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.

Hypomethylating agents for treatment and prevention of relapse after allogeneic blood stem cell transplantation

“…Besides known risk factors such as remission state or karyotype knowledge about specific somatic mutations will also be incorporated into such stratification algorithms. Potential candidates for this seem to be TP53 mutations, as several analyses indicated a dismal prognosis for MDS patients after allo-SCT [65][66][67][68]. The goal is to identify a patient population with an extraordinary high relapse risk for further studies to test innovative prophylactic strategies after transplant.…”

Immunohistochemical pattern of p53 is a measure of TP53 mutation burden and adverse clinical outcome in myelodysplastic syndromes and secondary acute myeloid leukemia

“…IHC is standardized, results are available faster than with NGS and costs are 30 to 50 times less, suggesting that IHC is a good alternative to facilitate management decisions. Since TP53 mutations are one of the most powerful prognostic factors in MDS, 1,3 it is imperative that clinicians have a quick, reliable surrogate tool to rapidly identify such mutations in settings where NGS is not readily available. Triaging patients via IHC results would potentially decrease health care costs while increasing the usefulness of available diagnostic tools to identify driver mutations.…”

“…TP53 mutations are found in 5-10% of MDS patients, are enriched in patients with isolated del(5q), complex cytogenetics, or MDS with fibrosis (MDS-F), and are associated with an overall worse prognosis. [1][2][3][4][5] Next-generation sequencing (NGS) is a valuable ancillary tool, however, the technology may not be economically feasible for routine community use.…”

Mutation in TET2 or TP53 predicts poor survival in patients with myelodysplastic syndrome receiving hypomethylating treatment or stem cell transplantation

“…We demonstrated that the TET2/TP53 mutation was an independent predictor for inferior survival in patients requiring HMT or SCT. The impact of genetic mutations on survival after SCT for MDS was recently reported by Bejar et al 15 In their multivariate analysis, mutations in TP53 (HR, 4.22; P ⩽ 0.001) and TET2 (HR, 1.68; P = 0.037) were each independently associated with shorter OS. We obtained the same result, and our analyses suggested the need for evaluating the mutational status of at least the TET2 and TP53 genes when considering and designing SCT for MDS.…”