Safety and tolerability of conditioning chemotherapy followed by CD19-targeted CAR T cells for relapsed/refractory CLL

BACKGROUND. Subgroups of patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) exhibit suboptimal outcomes after standard therapies, including oral kinase inhibitors. We and others have previously reported on the safety and efficacy of autologous CD19-targeted CART cells for these patients. Here, we report safety and long-term follow-up of CART cell therapy with or without conditioning chemotherapy for patients with RJR CLL and indolent B cell non-Hodgkin lymphoma (B-NHL). METHODS. We conducted a phase I clinical trial investigating CD19-targeted CART cells incorporating a CD28 costimulatory domain (19-28z). Seventeen of twenty patients received conditioning chemotherapy prior to CART cell infusion. Five patients with CLL received ibrutinib at the time of autologous T cell collection and/or CART cell administration. RESULTS. This analysis included 16 patients with RJR CLL and 4 patients with RJR indolent B-NHL. Cytokine release syndrome (CRS) was observed in all 20 patients, but grade 3 and 4 CRS and neurological events were uncommon (10% for each). Ex vivo expansion of T cells and proportions of CART cells with the CD62L(+)CD127(+) immunophenotype were significantly greater (P = 0.047; CD8 subset, P = 0.0061, am subset) in patients on ibrutinib at leukapheresis. Three of twelve evaluable CLL patients receiving conditioning chemotherapy achieved complete response (CR) (2 had minimal residual disease-negative CR). All patients achieving CR remained progression free at median follow-up of 53 months. CONCLUSION. Conditioning chemotherapy and 19-28z CAR T cells were acceptably tolerated across investigated dose levels in heavily pretreated patients with RJR CLL and indolent B-NHL, and a subgroup of patients achieved durable CR. lbrutinib therapy may modulate autologous T cell phenotype.