TP53 and IDH2 Somatic Mutations Are Associated With Inferior Overall Survival After Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome.

Abstract

Next-generation sequencing has identified somatic mutations that are prognostic of cancer. We evaluated the incidence and prognostic significance of somatic mutations in 89 myelodysplastic syndrome (MDS) patients who received an allogeneic hematopoietic cell transplantation. Next-generation sequencing was performed on paraffin embedded bone marrow, which was obtained at a median of 31 days before initiating the preparative regimen. The 3 most common subtypes of MDS were refractory anemia with excess blasts (RAEB)-1 (35%), RAEB-2 (29%), and refractory cytopenia with multilineage dysplasia (18%). Most patients (91%) received a myeloablative regimen of fludarabine with intravenous busulfan. Somatic mutations (> 0) were identified in 39 (44%) of analyzed samples. The 6 most commonly identified gene mutations were ASXL1 (8%), DNMT3A (8%), RUNX1 (7%), KRAS (6%), IDH2 (4%), and TP53 (4%). The low incidence of mutations in our study sample might be explained by tissue source and stringent variant-calling methodology. Moreover, we speculate that the low incidence of mutations might, perhaps, also be explained by previous azacitidine treatment in 82% of cases. Multivariate analysis identified TP53 (hazard ratio [HR], 3.82; 95% confidence interval [CI], 1.12-13.09; P= .03) and IDH2 mutations (HR, 4.74; 95% CI,1.33-16.91; P= .02) as predictors of inferior 3-year overall survival. This study furthers implementation of clinical genomics in MDS and identifies TP53 and IDH2 as targets for pre- or post-transplant therapy.