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13 th Annual Hematology & Breast Cancer Update Update in Lymphoma Craig Okada, MD, PhD Assistant Professor, Hematology January 20, 2010 Governors Hotel,

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Presentation on theme: "13 th Annual Hematology & Breast Cancer Update Update in Lymphoma Craig Okada, MD, PhD Assistant Professor, Hematology January 20, 2010 Governors Hotel,"— Presentation transcript:

1 13 th Annual Hematology & Breast Cancer Update Update in Lymphoma Craig Okada, MD, PhD Assistant Professor, Hematology January 20, 2010 Governors Hotel, Portland Oregon

2 Initial Treatment of Indolent Lymphoma l Expectant observation l Treatment » Rituximab » Immunochemotherapy –R-CHOP –R-CVP –R-Bendamustine –R-Fludarabine

3 Initial Treatment of Indolent Lymphoma l Expectant observation » Avoids treatment related toxicity » 3 RCTs failed to show an overall survival difference between watching and treatment –Young et al, Sem Hematol, 1988 –Brice et al, J Clin Oncol 1997 –Ardeshna et al, Lancet 2003 » Risk and time to transformation similar

4 What Oncologist in US are doing Freiberg et al, J Clin Oncol 2006;24:7527

5 ASH Intergroup study of rituximab vs watch and wait (Ardeshna, K et al) l Expectant observation – still relevant today? l Objective » Does initial treatment with rituximab in patients with asymptomatic advanced stage FL result in a significant delay in the initiation of chemotherapy or radiotherapy when compared with a watchful waiting approach? Thank Dr. Ardeshna for sharing his slides

6 Compulsory CT scan Compulsory CT scan only if clinical CR Bone marrow for histology and MRD only if CT shows CR RANDOMISATIONRANDOMISATION ARM A Watch and Wait ARM B Rituximab Induction ARM C Rituximab Induction & maintenance Continued follow up Progressive disease requiring therapy stops protocol treatment Clinic visits

7 EventsTotals W+W R4 R4 + M Proportion of patients progression- free Years from randomisation Progression-free survival HR (Rituximab vs W+W) = 0.46, 95%CI = 0.33, 0.65, p<0.001 HR (Rituximab + M vs W+W) = 0.21, 95%CI = 0.15, 0.29, p<0.001 HR (Rituximab + M vs Rituximab) = 0.43, 95%CI = 0.24, 0.72, p= yr PFS W+W=33% R4=60% R4+RM=81%

8 Proportion of patients with no new treatment initiated EventsTotals W+W R4 R4 + M Years from randomisation % not requiring Rx at 3yr W+W=48% R4=80% R4+RM=91% Time to Initiation of New Therapy (TTINT) HR (Rituximab vs W+W) = 0.37, 95%CI = 0.25, 0.56, p<0.001 HR (Rituximab + M vs W+W) = 0.20, 95% CI = 0.13, 0.29, p <0.001 HR (Rituximab + M vs Rituximab) = 0.57, 95% CI = 0.29, 1.12, p =0.10

9 EventsTotals W+W R4 R4 + M % of patients alive Years from randomisation Overall survival 3yr OS=95% HR (Rituximab vs W+W) = 0.63, 95%CI = 0.21, 1.92, p=0.42 HR (Rituximab + M vs W+W) = 0.84, 95%CI = 0.32, 2.18, p=0.72 HR (Rituximab + M vs Rituximab) = 1.21, 95%CI = 0.37, 3.97, p=0.75

10 Intergroup study of rituximab vs watch and wait (Ardeshna, K et al) l Comparing “apples to oranges” » Not fair to look at time to “new” treatment between no treatment and rituximab l More interesting questions to possibly come from the study » Overall survival » Time to second treatment » Transformation rate » Response to initial treatment l Still open question if asymptomatic FL patients benefit from treatment -> expectant observation is still appropriate management.

11 eastern cooperative oncology group Results of E4402 (RESORT): A Randomized Phase III Study Comparing Two Different Rituximab Dosing Strategies for Low Tumor Burden Follicular Lymphoma Brad Kahl, Fangxin Hong, Michael Williams, Randy Gascoyne, Lynne Wagner, John Krauss, Sandra Horning

12 eastern cooperative oncology group E4402: RESORT Rationale  Hypothesis:  After initial rituximab therapy, extended scheduled dosing (maintenance rituximab - MR) will prolong disease control compared to retreatment dosing administered upon disease progression (rituximab retreatment - RR)  Previously untreated, low tumor burden, FL an ideal patient population to test this hypothesis  Reasonably homogenous population  Hypothesis:  After initial rituximab therapy, extended scheduled dosing (maintenance rituximab - MR) will prolong disease control compared to retreatment dosing administered upon disease progression (rituximab retreatment - RR)  Previously untreated, low tumor burden, FL an ideal patient population to test this hypothesis  Reasonably homogenous population

13 eastern cooperative oncology group 13 E4402 (RESORT) Schema Rituximab re-treatment at progression* 375 mg/m 2 qw  4 RANDOMIZERANDOMIZE Rituximab 375 mg/m 2 qw  4 CR or PR Rituximab Maintenance* 375 mg/m 2 q 3 months *Continue until treatment failure No response to retreatment or PD within 6 months of R Initiation of cytotoxic therapy or Inability to complete rx

14 eastern cooperative oncology group E4402 Major Eligibility  Indolent NHL  Follicular grade 1 or 2  Small Lymphocytic  MALT  Marginal Zone nodal  Marginal Zone splenic  No prior lymphoma therapy  Stage III or IV disease  Measurable disease  Indolent NHL  Follicular grade 1 or 2  Small Lymphocytic  MALT  Marginal Zone nodal  Marginal Zone splenic  No prior lymphoma therapy  Stage III or IV disease  Measurable disease  Low tumor burden as defined by GELF  No tumor mass > 7cm  Fewer than 3 nodal masses > 3 cm  No system symptoms or B symptoms  No splenomegaly greater than 16 cm by CT scan  No risk of organ compression  No leukemic phase  No cytopenias

15 eastern cooperative oncology group E4402 (RESORT) Objectives  Primary  To compare the TTTF between the MR and the RR arms  Secondary  To compare time to first cytotoxic therapy between the MR and the RR arms  To compare QOL between the arms  To compare toxicities between arms  Primary  To compare the TTTF between the MR and the RR arms  Secondary  To compare time to first cytotoxic therapy between the MR and the RR arms  To compare QOL between the arms  To compare toxicities between arms

16 eastern cooperative oncology group E4402 (RESORT) Results  Activated Nov 2003 – Closed Sept 2008  Enrolled 545 patients  161 non-FL patients will be analyzed and reported separately  384 (71%) FL histology  274 (71%) responded to Induction rituximab  134 assigned to retreatment rituximab (RR)  140 assigned to maintenance rituximab (MR)  Activated Nov 2003 – Closed Sept 2008  Enrolled 545 patients  161 non-FL patients will be analyzed and reported separately  384 (71%) FL histology  274 (71%) responded to Induction rituximab  134 assigned to retreatment rituximab (RR)  140 assigned to maintenance rituximab (MR)

17 eastern cooperative oncology group Baseline Characteristics at Randomization RR (N=134)MR (N=140) Age59.5 (26-86)58.9 (25-86) Gender (M/F)46/54% PS (0/1)84/15%87/10% Stage III56%48% IV43%51% FLIPI 0-115%16% 246%43% 3-539%41% B2M elevated46%39%

18 eastern cooperative oncology group Disease status at randomization RR (N=134)MR (N=140) CR/Cru14%18% PR81%78% Missing data5%4% Median follow up for time to event data: 3.8 years

19 eastern cooperative oncology group Primary Endpoint: Time to Treatment Failure

20 eastern cooperative oncology group Time to First Cytotoxic Therapy

21 eastern cooperative oncology group Toxicity RR Grade 3 RR Grade 4 MR Grade 3 MR Grade 4 Neutrophils--2 Platelets1-- Fever w/o neutropenia-- 1 Infection-- 1 Fatigue1--3 LV dysfunction-- 1 Hypertension1--1 Syncope1-- Insomnia-- 1 Hearing loss-- 1 Larynx pain-- 1 TOTALS42100

22 eastern cooperative oncology group Toxicity  Second malignancies  9 RR arm  7 MR arm  One progressive multifocal leukoencephalopathy  MR arm  Deaths  10 RR arm  12 MR arm  Second malignancies  9 RR arm  7 MR arm  One progressive multifocal leukoencephalopathy  MR arm  Deaths  10 RR arm  12 MR arm

23 eastern cooperative oncology group Treatment Information  Analysis of # doses rituximab received, including 4 induction doses MinMaxMedianMean RR (n = 120) MR (n = 130)

24 eastern cooperative oncology group Conclusions  In this study of previously untreated low tumor burden FL:  Rituximab retreatment was as effective as maintenance rituximab for time to treatment failure  MR was superior to RR for time to cytotoxic therapy ● At a cost of 3.5x more R  No benefit in QOL or anxiety at 12 months with MR  In this study of previously untreated low tumor burden FL:  Rituximab retreatment was as effective as maintenance rituximab for time to treatment failure  MR was superior to RR for time to cytotoxic therapy ● At a cost of 3.5x more R  No benefit in QOL or anxiety at 12 months with MR

25 eastern cooperative oncology group Conclusions  Both strategies appear to delay time to chemotherapy compared to historical controls  How to interpret?  Given the excellent outcomes with RR ● 86% chemotherapy free at 3 years  Given the lack of QOL difference  Given fewer AE failures  Given fewer R doses required with RR  Rituximab retreatment is our recommended strategy if opting for rituximab monotherapy in LTB FL  Both strategies appear to delay time to chemotherapy compared to historical controls  How to interpret?  Given the excellent outcomes with RR ● 86% chemotherapy free at 3 years  Given the lack of QOL difference  Given fewer AE failures  Given fewer R doses required with RR  Rituximab retreatment is our recommended strategy if opting for rituximab monotherapy in LTB FL

26 Initial Treatment of Indolent Lymphoma l Expectant observation l Treatment » Rituximab » Immunochemotherapy –R-CHOP –R-CVP –R-Bendamustine –R-Fludarabine

27 Initial Treatment of Indolent Lymphoma l “R-CVP vs R-CHOP vs R-FM for the initial treatment of patients with advanced stage follicular lymphoma” - FOLL05 IIL trial l Federico M. et al » Fondazione Italiana Linfomi l Presented at the International Conference on Malignant Lymphoma » Lugano, Switzerland » June 15-18, 2011 Thank Dr. Federico for sharing slides

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35 Indolent Lymphoma l Watch and wait still reasonable l Initial treatment with single agent rituximab for low tumor burden FL » Prefer repeated treatment rather than maintenance rituximab l Initial immunochemotherapy with R-CHOP superior efficacy but more toxic l Thank you » Dr. Brad Kahl and Dr. M. Federico for slides » Dr. Andy Chen for Lugano meeting information


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