Tisagenlecleucel vs. historical standard of care in children and young adult patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia

Abstract

In the absence of randomized controlled trials comparing tisagenlecleucel vs. standard of care (SOC) in pediatric and young adult patients with relapsed or refractory acute lymphoblastic leukemia (r/r ALL), the objective was to compare the efficacy of tisagenlecleucel with historical controls from multiple disease registries using patient-level adjustment of the historical controls. The analysis is based on patient-level data of three tisagenlecleucel studies (ELIANA, ENSIGN and CCTL019B2001X) vs. three registries in Germany/Austria. Statistical analyses were fully pre-specified and propensity score weighting of the historical controls by fine stratification weights was used to adjust for relevant confounders identified by systematic literature review. Results showed high comparability of cohorts after adjustment with absolute SMD ≤ 0.1 for all pre-specified confounders and favorable outcomes for tisagenlecleucel compared to SOC for all examined endpoints. Hazard ratios for OS_{(Intention to treat)ITT,adjusted}, EFS_{(Full analysis set)FAS,naïve} and RFS_FAS,naïve were 0.54 (95% CI: 0.41-0.71, p < 0.001), 0.67 (0.52-0.86, p = 0.001) and 0.77 (0.51-1.18, p = 0.233). The OS_{ITT, adjusted}, EFS_FAS,naïve and RFS_FAS,naive survival probability at 2 years was 59.49% for tisagenlecleucel vs. 36.16% for SOC population, 42.31% vs. 30.23% and 59.60% vs. 54.57%, respectively. Odds ratio for ORR_ITT,adjusted was 1.99 (1.33-2.97, p < 0.001). Results for OS and ORR were statistically significant after adjustment for confounders and provide evidence supporting a superiority of tisagenlecleucel in r/r ALL given the good comparability of cohorts after adjustment for confounders.

Fig. 1. Comparison of OS for tisagenlecleucel vs. SOC, FAS, Kaplan–Meier plot.

CI Confidence interval, FAS Full analysis set, OS Overall survival, SOC Standard of care.

Fig. 2. Comparison of OS for tisagenlecleucel vs. SOC, ITT, Kaplan–Meier plot.

CI Confidence interval, ITT Intention to treat, OS Overall survival, SOC Standard of care.

Fig. 3. Comparison of EFS and RFS for tisagenlecleucel vs. SOC, FAS, Kaplan–Meier plot.

CI Confidence interval, EFS Event-free survival, FAS Full analysis set, RFS Relapse-free survival, SOC Standard of care.

Fig. 4. Comparison of OS for tisagenlecleucel vs. SOC according to subgroup categories, adjusted comparison, Forest plot, FAS.

CI Confidence interval, HR Hazard ratio, HSCT Hematopoietic stem cell transplantation, MLL Mixed-lineage leukemia, n.a. not available, OS Overall survival. Note: For this subgroup analysis fine stratification weights were applied from main analysis; only subgroups for which patients were available in both arms are presented; p-value calculated by log-rank test; interaction p-value calculated by using likelihood ratio test.

Fig. 5. Comparison of OS for tisagenlecleucel vs. SOC according to subgroup categories, adjusted comparison, Forest plot, ITT.

CI Confidence interval, HR Hazard ratio, HSCT Hematopoietic stem cell transplantation, MLL Mixed-lineage leukemia, n.a. not available, OS Overall survival. Note: For this subgroup analysis fine stratification weights were applied from main analysis; only subgroups for which patients were available in both arms are presented; p-value calculated by log-rank test; interaction p-value calculated by using likelihood ratio test.