Winship Cancer Institute of Emory University New Targets and Treatments for Follicular Lymphoma Jonathon B. Cohen, MD, MS Assistant Professor Div of BMT, Emory University
Intro/Outline Follicular lymphoma, presentation and indications for treatment Review of induction therapy options for advanced disease Evidence for maintenance therapy Novel therapies and investigational agents for relapsed follicular lymphoma
Clinical Presentation Often asymptomatic Slowly progressive adenopathy Incidental findings Patients are often not sick
Criteria for Treatment (GELF) Involvement of 3 sites, each measuring 3 cm Any nodal or extranodal tumor mass with a diameter of 7 cm B symptoms Splenomegaly Pleural effusions or peritoneal ascites Cytopenias Leukemic presentation
FLIPI Characteristic RR (Death) Age > 60 years 2.38 Stage III-IV 2.00 Hgb < 12.0g.dL 1.55 Elevated LDH 1.50 Nodal sites > 4 1.39 Solal-Céligny, et al. Blood. 2004;104:1258-1265.
FLIPI and OS Risk Group No. of Risk Factors 5-year OS, % 10-Year OS, % Low 0-1 91 71 Intermediate 2 78 51 High 3 53 36 Roughly half of all patients with FLIPI 3 or higher die within 5 years Original FLIPI score developed in the pre-rituximab era Solal-Céligny, et al. Blood. 2004;104:1258-1265.
FLIPI: Survival Probability Solal-Céligny, et al. Blood. 2004;104:1258-1265.
Induction Therapy: B-R vs R-CHOP Pts with previously untreated Stage III or IV NHL of the following types: Follicular Waldenström Marginal zone Small lymphocytic Mantle cell Age 18 years WHO PS 0-2 R Bendamustine-rituximab CHOP-rituximab Bendamustine 90 mg/m 2 Day 1, 2 + R Day 1, max 6 cycles, every 4 weeks. CHOP-R, max 6 cycles, every 3 weeks. Rummel MJ, et al. Blood. 2009;114: Abstract 405.
B-R vs CHOP-R: PFS Rummel MJ, et al. Lancet Oncol 2013.
B-R vs R-CHOP/R-CVP BRIGHT study (Flinn et al, Blood 2013) Patients randomized to B-R or R-CHOP/R-CVP (each site assigned one of the standard therapies) Non-inferiority study B-R non-inferior to both R-CHOP and R-CVP with respect to CR rate. Non-hematologic toxicity improved with B-R.
B-R + Bortezomib Novel Approaches Current ECOG study in comparison to B-R. Overall Response Rate is 88% in relapsed FL R-Lenalidomide CALGB Phase II Study Rituximab x 4, then cycles 4, 6, 8 and 10 Lenalidomide 20mg daily days 1-21 of a 28 day cycle x 12 Overall Response Rate: 93% 2-year PFS 89% Fowler et al, J Clin Oncol 2011; Martin et al, ASCO Abstracts 2014
Conclusions- Induction Therapy Bendamustine-Rituximab appropriate in most cases Studies underway to both intensify and lessen therapy Expect therapy to become more tailored based on individual risk factors
Registration High tumor burden untreated follicular lymphoma Rituximab Maintenance PRIMA: Study Design INDUCTION Immunochemotherapy 8 x Rituximab + 8 x CVP or 6 x CHOP or 6 x FCM Primary endpoint: Progression-free survival (PFS) from randomization (to rituximab maintenance or observation) CR/Cru PR PD/SD off study Secondary endpoints Event-free survival (EFS), overall survival (OS) Time to next anti-lymphoma treatment (TTNLT), time to next chemotherapy (TTNCT) Response rates at end of maintenance Safety and toxicity Quality of life (QoL) (FACT-G and EORTC scales) *Stratified by response after induction, regimen of chemo, and geographic region Frequency of clinical, biological and CT-scan assessments identical in both arms Five additional years of follow-up MAINTENANCE Rituximab maintenance 375 mg/m 2 every 8 weeks for 2 years Random 1:1* Observation Salles GA, et al. J Clin Oncol. 2010;28(7s): Abstract 8004.
Patient disposition Induction Maintenance Patients evaluable (N = 1202)* R-CHOP N = 885 Randomized N = 769 Patients registered: N = 1217 R-CVP N = 272 Randomized N = 222 Patients randomized: N = 1018 R-FCM N = 45 Randomized N = 28 * 15 pts in 3 sites closed prematurely 9 pts did not receive chemo 147 pts withdrew during or at the end of induction (failure to respond; toxicity) 28 pts failed to be randomized 1 pt died during the randomization process Observation N = 513 Rituximab N = 505
PRIMA- PFS OUTCOME 3-year PFS: 79% (R Maint) 57.6% (Obs) Salles G, Lancet 2011.
PRIMA - OS No significant OS benefit
E4402 (RESORT) Pts with low tumor burden treated with R x 4 followed by maintenance vs retreatment at progression. Time to Treatment Failure Time to Chemotherapy Kahl et al, ASH 2011
Maintenance Rituximab- Summary Likely a PFS benefit and opportunity to delay next therapy Unclear role after B-R (E2408 may help answer this) No evidence of OS benefit Should be discussed individually with each patient
Relapsed/Refractory FL B-cell receptor signaling pathway Woyach et al, Blood 2012
Ibrutinib BTK inhibitor Phase I Study of Ibrutinib MTD not reached; standard dose is 560mg ORR 54.5%, median duration of response 12.3 months Ongoing multisite study just completed enrollment Fowler et al, ASH 2012
Idelalisib PI3Kδ inhibitor Phase 2 Study of Idelalisib Dose 150mg twice daily Response rate 57%, median duration 12.5 months Toxicities: Neutropenia LFT abnormalities Diarrhea Pneumonia Gopal et al, NEJM 2014
Ofatumumab: CD20 Antibodies Phase III study in rituximab-refractory patients Dose 300mg week 1, 1000mg weekly on weeks 2-8 ORR 10-13% Median PFS: 5.8 months Czuczman et al, Blood 2012
Salles G, et al. J Clin Oncol 2013 CD20 Antibodies GA101 Obinutuzumab Phase II study in rel/ref follicular lymphoma ORR 55% at recommended dose Median PFS 11.9 months
BCL2 Inhibitor ABT199 Oral agent active in several subtypes of NHL Responses seen in 2/7 patients with follicular lymphoma in Phase I Study. Toxicities: Tumor lysis syndrome Cytopenias Febrile Neutropenia Davids et al, ASCO Abstracts 2013
Agents Under Investigation at Emory ABT-199 Nivolumab (PD1 inhibitor) Buparlisib (Pan-selective PI3K inhibitor) Alisertib (Aurora Kinase inhibitor)
Other Treatments for Rel/Ref FL Chemo-immunotherapy B-R R-CVP/R-CHOP Fludarabine Salvage NHL regimens Radioimmunotherapy Lenalidomide Autologous/Allogeneic Transplants
Conclusions Several options that are better than R-CHOP for induction therapy Consider maintenance rituximab in all cases, but with no clear OS benefit Numerous options for relapsed/refractory FL Strongly consider enrollment on clinical trial For fit/motivated patients, transplant can be considered