BLOG: CAR T cells for long-term cure in pediatric ALL
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Chimeric antigen receptor T-cell therapy targeting CD19 is highly effective for inducing remission among patients with relapsed or refractory B-cell acute lymphoblastic leukemia.
Despite that, 50% of patients relapse after CAR-T therapy, and curative options for patients who relapse after CD19 CAR-T are limited, with no standard approach to cure.
Allogeneic hematopoietic stem cell transplantation performed after remission reduces relapse risk among high-risk patients with B-ALL and may reduce risk for post-CD19 CAR-T relapse. However, HSCT is associated with risk for short-term morbidity and mortality, as well as long-term toxicities, making avoidance of HSCT desirable for patients who may be cured with CD19 CAR-T alone.
Optimizing cure following CAR-T therapy — and defining the role and timing of HSCT after CAR-T — was identified as a top priority in pediatric transplantation and cellular therapy at the 2021 Blood and Marrow Transplant Clinical Trials Network State-of-the-Science Symposium.
The next-generation sequencing measurable residual disease test is a highly sensitive method for residual disease detection, and it is more sensitive than flow cytometry.
Detection of minimal residual disease in the bone marrow by next-generation sequencing can stratify patients by risk for relapse after HSCT.
Data from the pivotal ELIANA trial next-generation sequencing minimal residual disease assays show that next-generation sequencing testing of the blood is more sensitive than flow cytometry on bone marrow samples in identifying B-ALL, and that any identifiable minimal residual disease measurement by next-generation sequencing in blood samples almost invariably precedes relapse by a median 168 days.
Patients with any next-generation sequencing detection by 6 months after CAR-T are at high risk for relapse, while patients with consistently next-generation sequencing-negative minimal residual disease results have improved EFS.
Combined with loss of B-cell aplasia as surrogate for loss of functional CAR-T, next-generation sequencing testing may identify patients at high risk for relapse after CAR-T who may be candidates for intervention — including HSCT — to prevent overt relapse and improve long-term leukemia-free survival.
Based on these data, the CAR-CURE trial (CAR T cells for long-term cure: A risk-based approach to post-CD19 CAR T-cell consolidation with hematopoietic stem cell transplantation for pediatric, adolescents and young adult B-cell acute lymphoblastic leukemia) will test the feasibility of time-intensive monitoring of peripheral blood samples by next-generation sequencing testing for minimal residual disease and flow cytometry for B-cell aplasia to enable timely pre-emptive HSCT in high-risk patients.
The trial will inform on the relationships between blood next-generation sequencing, bone marrow next-generation sequencing and standard bone marrow flow cytometry.
The trial is sponsored by the Pediatric Transplantation and Cellular therapy Consortium, with funding provided by Peach Bowl Inc. and the Peach Bowl LegACy Fund.
References:
- Bader P, et al. Blood Adv. 2019;doi:10.1182/bloodadvances.2019000449.
- Heslop HE, et al. Transplant Cell Ther. 2021;doi:10.1016/j.jtct.2021.08.016.
- Maude SL, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1709866.
- Pulsipher MA, et al. Blood. 2018;doi:10.1182/blood-2018-99-115460.
- Qayed M, et al. Curr Opin Hematol. 2021;doi:10.1097/MOH.0000000000000685.
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