Three decades of allogeneic transplantation showing improved survival, persistent relapse and post‑relapse outcomes of donor lymphocyte infusion versus second transplant

Abstract Background: Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative therapy for high-risk hematologic malignancies. Over the last three decades, transplant numbers have increased due to expanded age eligibility, the availability of alternative donors, adoption of reduced-intensity conditioning (RIC), and improved supportive care. Despite these advances, relapse remains the major barrier to cure, and post-relapse survival is poor. Salvage strategies include donor lymphocyte infusion (DLI) or a second allo-HCT (allo-HCT2), yet no randomized trial has compared these approaches. We evaluated temporal trends in allo-HCT outcomes and survival following relapse in a State-wide cohort. Methods: We retrospectively analyzed 864 consecutive allo-HCTs performed in South Australia from 1990 to 2023. Outcomes included overall survival (OS), non-relapse mortality, and relapse, assessed using Kaplan–Meier, competing risk, and multivariable Cox regression. Post-relapse outcomes were compared for patients receiving DLI versus allo-HCT2. Results: Allo-HCT practices evolved substantially over 35 years. Median patient age increased from 41 to 54 years, with patients ≥60 years rising from <15% to 41% of transplants in the most recent decade. Alternative donor use increased to >25%, and RIC was used in >70% of recent transplants. Three-year OS improved significantly from 40.5% (1990–1999) to 58.0% (2020–2023; P=0.0005), primarily due to a marked reduction in non-relapse mortality from 55.3% to 24.6% (P<0.0001). This was validated on a multivariable analysis, transplantation in the most recent decade independently predicted superior OS (HR 0.50, P<0.01). In contrast, relapse risk remained ~30% since the early 2000s, highlighting it as the key barrier to cure. Among 96 patients relapsing after first allo-HCT, 40 received DLI, 43 underwent second allo-HCT2, and 13 received DLI and allo-HCT2. Median OS was 15.5 months with DLI versus 8.6 months with allo-HCT2 (P=0.59). By disease subtype, OS was similarly poor for AML, MDS, and lymphoid malignancies regardless of salvage strategy. In contrast, myeloproliferative neoplasm (MPN) patients experienced longer OS with DLI compared to allo-HCT2 (167.5 vs 7.6 months; P=0.10), although not statistically significant probably due to small number of patients. High donor CD13+ chimerism (>90%) prior to DLI predicted superior survival, whereas no such association was seen with allo-HCT2. Conclusion: Allo-HCT survival has improved significantly over 35 years, largely due to reduced non-relapse mortality, despite increasing patient age and complexity. Relapse remains the principal limitation, and post-relapse outcomes are poor. DLI may offer selective benefit in MPN and in myeloid patients with high donor chimerism, supporting its evaluation and incorporation into risk-adapted post-relapse algorithms.