HuCART19 Achieved Durable, Robust Responses in Adult and Pediatric R/R B-ALL

Modified chimeric antigen receptor (CAR) product, human CAR T CD19 (huCART19), was found to yield long-term, efficacious remissions in adult and pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), according to the results of a phase 1 study (NCT02374333) published in the Journal of Clinical Oncology.¹

Patients who had not previously received any CAR T-cell therapy experienced a complete response (CR)/ CR with incomplete count recovery (CRi) of 98% (n = 40/41) and 100% (n = 39/39) at day 28 following the infusion. All responders were minimal residual disease (MRD)–negative. In the retreatment cohort, the rate CR/CRi was 79% at day 28, with 86% of responders being MRD-negative. However, five patients did not have biologic response because B-cell aplasia was not established. One month following infusion, patients in the CAR T­–naïve arm had an overall response rate (ORR) of 98% vs 64% in the retreatment cohort. and after 1 and 2 years 74% and 58% remission rate respectively.

“These results show that [huCART19] is an encouraging option for retreatment in a difficult-to-treat population,” Shannon L. Maude, MD, PhD, an attending physician in the Cancer Center at CHOP and senior author of the study, said in a press release.² “We are continuing to analyze the effectiveness of this approach in a phase 2 trial, which is ongoing.”

The open-label study enrolled 74 pediatric and young adults, from age 1 up to 29 years of age with either relapsed or refractory B-ALL (n = 72) or B-lymphoblastic lymphoma (BLL; n = 2). Investigators originally planned to administer a dose of 3 x 107 cells/kg with an acceptable range of 3 x 105 to 3 x 107 cells/kg with a maximum dose of 1.5 x 109 cells of huCART19 through an intravenous injection in patients who were 50 kg or more. Following an amendment to the base dose, the remaining 26 products were adjusted to 6 x 106huCART19 cells/kg with an acceptable range of 2 x 105 to 6 x 106 huCART19 cells/kg and a maximum dose of 5 x 108 huCART19 cells.

The study included 2 cohorts of patients who either had prior exposure or retreatment (B-ALL, n = 33) and patients who were CAR-naïve, without prior exposure 41 (B-ALL, n = 39; BLL, n = 2).

The primary end point of the study was safety and feasibility of huCART19 infusion, as well as duration of persistence. Key secondary end points included ORR at day 28, MRD-negative CR/CRi rate, event-free survival, OS, and an exploratory cytokine analysis.

The median follow-up was 21.2 months after infusion. Additional data from the study indicated patients in the CAR-naïve group experienced a 1-year relapse-free survival (RFS) rate of 84% (95% CI, 72-97) and a 2-year RFS rate of 74% (95% CI, 60-90), while the re-treatment arm had a 1- and 2-year RFS of 74% (95% CI, 56-97) and 58% (95% CI, 37-90), respectively. At 12 months, those who achieved CR/CRi with B-cell aplasia (n = 21) had a relapse-free survival rate of 74% (95% CI, 56%-97%). At 24 months, the RFS for this group was 58% (95% CI, 37%-90%). At 12 and 24 months, incidence of relapse was 24% (95% CI, 8%-44%) and 36% (95% CI, 15%-59%) respectively.

For patients who experienced a CR/CRi, 12 relapsed before undergoing additional therapy was received. Among this group, 6 were positive for CD19 cells, 4 were CD19-negative, and 2 had both positive and negative CD19 leukemic cells. At 6 months, patients who experienced B-cell aplasia had incidence of B-cell recovery 15% (95% CI, 6%-28%) in the CAR-naïve group and 58% (95% CI, 33%-77%) in retreatment group.

Some adverse effects (AEs) that patients experienced were cytokine release syndrome (CRS) occurring in 84% of patients, with 5 patients developing grade 4 effects. Neurologic toxicities occurred in 39% of patients that was of grade 3 (n=1) or grade 4 (n=1) and was fully resolved in all cases. Common serious AEs included CRS, febrile neutropenia, and encephalopathy. There were no treatment-related deaths noted by investigators during the study. All treatment-related AEs were reversible with the exception of persistent cytopenias past 8 weeks in 59% of the CAR-naïve cohort and 45% of the retreatment cohort.

“…The potential for improved persistence with huCART19, which may be associated with a decreased risk of relapse, warrants further study,” the authors of the study concluded.

References:

1. Myers RM, Li Y, Barz Leahy A, et al. Humanized CD19-targeted chimeric antigen receptor (CAR) T Cells in CAR-naive and CAR-exposed children and young adults with relapsed or refractory acute lymphoblastic leukemia. Published online ahead of print, June 22, 2021. J Clin Oncol. 2021. doi:10.1200/JCO.20.03458

2. CHOP researchers develop humanized CAR T-cell therapy that shows potential for patients with relapsed B-ALL. News Release. June 28, 2020. Accessed July 8, 2021. https://bit.ly/3xsCzE9