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296 A Phase II Trial of Nivolumab Combined with Ibrutinib for Patients with Richter Transformation

Program: Oral and Poster Abstracts
Type: Oral
Session: 642. CLL: Therapy, excluding Transplantation: Cellular Therapy and Immunomodulation in CLL
Hematology Disease Topics & Pathways:
Adult, Diseases, Leukemia, Biological, CLL, Therapies, Elderly, checkpoint inhibitors, Biological Processes, Study Population, Clinically relevant, Lymphoid Malignancies, immune mechanism, TKI
Sunday, December 2, 2018: 7:45 AM
Pacific Ballroom 20 (Marriott Marquis San Diego Marina)

Nitin Jain, MD1, Alessandra Ferrajoli, MD2, Sreyashi Basu, PhD3*, Philip A. Thompson, MBBS4, Jan A. Burger, MD, PhD1, Tapan M. Kadia, MD5, Zeev E. Estrov, MD1, Naveen Pemmaraju, MD6, Wanda Lopez, RN1*, Beenu Thakral, MD7*, Joseph David Khoury, MD7, Carlos E. Bueso-Ramos, MD, PhD7, Jorge Blando, DVM3*, Susan M. O'Brien, MD8, Hagop M. Kantarjian, MD1, James P Allison, PhD3*, Michael J Keating, MBBS1, Padmanee Sharma, MD, PhD3* and William G. Wierda, MD, PhD1

1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
3Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX
4Department of Leukemia, MD Anderson Cancer Center, Houston, TX
5Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX
6Department of Leukemia, The University of Texas MD Anderson Cancer Center, Bellaire, TX
7Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX
8University of California Irvine, Chao Family Comprehensive Cancer Center, Irvine, CA

Background: Outcomes of patients (pts) with Richter transformation (RT) remain dismal with a median survival of less than 1 year with chemoimmunotherapy (CIT). Dysfunction of T cells, NK cells and other immune subsets is common in pts with CLL. Checkpoint blockade is an emerging treatment approach for pts with RT (Ding et al. Blood 2017; Younes et al. ASH 2017).

Methods: We designed an investigator-initiated phase II clinical trial combining nivolumab (anti-PD1 monoclonal antibody) with ibrutinib in pts with R/R CLL or RT (NCT02420912). We report data on the RT cohort. Nivolumab was given 3 mg/kg IV every 2 weeks, starting cycle 1 day 1 for a total of 24 cycles. Ibrutinib was given 420 mg once daily starting cycle 2 day 1 (Ibrutinib could be added during cycle 1, in case of worsening disease) and continued until disease progression or unacceptable toxicities. Each cycle was 4 weeks. Eligibility criteria included age ≥18 years, adequate organ function (total bilirubin ≤1.5 x ULN, ALT and AST ≤3 x ULN, creatinine ≤1.5 x ULN). Pts were included if they had received at least one therapy for CLL or RT (pts with del(17p) could be treatment-naïve). Response assessments were done by PET scan and bone marrow after cycle 1, cycle 3, cycle 6, cycle 9, and cycle 12, cycle 18, and cycle 24.

Results: A total of 23 pts with RT have been enrolled. The median age was 65 years (range, 49-88); 10 women, 13 men. The median number of prior therapies for CLL/RT was 3 (range, 0-10); one pt with previously untreated CLL who developed RT with del(17p) was enrolled. Prior therapies included CIT (n=18), ibrutinib (n=11), acalabrutinib (n=1), P13K inhibitor (n=4), venetoclax (n=3), allo-SCT (n=2).

A total of 10 pts (43%) responded (complete metabolic response, n=8; partial metabolic response, n=2). The median duration of response (censored for allo-SCT) for the responding pts (n=10) is 9.3 months (Figure 1). Two pts previously treated with ibrutinib responded. A total of 4 pts underwent a subsequent allo-SCT after achieving a response to therapy. Four additional pts underwent allo-SCT after receiving a subsequent salvage therapy. The median overall survival for the entire group (n=23) is 13.8 months (Figure 1). One pt had G3 transaminitis and one pt had grade 4 lipase/amylase elevation. One pt developed grade 2 pneumonitis, and one pt had grade 2 uveitis. Correlative studies, including flow-cytometry and immunohistochemistry for PD1 and PDL1 are ongoing.

Conclusions: The combination of nivolumab and ibrutinib has clinical activity in pts with RT with a 43% response rate.

Disclosures: Jain: Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; BMS: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding. Thompson: AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kadia: Pfizer: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; BMS: Research Funding; Novartis: Consultancy; BMS: Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Novartis: Consultancy. Pemmaraju: novartis: Research Funding; samus: Research Funding; stemline: Consultancy, Honoraria, Research Funding; daiichi sankyo: Research Funding; abbvie: Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; plexxikon: Research Funding; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding. Khoury: Stemline Therapeutics: Research Funding. O'Brien: Celgene: Consultancy; Alexion: Consultancy; Gilead: Consultancy, Research Funding; Acerta: Research Funding; Vaniam Group LLC: Consultancy; Astellas: Consultancy; Amgen: Consultancy; Kite Pharma: Research Funding; Aptose Biosciences Inc.: Consultancy; Abbvie: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Research Funding; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Kantarjian: Pfizer: Honoraria, Research Funding; Orsenix: Honoraria; Novartis: Research Funding; Immunogen: Honoraria; BMS: Honoraria, Research Funding; Astex: Research Funding; ARIAD: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Actinium: Honoraria; AbbVie: Honoraria. Wierda: Genentech: Research Funding; AbbVie, Inc: Research Funding.

*signifies non-member of ASH