Background: Tisagenlecleucel is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell immunotherapy indicated for patients (pts) up to 25 y of age with B-ALL that is refractory or in second or later relapse. Since the pivotal ELIANA trial, pt characteristics now include pts < 3 y, pts with isolated central nervous system relapse, and pts with leukemia burden < 5%. Here we examine the impact of tisagenlecleucel on the pt treatment journey since FDA approval in 2017. Methods: Data were collected as a part of a noninterventional, prospective, longitudinal study using the CIBMTR registry. Pts were treated in the United States, Canada, Korea, or Taiwan. Results: As of May 4, 2023, 974 pts received tisagenlecleucel. Primary disease history has evolved since 2017. Notably, disease burden prior to infusion has decreased (≥50% blasts: 18% in 2018, 4% in 2022) and a higher proportion of pts received tisagenlecleucel while in morphological complete remission (34% in 2018, 51% in 2022). Between 2018 and 2022, the proportion of pts who were in third or greater relapse decreased (14% vs 2%, respectively). Pts ≥18 y had more prior exposure to blinatumomab and inotuzumab compared with pts < 18 y: 27% vs 16% and 17% vs 7%, respectively. The proportion of pts undergoing ≥1 hematopoietic stem cell transplantation (HSCT) before tisagenlecleucel infusion decreased (37% in 2018, 15% in 2022), coinciding with the use of tisagenlecleucel in earlier lines of therapy. Reporting of B-cell recovery was suboptimal. In total, 34.5% (314/911) of pts received postinfusion HSCT (reasons for HSCT were not captured for most pts); 8.5% (77/911) of pts received postinfusion HSCT to treat relapse, persistent/progressive disease, or positive minimal residual disease. Although the overall rate of postinfusion HSCT did not change, pts with high-risk cytogenetics showed a decrease in HSCT frequency. Previously, most pts < 3 y with KMT2A rearrangement received a HSCT. Since 2017, only 16% (12/75) of pts < 3 y received a prior HSCT despite 72% (54/75) having a KMT2A rearrangement. Furthermore, of the pts with rearrangement, only 43% (23/53) received a HSCT postinfusion. With censoring for HSCT, median RFS improved: 18 mo in 2018, 27 mo in 2020, and not estimable in 2021. OS was not substantially affected by HSCT censoring; 36-mo probabilities (95% CI) with and without censoring were 66 (61-71) and 62 (57-66), respectively. Conclusions: Pediatric and young adult pts with r/r B-ALL are receiving tisagenlecleucel earlier in the course of their disease treatment, reducing the use of HSCT for r/r disease, and prolonging RFS. As both real-world and clinical trial data supporting the curative potential of tisagenlecleucel grow, the use of HSCT in pts with remission after CAR-T should be carefully evaluated.