primelines chronic lymphocytic leukemia CD19-targeting CAR-T cells

CD19-Targeting CAR-T Cells Highly Effective in Relapsed Chronic Lymphocytic Leukemia

Patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL) with complex cytogenetics and/or del17 have dismal prognosis after failure on ibrutinib. A phase I/II study evaluated the safety and efficacy of CD19-targeting chimeric antigen receptor modified (CAR)-T cells after lymphodepleting therapy in heavily pretreated patients (N = 24) with CLL and found that CAR-T cells induce responses in two-thirds of patients.

Most of the patients (n = 19) received cyclophosphamide and fludarabine lymphodepletion and a single CAR-T cell infusion at or below maximum tolerated dose (≤2 x 106 CAR-T cells/kg). Four weeks following the CAR-T cell infusion, the overall response rate (ORR) according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria was 71%. In the 19 patients who had received cyclophosphamide and fludarabine lymphodepletion, the ORR was 74%. Of note, 15 of 17 (88%) who had bone marrow involvement before treatment had undetectable disease by flow cytometry at evaluation. Furthermore, 12 of these patients underwent deep immunoglobulin heavy chain (IGH) sequencing, and in 7 (58%) no malignant IGH was detectable in the marrow. At 6.6 months follow-up, all of these patients were alive and progression free.

Overall, toxicity was manageable. Cytokine release syndrome (CRS) occurred in 83% of patients (mostly grades 1-2) and 33% of patients developed neurotoxicity. All patients with neurotoxicity also had CRS. While most neurotoxicity was reversible, there was 1 death due to treatment-related neurotoxicity. Development of CRS and neurotoxicity were both strongly correlated with higher percentages of leukemic B cells in marrow before treatment.

The investigators concluded that CD19 CAR-T cells are highly effective in patients with high-risk relapsed and ibrutinib refractory CLL where treatment options are limited. Further studies of CD19 CAR-T cells in CLL, particularly in patients with high-risk cytogenetics, are warranted. Additionally, future studies should investigate strategies to mitigate treatment-related toxicity, including markers that may predict severe toxicity.