Clinical Effects of Driver Somatic Mutations on the Outcomes of Patients With Myelodysplastic Syndromes Treated With Allogeneic Hematopoietic Stem-Cell Transplantation

Abstract

Purpose: The genetic basis of myelodysplastic syndromes (MDS) is heterogeneous, and various combinations of somatic mutations are associated with different clinical phenotypes and outcomes. Whether the genetic basis of MDS influences the outcome of allogeneic hematopoietic stem-cell transplantation (HSCT) is unclear.

Patients and methods: We studied 401 patients with MDS or acute myeloid leukemia (AML) evolving from MDS (MDS/AML). We used massively parallel sequencing to examine tumor samples collected before HSCT for somatic mutations in 34 recurrently mutated genes in myeloid neoplasms. We then analyzed the impact of mutations on the outcome of HSCT.

Results: Overall, 87% of patients carried one or more oncogenic mutations. Somatic mutations of ASXL1, RUNX1, and TP53 were independent predictors of relapse and overall survival after HSCT in both patients with MDS and patients with MDS/AML (P values ranging from .003 to .035). In patients with MDS/AML, gene ontology (ie, secondary-type AML carrying mutations in genes of RNA splicing machinery, TP53-mutated AML, or de novo AML) was an independent predictor of posttransplantation outcome (P = .013). The impact of ASXL1, RUNX1, and TP53 mutations on posttransplantation survival was independent of the revised International Prognostic Scoring System (IPSS-R). Combining somatic mutations and IPSS-R risk improved the ability to stratify patients by capturing more prognostic information at an individual level. Accounting for various combinations of IPSS-R risk and somatic mutations, the 5-year probability of survival after HSCT ranged from 0% to 73%.

Conclusion: Somatic mutation in ASXL1, RUNX1, or TP53 is independently associated with unfavorable outcomes and shorter survival after allogeneic HSCT for patients with MDS and MDS/AML. Accounting for these genetic lesions may improve the prognostication precision in clinical practice and in designing clinical trials.

Fig 1.

Mutation patterns observed in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia evolving from MDS, who were treated with allogeneic hematopoietic stem-cell transplantation. (A) Whole patient population (N = 401); (B) patients with MDS diagnosed according to WHO criteria (n = 274); and (C) patients with acute myeloid leukemia evolving from MDS (n = 127). The plot represents a graphical summary of the distribution of somatic lesions in sequenced genes across the set of patients, grouped in categories as labeled in the legend. Columns represent samples and rows represent genes. Mutations are depicted by colored glyphs whose colors are used to distinguish different pathways, and their number per sample and per gene is summarized on the top and on the right side of the plot, respectively. In panel C, colors reflect ontogeny specificity of mutated genes, and genetic ontogeny groups are labeled on the top.

Fig 1.

Mutation patterns observed in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia evolving from MDS, who were treated with allogeneic hematopoietic stem-cell transplantation. (A) Whole patient population (N = 401); (B) patients with MDS diagnosed according to WHO criteria (n = 274); and (C) patients with acute myeloid leukemia evolving from MDS (n = 127). The plot represents a graphical summary of the distribution of somatic lesions in sequenced genes across the set of patients, grouped in categories as labeled in the legend. Columns represent samples and rows represent genes. Mutations are depicted by colored glyphs whose colors are used to distinguish different pathways, and their number per sample and per gene is summarized on the top and on the right side of the plot, respectively. In panel C, colors reflect ontogeny specificity of mutated genes, and genetic ontogeny groups are labeled on the top.

Fig 2.

Relationship between (A) number of mutations and (B) type of oncogenic mutations and overall survival of patients with myelodysplastic syndromes (MDS) receiving allogeneic hematopoietic stem-cell transplantation. (C) Posttransplantation overall survival among patients with acute myeloid leukemia (AML) evolving from MDS according to genetic ontogeny group. NS = not significant.

Fig 2.

Relationship between (A) number of mutations and (B) type of oncogenic mutations and overall survival of patients with myelodysplastic syndromes (MDS) receiving allogeneic hematopoietic stem-cell transplantation. (C) Posttransplantation overall survival among patients with acute myeloid leukemia (AML) evolving from MDS according to genetic ontogeny group. NS = not significant.

Fig 3.

Posttransplantation overall survival of patients with myelodysplastic syndromes classified by the revised International Prognostic Scoring System (IPSS-R) and stratified according to the presence of mutations in the ASXL1, RUNX1, and TP53 genes.