Outcomes of Hematopoietic Stem Cell Transplantation for High-Risk Marrow Features without Malignancy in Shwachman-Diamond Syndrome

Introduction: Shwachman-Diamond Syndrome (SDS) is an inherited bone marrow failure syndrome associated with a high risk of myeloid malignancies. Survival is poor once SDS patients develop myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment option for SDS patients with MDS or AML, but outcomes are poor due to refractory or relapsed disease and high treatment-related toxicities. Outcomes of transplant in patients with high-risk features (HRF) in the bone marrow (BM) without malignancy are unknown.

Objective: We aimed to investigate and compare the outcomes of SDS patients transplanted for HRF versus myeloid malignancy and to characterize the clinical features of patients with HRF.

Methods: We conducted a retrospective cohort study of 235 patients with biallelic SBDS mutations consented to the North American SDS Registry (SDSR). Data on patient demographics, clinical features, BM pathology, somatic mutational analysis, and outcomes were extracted from medical records of the SDSR. Heterozygous TP53 mutations are commonly present for years at low variant allele frequency (VAF) <2% in SDS patients without malignancy. Therefore, HRF was defined as a large or growing somatic mutation in TP53 or other known high-risk mutations with a VAF of ≥ 3.0% in at least two consecutive BM exams, progressive BM dysplasia, or high-risk cytogenetic abnormalities. Cumulative incidence of MDS and AML was estimated using the cumulative incidence function (CIF). Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Competing risks included death and prior transplant for other indications.

Results: We studied 235 patients with biallelic SBDS mutations with a median age of 13.9 years (range 0.3,52.8 years) at last follow-up (FU). There were 147 male (63%) and 88 female patients (37%). MDS was diagnosed in 22 patients at a median age of 17.2 years (range 5.4,45.0 years). Cumulative incidence (95% confidence interval (CI)) of MDS at 10, 25, and 50 years was 2.2% (0.7,5%), 12% (7,20%), and 30% (15,46%). Fourteen patients developed AML at a median age of 27.4 years (range 7.3,47.3 years). Cumulative incidence (95% CI) of AML at age 10, 25, and 50 years was 1.2% (0.2,4%), 5.9% (2,12%), and 29.8% (13,50%), respectively. HRF was identified in 21 patients at a median age of 13.2 years (range 1.6,45.4 years). A somatic TP53 mutation was diagnosed in 19 patients, while one patient carried a growing somatic RUNX1 variant, and one patient presented with 5% ring sideroblasts and worsening cytopenias. Overall survival percentage (OS%) (95% CI) after transplant for MDS (n=14) was 64% (44, 95%) at six months, 57% (36,90%) at one year, and 38% (18,79%) at two years. OS% (95% CI) after transplant for AML (n=10) was 89% (71,100%) at six months, 33% (13-84%) at one year, and 33% (13,84%) at two years. In 15 patients transplanted for HRF, OS% (95% CI) after transplant was 93% (80,100%) at six months, 84% (67,100%) at one year, 84% (67,100%) at two years. OS after transplant for MDS and AML was significantly different from OS of patients transplanted for HRF (p=0.05). All 11 patients transplanted for HRF at age ≤ 25 years (median age 12.3 years) were alive one year after HSCT with a median FU of 1.1 years (range 0.06,4.5 years). Data on graft-versus-host-disease (GVHD) was available for 9 of the 11 patients and none of the patients developed grade 3/4 acute GVHD or moderate/severe chronic GVHD. For patients transplanted with HRF above 25 years of age (n=4), 1-year OS% was 50% (19,100%), which was significantly worse than for the patients transplanted at ≤ 25 years (p=0.023). The two deaths were due to transplant-related complications on day 0 of HSCT (n=1, age 42 years) and sepsis 6 months post-transplant (n=1, age 41 years).

Conclusion: Given the poor survival of SDS patients once MDS or AML develops, the SDSR has observed a shift in clinical practice to initiate transplant prior to progression to malignancy. In this study, we observed excellent and superior outcomes in young SDS patients ≤ age 25 years transplanted for HRF compared to patients transplanted for MDS or AML. The benefit of transplant for HRF for older individuals remains unclear. These data may inform shared decision-making between physicians and patients with SDS regarding the appropriate timing of HSCT.