Outcomes After Nonresponse and Relapse Post-Tisagenlecleucel in Children, Adolescents, and Young Adults With B-Cell Acute Lymphoblastic Leukemia

Abstract

Purpose: Nonresponse and relapse after CD19-chimeric antigen receptor (CAR) T-cell therapy continue to challenge survival outcomes. Phase II landmark data from the ELIANA trial demonstrated nonresponse and relapse rates of 14.5% and 28%, respectively, whereas use in the real-world setting showed nonresponse and relapse rates of 15% and 37%. Outcome analyses describing fate after post-CAR nonresponse and relapse remain limited. Here, we aim to establish survival outcomes after nonresponse and both CD19+ and CD19- relapses and explore treatment variables associated with inferior survival.

Methods: We conducted a retrospective multi-institutional study of 80 children and young adults with B-cell acute lymphoblastic leukemia experiencing nonresponse (n = 23) or relapse (n = 57) after tisagenlecleucel. We analyze associations between baseline characteristics and these outcomes and establish survival rates and salvage approaches.

Results: The overall survival (OS) at 12 months was 19% across nonresponders (n = 23; 95% CI, 7 to 50). Ninety-five percent of patients with nonresponse had high preinfusion disease burden. Among 156 morphologic responders, the cumulative incidence of relapse was 37% (95% CI, 30 to 47) at 12 months (CD19+; 21% [15 to 29], CD19-; 16% [11 to 24], median follow-up; 380 days). Across 57 patients experiencing relapse, the OS was 52% (95% CI, 38 to 71) at 12 months after time of relapse. Notably, CD19- relapse was associated with significantly decreased OS as compared with patients who relapsed with conserved CD19 expression (CD19- 12-month OS; 30% [14 to 66], CD19+ 12-month OS; 68% [49 to 92], P = .0068). Inotuzumab, CAR reinfusion, and chemotherapy were used as postrelapse salvage therapy with greatest frequency, yet high variability in treatment sequencing and responses limits efficacy analysis across salvage approaches.

Conclusion: We describe poor survival across patients experiencing nonresponse to tisagenlecleucel. In the post-tisagenlecleucel relapse setting, patients can be salvaged; however, CD19- relapse is distinctly associated with decreased survival outcomes.

FIG 1.

(A) Cumulative incidence of relapse and OS after relapse in (B) the overall cohort and (C) patients with CD19+ and CD19– relapse. OS, overall survival.

FIG 2.

Interventions and outcomes across individual patients after relapse post-CAR T-cell therapy (swimmer's plot). CAR, chimeric antigen receptor.

FIG 3.

One hundred eighty–day landmark overall survival analysis post-tisagenlecleucel.

FIG A1.

OS after relapse by time from infusion to relapse. OS, overall survival.

FIG A2.

Salvage therapies and responses in the post-tisagenlecleucel relapse setting. CAR, chimeric antigen receptor; HSCT, hematopoietic stem cell transplantation; MRD, minimal residual disease; RT, radiotherapy; TKI, tyrosine kinase inhibitor.

FIG A3.

OS across patients who received secondary salvage CAR infusion after tisagenlecleucel nonresponse or relapse. Time 0 is the day of the second CAR infusion. CAR, chimeric antigen receptor; OS, overall survival.