Coadministration of CD19- and CD22-Directed Chimeric Antigen Receptor T-Cell Therapy in Childhood B-Cell Acute Lymphoblastic Leukemia: A Single-Arm, Multicenter, Phase II Trial

Abstract

PURPOSE We determined the safety and efficacy of coadministration of CD19- and CD22-chimeric antigen receptor (CAR) T cells in patients with refractory disease or high-risk hematologic or isolated extramedullary relapse of B-acute lymphoblastic leukemia. PATIENTS AND METHODS This phase II trial enrolled 225 evaluable patients age ≤ 20 years between September 17, 2019, and December 31, 2021. We first conducted a safety run-in stage to determine the recommended dose. After interim analysis of the first 30 patients treated (27 at the recommended dose) showing that the treatment was safe and effective, the study enrolled additional patients according to the study design. RESULTS Complete remission was achieved in 99.0% of the 194 patients with refractory leukemia or hematologic relapse, all negative for minimal residual disease. Their overall 12-month event-free survival (EFS) was 73.5% (95% CI, 67.3 to 80.3). Relapse occurred in 43 patients (24 with CD19+/CD22+ relapse, 16 CD19–/CD22+, one CD19–/CD22–, and two unknown). Consolidative transplantation and persistent B-cell aplasia at 6 months were associated with favorable outcomes. The 12-month EFS was 85.0% (95% CI, 77.2 to 93.6) for the 78 patients treated with transplantation and 69.2% (95% CI, 60.8 to 78.8) for the 116 nontransplanted patients ( P = .03, time-dependent covariate Cox model). All 25 patients with persistent B-cell aplasia at 6 months remained in remission at 12 months. The 12-month EFS for the 20 patients with isolated testicular relapse was 95.0% (95% CI, 85.9 to 100), and for the 10 patients with isolated CNS relapse, it was 68.6% (95% CI, 44.5 to 100). Cytokine release syndrome developed in 198 (88.0%) patients, and CAR T-cell neurotoxicity in 47 (20.9%), resulting in three deaths. CONCLUSION CD19-/CD22-CAR T-cell therapy achieved relatively durable remission in children with relapsed or refractory B-acute lymphoblastic leukemia, including those with isolated or combined extramedullary relapse.

Safety and efficacy of co-administration of CD19 and CD22 CAR-T cells in children with B-ALL relapse after CD19 CAR-T therapy

“…CR was defined as no circulating blasts and extramedullary disease, including negative CSF and < 5% BM blasts with full hematological recovery (platelets > 100,000/µL and absolute neutrophil count > 1000/µL) [ 16 , 22 ]. MRD-negative CR was defined as < 0.01% leukemia cells detected in BM by FCM.…”

“…Dual-antigen models mainly include (1) pooled CAR-T in which two separately targeted CAR-T cells are co-administered, (2) bispecific CAR-T in which two different single-chain fragment variables (scFv) are connected in a single CAR vector, or (3) bicistronic CAR-T, in which two individual CARs can exist in the same T cell [ 14 , 15 ]. Our institution has achieved a 99% minimal residual disease (MRD)-negative CR rate with co-administration of CD19 and CD22 CAR-T among children with B-ALL, seemingly better than results with single-targeted CD19 or CD22 and other dual-targeted structures [ 16 – 21 ].…”

CAR T-Cells for Cure in Pediatric B-ALL

“…In the two articles that accompany this editorial, 2,3 we get both a longitudinal perspective on the use of CD19 chimeric antigen receptor (CAR) T-cells to achieve durable remissions in children and young adults with B-cell acute lymphoblastic leukemia along with insights for the role of combinatorial treatment approach with the infusion of two unique CAR T-cell products in optimizing remission rates. Collectively, these efforts strongly support the critically important role for CAR T-cells in children and young adults with B-cell acute lymphoblastic leukemia in achieving a cure—while laying a foundation for what future iterations of CAR T-cell–based approaches may look like to improve upon current outcomes.…”

“…Shifting gears to the role of combinatorial CAR T-cell strategies, Wang et al 3 explored the hypothesis that coinfusion of CD19- and CD22-targeted CAR T-cells would improve durable remission. Building on the fundamental principles and success of combination chemotherapy in pediatric B-ALL, efforts in dual antigen-targeting strategies are rapidly expanding.…”

“…10,11 Although there has been limited data on the role of consolidative HSCT after tisagenlecleucel, Laetsch et al 2 reported that data were available for eight of the 11 patients who underwent consolidative HSCT, all of whom remain in remission with a median of 18 months of follow-up. Wang et al 3 incorporated a planned consolidative HSCT for patients at risk for myeloid lineage switch (KMT2Ar/ZNF384r) (n = 24). However, along with performing HSCT in 54 additional patients because of parental preference, a total of 78 patients received consolidative hematopoietic cell transplantation.…”