TP53, TET2, and DNMT3A Mutations Predict Poorer Survival After Hematopoietic Stem Cell Transplant in Patients With Myelodysplastic Syndrome
It is unclear whether somatic mutations that are strongly associated with phenotype and prognosis in myelodysplastic syndrome are also predictive of outcome after allogeneic hematopoietic stem cell transplantation. In a study reported in the Journal of Clinical Oncology, Bejar et al found that TP53, TET2, and DNMT3A mutations predict poorer survival after hematopoietic stem cell transplantation.
Mutations
In the study, massively parallel sequencing was used to examine tumor samples from 87 patients myelodysplastic syndrome before hematopoietic stem cell transplantation for coding mutations in 40 recurrently mutated myelodysplastic syndrome genes. Mutations were identified in 92% of patients, most frequently in ASXL1 (29%), TP53 (21%), DNMT3A (18%), and RUNX1 (16%). In univariate analyses, only TP53 mutations were associated with significantly reduced overall survival (hazard ratio [HR] = 3.74, P < .001) and progression-free survival (HR = 3.97, P < .001). No mutations were associated with longer progression-free survival or overall survival.
Adjusted Analyses
In analysis adjusting for blast percentage, conditioning regimen, complex karyotype, and donor type, mutations in TP53 (HR = 2.30, P = .027), TET2 (HR = 2.40, P = .033), and DNMT3A (HR = 2.08, P = .049) were associated with significantly decreased overall survival. In a multivariate model obtained from backward-elimination selection algorithm candidates that included variables with P < .20 on univariate 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 independently associated with reduced overall survival.
In a landmark analysis including 72 patients who survived until day 100, TP53 (HR = 3.78, P < .001) and DNMT3A mutations (HR = 2.62, P = .022) were predictive of poorer survival, along with complex karyotype.
Overall, 46% of patients had mutations in TP53, DNMT3A, or TET2 and these patients accounted for 64% of deaths. Three-year overall survival was 59% (95% confidence interval [CI] = 43%–72%) in patients without these mutations vs 19% (95% CI = 9%–33%) in patients with these mutations.
The investigators concluded, “Mutations in TP53, TET2, or DNMT3A identify patients with [myelodysplastic syndrome] with shorter [overall survival] after [hematopoietic stem cell transplantation].”
Benjamin L. Ebert, MD, PhD, of Brigham and Women’s Hospital, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by grants or awards from the National Institute of Diabetes and Digestive and Kidney Diseases, American Society of Hematology, National Heart, Lung, and Blood Institute, Leukemia and Lymphoma Society, and Yellow Diamond Foundation Fund. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
