Somatic mutations in myelodysplastic syndrome linked to shorter survival after HSCT
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Patients with myelodysplastic syndrome who harbored TP53, TET2 or DNMT3A mutations demonstrated significantly shorter OS after allogeneic hematopoietic stem-cell transplantation, according to study results.
Rafael Bejar, MD, PhD, assistant professor of medicine at University of California, San Diego, and colleagues evaluated tumor samples from 87 patients (median age, 58 years) before they underwent HSCT. Researchers used massively parallel sequencing to evaluate the samples for 40 genes commonly mutated in myelodysplastic syndrome.
Ninety-two percent of patients harbored at least one mutation, the most frequent of which were ASXL1 (29%), TP53 (21%), DNMT3A (18%) and RUNX1 (16%).
Results of a multivariate analysis indicated mutated TP53 was associated with significantly shorter OS (HR=3.74; 95% CI, 2.08-6.75) and shorter PFS (HR=3.97; 95% CI, 2.22-7.10).
Researchers did not identify any mutations associated with improved OS or PFS.
In an analysis adjusted for presence of complex karyotype, elevated blast proportion ˃5%, donor type and transplant conditioning regimen, TP53 remained significantly associated with shortened OS (HR=2.30; P=.037). TET2 (HR=2.40; P=.033) and DNMT3A (HR=2.08; P=.049) mutations also were linked to shorter survival.
Multivariable analyses indicated TP53 (HR=4.22; P≤.001) and TET2 (HR=1.68; P=.037) mutations each were independently associated with worse survival.
Forty-six percent of patients harbored a TP53, TET2 or DNMT3A mutation, and these patients accounted for 64% of the deaths that occurred in the study population. Researchers reported 3-year OS rates of 19% (95% CI, 9-33) among patients with at least one of these mutations, compared with 59% (95% CI, 43-72) among patients who harbored none of these mutations.
“The results of this study identify a clinical setting in which genetic profiling of tumor samples can inform care decisions for patients with myelodysplastic syndrome,” Bejar and colleagues concluded. “Although replication of these findings is required, our study demonstrates how mutations in TET2, DNMT3A and TP53 identify a significant fraction of HSCT recipients with poor long-term survival, for whom alternatives to standard transplantation options should be considered. Patients without mutations in these genes have relatively good OS and PFS and could potentially be prioritized for HSCT.”
Disclosure: The researchers report consultant or advisory roles with, as well as honoraria or research funding from Amgen, Celgene, Eleven Biotherapeutics, Genoptix, Millennium Pharmaceuticals, Novartis, OptumHealth Education, Otsuka, Prometheus Laboratories, Spectrum and Takeda Pharmaceuticals. They also report royalties on patents related to signatures for myelodysplastic syndrome.