Superior long-term survival with acceptable safety of ATG/G-CSF–based haplo-HSCT with intensified BU+MEL/TT conditioning in CR Pediatric Non-DS–AMKL

Background Non–Down syndrome acute megakaryoblastic leukemia (non–DS–AMKL) is a rare but high-risk subtype of pediatric AML with dismal outcomes. Allo-HSCT in first complete remission (CR1) is recommended as the preferred strategy for improving survival, yet the benefit of BU/CY intensification with melphalan (MEL) or thiotepa (TT) remains unclear. Methods We retrospectively analyzed 70 pediatric non–DS–AMKL patients undergoing ATG/G-CSF–based haplo-HSCT between March 2010 and February 2024, comparing standard BU/CY (n=25) with intensified BU+MEL/TT (n=45). Endpoints included OS, LFS, RI, NRM, and TRM. Survival was estimated by Kaplan–Meier and compared with the log-rank test, while cumulative incidences were analyzed using Gray’s test. Cox proportional hazards and Fine–Gray competing-risk regression models were applied for univariate and multivariate analyses, as appropriate. Results Baseline clinical characteristics were comparable between groups, whereas graft CD34+ (median, 10.40×10 6 /kg vs 5.85×10 6 /kg) and CD3+ (median, 4.54×10 8 /kg vs 1.89×10 8 /kg) cell doses were significantly higher in the BU+MEL/TT group (both P0.001). Median follow-up was 25 months (range, 13–91.2). Day-100 TRM was similar between groups (6.67% vs 8.00%, P = 0.81), with no significant differences in engraftment, GVHD, viral reactivations. No VOD/SOS or TMA events were observed. Among patients transplanted in CR, the BU+MEL/TT group demonstrated superior 5-year OS (75.2% vs 50.0%, P = 0.045) and LFS (76.3% vs 50.0%, P = 0.039), with numerically lower RI and NRM. In contrast, patients transplanted in NR/PR had poor outcomes in both groups, with 1-year OS and LFS of approximately 20%. In multivariable Cox analyses, intensified conditioning (BU+MEL/TT vs BU) improved OS (HR 0.20, P = 0.047) and LFS (HR 0.29, P = 0.034). Complex cytogenetics (OS: HR 2.38, P = 0.016; LFS: HR 2.58, P = 0.011) and pre-transplant NR/PR status (OS: HR 5.53, P = 0.001; LFS: HR 3.55, P = 0.004) were independent adverse factors. In competing-risk models, conditioning was not associated with RI or NRM, whereas NR/PR status significantly increased relapse (HR 3.39, P = 0.019) and NRM (HR 3.73, P = 0.007). Conclusions In pediatric non–DS–AMKL, intensified conditioning (BU+MEL/TT) independently improved OS and LFS in patients transplanted in CR without increasing early NRM. Pre-transplant NR/PR status was the strongest adverse factor, markedly increasing RI and NRM, underscoring the importance of achieving remission before transplantation.