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.
Highlights
Outcomes among paediatric patients and adolescents and young adults (AYAs) with B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) have continuously improved in recent decades, with long-term survival rates reaching 90% in children and 70% in young adults treated on contemporary protocols [1,2,3]
Responses varied by cell dose infused, with response rates comparable to the results reported with CD19 chimeric antigen receptor (CAR)-T when the recommended Phase II dose was applied [11 of 15 (73%) patients achieved CR]
For patients who weighed >50 kg, the analysis showed a decreased probability of response with doses
Summary
Outcomes among paediatric patients and adolescents and young adults (AYAs) with B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) have continuously improved in recent decades, with long-term survival rates reaching 90% in children and 70% in young adults treated on contemporary protocols [1,2,3]. The addition of a costimulatory domain (e.g., 4-1BB, CD28, or OX40) in second-generation CARs or two costimulatory domains (CD28.4-1BB) in third-generation CARs provides clinically meaningful activity and persistence of CAR T cells [10, 11] (Figure 1A) Because of such properties, CART is being investigated as a potential stand-alone treatment in R/R BCP-ALL. We summarise the current data on tisagenlecleucel and other CAR-T products in paediatric BCPALL, focusing on: [1] the fraction of patients receiving HSCT or other post-infusion interventions, either prophylactically, pre-emptively or for relapse post infusion; and [2] reported factors that influence the efficacy and long-term performance of CAR-T, including CAR design and pre-infusion therapies, to identify evidence that might guide decisions regarding if and when consolidative HSCT should be performed. Tisagenlecleucel, formerly known as CTL019 and commercialised as KYMRIAH R , is an autologous,
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