A Phase II Trial of Nivolumab Combined with Ibrutinib for Patients with Richter Transformation
Authors: Jain Nitin , Ferrajoli Alessandra , Basu Sreyashi , Thompson Philip A. , Burger Jan A. , Kadia Tapan M. , Estrov Zeev E. , Pemmaraju Naveen , Lopez Wanda , Thakral Beenu , Khoury Joseph David , Bueso-Ramos Carlos E. , Blando Jorge , O'Brien Susan M. , Kantarjian Hagop M. , Allison James P , Keating Michael J , Sharma Padmanee , Wierda William G. 
Published: October 2019

Abstract
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: Pfizer: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BMS: Research Funding; Astra Zeneca: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Seattle Genetics: Research Funding; ADC Therapeutics: Research Funding; Verastem: Research Funding; Servier: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Servier: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Abbvie: Research Funding; Adaptive Biotechnologioes: Research Funding; Genentech: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Adaptive Biotechnologioes: Research Funding; Cellectis: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Celgene: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Abbvie: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees. 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:Aptose Biosciences Inc.: Consultancy; Vaniam Group LLC: Consultancy; Pfizer: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Regeneron: Research Funding; Alexion: Consultancy; Gilead: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Kite Pharma: Research Funding; Abbvie: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Pharmacyclics: Consultancy, Research Funding; Acerta: Research Funding; Amgen: Consultancy; Janssen: Consultancy; Sunesis: Consultancy, Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding.