A lower dose of anti-CD19 chimeric antigen receptor (CAR) T-cell (CAR-T) therapy resulted in similar overall survival (OS) as a higher dose among patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to data from a phase 2 trial.
Previous studies demonstrated that CAR T cells can have substantial activity in a subset of patients with relapsed/refractory CLL. In the authors’ prior study, the overall response rate (ORR) to anti-CD19 CAR T cells was 57%, with no clear relationship to dose. The purpose of this study was to determine an optimal dose for future clinical trials with anti-CD19 CAR T cells for the treatment of relapsed/refractory CLL.
This phase 2 study randomly assigned 38 patients with relapsed/refractory CLL to receive 5 x 107 (low dose) or 5 x 108 (high dose) anti-CD19 CAR T cells. The trial was conducted in 2 phases: phase 1 randomly assigned 30 patients to receive low- or high-dose CAR-T therapy; phase 2 was an expansion cohort in which an additional 10 patients were treated with high-dose CAR-T. All patients had received at least 2 prior lines of therapy.
Prior to the CAR-T infusion, patients were recommended to undergo lymphodepleting chemotherapy using standard regimens, but this was not required.
The primary endpoint was the proportion of patient who achieved a complete response (CR) at the end of 3 months. Key secondary endpoints included progression-free survival (PFS), OS, cytokine release syndrome (CRS), and toxicities.
At infusion, the median age was 61 years, and 78% of patients were male. Mutated TP53 or deletion 17p was presented in 28%, and IHGV status was mutated in 6%.
The ORR for the entire cohort was 44%, including CR in 28% and partial response (PR) in 16%. In the high-dose group, the ORR was 53%, which included 37% who achieved a CR and 16% who achieved a partial response (PR). In the low-dose group, the ORR was 29%; however, 1 patient did not reach the prespecified dose.
During a median follow-up of 31.5 months for the entire evaluable cohort, the median OS was 64 months and the median PFS was 1 month. There was no difference in OS by dose group, as the median was 64 months for the high-dose group and 68 months for the low-dose group (P =.84).
OS and PFS were longer among patients who achieved CR. The 36-month OS was 89% among patients who achieved CR compared with 50% among patients who did not reach CR. Among patients who achieved CR, the 36-month OS was similar at 62% and 60% for patients in the low-dose and high-dose groups. The 36-month PFS was 7.7% for the low-dose group and 26% in the high-dose group.
Among all patients, CRS developed in 63%, including 24% who experienced grade 3 to grade 4 CRS. By dose groups, CRS occurred in 39% of patients who received the low dose and 72% of patients who received the high dose.
Acknowledging that the small numbers in the study limited the statistical significance, the authors concluded that these data suggest that “the higher target dose (5 x 108 CART-19) using an adaptive split-dosing strategy was safe and possibly more effective than the lower dose.”
Based on this study, the authors also stated that “strategies to further increase the CR rate to CART cells in CLL are warranted and many be supported by optimization of dose and scheduling.”
Disclosure: Some of the authors disclosed financial relationships with pharmaceutical and/or medical companies. For a full list of disclosures, please refer to the original study.
Frey NV, Gill S, Hexner EO, et al. Long-term outcomes from a randomized dose optimization study of chimeric antigen receptor modified T cells in relapsed chronic lymphocytic leukemia. J Clin Oncol. Epub 2020 April 16.