Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for secondary acute myeloid leukemia (sAML). Post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has improved outcomes. For patients (pts) without an HLA-matched donor, haploidentical (HaploSCT) and mismatched unrelated donor (MMUD) HSCT are viable alternatives. However, whether HaploSCT or MMUD offers superior outcomes in sAML remains unclear.

Methods:We retrospectively compared HaploSCT and MMUD (9/10 HLA match) HSCT in pts with sAML in first complete remission (CR1) between 2010 and 2022. Outcomes were assessed using a multivariate Cox regression model.

Results: A total of 711 pts were included: 602 underwent HaploSCT, 109 received MMUD. Median follow-up was 2.6 years (interquartile range [IQR], 2.3-2.9). HaploSCTs were more recent (median year 2019 vs 2019, IQR, 2017-2021 vs. 2014-2022, p=0.012). The median age was similar between the HaploSCT and MMUD groups (60.6 vs. 60.3 years, p = 0.77), as were other baseline characteristics, including sex, cytogenetic risk, Karnofsky performance status (KPS), cytomegalovirus serostatus, and female donor to male recipient combination. The antecedent hematological disease was myelodysplastic or myeloproliferative disorder in 81.8% of Haplo SCT pts vs. 93.6% of MMUD pts. Median time from diagnosis to transplant was 5.4 months for HaploSCT vs. 5.5 months for MMUD (p=0.7). Bone marrow (BM) grafts (22.9% vs. 3.7%, p<0.001) and myeloablative conditioning (53.2% vs. 39.4%, p=0.008) were more common in HaploSCT, Thiotepa/busulfan (Bu)/fludarabine (Flu) was most used in HaploSCT (46.5%), while Bu/Flu in the MMUD group (31.2%). PTCy with cyclosporine A /mycophenolate mofetil (MMF) was used in 55.8% vs. 52.3%, respectively.

Cumulative incidence of absolute neutrophil count >0.5 x 109/L at day 30 was 86.9% (95%CI 83.9% - 89.4%) for HaploSCT and 91.8% (95%CI 84% - 95.9%) for MMUD, with neutrophil recovery significantly faster in the MMUD group (hazard ratio (HR)=1.43 (1.09-1.86), p=0.009). Platelet recovery >20 x 109/L at day 60 was 79.9% (95%CI 76.2% - 83.1%) in the HaploSCT group and 87.5% (95%CI 78.8% - 92.8%) in the MUUD group, with no significant difference between groups. At day 180 acute (a) GVHD grade II-IV occurred in 27.2% of HaploSCT and 28.9% of MMUD patients (HR=0.91, 95%CI 0.6-1.39, p=0.66), while grade III-IV occurred in 9.8% and 12.4%, respectively (HR=1.26, 95%CI 0.64-2.46, p=0.51), with no significant difference between groups. The 2-year (y) cumulative incidence of total chronic (c) GVHD was 30.5% for HaploSCT and 27.2 % for MMUD (HR = 0.67 (95%CI 0.41-1.11, p=0.12), and extensivecGVHD was 10.1% vs.14.1%, respectively (HR = 1.04, 95%CI 0.5-2.15, p=0.92), with no significant difference between groups. Incidence of aGVHD grade II-IV was lower with reduced-intensity conditioning HR = 0.61 (95%CI 0.43-0.86, p=0.004), while incidence of total cGVHD was higher with PB grafts (HR = 1.88, 95%CI 1.15-3.08, p=0.01), and adverse-risk genetics (HR = 1.49, 95%CI 1.03-2.14, p=0.03) and lower with increasing year of transplantation(per 5y, HR = 0.68, 95%CI 0.47-0.99, p=0.04). The 2-y non-relapse mortality (NRM) was similar between HaploSCT compared to MMUD, being 25.7% vs.16.6%, HR=0.61 (95%CI 0.35-1.07, p=0.09). The leukemia was the main cause of death in 39.7% and 51.4% of those who died, respectively. Relapse incidence (RI) at 2-y was comparable as well, 21.9% vs.26.7% (HR = 1.22, 95%CI 0.76-1.94, p=0.41). The 2-y overall survival (OS), leukemia-free survival (LFS), and GVHD-free/relapse-free survival (GRFS) did not differ significantly between HaploSCT and MMUD 58.7% vs.64.1% HR = 0.81 (95%CI 0.55-1.18, p=0.27), 52.4% vs.56.9% HR = 0.86 (95%CI 0.6-1.22, p=0.39), and 41.3% vs.44.4% HR = 0.95 (95%CI 0.69-1.31, p=0.76), respectively. Lower KPS was a poor prognostic factor for NRM, OS, LFS, and GRFS, and higher age (per 10y) was a poor prognostic factor for OS and GRFS. Adverse-risk cytogenetics was a poor prognostic factor for RI, LFS, OS, GRFS.

Conclusions: In this large retrospective study comparing HaploSCT and MMUD HSCT with PTCy-based GVHD prophylaxis in sAML at CR1, outcomes were comparable between the two groups, except for faster neutrophil recovery with MMUD. Results appear improved compared to historical data, likely due to PTCy. In the absence of an HLA-matched donor, both HaploHSCT and MMUD are potential alternatives.

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2025
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