Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation

Abstract

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. (Funded by the Edward P. Evans Foundation and others.)

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.…”

Genotoxic stresses promote clonal expansion of hematopoietic stem cells expressing mutant p53

“…8 Further, TP53 mutations are associated with poor prognosis and decreased survival in MDS and AML. 7–9 However, the role of TP53 mutations in clonal hematopoiesis and the pathogenesis of hematological malignancies is largely unknown.…”

Mutations in DNA Methylation Pathway and Number of Driver Mutations Predict Response to Azacitidine in Myelodysplastic Syndromes

“…The inclusion of molecular markers in prognostic scores for MDS, together with other clinical and genetic data, is likely to lead to a better prediction of patient outcomes in the near future. Previous studies have assessed the role of candidate gene mutations in the context of MDS therapy, including response to erythropoietic stimulating agents [24], to hypomethylating agents [1,12,13,17,22,23,25,26], or in the bone marrow transplantation setting [27][28][29]. In the present study, no clinical characteristic was associated with overall response to azacitidine, and the same was true for any single mutated gene.…”