Publication Date:
2016-12-02
Description:
Background: Allogeneic hematopoietic stem cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndrome (MDS). However, mortality after HCT for MDS is high, with deaths attributable to both relapsed disease and transplant-related complications. The genetic lesions that drive MDS pathogenesis have the potential to predict the outcome of patients following HCT. Methods: We performed targeted sequencing of 127 genes on pre-HCT blood samples from 1514 patients who received allogeneic HCT for MDS between 2005 and 2014. All MDS patients enrolled in the Center for International Blood and Marrow Transplant Research (CIBMTR) Repository were considered for inclusion. Patients were excluded only if blasts were 〉/= 20% or if they had diagnosis of CMML or MDS/MPN overlap. The median age of patients was 59 years (range 0.4 - 77 years), including 241 (16%) 〈 40 years of age. Donors were 8/8 HLA-matched unrelated donors (n = 862, 57%), HLA-identical siblings (n = 181, 12%), 〈 8/8 HLA-matched unrelated donors (n = 296, 20%), or umbilical cord blood (n = 174, 11%). Results: TP53 mutations were independently associated with poor overall survival (HR 1.71, 95% CI 1.45-2.02, p 〈 0.0001) and a shorter time to relapse (HR 2.34, 1.85-3.00, p 〈 0.0001). In a multivariable model the adverse prognostic significance of TP53 mutations was independent of recipient age, performance status, hematologic status at time of HCT, bone marrow blast count, and karyotype. RAS pathway mutations were independently associated with a shorter time to relapse (HR 1.73, 1.34-2.23, p 〈 0.0001) and JAK2 V617F mutations were associated with higher transplant-related mortality (TRM) (HR 2.13, 1.38-3.27, p = 0.0006). Patients with therapy-related MDS (t-MDS) comprised 21% of the cohort (n = 311) and had significantly worse survival than patients with primary MDS (HR 1.4, 1.2-1.6, p = 0.0002). Only TP53 (OR 3.8, p /= 15%). Patients 〈 40 years old with at least one high-risk feature had 3 year OS of 49.0%, associated with high TRM (p 〈 0.001), while those with no high-risk features had 3 year OS of 81.4%. Conclusions: We found that TP53 mutations are the most important predictor of prognosis in allo-HCT for MDS, independent of other clinical and genetic variables, and that the adverse outcome in TP53 mutated MDS is not influenced by conditioning intensity, donor type, or graft source. TP53 mutations account for the characteristically poor outcomes of clinically distinct subgroups, including t-MDS and genetically-defined SDS. We present a multivariable model that identifies 6 distinct MDS subgroups with differential post-HCT survival and differences in relapse and TRM. Disclosures Lindsley: Takeda Pharmaceuticals: Consultancy; MedImmune: Research Funding. Mar:H3 Biomedicine: Other: Spouse's employment.
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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