Michael E. Williams, MD, ScM Debate - Optimal management of low-tumor burden advanced-stage, asymptomatic follicular lymphoma? Rituximab weekly x 4 with Maintenance Michael E. Williams, MD, ScM Byrd S. Leavell Professor of Medicine Chief, Hematology/Oncology Division University of Virginia Cancer Center Charlottesville, VA

Disclosures Michael E. Williams, MD Research support: Allos, Celgene, Gilead, Genentech, Janssen, Millennium, Novartis, Onyx, Pharmacyclics Data Safety Monitoring Committees: Celgene, Millennium Consultant: Celgene, Millennium, TG Therapeutics ECOG-ACRIN Lymphoma Committee Vice-chair ABIM Hematology Subspecialty Board Chair

Recommended approach for a 62 yo with low tumor burden FL? Watch and Wait?? Rituximab induction  R maintenance?? R-chemo?? Fortunately, we have recent Phase III trials that inform the answer!

SAKK Trial: Follicular lymphoma Grade I, II, IIIA or IIIB (Taverna et al, ASH 2013) To investigate if maintenance rituximab every 2 months for 5 years or until relapse/progression, unacceptable toxicity or death is superior to maintenance R every 2 months x 4 doses only Any of the following disease status Untreated Relapsed/progressed Chemotherapy resistant Stable disease (last systemic treatment at least 12 weeks before registration)

R Study design SAKK 35/03 Short-term maintenance Induction 375 mg/m² every 2 months x 4 375 mg/m² weekly x 4 PR,CR 375 mg/m² every 2 months for a maximum of 5 years or until progression, relapse or unacceptable toxicity PD, SD off study Long-term maintenance 5 Christian Taverna _ 12.11.2013

Short-term maintenance (n=82) Long-term maintenance (n=83) SAKK - Adverse events Short-term maintenance (n=82) Long-term maintenance (n=83) At least 1 AE 41 (50%) 63 (76%) Highest grade 1 2 3 4 25 (31%) 15 (18%) 1 (1%) 0 (0%) 18 (22%) 31 (37%) 12 (15%) 2 (2%) Infection ≥ grade 3 hypogammaglobulinemia 22% 5 (6%) 44% Secondary malignancy 6 (7%) 8 (10%)

SAKK - Event-free survival ITT (primary study endpoint) Median EFS 3.4 years vs 5.3 years, p=0.14

SAKK - Overall survival ITT

SAKK - Conclusions EFS, the primary endpoint, was not met mainly due to unexplained early separation of the EFS curves favoring arm A, at a time when the treatment in both arms was the same A retrospectively defined analysis considering only EFS events from the time when treatment was different in the 2 arms, shows a statistically significant increase in EFS with long-term maintenance Long-term R maintenance doubles the median PFS

SAKK - Event-free survival Only patients at risk after 8 months from randomization Median EFS 2.9 years vs 7.1 years p=0.004

Rituximab +/- Maintenance R versus Watch & Wait in Non-bulky FL UK Intergroup trial Stage II-IV, asymptomatic, no prior therapy 3 arms: Watch/Wait R weekly x 4 (closed early) R x 4  R q 2 months x 2 years Primary endpoints: Time to next Rx & QOL Indications for additional line of therapy: Symptomatic increase in nodes or spleen B symptoms or pruritis Mass > 7 cm if > 25% increase > 3 nodal masses > 5 cm Ardeshna K et al. ASH 2010 (Plenary); Lancet Oncol 2014; 15:424

Rituximab  Maintenance R versus Watch & Wait in Non-bulky FL: Results Ardeshna K et al. ASH 2010 (Plenary); Lancet Oncol 2014; 15:424-35

Rituximab +/- Maintenance R versus Watch & Wait in Non-bulky FL: Results Ardeshna, Lancet Oncol 2014

Summary: Ardeshna et al, Lancet Oncol 2014 R x 4  Maint R > R x 4 > W&W Significantly improves PFS and TTNT But more SAE: infection, allergic rxn, neutropenia Maint R improved QOL scores vs W&W No OS advantage for maintenance R No difference in histologic transformation Not tested in this trial: How would rituximab retreatment at progression compare with maintenance rituximab??

Rituximab Maintenance vs Re-treatment at Time of Progression Previously-treated patients 45 pts/arm (FL~30/arm) Maintenance improved PFS (32 mo vs 7 mo) At a median follow up of 41 months, overall R “benefit” similar to re-Rx at time of progression (31 mo vs 27 mo) Hainsworth JD, et al. J Clin Oncol; 23:1088-1095 2005

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

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

Rituximab re-treatment at progression* E4402 (RESORT) Schema R A N D O M I Z E Rituximab Maintenance* 375 mg/m2 q 3 months Rituximab 375 mg/m2 qw  4 CR or PR Rituximab re-treatment at progression* 375 mg/m2 qw  4 *Continue until treatment failure No response to retreatment or PD within 6 months of R Initiation of cytotoxic therapy or Inability to complete rx

E4402 Major Eligibility Indolent NHL No prior lymphoma therapy 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

E4402 (RESORT) Objectives Primary Secondary 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

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)

Disease 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 Failure

Breakdown of Treatment Failure by Type Failure Type RR MR Total No response (RR) 18 TTP < 6 mos 11 25 36 Alternative Rx 8 1 9 Adverse event 7 Complicating Dz 6 12 Death 2 Patient withdrawal 16 26 42 Other/unknown 4 3 65 69 134

Time to First Cytotoxic Therapy

Toxicity RR Grade 3 Grade 4 MR Neutrophils -- 2 Platelets 1 Fever w/o neutropenia Infection Fatigue 3 LV dysfunction Hypertension Syncope Insomnia Hearing loss Larynx pain TOTALS 4 10

Treatment Information Analysis of # doses rituximab received, including 4 induction doses Min Max Median Mean RR (n = 120) 4 16 4.5 MR (n = 130) 5 31 15.5 15.8

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

Summary: Kahl et al, ASH 2011 R x 4  Maint R > Retreatment R Significantly improves time to first cytotoxic Rx Both strategies appear to delay time to chemotherapy compared to historical controls Could Retreatment be considered an alternative form of “Maintenance”?? 86% chemo-free at 3 yr on Retreatment Lack of QOL difference Fewer AE failures than Maintenance Fewer R doses required than Maintenance

For asymptomatic, stage IV, grade 1-2 FL….. The Goldilocks Paradigm Just Right! Rituximab weekly x 4  “Maintenance” R Too Cold! Watch and Wait “Follicular Lymphoma: W&W is Watch and Worry” (S. Ansell, Lancet Oncol 2014; 15:368-9) Too Hot! R-Chemotherapy