Comparative Outcomes of Relapsed Follicular Lymphoma Patients Treated with Novel Agents: A Multi-Center Analysis
Authors: Winter Allison M. , Wei Wei , Ayers Emily C. , Landsburg Daniel J. , Raya Saba , Kahl Brad S. , Rogers Andrew , Maddocks Kami J. , Khan Mohammad , Kittai Adam S. , Danilov Alexey , Ujjani Chaitra S. , Lynch Ryan C. , Nastoupil Loretta J. , Becnel Melody R. , Zurbriggen Luke , Kenkre Vaishalee P. , Sheela Sheenu , Ghosh Nilanjan , Hu Boyu , Stephens Deborah M. , Ayers Amy , Cohen Jonathon B. , Hill Brian T. 
Published: November 2019

Background: Follicular lymphoma (FL) is the most common indolent lymphoma and is generally characterized by prolonged survival with multiple relapses throughout the disease course. There is no standard of care as to the initial choice or sequencing of treatments for relapsed disease. Novel agents approved in the relapsed setting include lenalidomide in combination with rituximab (R2) and PI3K inhibitors (PI3Ki) including idelalisib, duvelisib, and copanlisib. However, there are no prospective data comparing the safety/efficacy of these novel agents to guide treatment selection. We aimed to examine the characteristics and outcomes of patients with relapsed follicular lymphoma treated with these novel agents.
Methods: We conducted a retrospective analysis of adult patients with FL treated with commercially-available novel agents at 10 US academic cancer centers. Patients were excluded if they received one of these therapies as first line therapy or for the treatment of transformed disease. Treatment with lenalidomide or PI3Ki was determined by the treating physician, as was the decision to incorporate monoclonal antibody (mAb). For patients who received both classes of novel agent, baseline and treatment characteristics were grouped by first novel class used. The Fisher's Exact test was used to compare categorical variables and the Mann Whitney U test for continuous variables. Progression-free survival (PFS) was defined as time from the initiation of the first novel agent to progression of disease (POD), either FL or transformed disease, or death from any cause. Overall survival (OS) was defined as time from the initiation of the first novel agent to death from any cause. Outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test.
Results: 98 patients were included. Available baseline characteristics at diagnosis are described in Table 1. The median time from the end of the last FL treatment to the start of the first novel agent was 12 months (range 0-79). The first novel agent was lenalidomide +/-mAb in 49% (n=48) of the patients and a PI3Ki +/- mAb in 51% (n=50) of patients. Idelalisib was the most commonly used PI3Ki (n=47) followed by copanlisib (n=2) and duvelisib (n=1). The median number of therapies prior to the first novel agent was 2 (range 1-8) and not significantly different between treatment classes. Reason for discontinuation of novel agent was significantly different between groups with greater discontinuations due to toxicity (40% vs 28%) and transformed disease (15% vs. 3%) for the PI3Ki ± mAb group vs. lenalidomide ± mAb group, respectively (p = 0.02). The median PFS and OS for the entire cohort was 10 months (95% CI 7.6-14) and 120 months (95% CI, 49-NA), respectively (Figure A). When comparing outcomes to current FDA approvals-lenalidomide + mAb (n=43) versus PI3Ki monotherapy (PI3Ki, n=38), the median PFS was significantly longer in the lenalidamide + mAb group compared to the PI3Ki group (15 vs. 6 months, p=0.016), as was the OS (120 vs. 37 months, p=0.002, respectively, Figure B).
Conclusions: In this multi-center analysis, despite multiple relapses, the median survival for FL patients treated with novel agents was 120 months from the initiation of the first novel therapy. With the caveat of retrospective comparison, lenalidomide + mAb (i.e. R2) appears superior to PI3Ki as first novel agent in the relapsed setting with the recognition that a high proportion of patients discontinued PI3Ki due to toxicity. Because the majority of the patients received idelalisib conclusions cannot be drawn about alternative PI3Ki which may have lower toxicity profiles or intermittent dosing strategies, allowing for safer and more prolonged treatment. Future prospective studies are needed to directly compare these agents and determine optimal sequencing of therapies.

Disclosures
Landsburg: Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding; Takeda: Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kahl:AbbVie Inc, Acerta Pharma - A member of the AstraZeneca Group, AstraZeneca Pharmaceuticals LP, BeiGene, Celgene Corporation, Genentech, Pharmacyclics LLC, an AbbVie Company, Roche Laboratories Inc.: Consultancy. Maddocks:Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Novartis: Research Funding. Danilov:TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; Bristol-Meyers Squibb: Research Funding; MEI: Research Funding; Janssen: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy; Gilead Sciences: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding. Ujjani:Pharmacyclics: Honoraria; PCYC: Research Funding; Atara: Consultancy; Atara: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Consultancy; Pharmacyclics: Honoraria; PCYC: Research Funding; Astrazeneca: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding. Lynch:Juno Therapeutics: Research Funding; Rhizen Pharmaceuticals S.A: Research Funding; T.G. Therapeutics: Research Funding; Incyte Corporation: Research Funding; Takeda Pharmaceuticals: Research Funding; Johnson Graffe Keay Moniz & Wick LLP: Consultancy. Nastoupil:Gilead: Honoraria; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Spectrum: Honoraria; TG Therapeutics: Honoraria, Research Funding; Novartis: Honoraria; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding. Ghosh:Forty Seven Inc: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Genentech: Research Funding; T G Therapeutics: Consultancy, Research Funding; Gilead/Kite: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Spectrum: Consultancy, Speakers Bureau; Astra Zeneca: Speakers Bureau. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Cohen:ASH: Research Funding; Lymphoma Research Foundation: Research Funding; Astra Zeneca: Research Funding; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy. Hill:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Takeda: Research Funding; Genentech: Consultancy, Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; TG therapeutics: Research Funding; AstraZeneca: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy, Honoraria.