MDS-431 Outcomes of Transformation to Acute Myeloid Leukemia after Hypomethylating Agent Therapy in Patients With Myelodysplastic Syndromes

Abstract

Most patients with myelodysplastic syndrome (MDS) have progression of disease after hypomethylating agent (HMA) failure, including transformation to acute myeloid leukemia (AML). We aimed to understand the clinical characteristics and outcomes of AML transformation after HMA failure in MDS. We conducted a retrospective review of 147 patients with newly-diagnosed MDS from 2017-2021 who later developed HMA failure, focusing on AML transformation. With a median follow-up time of 19.5 months, 71 patients (48%) developed AML after HMA failure. Patients with eventual transformation were more likely to be younger, have higher bone marrow or peripheral blasts, and lower platelet counts at the time of MDS diagnosis. Moreover, these transformed patients had higher-risk MDS by IPSS-R, more adverse cytogenetics (CG), and more frequent TP53 mutations and less frequent SF3B1 mutations at MDS diagnosis. Patients with AML transformation had a shorter time from diagnosis to HMA failure (7.5 vs. 15.0 months, p<0.001) and overall survival (OS) from HMA failure (4.2 vs. 8.4 months, p=0.003). Age <65 years old, higher-risk IPSS-R, and HMA response was associated with AML transformation by multivariate analysis. In patients with AML transformation, the median overall survival (OS) after AML diagnosis was 4.0 months. After transformation, the median number of treatment lines was 1 with 17% not receiving AML-directed therapy. 52% patients continued HMA-based therapy, and 51% received venetoclax. Out of 44 patients with evaluable responses, 6 achieved complete remission (CR) and 17 attained CR with incomplete hematologic recovery, with an overall response rate of 52%. However, most patients died of refractory disease (73%) and/or complications from pancytopenia (19%). The 60-day and 180-day mortality were high at 33% and 69%, respectively. The type or intensity of treatment was not associated with survival. Therapy-related disease, ELN adverse risk, higher risk CG, and TP53 and KRAS mutations were associated with worse survival. Four of 5 patients who underwent allogeneic stem cell transplantation achieved survival over 1 year (17.7-39.6 months). The outcomes of AML transformation after HMA failure MDS remain extremely poor. Further understanding of the biology and disease characteristics of this patient population is warranted for better treatment approaches.