Modified chimeric antigen receptor (CAR) product, human CAR T CD19 (huCART19), has been shown to provide long-lasting, effective 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
Patients who had not previously received CAR-T cell therapy experienced a complete response (CR)/CR with incomplete recovery of count (CRi) of 98% (n = 40/41) and 100% (n = 39/39 ) on day 28 after the infusion. All responders were minimally residual disease (MRD) negative. In the retreatment cohort, the CR/CRi rate was 79% at Day 28, with 86% of responders being MRD negative. However, five patients had no biological response because B cell aplasia had not been established. One month after the infusion, patients in the CAR T naive arm had an overall response (ORR) of 98% versus 64% in the retreatment cohort. and after 1 and 2 years, 74% and 58% remission, 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 of this approach in a phase 2 study, which is underway.”
The open-label study enrolled 74 pediatric and young adults, ages 1 to 29 years with either relapsed or refractory B-ALL (n=72) or B-lymphoblastic lymphoma (BLL; n=2). Originally, the researchers 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 via an intravenous injection in patients weighing 50 kg or more. After a change in the base dose, the remaining 26 products were adjusted to 6 x 106 huCART19 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 were either previously exposed or re-treated (B-ALL, n = 33) and patients who were CAR naive, with no prior exposure 41 (B-ALL, n = 39; BLL, n = 2) .
The primary endpoint of the study was the safety and feasibility of huCART19 infusion, as well as the duration of persistence. Key secondary endpoints were 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 that patients in the CAR-naïve group had a 1-year recurrence-free survival (RFS) of 84% (95% CI, 72-97) and a 2-year RFS rate of 74% (95% CI, 60-90), while the retreatment 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 74% relapse-free survival (95% CI, 56%-97%). At 24 months, the RFS for this group was 58% (95% CI, 37%-90%). At 12 and 24 months, the incidence of relapse was 24% (95% CI, 8%-44%) and 36% (95% CI, 15%-59%), respectively.
Of patients undergoing a CR/CRi, 12 patients relapsed before undergoing additional therapy. Of 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 experiencing B cell aplasia had an incidence of B cell recovery 15% (95% CI, 6%-28%) in the CAR naive group and 58% (95% CI, 33%-77%) in the retreatment group.
Some adverse events (AEs) experienced by patients were Cytokine Release Syndrome (CRS) which occurred in 84% of patients with 5 patients developing Grade 4 effects. Neurologic toxicity occurred in 39% of Grade 3 (n=1) or Grade 4 (n=1) patients and completely resolved in all cases. Common serious adverse events were CRS, febrile neutropenia, and encephalopathy. There were no treatment-related deaths noted by investigators during the study. All treatment-related adverse events were reversible, with the exception of persistent cytopenias within the 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 reduced risk of relapse, warrants further investigation,” the study authors concluded.
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 for print, June 22, 2021. J Clin Oncol. 2021. doi:10.1200/JCO.20.03458
2. CHOP researchers develop humanized CAR T-cell therapy showing potential for patients with relapsed B-ALL. news item. June 28, 2020. Accessed July 8, 2021. https://bit.ly/3xsCzE9