A Phase 2 Study of Nivolumab Combined With Ibrutinib in Patients With Diffuse Large B-Cell Richter Transformation of CLL

Authors

Nitin Jain
Jayastu Senapati
Beenu Thakral
Alessandra Ferrajoli
Philip Thompson
Jan Burger
Sreyashi Basu
Tapan Kadia
Naval Daver
Gautam Borthakur
Marina Konopleva
Naveen Pemmaraju
Erin Parry
Catherine J Wu
Joseph Khoury
Carlos Bueso-Ramos
Naveen Garg
Xuemei Wang
Wanda Lopez
Ana Ayala
Susan O'Brien
Hagop Kantarjian
Michael Keating
James Allison
Padmanee Sharma
William Wierda

Publication Date

5-23-2023

Journal

Blood Advances

Abstract

Richter transformation (RT) is a rare complication of chronic lymphocytic leukemia (CLL) that has dismal outcomes. Upregulation of PD-1/PD-L1 drives immunological evasion in patients with RT. We hypothesized that combining nivolumab, a PD-1 blocking antibody, with the BTK inhibitor (BTKi) ibrutinib could potentiate tumor-cell killing. We conducted an investigator-initiated phase 2 clinical trial to assess the efficacy of combined nivolumab and ibrutinib in patients with diffuse large B-cell lymphoma (DLBCL) RT and CLL. Patients included were ≥18 years of age with adequate hepatic and renal function. Patients received nivolumab every 2 weeks of a 4-week cycle for a maximum of 24 cycles. A standard dose ibrutinib was initiated from cycle 2 onward and continued daily until progression. For patients who were already on ibrutinib at the time of study entry, the same was continued while nivolumab was initiated. A total of 24 patients with RT with a median age of 64.5 years (range, 47-88) were enrolled. Ten patients (42%) had received prior treatment for RT and 13 patients (54%) had received a prior BTKi. A total of 10 patients (42%) responded with a median duration of response of 15 months. The median overall survival was 13 months. Four of 24 (17%) patients had checkpoint inhibition-related immunological toxicities. In the CLL cohort, 10 patients were enrolled, of whom 3 patients converted from partial to complete remission; 1 patient had a grade 2 immunological toxicity. Combined nivolumab and ibrutinib is an active regimen for patients with DLBCL RT with an overall response rate of 42%. Given the limited treatment options for patients with RT, checkpoint inhibition provides a potential therapeutic option. This trial is registered at www.clinicaltrials.gov as #NCT02420912.

Keywords

Humans, Middle Aged, Aged, Aged, 80 and over, Leukemia, Lymphocytic, Chronic, B-Cell, Nivolumab, Programmed Cell Death 1 Receptor, B-Lymphocytes, Lymphoma, Large B-Cell, Diffuse

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Supplementary Materials

PMID: 36287248