Locally produced CD19 CAR T cells leading to clinical remissions in medullary and extramedullary relapsed acute lymphoblastic leukemia

Abstract

Autologous CD19 chimeric-antigen receptor (CAR) T cells demonstrated remarkable remission rates in relapsed and refractory acute lymphoblastic leukemia (R/R ALL). Here, we report results from a phase 1b/2 study of in-house produced CD19 CAR with a CD28 costimulatory domain. Twenty-one patients with R/R ALL were enrolled, and 20 infused. The median age was 11 years (range, 5-48). Patients had a median of 4 prior regimens, including blinatumomab in 6 and prior stem-cell transplantation in 10. In total 8 patients had extramedullary (EM) leukemic involvement, and prior to lymphodepletion and CAR 7 had active lesions, a group underrepresented in previous trials. In vivo expansion of CAR T cells was observed in 18 patients. In total 16 patients developed cytokine release syndrome, and 11 patients developed neurotoxicity, with no toxic deaths. All responding patients were referred to an allogeneic hematopoietic stem-cell transplantation. The remission rate was 90%, including resolution of all refractory EM sites. Four responding patients relapsed, 3 who had a PCR-MRD positive remission at 28 days following CAR-T cells and 1 patient 21 months after an MRD-negative response. The estimated 1-year event-free survival and overall survival are 73% and 90%, respectively. Patients with R/R EM ALL may also benefit from CAR-T cell therapy.

Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B‐cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia

“…Nine patients with MRD‐negative disease prior to blinatumomab retained this status. Of two treated with measurable MRD, one had an MRD‐negative response and one patient had no MRD response and developed active extramedullary disease at the end of the first blinatumomab cycle, further treated with chemotherapy and CD19 chimeric antigen receptor T cells . Two patients eventually died of toxicities following subsequent treatment phases—one of septic shock during maintenance and one of transplant‐related toxicity.…”

Chimeric Antigen Receptor T-Cells in B-Acute Lymphoblastic Leukemia: State of the Art and Future Directions

“…Aside from the unique systemic toxicities associated with CAR-T therapy, the major challenge to CAR-T therapy has been difficulty in obtaining durable responses, especially in the adult B-ALL population. Despite initial impressive deep responses obtained with this therapy, more than half of the adult B-ALL patients experience relapse (22,23,26,(33)(34)(35)(36)(37) if not bridged to allo-HCT. Moreover, we are currently unable to accurately predict which patients will achieve long-term remission and/or persistence of in vivo CAR-T. As CAR-T and gene therapy fields continue to evolve, we will likely see more effective products aimed at improving the potency, safety, and persistence of CAR-T therapy.…”

Updates on CAR T‐cell therapy in B‐cell malignancies

“…Data from international centers play a critical role in informing the applicability of CAR T‐cell therapies in setting with different patient populations and/or resources and are highly informative to understanding challenges in other settings and making this therapy available globally. oRecently, a group from Israel completed a Phase Ib/II trial with an intention to treat analysis, including administration of a CD28‐based second‐generation CAR T cell that was gammaretrovirally transduced. Patients received lymphodepletion with fludarabine and cyclophosphamide and CAR T‐cell dose of 1 × 10 6 CAR T cells/kg.…”