BACKGROUND Genetic mutations drive the pathogenesis of the myelodysplastic syndrome (MDS) and are closely associated with clinical phenotype. Therefore, genetic mutations may predict clinical outcomes after allogeneic hematopoietic stem-cell transplantation. METHODS We performed targeted mutational analysis on samples obtained before transplantation from 1514 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014. We evaluated the association of mutations with transplantation outcomes, including overall survival, relapse, and death without relapse. RESULTS TP53 mutations were present in 19% of the patients and were associated with shorter survival and a shorter time to relapse than was the absence of TP53 mutations, after adjustment for significant clinical variables (P<0.001 for both comparisons). Among patients 40 years of age or older who did not have TP53 mutations, the presence of RAS pathway mutations was associated with shorter survival than was the absence of RAS pathway mutations (P = 0.004), owing to a high risk of relapse, and the presence of JAK2 mutations was associated with shorter survival than was the absence of JAK2 mutations (P = 0.001), owing to a high risk of death without relapse. The adverse prognostic effect of TP53 mutations was similar in patients who received reduced-intensity conditioning regimens and those who received myeloablative conditioning regimens. By contrast, the adverse effect of RAS pathway mutations on the risk of relapse, as compared with the absence of RAS pathway mutations, was evident only with reduced-intensity conditioning (P<0.001). In young adults, 4% of the patients had compound heterozygous mutations in the Shwachman-Diamond syndrome-Associated SBDS gene with concurrent TP53 mutations and a poor prognosis. Mutations in the p53 regulator PPM1D were more common among patients with therapy-related MDS than those with primary MDS (15% vs. 3%, P<0.001). CONCLUSIONS Genetic profiling revealed that molecular subgroups of patients undergoing allogeneic hematopoietic stem-cell transplantation for MDS may inform prognostic stratification and the selection of conditioning regimen.
Bibliographical noteFunding Information:
Supported by a grant from the Edward P. Evans Foundation (to Drs. Lindsley and Ebert), a Harvard Catalyst KL2-CMeRIT Award (to Dr. Lindsley), and a National Marrow Donor Program Immunobiology Research Study Grant (to Dr. Lindsley), by grants from the NIH (R01HL082945, R24DK099808, and 5P30 CA006516, to Dr. Ebert), and by a grant from the Leukemia and Lymphoma Society (to Dr. Ebert). The Center for International Blood and Marrow Transplant Research is supported by a Public Health Service grant (5U24-CA076518) from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases, by a grant (5U10HL069294) from the NHLBI and NCI, by a contract (HHSH250201200016C) with the Health Resources and Services Administration, by grants (N00014-14-1- 0028 and N00014-15-1-0848) from the Office of Naval Research, by grants from Alexion and Amgen, by an anonymous donation to the Medical College of Wisconsin, and by grants from the Be the Match Foundation, Bristol-Myers Squibb Oncology, Celgene, Chimerix, Fred Hutchinson Cancer Research Center, Gamida Cell, Genentech, Genzyme, Gilead Sciences, Health Research, Roswell Park Cancer Institute, HistoGenetics, Incyte, Jazz Pharmaceuticals, Jeff Gordon Children's Foundation, the Leukemia and Lymphoma Society, the Medical College of Wisconsin, Merck, Mesoblast, Millennium (Takeda Oncology), Miltenyi Biotec, National Marrow Donor Program, Neovii Biotech, Novartis Pharmaceuticals, Onyx Pharmaceuticals, Optum Healthcare Solutions, Otsuka America Pharmaceutical, Otsuka Pharmaceutical Japan, Oxford Immunotec, Perkin Elmer, Pharmacyclics, Sanofi U.S., Seattle Genetics, Sigma-Tau Pharmaceuticals, Spectrum Pharmaceuticals, St. Baldrick's Foundation, Sunesis Pharmaceuticals, Swedish Orphan Biovitrum, Telomere Diagnostics, Terumo BCT, Therakos, the University of Minnesota, and Wellpoint.
© 2017 Massachusetts Medical Society.