MDS-407 Disease Characteristics and Outcomes of Hypomethylating Agent Failure in Patients With Myelodysplastic Syndromes

Background: Hypomethylating agents (HMA) improve cytopenias and delay progression of myelodysplastic syndromes (MDS), but most patients eventually lose their response. Although patients with HMA failure (HMA-F) pose significant treatment challenges with dismal outcomes, the clinicopathologic characteristics of MDS patients at the time of HMA-F are still poorly understood. Methods: We retrospectively evaluated 135 untreated patients with MDS diagnosed between 2017-2021 who later developed HMA-F. Pt characteristics, laboratory values, and bone marrow (BM) data, including cytogenetics and next generation sequencing, were assessed at both diagnosis and the time of HMA-F. Results: The median age was 70 at diagnosis, with therapy-related MDS (t-MDS) in 39%. Most patients had higher-risk MDS with IPSS-R high (30%) or very high (42%) disease, and complex karyotype was seen in 47%. The median number of mutations identified was 2 with TP53 (46%) and ASXL1 (21%) the most frequently discovered mutations. Regarding treatment, 67% received HMA monotherapy and 33% received HMA in combination with various agents. The median number of cycles of HMAs received was 7 (range: 1-37). At the time of HMA-F, patients presented with higher BM blasts (p<0.001), lower platelet counts (p<0.001), and more cytogenetic abnormalities (p=0.002) and mutations (p<0.001) than at diagnosis. The median time from diagnosis to HMA-F was 10.6 mo, and the median overall survival (mOS) from HMA-F was 6.5 mo. Survival was well-stratified by both IPSS-R at diagnosis (p=0.066) and at HMA-F (17.8 mo in lower-risk vs 3.8 mo in higher-risk MDS, p<0.001). There was no difference in mOS from HMA-F by number of HMA cycles, response to HMA, and treatment regimen at HMA-F; however, in patients with higher-risk MDS, stem cell transplantation (p<0.001) was associated with improved mOS and upfront HMA combination therapy (p=0.008) with inferior survival. Conclusions: Patients with HMA-F MDS have high-risk features which are often therapy-related. At the time of HMA-F, patients present with higher BM blasts, worsening thrombocytopenia, and more genomic aberrations. Unfortunately, after failure of HMA, patients have poor prognosis. Further understanding of the underlying biology of HMA-F MDS is warranted with an urgent need for therapeutic interventions after failure of HMA therapy.