Predictors of survival with and without allogeneic stem cell transplantation after first salvage therapy with blinatumomab and/or inotuzumab ozogamicin for Relapsed/Refractory B-cell acute lymphoblastic leukemia

Abstract Background: B-cell–directed targeted agents, including blinatumomab (blina) and inotuzumab ozogamicin (InO), have improved outcomes in relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, the benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients (pts) who achieve a complete remission (CR) following optimal salvage therapy with these agents remains unclear. Methods: This retrospective analysis aims to evaluate the impact of subsequent allo-HSCT in adult pts with R/R B-ALL who achieved CR with a blina- and/or InO-based regimen as first salvage therapy. Results: A total of 203 pts were treated in first salvage, 172 (85%) of whom achieved CR and were included in this analysis. The median age at R/R disease was 46 years (range, 18-88). 34 pts (20%) had refractory disease, 45 (26%) relapsed 12 months of frontline therapy (early relapse), and 93 (54%) relapsed ≥12 months after frontline therapy (late relapse). 137 pts (80%) had Ph-negative B-ALL, 67% of whom had high-risk cytomolecular features. 15 pts (9%) had received blina and/or InO as part of frontline therapy, and 18 (11%) had undergone allo-HSCT in CR1. 65 pts (38%) received both blina and InO in first salvage; 71 (41%) received InO without blina, and 36 (21%) received blina without InO. Overall, 117 pts (68%) received chemotherapy combined with blina and/or InO. Of 163 tested pts, 104 (64%) achieved MRD negativity by flow cytometry after one cycle of salvage therapy. 80 pts (47%) proceeded to allo-HSCT at a median of 4 months after treatment initiation. 18 pts (10%) received CD19 CAR T-cell as consolidation; 2 subsequently underwent allo-HSCT. With a median follow-up of 56 months, the 4-year RFS and OS for the entire cohort were 38% and 46%, respectively. Independent predictors of worse OS included MRD positivity by flow after one cycle of salvage therapy (HR 2.4, 95% CI: 1.4-4.1, p=0.002), and age (HR 1.01, 95% CI: 1.0-1.03, p=0.03). Conversely, late relapse (HR 0.5, 95% CI: 0.3-0.9, p=0.02) and refractory disease (HR 0.3, 95% CI: 0.1-0.6, p=0.001) were associated with better OS. Similarly, MRD positivity by flow was independent associated with worse RFS (HR 3.0, 95% CI: 1.8-5.1, p0.001), while late relapse (HR 0.5, 95% CI 0.3-0.9, p=0.01) and refractory disease (HR 0.3, 95% CI 0.1-0.5, p=0.004) were associated with better RFS. Neither allo-SCT nor cytomolecular risk were independently associated with OS (p=0.26 and p=0.41, respectively) nor RFS (p=0.30 and p=0.16, respectively) In a landmark analysis restricted to pts aged ≤70 years (n=133), there was a trend towards better outcomes in those who underwent allo-HSCT. Transplanted pts had a 4-year RFS of 50% and OS of 58%, compared with 37% and 43%, respectively, for non-transplanted pts (p=0.10 for RFS; p=0.16 for OS). To assess which pts with R/R B-ALL might benefit from allo-HSCT after first salvage, pts were stratified based on relapse timing and flow MRD status after the first cycle. Among pts with early relapse and/or MRD positivity, allo-HSCT was associated with improved outcomes, with a 4-year RFS of 43% compared with 6% in those who did not undergo allo-HSCT (p=0.01). Similarly, the 4-year OS was 48% vs. 11%, respectively (p=0.007). In contrast, among pts with late relapse or refractory disease who achieved early flow MRD negativity, there was no significant benefit with allo-HSCT. The 4-year RFS was 62% in pts who underwent allo-HSCT vs. 59% in those who did not (p=0.77), and the 4-year OS was 74% vs. 67%, respectively (p=0.84). Among the 18 pts who received CAR T-cell therapy as consolidation (n=18), 4 (22%) had an early relapse and 13/16 evaluable pts (81%) achieved early flow MRD negativity. With a median follow-up of 21 months, the estimated 2-year RFS and OS for these pts were 62% and 59%, respectively.Conclusion: Pts with R/R B-ALL who achieve CR with blina and/or InO-based therapy as first salvage can experience favorable long-term survival, even without allo-HSCT. Those with late relapse or refractory disease who achieve early flow MRD negativity (approximately 50% of our cohort) had a 4-year OS rate of 67% without allo-HSCT. In contrast, pts with early relapse and/or MRD positivity have poor outcomes (4-year OS ~10%) if not bridged to allo-HSCT. Emerging strategies including CAR T-cell consolidation and more sensitive NGS-based MRD may further refine risk stratification and guide post-remission management of these pts.