Improved outcomes following allogeneic hematopoietic stem cell transplantation in patients with DDX41-mutated myeloid neoplasms: A prospective analysis of survival, GVHD, and transplant-related mortality

Abstract Introduction: Germline mutations in DDX41 represent a unique subgroup of hereditary myeloid neoplasms, most commonly acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS). Unlike other inherited mutations, DDX41-mutated cases typically present later in life and are characterised by hypocellular bone marrow and increased sensitivity to hypomethylating agents. The optimal management strategy, including the role and expected outcomes, higher transplant-related mortality (TRM) of allogeneic hematopoietic stem cell transplantation (HCT), remains incompletely defined due to limited real-world prospective data. To address these gaps, we evaluated the clinical characteristics and transplant outcomes in adult patients with DDX41-mutated myeloid neoplasms undergoing allogeneic HCT, with an emphasis on survival metrics and transplant-related complications. Methods: We prospectively evaluated 26 adult patients with confirmed DDX41-mutated myeloid neoplasms who underwent allogeneic HCT between 2015 and 2025. Data were collected from electronic patient records. Outcomes analysed comprised rates of acute and chronic graft-versus-host disease (GVHD) and survival endpoints. Overall survival (OS) and relapse-free survival (RFS) at 1 year were estimated using the Kaplan-Meier method. Descriptive statistics summarised patient and transplant variables. Results: The cohort was predominantly male (73%, n=19), with a median age at HSCT of 63.1 years (range 51–71.6). Underlying diagnoses included AML (50%, n=13), MDS (42.3%, n=11), Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN, 3.85%, n=1), and hypoplastic MDS (3.85%, n=1). All except three patients had a normal karyotype. Germline DDX41 variants were confirmed on skin fibroblasts in 57.7% (n=15). Somatic TP53 mutations were present in 19.2%(n=5) patients. The median interval between diagnosis and transplant was 10.3 months ( 5.3–58.5). In keeping with the advanced age and comorbidities in this cohort, reduced-intensity conditioning regimens with fludarabine, busulphan and Alemtuzumab (57.8%) were predominantly used. Most patients received HCT from matched unrelated donors (MUD, 88.5%), with the remainder from matched related donors (MRD, 7.7%, negative for germline DDX41) and cord blood (3.8%). Most donors were fully HLA matched with the recipients. (10/10 in 86.9%, 9/10 in 8.7%, and haploidentical (cord) in 4.4%). Peripheral blood stem cells (PBSC) constituted the primary graft source (95.7%). Acute GVHD occurred in 31.8% of evaluable patients (7/22), primarily stage 2 (57.1%), with stage 1 (28.6%) and stage 3 (14.3%) cases also observed. Chronic GVHD developed in 27.3% (6/22) of evaluable patients, with severe grades reported in 3 (13.6%). All patients engrafted with no primary graft failures. Nine patients (n=9, 34%) suffered relapse after HSCT at a median time of 24 months (range 5-58). Median follow-up time was 20 months (range 1-208) One-year and 3-year OS was 86.6% and 72.1%, and 1-year and 3-year RFS was 66.6% and 44.4%, with transplant-related mortality and relapse rates comparable to those reported in other high-risk molecular subgroups. Conclusions: Allogeneic HSCT in patients with DDX41-mutated myeloid neoplasms yielded favourable one-year overall and relapse-free survival rates, despite the cohort's older age and mixed disease spectrum. The predominance of reduced-intensity conditioning facilitated transplantation in this higher-risk group without excess early toxicity or graft failure. Rates of acute and chronic GVHD were manageable and consistent with patients with wild-type DDX41. These results support the safety and efficacy of HSCT as a curative modality for DDX41-mutated myeloid neoplasms. Comparison with non-HSCT-treated cohorts and prospective, multi-institutional studies with longer-term follow-up is needed to elucidate the impact of specific conditioning regimens, donor selection strategies, and post-transplant interventions in this unique genomic subgroup.