Characteristics and outcome determinants in children, adolescents and young adults who failed tisagenlecleucel for B-cell acute lymphoblastic leukemia.

Tisagenlecleucel (tisa-cel), an autologous anti-CD19 CAR T-cell therapy, has significantly improved outcomes in pediatric, adolescents and young adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R BCP-ALL). However, 30-50% experience early failure or relapse. We retrospectively analyzed 52 cases of early failures (n = 13) or relapses (n = 39), evaluating post-tisa-cel outcomes and prognostic factors. CD19 antigen loss was the only factor associated with a lower complete remission rate after salvage therapy (OR = 0.16, 95%CI [0.03-0.90], p = 0.04). Median overall survival (OS) was 14.5 months, with a 2-year OS of 37.4% (95%CI [24.4-50.4]), similar between early failure (38.5%) and relapse (37.0%) groups (p = 0.78). Patients with measurable residual disease only at salvage initiation had significantly improved 2-year OS (61.9%, (95%CI [38.1-78.8])) compared to those with overt disease (20.7%, (95%CI [8.4-36.7], p = 0.008)). Factors associated with inferior OS included high pre-infusion tumor burden (HR = 3.57, p < 0.01), and prior inotuzumab ozogamicin exposure (HR = 3.81, p < 0.01). Although salvage therapies and hematopoietic stem cell transplantation benefit some patients, 5 of 18 transplanted patients died from treatment-related toxicity, underscoring the significant associated risks. These findings highlight the poor prognosis of tisa-cel failures and the urgent need for novel strategies.