab regardless ofnumber of cycles of chemotherapy

Only 80% with DLBCL60% IPI 0–2All patients received a pre-phase

Only 80% with DLBCL60% IPI 0–2All patients received a pre-phase

Pfreundschuh M, et al. Blood 2006;108:64a (Abstract 205)Pfreundschuh M, et al. Lancet Oncol 2008. In press

Pfreundschuh M, et al. Blood 2006;108:64a (Abstract 205)Pfreundschuh M, et al. Lancet Oncol 2008. In press

Random2 x 2

factorialdesign

Months

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n

0 10 20 30 40 50 60 70 80

6 x CHOP-14

8 x CHOP-14

6 x CHOP-14 + 8 x rituximab

8 x CHOP-14 + 8 x rituximab

RiCOVER-60

8 x CHOP-14

6 x CHOP-14

6 x CHOP-14 + 8 x rituximab

8 x CHOP-14 + 8 x rituximab

OSEFS

Pfreundschuh M, et al. Lancet Oncol 2008;Jan 14:Epub ahead of printPfreundschuh M, et al. Lancet Oncol 2008;Jan 14:Epub ahead of print

Months0 10 20 30 40 50 60 70 80

1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n

Questions

Question 1: R-CHOP-21 or R-CHOP-14?

R-CHOP-14 or -21?

No randomised study published

Tolerability is good but pre-phase and six cycles in German study

Other phases II seemed to find a poorer tolerability

Probability that R-CHOP-14 can be superior to R-CHOP-21 is low

Equivalent results if eight rituximab infusions

Prophylactic darbepoietin alfa

Supportive care

LNH 03-6B: 66–80 years, aaIPI = 1,2,3(R Delarue, A Bosly)

4 IT MTXR

R-CHOP-21

0 3 6 9 Weeks12 15 18 21

0 2 4 6 10 14 Weeks8 12

R-CHOP-14

Primary endpoint: EFS Expected improvement: 10% at 3 years with R-CHOP-14 (55–65%)600 patients required (4 years)IT = intrathecalMTX =methotrexate

Abstract 2436

Delarue R, et al.

Questions

Question 2: dose-dense/dose-intense regimens?

ConsolidationInduction

MTX 3g/m²

Ara-C 100mg/m²/day x 4 days

Doxorubicin 75mg/m² day 1Cyclophosphamide 1,200mg/m² day 1Vindesine 2mg/m² day 1, day 5Bleomycin 10mg day 1, day 5Prednisone 60mg/m² day 1–5IT MTX 15mg day 2G-CSF 5µg/kg day 6–13

ACVB plus sequential consolidation

ACVB = adriamycin, cyclophosphamide, vindesine, bleomycinG-CSF = granulocyte-colony stimulating factor; IFM = ifosfamide; MTX = methotrexate

Week

ACVB

ResponseResponse

0 2 4 6 10 12 14 16 18 20 22 26

MTX IFM 1,500mg/m²

VP16 300mg/m²

Ara-C

S.C.

I II III IV

Survival with ACVB in LNH regimens

Years

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20

Su

rviv

al p

rob

abil

ity

NHL = non-Hodgkin’s lymphoma

LNH-80

LNH-84

LNH-87

LNH-93

ACVBP

CHOP

p=0.03

R0 3 6

60 3

9

12

13

15

17

18

19 21 23 25 27

9

15

21

ACVBP

CHOP

MTX IFM – VP16 Ara-C

Week

Week

ACVBP

CHOP

p=0.005

SurvivalDFS100

80

60

40

20

00 2 4 6 8 10

Years

Su

rviv

al (

%)

Year

Tilly H, et al. Blood 2003;102:4284–9

ACVBP regimen versus CHOP in advanced aggressive lymphoma

100

80

60

40

20

0

Su

rviv

al (

%)

0 2 4 6 8 10

ACVBP = adviamycin, cyclophosphamide, viudesine, bleomycin, prednisone

LNH 03-2B: <60 years, aaIPI = 1(C Recher, H Tilly)

R

60 3 12 15 189 21

R-ACVBP-14

R-CHOP-21Weeks

MTX

IFM – VP16

ARA-C

0 2 4 6 10 14 24 Weeks

4 x IT MTX

Primary endpoint = EFS Expected improvement: 10% at 2 years with R-ACVBP (75–85%)380 patients required (in 4 years)

Questions

Question 3: high-dose therapy and autotransplant?

SurvivalDFS

p=0.02 p=0.04

Induction phase ACVB four cycles CR

Sequential consolidation

MTX/IFM – VP16/L-Aspa/Ara-C

MTX/CBV + ABMT

RANDOMISATION

IPI 2–3: n=236

0 24 48 72 96 120 144Months

Su

rviv

al

(%)

100

80

60

40

20

0

Months

Su

rviv

al

(%)

ASCT = autologous stem cell transplantation; CBV = cytarabine, BCNU, etoposide; HDT = high-dose therapy

Benefit of HDT with ASCT in first CR

0 24 48 72 96 120 144

100

80

60

40

20

0

Interim PET scanning as a prognostic tool in DLBCL

Pretreatment Mid-treatment

PET = positron emission tomography

PET positive (n=32) 2 years EFS = 46%

PET negative (n=49) 2 years EFS = 80%

p=0.0003

Years

EFS according to PET status after two cycles

1.00

0.75

0.50

0.25

0 0 1 2 3 4 5

Pro

bab

ilit

y

LNH07-3B study: patients with aaIPI >2 and <61 years

2 x R-ACVBP-14

Sequential consolidation

Negative

2 x R-ACVBP-14

Positive Negative

Positive

Z-BEAM

SalvageCORAL study if biopsy

Negative

2 x R-CHOP-14

4 x R-CHOP-14

Negative

2 x R-CHOP14

Positive

Negative

Positive

Z-BEAM

SalvageCORAL study if biopsy

Negative

TEP C4TEP 0 TEP C2

R

Athens, February 2007Z-BEAM = 90Y ibritumomab, BCNU, ara-c, etoposide, melphalan

Questions

Question 4: which ways to improve these results?

Day of treatment

Ser

um

lev

els

(mg

/ml)

Courtesy of Reiser M, Cologne

Rituximab PK: trough serum levels200

180

160

140

120

100

80

60

40

20

0

R-CHOP-14

PK = pharmacokinetics

1 9 17 25 33 41 49 57 65 73 81 89 97 105 113

PK model based on median values of PK parameters for KELM, V1 (l/kgLBMc), K12, and K21 of 20 patients treated with R-CHOP-14 according to a two-compartment model. Model was then calculated for 21 days interval

PK model R-CHOP-14 versus R-CHOP-21

mg

/mL

300

225

150

75

0

R-CHOP-14R-CHOP-21

09.00

CHOP

CHOP

CHOP

CHOP

CHOP

CHOPDense-R-CHOP-14

(12 x R)

12 14

CHOP

CHOP

CHOP

CHOP

CHOP

CHOP

12 14

R-CHOP-14(8 x R)

Rituximab schedules for DLBCL

Rituximab PK: trough serum levels

Day of treatment

Ser

um

leve

l (m

g/m

L)

200

180

160

140

120

100

80

60

40

20

01 9 17 25 33 41 49 57 65 73 81 89 97 105 113

Dense-R-CHOP-14

R-CHOP-14

Dense-R-CHOP-14 (n=47)versus R-CHOP-14 (n=306)

Dense-R-CHOP-14: IPI=1–2Dense-R-CHOP-14: IPI=3–5R-CHOP-14: IPI=1–2R-CHOP-14: IPI=3-5

1.0

0.8

0.6

0.4

0.2

00 2 4 6 8 10 12

Months

Per

cen

tag

e

Potential applications of RIT in DLBCL

Is there a role for RIT rather than radiotherapy in localised disease?

Is there a role of RIT as ‘consolidation’ therapy to improve the quality of response?

What is the optimal way to incorporate RIT into R-CHOP regimens?

RIT = radioimmunotherapy

Can RIT improve the quality of response after R-CHOP in those failing to achieve CR?

Numerous mature phase II trials in follicular lymphoma showing improvements in quality of response (conversion from PR to CR 60–90%)

Single agent phase II data 90Y-ibritumomab demonstrating high response rate in chemotherapy refractory DLBCL

Emerging phase II data all confirm feasibility of integrating RIT with R-chemotherapy in DLBCL

RIT toxicity mainly haematological, predictable and manageable, otherwise non-overlapping

Studies combining chemotherapy and RIT for untreated DLBCL

Group Patients Study

SWOG Early stage; unfavorable CHOP (x3), IFXRT, 90Y-ibritumomab tiuxetan

ECOG Stage I–II disease R-CHOP (x2); if CR: CHOP (x2) + 90Y-ibritumomab tiuxetan; if PR: CHOP (x4), + 90Y-ibritumomab tiuxetan, IFXRT

SWOG >60 years; bulky II, III, IV R-CHOP (x6), CHOP (x2), 131I tositumomab

MSKCC >60 years, aaIPI 2 R-CHOP (x6), 90Y ibritumomab tiuxetan

European >60 years R-CHOP (x6), if CR: 90Y-ibritumomab tiuxetan versus observation; if PR: 90Y- ibritumomab tiuxetan

European >60 years R-CHOP (x2), 90Y-ibritumomab tiuxetan and repeat the sequence

IFXRT = involved-field external radiation therapy; MSKCC = Memorial Sloan-Kettering Cancer Center; SWOG = Southwest Oncology Group

New molecules?

New monoclonal antibodies– same antigen– different antigens: CD19, CD22, CD80– conjugated, toxine, isotope– bispecific antibodies

Bortezomib, revlimid

Bevacizumab

SAHA, HDACi

Questions

Question 5: at time of relapse

Relapse/refractory/PR

Relapse: PD after CR

PR: response but incomplete– presence of persisting lymphoma cells– tumour fixing with PET scan

Refractory: PD during treatment or just after the end of treatment

Highly different outcome

PD = progressive disease

Management of aggressive NHL

Induction chemotherapy

Responsive Primary refractory

Relapse

HDT with ASCT

Second-line therapy Second-line therapy

NR CR/PR CR/PR NR

NR = no response

Second-line therapy for aggressive NHL

Ideal second-line therapy

– provides effective cytoreduction to achieve an optimal response

– results in minimal non-haematological toxicity

– is not stem-cell toxic

– effectively mobilises stem cells into the peripheral blood

Rituximab significantly improves outcomes when combined with HDT and ASCT

Khouri IF, et al. J Clin Oncol 2005;23:2240–7

OS

Months post-transplant

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 27 42 30

p=0.004

No rituximab (n=30)

Rituximab (n=67)

p=0.002

No rituximab (n=30)

Rituximab (n=67)

Historical comparison

DF

S

1.0

0.8

0.6

0.4

0.2

0

Months post-transplant

0 3 6 9 12 15 18 21 27 42 30

CORAL study: R-ICE versus R-DHAP followed by ASCT ± maintenance

R1

R-DHAP

Clinical evaluation

R2

Clinicalevaluation

Observation

BEAM ASCT

Rituximab 375mg/m²

every 8 weeks for 12 months

OFF

R-ICE

R-DHAP

R-ICER-DHAP

R-ICE

PBPC

PD/SD

CR/PR

Hagberg H, et al. Ann Oncol 2006;17(Suppl. 4):iv31–iv32

400 patients neededRecruitment complete

*With lenograstim 150µg/m²R-ICE = rituximab, ifosfamide, carboplatin, etoposideR-DHAP = rituximab, dexamethasone, ara-c, cisplatinPBPC = peripheral blood progenitor cell

*With lenograstim 150µg/m²R-ICE = rituximab, ifosfamide, carboplatin, etoposideR-DHAP = rituximab, dexamethasone, ara-c, cisplatinPBPC = peripheral blood progenitor cell

CORAL toxicity

R-ICEn, (%)

R-DHAPn, (%)

Infection with neutropenia Grade 3–4 Yes 16 (17) 18 (21)

Infection without neutropenia Grade 3–4 Yes 6 (7) 8 (9)

Renal Grade 3–4 Yes 0 6 (7)

CORAL efficacy

ResponseR-ICE/R-DHAP

(%) p value

CR/CRu/PR ORR 66/70 0.8

CR/CRu 42/40 0.8

MARR

CR/CRu/PR 55/64 0.2

Cru = unconfirmed CRORR = overall response rateMARR = mobilization adjusted response rate

Cru = unconfirmed CRORR = overall response rateMARR = mobilization adjusted response rate

Response rate prognostic factors CR/CRu/PR: logistic model

p value

Prior rituximab 0.1

Relapse <12 months 0.0002

IPI >1 0.003

Treatment arm 0.1

Efficacy analysis: secondary criteriaEFS – ITT

GELA data on file

1.0

0.8

0.6

0.4

0.2

0

Su

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rob

abil

ity

0 10 20 30 40EFS (months)

No. of subjects Event Censored Median survival (95% CI)Arm A/R-ICE 100 49% (49) 51% (51) 20.96 (9.26 NYR)Arm B/R-DHAP 94 44% (41) 56% (53) NA (8.51 NYR)

Log-rank p=0.4589

Arm A/R-ICEArm B/R-DHAP

NYR = not yet reached; CI = confidence interval; ITT = intent to treat

Prognostic factors failure EFS

GELA data on file

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al p

rob

abil

ity

0 10 20 30 40EFS (months)

Log-rank p<0.0001

<12 months12 months

No. of subjects Event Censored Median survival (95% CI)<12 months 108 60% (65) 40% (51) 5.45 (3.61 10.15) 12 months 86 29% (25) 71% (53) NA (27.47 NA)

Maintenance

Maintenance in responding patients has proven efficacy in follicular lymphoma and mantle cell lymphoma

Role in more aggressive lymphomas?

It might be easier to demonstrate a difference in PR or relapsed patients

Week

Week

ACVBP

AC/ACE

Arm A

Arm B

0 2 4 6

I II III IV

AC ACE ACEACE

Induction

0 2 4 6

Leukaphereses

MTX21 22 23 24

Rituximab375mg/m2

Observation

day 60

d’ 0day 0

10 12

Response

day 80–90

Autotransplant (ASCT)

Response

Response50%R1

day 45–60

CBV-Mitox

Haioun C, et al. J Clin Oncol 2007;25(Suppl. 18):444s (Abstract 8012)Haioun C, et al. J Clin Oncol 2007;25(Suppl. 18):444s (Abstract 8012)

Can we reduce post transplant relapse rate? NHL 98-B3 study: design

Mitox = mitoxantrone

R2

*Calculated from randomisation for post-HDT treatment

Median follow-up from R2*: 4 years

Rituximab: 80% (95% CI: 72–86)Observation: 71% (95% CI: 62–78)

n=139

n=130

p=0.098

EFS according to post-HDT treatment arm (ITT analysis, n=269)

1.0

0.8

0.6

0.4

0.2

0

Su

rviv

al p

rob

abil

ity

0 1 2 3 4 5 6

p=0.0989

ObservationRituximab

Years

Haioun C, et al. J Clin Oncol,2007;25(Suppl. 18):444s (Abstract 8012)

CR CRu + PR

n=70

n=60

n=69

n=70

Rituximab: 86% (95% CI: 75–92)Observation: 68% (95% CI: 53–79)

Rituximab: 74% (95% CI: 62–83)Observation: 73% (95% CI: 61–82)

p=0.023 p=0.916

EFS by post-HDT response status

Haioun C, et al. J Clin Oncol 2007;25(Suppl. 18):444s (Abstract 8012)

1.0

0.8

0.6

0.4

0.2

0

Su

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rob

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ity

1.0

0.8

0.6

0.4

0.2

0

Su

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rob

abil

ity

0 1 2 3 4 5 6 0 1 2 3 4 5 6

Years Years

ObservationRituximab

ObservationRituximab

Rituximab maintenance following HDT and autologous cell rescue after R-ICE

cytoreduction improves EFS and OS

Retrospective analysis Patients treated with R-ICE

1999–2006 Who had PR or CR No rituximab (n=38) Rituximab weekly x 4 at day 42 plus

day 180 (n=26) Rituximab every 8 weeks x 6 starting

on day 29 (n=17)

Multivariate analysis Disease status (p=0.04) and Rituximab maintenance (p=0.003) Were significant for OS Only maintenance rituximab Was significant for EFS (p<0.001)

Rice RD, et al. Blood 2007;110:385a (Abstract 1280)

EFS1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n e

ven

t fr

ee

0 1 2 3 4 5 6 7Years

Maintenance (n=43)

No maintenance (n=38)

p=0.0002

Conclusion

Rituximab has completely transformed the outcome of patients with DLBCL

R-CHOP is the most widely used regimen

Prognostic parameters with R-CHOP need some redefinition

New molecules?– combination with another drug having a different

mechanism of action (targeting a different intracellular pathway) looking for a synergy