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1706 Clinical Outcomes of Venetoclax Therapy in Patients with Relapsed/Refractory (r/r) Non Hodgkin Lymphomas (NHL)

Program: Oral and Poster Abstracts
Session: 627. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Retrospective/Observational Studies: Poster I
Hematology Disease Topics & Pathways:
Diseases, Non-Hodgkin Lymphoma, B-Cell Lymphoma, Lymphoid Malignancies
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Mitchell E. Hughes, PharmD1*, Daniel J. Landsburg, MD2, Daniel J Rubin, PharmD1*, Stephen J. Schuster, MD1, Jakub Svoboda, MD2, Donald Edward Tsai, MD, PhD1, Kyle Robinson, MD1*, Saar I. Gill, MD, PhD1, Anthony R. Mato, MD MSCE3, James Nathan Gerson, MD1, Danielle Land, CRNP1*, Brenda Shelly, CRNP1*, Alicia McLeish, CRNP1*, Allison Rago, CRNP1*, Jennifer Gill, CRNP1*, Kristy Walsh, BS1*, Tanya Latorre, RN1*, Jessica K. Altman, MD1, Colleen Timlin, PharmD1*, Donna Capozzi, PharmD, BCOP1* and Sunita Dwivedy Nasta, MD1

1Univeristy of Pennsylvania, Lymphoma Program, Abramson Cancer Center, Philadelphia, PA
2Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA
3CLL Program, Leukemia Service, Memorial Sloan-Kettering Cancer Center, New York, NY

Introduction: Venetoclax (VEN) is a highly effective agent for chronic lymphocytic leukemia (CLL) that targets BCL-2. Thus, it has been hypothesized to have efficacy in NHL and tested in phase-1/2 studies (Gerecitano JF, Blood 2015; de Vos S, Blood 2015; Davids MS, J Clin Oncol 2017). Overall response rates (ORR) observed in r/r NHL were 44% for all subtypes combined, 38% for follicular lymphoma (FL), 75% for mantle cell lymphoma (MCL), and 18% for diffuse large B-cell lymphoma (DLBCL). The adverse effect profile was consistent with the labeling despite dose escalation to doses higher than used in CLL. Additionally, VEN is a potential option in the r/r NHL setting, potentially providing less T cell toxicity compared to other agents used as bridging to T-cell therapies (Cummins NW, mBio, 2016; Dzhagalov I, J Immunol, 2008). We performed an analysis of all NHL patients (pts) treated with VEN at our institution to assess efficacy and safety of VEN in r/r NHL.

Patients and Methods: We conducted a retrospective cohort study of all adult pts who received VEN for r/r NHL at the University of Pennsylvania between 4/2016 and 6/2018. Demographics, tumor lysis syndrome (TLS; events, prophylaxis and management), duration of therapy, reason for discontinuation, overall response, survival, and toxicities were examined. The primary endpoints were progression-free survival (PFS; defined as time from VEN start to disease progression or regimen change, death due to NHL or last-follow-up in remission), and overall survival using the Kaplan-Meier method. All other analyses were descriptive.

Results: We identified 23 NHL pts for this analysis. NHL subtypes included DLBCL (35%; n=8), MCL (30%; n=7), Richter transformation (RT) (9%; n=2), transformed FL (tFL) (12%; n=4), post-transplant lymphoproliferative disease (PTLD) (4%; n=1), and marginal zone lymphoma (MZL; n=1) (4%). Median age at VEN start was 65 years; most pts were Ann Arbor stage IV (87%) and ECOG performance 2-4 (57%). NHL characteristics were MYC rearrangement (35%), BCL2 rearrangement (22%), double-hit lymphoma (26%), BCL2 IHC+ (22%), non-germinal center phenotype (13%). Median number of prior therapies was 4 (range: 2-13) with 17% having a prior autologous stem cell transplant. Median time to VEN initiation from prior therapy was 1 month (range, 0.5-9). Median VEN dose achieved was 400 mg (Range, 100-1200). Data for TLS are in Table 1. Median time on VEN was 2 months. While on VEN, 17% received radiation and 43% were on other anti-neoplastic therapy. Overall response rate (ORR) for the entire cohort was 26% (100% Partial Response [PR]). Subtypes with PR included MCL (13%), DLBCL (9%), and RT (4%). No PRs were observed with tFL, PTLD, nor MZL. Pts most commonly discontinued VEN for disease progression (74%); 2 pts (9%) remain on VEN therapy (range: 2-11 months). Median PFS and OS for the entire cohort were 2 months and 3 months, respectively, (Figure 1). Analyzed as histologic cohorts, large B-cell lymphomas (DLBCL, RT, PTLD, tFL) had similar median PFS and OS. However, small B-cell lymphomas (MCL, MZL) had median PFS and OS of 2.5 and 4 months, respectively. Two pts subsequently received CAR T-cell therapy post-VEN; one collected T-cells during VEN therapy and one collected T-cells prior to VEN start.

Adverse events (AEs) occurred in approximately 65% while on VEN. AEs included: neutropenia (48%), thrombocytopenia (43%), TLS (30%), infection (26%), neutropenic fever (26%), and diarrhea (22%). One pt had an opportunistic infection (Pneumocystis jiroveci pneumonia) while on VEN and concurrent high-dose steroids.

Conclusion: VEN monotherapy appears effective for NHL in phase I clinical trials. We describe our experience outside the setting of a clinical trial, including VEN used as part of multi-agent salvage therapy. Median PFS for our entire cohort is 2 months; AEs, while expected, were observed frequently, reflecting comorbidities. Clinical TLS events are attributed to pre-existing renal dysfunction (61% below 80 mL/min) during VEN escalation. The wide heterogeneity of VEN dose escalation, multi-agent combinations, and timing of initiation of VEN therapy are factors that require further investigation best designed as prospective clinical trials using other agents in combination with VEN.

Disclosures: Landsburg: Celgene: Membership on an entity's Board of Directors or advisory committees; Triphase: Research Funding; Takeda: Research Funding; Curis, INC: Consultancy, Research Funding. Schuster: Genentech: Honoraria, Research Funding; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Research Funding; OncLive: Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Consultancy, Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Physician's Education Source, LLC: Honoraria. Svoboda: Bristol-Myers Squibb: Consultancy, Research Funding; Regeneron: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy, Research Funding; TG Therapeutics: Research Funding; KITE: Consultancy; Kyowa: Consultancy; Pharmacyclics: Consultancy, Research Funding. Gill: Novartis: Research Funding; Extellia: Consultancy, Membership on an entity's Board of Directors or advisory committees; Carisma Therapeutics: Equity Ownership. Mato: TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy; Portola: Research Funding; Johnson & Johnson: Consultancy; Regeneron: Research Funding; Acerta: Research Funding; Celgene: Consultancy; Prime Oncology: Honoraria; Pharmacyclics, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Medscape: Honoraria. Altman: Epizyme: Other: payment to the institution to conduct clinical trial work; Cyclacel: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Bayer: Other: payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ariad: Other: payment to the institution to conduct clinical trial work; Syros: Membership on an entity's Board of Directors or advisory committees; FujiFilm: Other: payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work; Pfizer: Other: payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; Astellas Pharma: Other; Agios: Other: Payment to the institution to conduct the trial ; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Dwivedy Nasta: Pharmacyclics: Research Funding; Incyte: Research Funding; Roche: Research Funding; Aileron: Research Funding; Rafael/WF: Research Funding; Debiopharm: Research Funding; Merck: Other: DSMC; Takeda/Millenium: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees.

*signifies non-member of ASH