Abstract
Background: Shwachman Diamond syndrome (SDS) is characterized by bone marrow failure (BMF) and an increased risk of myeloid and lymphoid malignancies. Prognosis of myelodysplasia (MDS) or acute myeloid leukemia (AML) is poor, so regular surveillance is recommended to screen for early signs of clonal evolution. However, decisions regarding early transplant timing remain especially challenging due to the paucity of data regarding cumulative risks of hematologic complications with age, and reliance on published literature of outcomes utilizing outdated criteria for myeloid malignancy diagnosis. These barriers to clinical decision-making are especially difficult for rare leukemia predisposition conditions such as SDS.
Objective: The goals of this study were to determine the cumulative risks with age and overall survival for: 1. myeloid malignancy, and 2. hematopoietic stem cell transplant (HSCT) for non-malignant indications.
Methods: To study this rare disease, a collaborative retrospective study was developed collating data extracted from medical records and international registries for 865 patients with SBDS-associated SDS from 13 different counties and national/international registries. Third party honest broker review was conducted to identify potential overlap between patient cohorts. Severe BMF was defined as requiring transplant for BMF. For 91% of patients with MDS/AML, sufficient data were available for central review applying diagnostic criteria from the updated WHO and ICC classifications, while the local diagnosis was utilized for the remaining 9%. Competing risks were integrated into all cumulative risk analyses.
Patient Characteristics: The median age at diagnosis of SDS was 2 years with a range of 0-69 years. Nine patients were diagnosed with SDS between age 40-69 years, of whom 7 initially presented with myeloid malignancy prior to SDS diagnosis. Median age at last follow up was 14.3 years with a span of 0-70 years of age. The median age at MDS and AML was 16 years (range 0-69) and 26 years (range 0.4-57), respectively. The median age at HSCT for severe BMF was 5.7 years. The median year of diagnosis for MDS/AML was 2017, with 96% diagnosed between 2000-2024. The median year of transplant unrelated to MDS/AML was 2019, with 96.3% transplanted between 2000-2024.
Results: Of 865 patients, 71 developed MDS, 42 developed AML (without prior MDS), and 69 were transplanted for severe BMF. The age-associated cumulative incidence (95% CI) of myeloid malignancy (MDS or AML) was 2.0% (1.2-3.1%) at 5 years , 5.2% (3.7- 7.0%) at 10 years, 15.1% (11.8-18.9%) at 25 years, and 49.7% (40.0-58.6%) at 50 years of age. Median survival time from diagnosis of malignancy with central review was 3.2 years for MDS and 1 year for AML. No association between SBDS germline mutation and MDS/AML risk was identified. The cumulative risk of HSCT for BMF with age was 4.2% (2.9-5.7%) at 5 years, 6.0% (4.5-7.9%) at 10 years, 10.0% (7.7-12.6%) at 25 years, and 14.8% (10.2-20.2%) at 50 years of age. Additional indications for HSCT included high risk features of clonal evolution (n=24), ALL (n=1), Refractory Cytopenia of Childhood (n=1), infections (n=1), and unspecified (n=5). Seven received HSCT for del20q, i7q, or trisomy 8. Five year survival post-HSCT was 87.8% (79.6-96.8%) for severe BMF, 81.8% (67.1-99.9%) for high risk features, 47.8% (34.0-67.3%) for MDS, 28.9% (14.0-59.6%) for AML, and 85.6% (68.8-100.0%) for other indications. Overall survival was 86.2% (82.6-89.9%) by age 25 and 27.3% (16.1-46.2%) by age 50. In summary, the cumulative incidence of myeloid malignancy, severe BMF, or HSCT by age 50 years was 77.7% (95% CI: 67.3-85.1%), with death from other causes as a competing risk.
Conclusion: SBDS-associated SDS carries a high cumulative risk of severe hematologic complications, with 78% of patients developing myeloid malignancy or requiring HSCT by age 50. In the context of recent advances in reduced toxicity HSCT regimens, this high lifetime risk of hematologic complications in SDS guides considerations of HSCT at younger ages when transplant outcomes are superior, and informs changes in transplant practice.
