IDH mutant MDS: Proposal for disease subset recognition based on molecular and clinical features, and the availability of targeted therapies

Abstract Introduction IDH1 5% of MDS, but the impact of lenalidomide treatment emphasizes the need to identify those patients (pts). We explored the molecular and clinical phenotype, outcomes, and therapeutic implications of IDH MT MDS. Methods We identified pts with IDH1 5% blasts) (IDH2 vs WT p0.005, IDH1 vs WT p=0.067, IDH2 vs IDH1 p=0.04). Both IDH2 0.005, IDH2 vs IDH1 p=0.001). Both IDH 1 0.005). Both IDH MThad significantly lower ANC compared to WT (p 0.001). Hgb was higher among IDH1 than WT (p=0.013). Autoimmune-related diseases (AIRD) were observed more in IDH1 compared to IDH2 and WT, 28%, 18.8%, and 19.5%, respectively (p=0.036). SRSF2 MT were more common along both IDH 1 0.001) and RUNX1 (24.3%, 18.2%, and 11.1%, respectively, p 0.001). Both IDH 1 0.001) and fewer TET2 (15.9%, 9.1%, and 23.6%, respectively, p0.001). For IDH2 compared to WT, ASXL1 MT were increased (37% vs 21.5%) and SF3B1 decreased (9.1% vs 20.7%) (p0.001). Reponses to azacitidine were higher among IDH1 0.005 compared to WT and p=0.2 between IDH1 and IDH2). IDH1 0.001, IDH2 HR 0.7 p=0.001). Conclusions IDH MT MDS have unique molecular and clinical features. Pts have higher blasts and higher risk IPSS-M but less complex cytogenetics compared to WT. SRSF2 and RUNX1 are common concomitant MT. Despite higher AML transformation, the OS is better than WT when adjusted for IPSS-M, either because of different biology or response to treatments. Treatment with IDH inhibitors during the disease course suggests survival benefit among those pts. Our findings suggest the recognition of IDH MT MDS as a unique disease subset.