Introduction: NUP98::NSD1, a frequent aberration in acute myeloid leukemia (AML) with NUP98 rearrangements, is characterized by poor remission rates and adverse prognosis. Critically, its co-expression with FLT3-ITD synergistically worsens survival outcomes. Allogeneic stem cell transplantation (allo-HSCT) could overcome this adverse molecular profile. We aimed to refine the transplant timing and strategy to optimize post-HSCT survival.

Methods: This retrospective study consecutively enrolled NUP98::NSD1 AML patients co-expressed FLT3-ITD undergoing allo-HSCT at the Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences between 2020 and 2025. Categorical variables were analyzed by Fisher's exact test, and continuous variables by Mann-Whitney U test. Overall survival (OS) and event-free survival (EFS) were calculated according to Kaplan-Meier. Institutional Review Board (IRB) approval was obtained in accordance with the Declaration of Helsinki.

Results: A total of 14 AML patients (median age 34, range 15-50) with co-expressed NUP98::NSD1 and FLT3-ITD mutations were consecutively registered and enrolled. Half of the patients (50%) had hyperleukocytosis at diagnosis. Twelve patients (85.7%) obtained additional co-mutations, including WT1 (35.7%), CEBPA (21.4%), CCND3 (14.2%), BCOR (7.1%), NRAS (7.1%), IDH2 (7.1%), and PAX5 (7.1%). Patients demonstrated marked poor responses to chemotherapy. Only 35.7% patients achieved hematologic complete remission (CR) after induction chemotherapy, CR rates 25% (2/8) using standard “7+3” intensive chemotherapy, 75% (3/4) in Venetoclax-involved and 66.7% (2/3) in Gilteritinib-involved regimens, respectively. Almost half (6/14, 42.8%) were defined as refractory/relapse AML. At transplantation, only 7 patients (50%) achieved CR, with 35.7% (5/14) attaining flow cytometry confirmed MRD negativity.

Patients were stratified by duration from diagnosis to transplantation into two cohorts: early-HSCT group (≤100d, n=6) and late-HSCT group (>100d, n=8). Baseline disease characteristics were balanced between the two cohorts. Prior to transplantation, early-HSCT group underwent a median of 2 cycles (range: 1-2) of chemotherapy and late-HSCT group underwent a median of 4 cycles (range: 3-6). All patients received myeloablative conditioning (MAC) regimen. Haploidentical transplantation was the predominant type in both cohorts (100% vs 75%). No graft failure was reported.

With a median follow-up of 491 days (range: 68-1488), a total of 10 patients survived. In the late-HSCT cohort, two patients relapsed and three died of treatment-related complications in late HSCT cohort, whereas only one GVHD-related death occurred in the early-HSCT group. Notably, early-HSCT demonstrated lower incidences in post-HSCT infectious complications: bacterial/fungal infection (33.3% vs 62.5%), CMV viremia (16.7% vs 37.5%). The difference in rate of grade II-IV aGVHD (50% vs 25%) was not significant. Although with no statistical significance, the early-HSCT cohort showed improved survival in 1-year OS (83.3% vs 62.5%), 1-year EFS (83.3% vs 50%), with lower non-relapsed mortality (NRM) (16.7% vs 25.0%) and a trend toward reduced relapse incidence (0% vs 25.0%).Conclusions: This exploratory study suggests that early allo-HSCT may offer survival advantages in AML patients with co-occurring NUP98::NSD1 and FLT3-ITD mutations, who exhibited poor response to chemotherapy, by avoiding toxicities from multiple cycles of intensive chemotherapy prior to transplantation. Large-scale prospective studies are required to define the optimal transplantation timing.

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2025
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