Zanubrutinib and Lisocabtagene Maraleucel for the Treatment of Richter's Syndrome

PRIMARY OBJECTIVE: I. To evaluate the efficacy of the combination of zanubrutinib and lisocabtagene maraleucel (liso-cel) for the treatment of Richter's syndrome (RS). SECONDARY OBJECTIVES: I. To describe the safety profile of the combination of zanubrutinib and liso-cel for RS. II. To evaluate duration of the efficacy of the combination of zanubrutinib and liso-cel for RS CORRELATIVE OBJECTIVES: I. Describe T-cell subsets before and after zanubrutinib initiation, as well as post liso-cel infusion. II. To describe the persistence of liso-cel. III. To describe the tumor microenvironment post liso-cel infusion at relapse. IV. Investigate the correlation between inflammatory cytokines and measures of inflammation and outcomes and rates of adverse events including cytokine release syndrome (CRS). V. Investigate chronic lymphocytic leukemia (CLL) persistence post treatment. OUTLINE: Patients receive zanubrutinib orally (PO) twice daily (BID) for up to day 90 and undergo leukaphereis at least 14 days after starting zanubrutinib. Patients receive fludarabine intravenously (IV) and cyclophosphamide IV on days -5 to -3 and liso-cel IV over 5-30 minutes on day 0. Patients also undergo bone marrow (BM) biopsy and lymph node biopsy at screening and follow up, and undergo collection of blood samples and computed tomography (CT), positron emission tomography (PET)/CT, and/or magnetic resonance imaging (MRI) throughout the trial. After study completion, patients are followed for 24 months, and then every 6 months until disease progression or death.