Outcomes of myeloablative vs reduced and non-myeloablative conditioning in MRD-negative AML and ALL with ptcy-based GVHD prophylaxis

Abstract Introduction: The optimal conditioning intensity for patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) who achieve minimal residual disease (MRD)-negative remission at the time of allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains uncertain. Myeloablative conditioning (MAC) is associated with increased toxicity and transplant-related mortality (TRM), while reduced intensity conditioning (RIC) and non-myeloablative (NMA) regimens may offer reduced toxicity. However, whether these regimens offer comparable outcomes in MRD-negative patients remains uncertain. In the current post-transplant cyclophosphamide (PTCY) era, outcomes may differ given the widespread use of PTCY-based graft-versus-host disease (GVHD) prophylaxis. Methods: We conducted a single-center retrospective study of adult patients (≥18 years) with AML or ALL who underwent allo-HSCT at Thomas Jefferson University between 2018 and 2025. All patients were in first or second complete remission (CR1 or CR2) and MRD-negative by multi-parametric flow cytometry and/or quantitative PCR (qPCR) with a sensitivity of at least 0.01%, based on bone marrow biopsies performed within 30 days prior to admission. Conditioning regimens were stratified by intensity into MAC, RIC, and NMA subgroups. MAC regimens consisted of total body irradiation (TBI) 12 Gray (Gy) over 4 days. Reduced intensity conditioning included fludarabine 30mg/m2 for 4 consecutive days plus 8 Gy TBI, or fludarabine plus either melphalan or busulfan, with 2 Gy TBI. Non-myeloablative regimen consisted of fludarabine 30mg/m2 for 3 consecutive days plus 4 Gy TBI. All patients received PTCY in combination with a calcineurin inhibitor and mycophenolate mofetil as GVHD prophylaxis. The primary endpoint was overall survival (OS). Secondary endpoints included non-relapse mortality (NRM), relapse incidence, and the incidence, severity, and timing of acute and chronic graft-versus-host disease (GVHD). Results: A total of 64 patients were included (38 AML, 26 ALL), all MRD-negative at the time of transplant. 61 (95.3%) patients were in CR1, and 3 (4.7%) patients were in CR2 at the time of transplant. Of the 64 patients, 26 (40.6%) underwent MAC, 18 (28.1%) underwent RIC, and 20 (31.1%) underwent NMA. Among the 64 patients, 6 (9.4%) received a matched related donor, 9 (14.1%) a matched unrelated donor, 12 (18.8%) a mismatched donor, and 37 (57.8%) a haploidentical donor. Baseline characteristics were balanced across conditioning groups, except for older age in the NMA group and a higher proportion of ALL patients receiving MAC. Overall survival was 75.6% at 1 year (95% CI: 65.5–87.2) and 73.8% at 4 years (95% CI: 63.5–85.8), with no difference between AML and ALL (p = 0.93). Progression-free survival was 69.5% at 1 year (95% CI: 59–82) and 65% at 4 years (95% CI: 53.7–78.6). One-year NRM and relapse rates were 14.3% and 16.2%, respectively; at 4 years, they were 14.3% and 20.7%. The cumulative incidence (CI) of grade 2–4 acute GVHD was 22% at 100 days and 33% at 6 months; CI of moderate-to-severe chronic GVHD was 15% at 1 year and 19% at 3 years. At 3 years, OS was higher in the MAC and NMA groups compared to RIC, with a trend toward statistical significance (MAC: 85%, NMA: 79%, RIC: 50%; p = 0.056). When directly comparing MAC and NMA (n = 46; MAC: 26, NMA: 20), OS was similar (85% vs 79%, p = 0.6), with comparable NRM (4% vs 10%, p = 0.42) and relapse rates (16% vs 32%, p = 0.16). No significant differences were observed in acute GVHD at 100 days (24% vs 26%, p = 0.31) or chronic GVHD (18% vs 13%, p = 0.74). Conclusion: In MRD-negative AML and ALL patients undergoing allo-HSCT with PTCY-based GVHD prophylaxis, NMA regimens appear to offer comparable survival and GVHD outcomes to MAC, with potentially lower toxicity. These findings suggest NMA conditioning may be a viable and safer alternative to MAC in select MRD-negative patients in the PTCY era.