There remains an unmet need for effective therapies for patients who have progressed on targeted therapies or chemoimmunotherapy in chronic lymphocytic leukemia (CLL). In the ongoing phase 1/2 TRANSCEND CLL 004 study, researchers assessed the safety, pharmacokinetics, and efficacy of lisocabtagene maraleucel (liso-cel), an investigational, anti-CD19, chimeric antigen receptor (CAR) T-cell therapy administered as a defined composition of CD4+/CD8+ CAR T-cells.
To be eligible for participation in the study, patients had confirmed CLL/small lymphocytic leukemia (SLL), failed or were ineligible for a Bruton’s tyrosine kinase (BTK) inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0 to 1. In addition, patients with high-risk and standard-risk disease were required to fail at least 2 and at least 3 prior therapies, respectively. After lymphodepleting chemotherapy, 23 patients received liso-cel infusion at 1 of 2 dose levels: dose-level (DL)1 (50 × 106 total CAR+ T-cells; n = 9) or DL2 (100 × 106 total CAR+ T-cells; n = 14). Response was assessed according to International Workshop on CLL 2008 criteria.
Seventeen of 23 patients received bridging therapy, 5 at DL1 (56%) and 12 at DL2 (86%). A total of 83% of patients had high-risk disease features, which included TP53 mutation (61%), complex karyotype (48%), or del17p (35%). All patients had received prior ibrutinib therapy and more than half (57%) had received prior venetoclax treatment. The median number of prior lines of therapy was 5.
In terms of safety, 2 patients in the DL2 group experienced dose-limiting toxicities, namely, grade 4 hypertension in 1 patient and grade 3 encephalopathy, grade 3 muscle weakness, and grade 4 tumor lysis syndrome in the other. The most common grade 3 or 4 treatment-emergent adverse events included anemia (78%), thrombocytopenia (70%), neutropenia (57%), and leukopenia (44%). In addition, 6 patients had cytokine release syndrome, 5 of whom were dosed at DL2. There were 6 study deaths in this heavily pretreated population.
In the 22 evaluable patients, the best overall response rate was 82% (18/22), and 8 (36%) patients achieved complete remission with or without complete blood count recovery. Six of 9 (67%) patients at DL1 achieved complete response compared with 4 of 13 patients (31%) at DL2. Twelve of 20 (60%) patients achieved undetectable minimal residual disease (MRD) in bone marrow by day 30. MRD-negative complete responses were seen in patients who had failed both BTK inhibitors and venetoclax.
In this study of heavily pretreated patients with CLL/SLL and previous ibrutinib treatment, an impressive proportion of patients receiving liso-cel achieved complete remission and undetectable MRD, with generally manageable toxicities. Additional follow-up analyses will be presented at future congresses.
Abstract 7501; Siddiqi T, et al.