A phase II multi-institutional Study evaluating the safety and efficacy of the combination of lisocabtagene maraleucel and zanubrutinib in patients with richter transformation

Abstract Richter transformation (RT) occurs in ~4% of patients with chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL) and is associated with dismal prognosis. Lisocabtagene maraleucel (liso-cel) is an anti-CD19 Chimeric Antigen Receptor T-cell therapy (CAR-T) that is approved for treatment in CLL and diffuse large B-cell lymphoma (DLBCL). Despite its efficacy, the durability of responses seen with CAR-T in CLL has been limited. Data suggests that combining Bruton tyrosine kinase inhibitors (BTKi) with CAR-T results in enhanced responses. In patients where it was given for CLL, combination ibrutinib and liso-cel resulted in an objective response rate (ORR) of 84% and a complete response rate of 45%, twice as high as what was observed with liso-cel alone. The median progression free survival (PFS) was 31.4 months (Wierda et. al. Blood 2024, supp1:887). Supporting the efficacy of CAR-T for RT, we performed a multicenter retrospective study showing that when CAR-T is used for RT, the ORR was 63.8%, with a duration of response of 27.6 months. Building on this observed efficacy, and the hypothesis that BTK inhibition improved CAR-T function, we designed a study to investigate the combination of BTKi with CAR-T therapy in RT. Here we present a muti-institutional phase II study evaluating the safety and efficacy of combination zanubrutinib, a second generation BTKi, and liso-cel for treatment of RT. The study is currently open and is enrolling at the Ohio State University Comprehensive Cancer Center in Columbus, OH, Mount Sinai Hospital in New York City, NY, and the University of Utah in Salt Lake City, UT. The study is registered in clinicaltrials.gov (NCT05873712). Patients are eligible if they are ≥18 years of age, have a confirmed diagnosis of RT with DLBCL histology with antecedent or concurrent CLL, have received at least one prior line of treatment for RT or have developed RT while on active treatment for CLL, have adequate organ function and marrow reserve, and have an ECOG performance status≤ 2. Patients should be eligible to receive CAR-T according to institutional guidelines. Patients are excluded if they meet any of the following criteria: have received prior CD19 directed therapy, prior allogenic stem cell transplant or donor lymphocyte infusion within 2 months, have graft-versus-host disease that is active or requiring treatment, have active bleeding or bleeding diathesis, active or uncontrolled autoimmune disease, clinically significant cardiovascular disease or active treatment with warfarin, inability to receive any of the study treatments or adhere with study procedures. Zanubrutinib will be given at a dose of 160 mg twice daily at least 14 days prior to leukapheresis and will continue until 90 days after liso-cel infusion. Fludarabine and cyclophosphamide will be given on days -5 to -3 for lymphodepletion. Liso-cel infusion will occur on day 0. Bridging therapy in addition to zanubrutinib is allowed. Zanubrutinib will be held days -5 to -3 during lymphodepleting therapy administration. The primary objective is to determine the ORR of combination zanubrutinib and liso-cel in patients with RT 90 days after liso-cel infusion. Response will be assessed using the 2014 Lugano criteria. Secondary objectives include the evaluation of the incidence of adverse events, PFS, overall survival, duration of response, and time to next treatment. Key correlative studies will evaluate the T-cell subsets, CLL and CAR-T cell persistence, and tumor microenvironment changes prior to and throughout treatment. We will also perform inflammatory cytokine profiling in patients who experience cytokine release syndrome. Simon's two-stage design was used for this study. Based on a historical ORR of 30% (with anthracycline therapy), 20 evaluable patients are needed to show a clinically meaningful improvement in ORR to 60% with a power of 90% and a one-sided type I error rate of 10%. An interim analysis will occur after the first 8 patients are evaluated; if 2 or fewer patients achieve an overall response, then the study will be stopped for futility. Otherwise, the study continues to enroll 12 more patients. If 9 or more patients out of 20 achieve an overall response at the end of the study, it will be considered sufficient evidence that the regimen is active in patients with RT to warrant further study. Through completion of this study, we expect to learn if combination liso-cel and zanubrutinib is an effective combination for RT.