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

13th Annual Hematology & Breast Cancer Update

Update in Lymphoma

Craig Okada, MD, PhD

Assistant Professor, Hematology

January 20, 2010

Governors Hotel, Portland Oregon

Initial Treatment of Indolent Lymphoma

Expectant observation Treatment

» Rituximab» Immunochemotherapy

–R-CHOP–R-CVP–R-Bendamustine–R-Fludarabine


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

What Oncologist in US are doing

Freiberg et al, J Clin Oncol 2006;24:7527

ASH 2010 - Intergroup study of rituximab vs watch and wait (Ardeshna, K et al)

Expectant observation – still relevant today? 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

Compulsory CT scan

Compulsory CT scan

CT scan only if

clinical CR

Bone marrow for histology and MRD only if CT shows CR

RANDOMISATION

ARM AWatch and Wait

ARM BRituximab Induction

ARM CRituximab Induction

& maintenance

Continued follow up

Progressive disease requiring therapystops protocol

treatment

Clinic visits

33 189

33 83108 181

Events Totals

W+W R4 R4 + M

Proportion of

patients progression-

free

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Years from randomisation0 1 2 3 4 5

Progression-free survival

HR (Rituximab vs W+W) = 0.46, 95%CI = 0.33, 0.65, p<0.001HR (Rituximab + M vs W+W) = 0.21, 95%CI = 0.15, 0.29, p<0.001HR (Rituximab + M vs Rituximab) = 0.43, 95%CI = 0.24, 0.72, p=0.001

3yr PFS W+W=33% R4=60% R4+RM=81%

Proportion of patients

with no new

treatment initiated

19 19219 8483 187

Events TotalsW+W R4 R4 + M

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


% 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<0.001HR (Rituximab + M vs W+W) = 0.20, 95% CI = 0.13, 0.29, p <0.001HR (Rituximab + M vs Rituximab) = 0.57, 95% CI = 0.29, 1.12, p =0.10

8 1924 849 187

Events TotalsW+W R4 R4 + M

% of patients

alive

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0


Overall survival

3yr OS=95%

HR (Rituximab vs W+W) = 0.63, 95%CI = 0.21, 1.92, p=0.42HR (Rituximab + M vs W+W) = 0.84, 95%CI = 0.32, 2.18, p=0.72HR (Rituximab + M vs Rituximab) = 1.21, 95%CI = 0.37, 3.97, p=0.75

Intergroup study of rituximab vs watch and wait (Ardeshna, K et al)

Comparing “apples to oranges”» Not fair to look at time to “new” treatment between

no treatment and rituximab More interesting questions to possibly come from the

study» Overall survival» Time to second treatment» Transformation rate» Response to initial treatment

Still open question if asymptomatic FL patients benefit from treatment -> expectant observation is still appropriate management.

eastern cooperativeeastern cooperative oncology grouponcology group

Results of E4402 (RESORT): A Randomized Phase III Study

Comparing Two Different Rituximab Dosing Strategies for Low Tumor

Burden Follicular Lymphoma

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

Brad Kahl, Fangxin Hong, Michael Williams, Randy Gascoyne, Lynne Wagner, John Krauss, Sandra Horning

eastern cooperative oncology groupeastern cooperative oncology group

E4402: RESORT RationaleE4402: RESORT RationaleE4402: RESORT RationaleE4402: RESORT Rationale

Hypothesis: Hypothesis: After initial rituximab therapy, extended scheduled After initial rituximab therapy, extended scheduled

dosing (maintenance rituximab - MR) will prolong dosing (maintenance rituximab - MR) will prolong disease control compared to retreatment dosing disease control compared to retreatment dosing administered upon disease progression (rituximab administered upon disease progression (rituximab retreatment - RR)retreatment - RR)

Previously untreated, low tumor burden, FL an ideal Previously untreated, low tumor burden, FL an ideal patient population to test this hypothesispatient population to test this hypothesis

Reasonably homogenous populationReasonably homogenous population

Hypothesis: Hypothesis: After initial rituximab therapy, extended scheduled After initial rituximab therapy, extended scheduled

dosing (maintenance rituximab - MR) will prolong dosing (maintenance rituximab - MR) will prolong disease control compared to retreatment dosing disease control compared to retreatment dosing administered upon disease progression (rituximab administered upon disease progression (rituximab retreatment - RR)retreatment - RR)

Previously untreated, low tumor burden, FL an ideal Previously untreated, low tumor burden, FL an ideal patient population to test this hypothesispatient population to test this hypothesis

Reasonably homogenous populationReasonably homogenous population

eastern cooperative oncology groupeastern cooperative oncology group13

E4402 (RESORT) SchemaE4402 (RESORT) SchemaE4402 (RESORT) SchemaE4402 (RESORT) Schema

Rituximabre-treatment atprogression*

375 mg/m2 qw 4

RANDOMIZE

Rituximab375 mg/m2 qw

4CR or PR

RituximabMaintenance*

375 mg/m2 q 3 months

*Continue until treatment failureNo response to retreatment or PD within 6 months of R

Initiation of cytotoxic therapy or Inability to complete rx


E4402 Major EligibilityE4402 Major EligibilityE4402 Major EligibilityE4402 Major Eligibility

Indolent NHL Indolent NHL Follicular grade 1 or 2Follicular grade 1 or 2 Small Lymphocytic Small Lymphocytic MALTMALT Marginal Zone nodal Marginal Zone nodal Marginal Zone splenicMarginal Zone splenic

No prior lymphoma No prior lymphoma therapytherapy

Stage III or IV diseaseStage III or IV disease

Measurable diseaseMeasurable disease

Indolent NHL Indolent NHL Follicular grade 1 or 2Follicular grade 1 or 2 Small Lymphocytic Small Lymphocytic MALTMALT Marginal Zone nodal Marginal Zone nodal Marginal Zone splenicMarginal Zone splenic

No prior lymphoma No prior lymphoma therapytherapy

Stage III or IV diseaseStage III or IV disease

Measurable diseaseMeasurable disease

Low tumor burden as defined Low tumor burden as defined by GELFby GELF No tumor mass No tumor mass >> 7cm 7cm Fewer than 3 nodal Fewer than 3 nodal

masses > 3 cmmasses > 3 cm No system symptoms or No system symptoms or

B symptomsB symptoms No splenomegaly greater No splenomegaly greater

than 16 cm by CT scanthan 16 cm by CT scan No risk of organ No risk of organ

compressioncompression No leukemic phase No leukemic phase No cytopenias No cytopenias

Low tumor burden as defined Low tumor burden as defined by GELFby GELF No tumor mass No tumor mass >> 7cm 7cm Fewer than 3 nodal Fewer than 3 nodal

masses > 3 cmmasses > 3 cm No system symptoms or No system symptoms or

B symptomsB symptoms No splenomegaly greater No splenomegaly greater

than 16 cm by CT scanthan 16 cm by CT scan No risk of organ No risk of organ

compressioncompression No leukemic phase No leukemic phase No cytopenias No cytopenias


E4402 (RESORT) ObjectivesE4402 (RESORT) ObjectivesE4402 (RESORT) ObjectivesE4402 (RESORT) Objectives

Primary Primary To compare the TTTF between the MR and the RR To compare the TTTF between the MR and the RR

armsarms

SecondarySecondary To compare time to first cytotoxic therapy between To compare time to first cytotoxic therapy between

the MR and the RR armsthe MR and the RR arms To compare QOL between the armsTo compare QOL between the arms To compare toxicities between armsTo compare toxicities between arms

Primary Primary To compare the TTTF between the MR and the RR To compare the TTTF between the MR and the RR

armsarms

SecondarySecondary To compare time to first cytotoxic therapy between To compare time to first cytotoxic therapy between

the MR and the RR armsthe MR and the RR arms To compare QOL between the armsTo compare QOL between the arms To compare toxicities between armsTo compare toxicities between arms


E4402 (RESORT) ResultsE4402 (RESORT) ResultsE4402 (RESORT) ResultsE4402 (RESORT) Results

Activated Nov 2003 – Closed Sept 2008Activated Nov 2003 – Closed Sept 2008

Enrolled 545 patientsEnrolled 545 patients 161 non-FL patients will be analyzed and reported 161 non-FL patients will be analyzed and reported

separatelyseparately

384 (71%) FL histology384 (71%) FL histology

274 (71%) responded to Induction rituximab 274 (71%) responded to Induction rituximab 134 assigned to retreatment rituximab (RR)134 assigned to retreatment rituximab (RR) 140 assigned to maintenance rituximab (MR)140 assigned to maintenance rituximab (MR)

Activated Nov 2003 – Closed Sept 2008Activated Nov 2003 – Closed Sept 2008

Enrolled 545 patientsEnrolled 545 patients 161 non-FL patients will be analyzed and reported 161 non-FL patients will be analyzed and reported

separatelyseparately

384 (71%) FL histology384 (71%) FL histology

274 (71%) responded to Induction rituximab 274 (71%) responded to Induction rituximab 134 assigned to retreatment rituximab (RR)134 assigned to retreatment rituximab (RR) 140 assigned to maintenance rituximab (MR)140 assigned to maintenance rituximab (MR)


Baseline Characteristics at RandomizationBaseline Characteristics at RandomizationBaseline Characteristics at RandomizationBaseline Characteristics at Randomization

RR (N=134) MR (N=140)

Age 59.5 (26-86) 58.9 (25-86)

Gender (M/F) 46/54% 46/54%

PS (0/1) 84/15% 87/10%

Stage

• III 56% 48%

• IV 43% 51%

FLIPI

• 0-1 15% 16%

• 2 46% 43%

• 3-5 39% 41%

B2M elevated 46% 39%


Disease status at randomizationDisease status at randomizationDisease status at randomizationDisease status at randomization

RR (N=134) MR (N=140)

CR/Cru 14% 18%

PR 81% 78%

Missing data 5% 4%

Median follow up for time to event data: 3.8 years


Primary Endpoint: Time to Treatment FailurePrimary Endpoint: Time to Treatment FailurePrimary Endpoint: Time to Treatment FailurePrimary Endpoint: Time to Treatment Failure


Time to First Cytotoxic TherapyTime to First Cytotoxic TherapyTime to First Cytotoxic TherapyTime to First Cytotoxic Therapy


ToxicityToxicityToxicityToxicity

RRGrade 3

RR Grade 4

MR Grade 3

MR Grade 4

Neutrophils -- 2 -- --

Platelets 1 -- -- --

Fever w/o neutropenia -- -- 1 --

Infection -- -- 1 --

Fatigue 1 -- 3 --

LV dysfunction -- -- 1 --

Hypertension 1 -- 1 --

Syncope 1 -- -- --

Insomnia -- -- 1 --

Hearing loss -- -- 1 --

Larynx pain -- -- 1 --

TOTALS 4 2 10 0


ToxicityToxicityToxicityToxicity

Second malignanciesSecond malignancies 9 RR arm9 RR arm 7 MR arm7 MR arm

One progressive multifocal leukoencephalopathyOne progressive multifocal leukoencephalopathy MR armMR arm

DeathsDeaths 10 RR arm 10 RR arm 12 MR arm12 MR arm

Second malignanciesSecond malignancies 9 RR arm9 RR arm 7 MR arm7 MR arm

One progressive multifocal leukoencephalopathyOne progressive multifocal leukoencephalopathy MR armMR arm

DeathsDeaths 10 RR arm 10 RR arm 12 MR arm12 MR arm


Treatment InformationTreatment InformationTreatment InformationTreatment Information

Analysis of # doses rituximab received, including 4 Analysis of # doses rituximab received, including 4 induction dosesinduction doses

Analysis of # doses rituximab received, including 4 Analysis of # doses rituximab received, including 4 induction dosesinduction doses

Min Max Median Mean

RR (n = 120) 4 16 4 4.5

MR (n = 130) 5 31 15.5 15.8


ConclusionsConclusionsConclusionsConclusions

In this study of previously untreated low tumor In this study of previously untreated low tumor burden FL:burden FL:

Rituximab retreatment was as effective as Rituximab retreatment was as effective as maintenance rituximab for time to treatment maintenance rituximab for time to treatment failure failure

MR was superior to RR for time to cytotoxic therapyMR was superior to RR for time to cytotoxic therapy

● At a cost of 3.5x more RAt a cost of 3.5x more R

No benefit in QOL or anxiety at 12 months with MRNo benefit in QOL or anxiety at 12 months with MR

In this study of previously untreated low tumor In this study of previously untreated low tumor burden FL:burden FL:

Rituximab retreatment was as effective as Rituximab retreatment was as effective as maintenance rituximab for time to treatment maintenance rituximab for time to treatment failure failure

MR was superior to RR for time to cytotoxic therapyMR was superior to RR for time to cytotoxic therapy

● At a cost of 3.5x more RAt a cost of 3.5x more R

No benefit in QOL or anxiety at 12 months with MRNo benefit in QOL or anxiety at 12 months with MR


ConclusionsConclusionsConclusionsConclusions

Both strategies appear to delay time to Both strategies appear to delay time to chemotherapy compared to historical controlschemotherapy compared to historical controls

How to interpret?How to interpret? Given the excellent outcomes with RRGiven the excellent outcomes with RR

● 86% chemotherapy free at 3 years86% chemotherapy free at 3 years

Given the lack of QOL differenceGiven the lack of QOL difference Given fewer AE failuresGiven fewer AE failures Given fewer R doses required with RRGiven fewer R doses required with RR

Rituximab retreatment is our recommended strategy Rituximab retreatment is our recommended strategy if opting for rituximab monotherapy in LTB FLif opting for rituximab monotherapy in LTB FL

Both strategies appear to delay time to Both strategies appear to delay time to chemotherapy compared to historical controlschemotherapy compared to historical controls

How to interpret?How to interpret? Given the excellent outcomes with RRGiven the excellent outcomes with RR

● 86% chemotherapy free at 3 years86% chemotherapy free at 3 years

Given the lack of QOL differenceGiven the lack of QOL difference Given fewer AE failuresGiven fewer AE failures Given fewer R doses required with RRGiven fewer R doses required with RR

Rituximab retreatment is our recommended strategy Rituximab retreatment is our recommended strategy if opting for rituximab monotherapy in LTB FLif opting for rituximab monotherapy in LTB FL


Expectant observation Treatment

» Rituximab» Immunochemotherapy

–R-CHOP–R-CVP–R-Bendamustine–R-Fludarabine


“R-CVP vs R-CHOP vs R-FM for the initial treatment of patients with advanced stage follicular lymphoma” - FOLL05 IIL trial

Federico M. et al» Fondazione Italiana Linfomi

Presented at the International Conference on Malignant Lymphoma » Lugano, Switzerland» June 15-18, 2011

Thank Dr. Federico for sharing slides

Indolent Lymphoma

Watch and wait still reasonable Initial treatment with single agent rituximab for low

tumor burden FL» Prefer repeated treatment rather than

maintenance rituximab Initial immunochemotherapy with R-CHOP

superior efficacy but more toxic

Thank you » Dr. Brad Kahl and Dr. M. Federico for slides» Dr. Andy Chen for Lugano meeting information

Documents

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