Sequential conditioning in hematopoietic stem cell transplantation in elderly high-risk myeloid blood cancer patients: long-term survival, disease control, and immune recovery across donor types in a matched-pair analysis.

Background: Sequential conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) regimens might offer improved disease control in high-risk myeloid patients. But concerns remain regarding toxicity, infection risk and delayed immune reconstitution (IR), particularly in older and HLA-haploidentical transplant recipients. To address these concerns, we comprehensively compared safety, feasibility and clinical outcome across HLA-matched related (MRD), matched unrelated (MUD) and haploidentical donor (Haplo) HSCT and longitudinally characterize IR patterns and their associations with post-transplant outcomes. Methods: We conducted a retrospective matched-pair analysis comparing MRD-, matched MUD- and Haplo-HSCT in elderly patients matched for (1) disease activity: p = 1.0; (2) disease status: p = 1.0; (3) modified disease risk index (DRI): p = 0.9; (4) hematopoietic cell transplantation comorbidity index (HCT-CI): p = 0.92; and (5) age: p = 0.95. Outcomes included disease-free (DFS) and overall survival (OS), relapse, non-relapse mortality (NRM), graft-versus-host disease (GvHD), toxicity, infections, and donor-specific IR dynamics and their impact on clinical outcomes. Results: With a median follow-up of more than 9 years, no significant differences were observed in long-term disease control and survival among the three groups (5-y DFS/OS: MRD = 41%/41%, MUD = 56%/63%, Haplo = 58%/58%; p = 0.52/0.55). Cumulative incidences (CI) of 5-y-NRM and 1-y moderate and severe chronic GvHD (cGvHD) rates were comparable among the three groups (NRM/cGvHD: MRD = 19%/13%, MUD = 29%/6%, Haplo = 18%/19%; p = 0.3/0.57). Overall immune cell recovery after one year was comparable among groups, though early recovery of CD3+ T and NK cells was delayed after Haplo-HSCT. Subgroup analysis revealed that higher early CD4+ T and lower B cell counts were associated with increased CI of acute GvHD III-IV° (p = 0.04/0.03). Additionally, NK recovery at one year was associated with improved DFS and OS as well as lower relapse incidence. Conclusions: Sequential therapy is safe and feasible in elderly patients with high-risk or active disease across all three transplant platforms. The observed associations between IR and clinical outcomes highlight the relevance of immune monitoring for anticipating post-transplant complications and guiding individualized prophylactic and therapeutic strategies. Prospective studies are needed to further investigate these findings and define the underlying mechanisms.