SUPERIOR SURVIVAL FOLLOWING HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR HIGH-RISK MARROW FEATURES IN PATIENTS WITH SHWACHMAN-DIAMOND SYNDROME

Background: Shwachman-Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome with a high risk for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).Outcomes following allogeneic hematopoietic stem cell transplantation (HSCT) for SDS-associated MDS/AML are poor.The role of HSCT for bone marrow (BM) high-risk features (HRF) in the absence of overt malignancy remains undefined.Objective: To evaluate outcomes of HSCT for HRF compared to HSCT for MDS/AML in SDS patients.Methods: We retrospectively analyzed 254 patients enrolled in the North American SDS Registry.HRF was defined as the presence of a somatic mutation in TP53 or other high-risk genes with variant allele frequency 3.0% in at least two consecutive BM samples, with or without morphologic abnormalities.Survival was estimated using the Kaplan-Meier method and compared by log-rank testing, accounting for HSCT and death as competing risks.Results: MDS and AML were diagnosed in 21 (median age 18 years) and 14 (median age 28 years) patients, respectively.HRF was identified in 26 patients (median age 13 years), of whom 24 (92%) harbored somatic TP53 mutations.Morphologic abnormalities were present in nine patients (35%).Nineteen patients underwent HSCT for HRF (median age 20 years).The 2-year overall survival (OS, 95% CI) after HSCT was 35.0%(11.8-59.8)for MDS (n=15), 37.5% (8.7-67.4) for AML (n=9), and 87.7% (58.8-96.8)for HRF (n=19; p=0.035).Notably, all 14 patients transplanted for HRF at 25 years were alive at last follow-up, while OS for those >25 years was 60.0% (12.6-88.2).Conclusions: HSCT for HRF in SDS was associated with favorable outcomes, particularly in patients 25 years.These findings support early identification and consideration of HSCT prior to malignant transformation.The benefit of HSCT for HRF in older patients warrants further investigation.