Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation

Abstract

Purpose: Recurrently mutated genes in myelodysplastic syndrome (MDS) are pathogenic drivers and powerfully associated with clinical phenotype and prognosis. Whether these types of mutations predict outcome after allogeneic hematopoietic stem-cell transplantation (HSCT) in patients with MDS is not known.

Patients and methods: We used massively parallel sequencing to examine tumor samples collected from 87 patients with MDS before HSCT for coding mutations in 40 recurrently mutated MDS genes.

Results: Mutations were identified in 92% of patients, most frequently in the ASXL1 (29%), TP53 (21%), DNMT3A (18%), and RUNX1 (16%) genes. In univariable analyses, only TP53 mutations were associated with shorter overall (OS; hazard ratio [HR], 3.74; P < .001) and progression-free survival (HR, 3.97; P < .001). After adjustment for clinical variables associated with these end points, mutations in TP53 (HR, 2.30; P = .027), TET2 (HR, 2.40; P = .033), and DNMT3A (HR, 2.08; P = .049) were associated with decreased OS. In multivariable analysis including clinical variables, complex karyotype status, and candidate genes, mutations in TP53 (HR, 4.22; P ≤ .001) and TET2 (HR, 1.68; P = .037) were each independently associated with shorter OS. Nearly one half of patients (46%) carried a mutation in TP53, DNMT3A, or TET2 and accounted for 64% of deaths. Three-year OS in patients without these mutations was 59% (95% CI, 43% to 72%), versus 19% (95% CI, 9% to 33%) in patients with these mutations.

Conclusion: Mutations in TP53, TET2, or DNMT3A identify patients with MDS with shorter OS after HSCT.

Fig 1.

Spectrum of mutations in 87 patients in select myelodysplastic syndrome–associated genes. Each column represents an individual patient sample, and each colored cell represents mutation of gene or gene group listed to left of that row. No. of mutations for each row is indicated in column to right. Tyrosine kinase (TK) pathway genes include JAK2, NRAS, CBL, KRAS, PTPN11, BRAF, and CBLB.

Fig 2.

Overall survival (OS) by TP53 and DNMT3A mutation status. OS of patients (A) with and without complex karyotype and (B) with complex karyotype stratified by TP53 mutation status and compared with survival of patients with noncomplex karyotype; (C) OS and mutation distribution showing overlap between patients with TP53, TET2, and DNMT3A mutations. Each column indicates individual patient; colored bars represent mutations of genes in that row.