MDS-353 Clinical Outcome of Myelodysplastic Syndrome Progressing on Hypomethylating Agents With Evolving Frontline Therapies: Continued Challenges and Unmet Needs

Introduction: Historically, the clinical outcome of myelodysplastic syndrome (MDS) patients progressing on hypomethylating agent (HMA) therapy is dismal. We sought to explore the outcome of MDS patients progressing after HMA therapy in the era of novel therapies. Methods: We retrospectively analyzed treatment outcomes of 71 MDS patients who progressed on HMA and were treated at Mayo Clinic between 2015 and 2021. Results: The median age of patients was 67 years (range, 36–91 years). Therapy-related MDS was diagnosed in 24% (n=17) of patients, whereas 48% of patients (n=34) had complex cytogenetics (CG). Large proportions of patients had IPSS-R high-risk (27%) and very-high-risk disease (46%) at baseline. The most commonly occurring mutations (≥10% of cases) were TP53 (44%), ASXL1 (21%), RUNX1 (14%), RAS (13%), and TET2 (11%). Among patients with MDS-EB1/EB2 (n= 23), 7 (30%) patients achieved complete remission (CR) and 2 (9%) had marrow CR. Among the 42 AML patients who progressed after HMA therapy and received induction chemotherapy, 36% achieved CR (n=8) or CR with incomplete count recovery (CRi, n=7). Five (10%t of 48 patients who progressed to AML did not receive induction chemotherapy due to poor performance status. Overall, 14 (20%) patients progressing on HMA successfully bridge to alloHCT. The proportions of patients who achieved CR based on therapy at HMA progression were 46% (n=19), 14% (n=2), 67% (n=2), and 12.5% (n=1) with Venetoclax-based combination, CPX-351, intensive chemotherapy, and other low-intensity therapies, respectively (p=0.053). Complex CG (p=0.04) and TP53 mutation (p=0.04) predicted significantly inferior CR rates. After excluding 5 patients who did not receive further therapy after HMA progression, the median OS was 9.3 months (95% CI: 4.65–14.0 months). On multivariate analysis (MVA), achievement of CR/CRi retained significance for improved OS (p=0.01), whereas TP53 mutation (p=0.001) and AML diagnosis at HMA progression (p=0.01) retained significance for inferior OS (p=0.004). Despite demonstrating favorable significance for OS in the univariate analysis, alloHCT did not retain significance for better OS in the MVA (p=0.38). Conclusions: Our report suggests modest improvement in survival of MDS patients progressing on HMA compared to historical data. Effective therapies are needed to improve outcomes for these patients.