The journey to CAR T cell therapy: the pediatric and young adult experience with relapsed or refractory B-ALL

Abstract

Outcomes of pediatric and young adult patients diagnosed with acute lymphoblastic leukemia (ALL) have improved significantly in the past few decades. Treatment advances have provided 5-year survival rates ranging from 78 to 91% depending on the age at diagnosis. However, approximately 2-3% of patients will present with refractory disease that is unresponsive to chemotherapy, and 10-15% of patients will relapse. Outcomes post-relapse show significantly reduced 5-year survival rates that continue to decrease with each subsequent relapse. Despite our increased understanding of risk factors and disease predictors, treatment strategies for patients with relapsed or refractory (r/r) disease, including variations of chemotherapy and stem cell transplant, remain ineffective for many patients. To improve outcomes of patients with r/r disease, immunotherapies targeting specific B cell antigens are being developed. Tisagenlecleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy recently approved by the US Food and Drug Administration for patients with refractory leukemia or those with second or later relapse. In this treatment strategy, a patient's own T cells are transduced to express an anti-CD19 CAR that, when reintroduced into the patient, directs specific binding and killing of CD19+ B cells. In a phase 2, single-arm, multicenter, global study, tisagenlecleucel resulted in a remission rate of 81% in pediatric and adolescent patients with r/r B cell ALL. This review article summarizes four typical cases of pediatric and adolescent r/r B-cell ALL, focusing on the patient's journey from initial diagnosis to treatment with CAR T cell therapy.

Fig. 1. Diagram of CAR T cell treatment process.

The treatment process for patients receiving CAR T cell therapy begins with leukapheresis of the patient’s T cells. Once isolated, autologous T cells are sent for manufacturing to produce genetically modified CAR T cells, which are reprogrammed to facilitate targeted killing of CD19+ B cells. The treatment process is completed with intravenous infusion of CAR T cells back to the patient. CAR chimeric antigen receptor

Fig. 2. Timeline of patient journey to CAR T cell therapy.

The journey of CAR T cell therapy for each individual patient. All patients proceeded to CAR T cell therapy after failing conventional salvage treatments or presenting with refractory disease. B-ALL B cell acute lymphoblastic leukemia, CAR chimeric antigen receptor, CNS central nervous system, Dx diagnosis, Ph Philadelphia chromosome, SCT stem cell transplant, SR standard risk

Fig. 3. Diagram of treatment paradigms that include CAR T cell therapy.

Integration of CAR T cell therapy into the treatment algorithm for patients with B-ALL. B-ALL B cell acute lymphoblastic leukemia, CAR chimeric antigen receptor, CNS central nervous system, Ph Philadelphia chromosome, SCT stem cell transplant, TKI tyrosine kinase inhibitor