Chimeric Antigen Receptor T-Cell Therapy in Paediatric B-Cell Precursor Acute Lymphoblastic Leukaemia: Curative Treatment Option or Bridge to Transplant?

Abstract

Chimeric antigen receptor T-cell therapy (CAR-T) targeting CD19 has been associated with remarkable responses in paediatric patients and adolescents and young adults (AYA) with relapsed/refractory (R/R) B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). Tisagenlecleucel, the first approved CD19 CAR-T, has become a viable treatment option for paediatric patients and AYAs with BCP-ALL relapsing repeatedly or after haematopoietic stem cell transplantation (HSCT). Based on the chimeric antigen receptor molecular design and the presence of a 4-1BB costimulatory domain, tisagenlecleucel can persist for a long time and thereby provide sustained leukaemia control. “Real-world” experience with tisagenlecleucel confirms the safety and efficacy profile observed in the pivotal registration trial. Recent guidelines for the recognition, management and prevention of the two most common adverse events related to CAR-T — cytokine release syndrome and immune-cell–associated neurotoxicity syndrome — have helped to further decrease treatment toxicity. Consequently, the questions of how and for whom CD19 CAR-T could substitute HSCT in BCP-ALL are inevitable. Currently, 40–50% of R/R BCP-ALL patients relapse post CD19 CAR-T with either CD19− or CD19+ disease, and consolidative HSCT has been proposed to avoid disease recurrence. Contrarily, CD19 CAR-T is currently being investigated in the upfront treatment of high-risk BCP-ALL with an aim to avoid allogeneic HSCT and associated treatment-related morbidity, mortality and late effects. To improve survival and decrease long-term side effects in children with BCP-ALL, it is important to define parameters predicting the success or failure of CAR-T, allowing the careful selection of candidates in need of HSCT consolidation. In this review, we describe the current clinical evidence on CAR-T in BCP-ALL and discuss factors associated with response to or failure of this therapy: product specifications, patient- and disease-related factors and the impact of additional therapies given before (e.g., blinatumomab and inotuzumab ozogamicin) or after infusion (e.g., CAR-T re-infusion and/or checkpoint inhibition). We discuss where to position CAR-T in the treatment of BCP-ALL and present considerations for the design of supportive trials for the different phases of disease. Finally, we elaborate on clinical settings in which CAR-T might indeed replace HSCT.

Impact of disease burden and late loss of B cell aplasia on the risk of relapse after CD19 chimeric antigen receptor T Cell (Tisagenlecleucel) infusion in pediatric and young adult patients with relapse/refractory acute lymphoblastic leukemia: role of B-cell monitoring

“…In contrast, response was not reached in the patients who experienced loss of BCA at later time points ( 12 ). For this reason, many studies establish six months as the predictive cut-off time-point that identifies patients at a higher or lower risk of relapse ( 19 – 21 ). Accordingly, allo-SCT is recommended when loss of BCA takes place in less than six months.…”

The Philadelphia Chromosome, from Negative to Positive: a Case Report of Relapsed Acute Lymphoblastic Leukemia Following Allogeneic Stem Cell Transplantation

“…(20)There is a lack of randomised trials comparing approaches with consolidating HSCT to approaches in which patients do not progress to HSCT but are strictly followed for T cell persistence and MRD remission after infusion. (21) We are also looking for an unrelated donor for a possible second allo-HSCT.…”

Reliable Flow-Cytometric Approach for Minimal Residual Disease Monitoring in Patients with B-Cell Precursor Acute Lymphoblastic Leukemia after CD19-Targeted Therapy

“…The wide implementation of CD19-directed therapy in the treatment algorithms for both primary and R/R BCP-ALL [ 5 , 6 , 7 , 45 , 46 , 47 ] significantly complicated the rather routine procedure of MFC-MRD monitoring. More sensitive molecular techniques seem to be more applicable after immunotherapy [ 10 , 48 ], as their reproducibility is not directly linked with the expression of therapeutic targets.…”