Follicular Lymphoma 2016: Evolving Management Strategies Randeep Sangha, MD Medical Oncology, Cross Cancer Institute Associate Professor, University of Alberta Edmonton, AB
Disclosures I have no actual or potential conflict of interest in relation to this presentation Honoraria: Pfizer, Boehringer-Ingelheim, Astra-Zeneca, Roche, Lundbeck, Eli-Lilly, Bristol-Myers Squibb, Merck Advisory Boards: Boehringer-Ingelheim, Astra-Zeneca, Roche, Eli-Lilly, Bristol-Myers Squibb, Merck, Novartis
Outline 1. Non-Hodgkin Lymphoma Epidemiology 2. Follicular Lymphoma Pathobiology 3. First-line Management of Follicular Lymphoma 4. Treating Relapsed/Refractory Follicular Lymphoma 5. Investigational Agents in Relapsed/Refractory Follicular Lymphoma
Non-Hodgkin Lymphoma Non-Hodgkin Lymphoma (NHL) Heterogeneous group of > 40 lymphoproliferative malignancies Result from clonal expansion of B- or T- or NK-cells Variable patterns of behavior and response to treatment In 2015, 6 th most common cancer in Canada 8200 diagnosed 2700 die age adjusted incidence/100,000/yr 70 60 50 40 30 20 10 0 1985 1990 1995 2000 Year lung colorectal breast NHL Hodgkin lymphoma Canadian Cancer Statistics 2016
NHL: Subtype Frequency Follicular lymphoma Most common indolent (low-grade) NHL and considered incurable
Question 1 A 50 year old male hematologist with no significant comorbidities is diagnosed with Stage IIIA NHL. The pathology subtype remains pending. Which of the following subtypes do you believe he would prefer to have? A. Follicular lymphoma, grade I-II B. Diffuselarge B-cell lymphoma C. Peripheral T-cell lymphoma, NOS D. Burkitt Lymphoma
Pathobiology of Follicular Lymphoma (FL) Common Mutational Alterations: t(14;18) in 85% of FL and inactivating mutations of MLL2 in >80% of FL Roulland et al, J Exp Med, 2006 Kahl and Yang, Blood, 2016
FL Microenvironment Kahl and Yang, Blood, 2016
Prognosis FLIPI FLIPI-2 Solal-Celigny et al, Blood, 2004 Federico et al, JCO, 2009
Prognosis: m7-flipi m7-flipi Integration of mutational status of 7 genes (EZH2, ARID1A, MEF2B, EP300, FOX01, CREBBP, and CARD11) with FLIPI Superior at identifying high-risk population compared to FLIPI alone (5-yr FFS of 25% vs 46%, respectively) Requires prospective validation Pastore et. al., Lancet Oncol, 2015
FL Overarching Management Principles 1. Disease has a long, incurable, remitting/relapsing natural history so several treatment approaches are reasonable 2. Mere presence of disease along does not imply need for treatment
Alberta Treatment Algorithm Alberta Lymphoma Clinical Practice Guideline, Version 10
Watch & Wait vs Early Treatment Era Before Rituximab No survival advantage to starting therapy early Rituximab Era Young RC, Longo DL, Glatstein E, et al. Semin Hematol 1988;25:11-6 Brice P, Bastion Y, Lepage E, et al. J Clin Oncol 1997;15:1110-7 Ardeshna KM, Smith P, Norton A, et al. Lancet 2003;362:516-22 Ardeshna et. al., Lancet Oncol, 2014 Kuruvilla et al, Clin Lymphoma, Myeloma, and Leukemia, 2015
Alberta Treatment Algorithm Alberta Lymphoma Clinical Practice Guideline, Version 10
FOLL05: Study Design Federico et. al., JCO, 2013
FOLL05: Time to Treatment Failure Federico et. al., JCO, 2013
StiL NHL 1-2003: Phase III Non-Inferiority Trial N=549 (FL with BR = 139 pts; FL with R-CHOP = 140 pts) No maintenance or consolidation treatment allowed Rummel et. al., The Lancet, 2013
StiL NHL 1-2003: PFS Rummel et. al., The Lancet, 2013 Median F/U: 45 mo
StiL NHL 1-2003: PFS for FL Rummel et. al., The Lancet, 2013
StiL NHL 1-2003: TTNT Median F/U: 87 mo Median TTNT not reached in BR group and 42.3 mo in R-CHOP group Rummel et. al., ASH 2014; Abs 4407
StiL NHL 1-2003: Overall Survival in FL Rummel et. al., ASH 2014; Abs 4407
First-Line Treatment for FL Based on the StiL and confirmatory BRIGHT study, the recommended chemoimmunotherapy for first-line symptomatic advanced stage FL is Rituximab + Bendamustine for a total of 6 cycles.
PRIMA: Maintenance R after 1 st -Line Treatment of FL Primary Endpoint: PFS
PRIMA: Results UPDATED 6-year PFS: 60% vs 42% (p <.0001) Salles et. al., Lancet, 2011 Salles et al., ASH 2013, abstr 509
StiL NHL 7-2008 MAINTAIN Trial: Study Design
Relapsed/Refractory Follicular Lymphoma
Response Duration with Consecutive Treatments in FL Johnson et. al., JCO, 1995
Relapse within 2-yrs Associated with Poor Outcome National LymphoCare study 588 patients with R-CHOP as 1 st line therapy 20% with progressive disease within 2 years of diagnosis (early-pd) 5-yr OS of 50% compared to 5-yr OS of 90% without early-pd Casulo et. al., JCO, 2015
Question 2 A 55 year old female with Stage IVA follicular lymphoma, FLIPI 3, was treated with 6 cycles of R-bendamustine and achieved a CR. Approximately, 15 months later, new symptomatic, supra- and subdiaphragmatic lymphadenopathy was confirmed on CT imaging. Repeat biopsy showed follicular lymphoma without evidence of transformation. Whattreatment wouldyou recommend? A. Watch and Wait B. R-Bendamustine re-challenge C. R-CHOP D. HDCT and Autologous Stem-Cell Transplant (ASCT) E. Compassionate Access of a New Targeted Therapy F. Allogeneic Stem-Cell Transplant
Approach to R/R FL Kahl and Yang, Blood, 2016
CUP Trial: Improved Survival wit ASCT for R/R FL P F S 2-yr PFS for C (26%); U (58%); P(55%) 4-yr OS for C (46%); U (71%); P (77%) Schouten et. al., JCO, 2003
Durable EFS with ASCT in R/R FL 100 consecutive patients in Calgary 25 primary refractory, 29 in 2 relapse, and 24 transformed Post-ASCT, 5-year EFS and OS rates 56% and 70%, respectively Peters et. al., Leuk Lymph, 2011
Bendamustine for Rituximab Refractory FL Rituximab-refractory = no response or PD within 6 months of receiving rituximab (single-agent, maintenance, or with chemo) Phase II multicenter trial; N=100 with 62 pts FL ORR 75% (14% CR, 3%Cru); DOR 9.2 mo; PFS 9.3 mo Kahl et al, Cancer, 2010
GADOLIN: Phase III Trial in Rituximab Refractory Indolent NHL Kahl et al, Lancet Oncol, 2016
GADOLIN: IRF-assessed PFS Kahl et al, Lancet Oncol 2016
GADOLIN: PFS by Sub-group Kahl et al, Lancet Oncol, 2016
Question 3 A 74 year old male with follicular lymphoma, FLIPI 2, has been treated over the past decade with R-CVP x 8 cycles (CR ~ 5 years), R- bendamustine x 6 cycles with maintenance Rituximab (CR ~ 3 years). He has undergone radiotherapy for a bothersome left axillary lymph node but now presents with more widespread symptomatic lymphadenopathy (no evidence of transformation). What do you recommend? A. R-CVP B. R-CHOP C. Ibrutinib D. Lenalidomide E. Idelalisib F. Anti-PD-1/PD-L1 therapy G. None of the above
Investigational Agents in Relapsed/Refractory Follicular Lymphoma
CALGB 50401: Lenalidomide Randomized Trial of Lenalidomide Alone Versus Lenolidamide Plus Rituximab in Patients with Recurrent Follicular Lymphoma Leonard et al, JCO 2014
CALGB 50401: Response and TTP Lenalidomide active as monotherapy and improved in combination with rituximab Gr 3 toxicities 58% vs 53%; Gr 3 ANC 16% vs 20%, L and LR respectively 36% of L vs 63% of LR completed 12 cycles. Leonard et al, JCO 2014
Lenalidomide Trials RELEVANCE: Phase III open-label randomized study to compare efficacy and safety of LR versus chemotherapy + R in previously untreated FL AUGMENT: Phase III double-blind, randomized study to compare the efficacy and safety of of LR versus R plus placebo in R/R indolent lymphoma ALLIANCE 051103 Phase I study of LR + Ibrutinib in previously untreated FL
DELTA Trial: Idelalisib (PI3Kδ Inhibitor) Phase II Trial (N=125; FL=72); Primary Endpoint of ORR Received 2 lines of therapy and refractory to both R and Alkylating Agent Median prior treatments = 4 (Range 2 to 12) Gopal et al, NEJM 2014 Median DOR 12.5 mo; PFS 11 mo
Polatuzumab Vedotin: ADC against CD79b
ROMULUS Phase II Trial Morschhauser et al, ASCO 2014 N=20 for FL; ORR 70%; CR 40%
Investigational Agents in Relapsed FL Kahl and Yang, Blood 2016
The Concept of Value
Back to Outline 1. Non-Hodgkin Lymphoma Epidemiology 2. Follicular Lymphoma Pathobiology 3. First-line Management of Follicular Lymphoma 4. Treating Relapsed/Refractory Follicular Lymphoma 5. Investigational Agents in Relapsed/Refractory Follicular Lymphoma
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