Conference Abstracts - 2026 National Summit on Hematologic Cancers
Vol. 6, Issue Supplement 2, 2026 · S1-2
Outcomes with Hypomethylating Agent and Venetoclax Combination in Patients with TP53-mutated Myelodysplastic Syndromes
Somedeb Ball, MD,Michael Canonico, MD,Parth Patel, DO,Najhla H Al Ali, MS,Ashwin Kishtagari, MD,Kateryna Fedorov, MD,Laura A. Lee, MD, PhD,Sanjay Mohan, MD,Rami Komrokji, MD,Emily Mason, MD, PhD,Michael R Savona, MD,David Sallman, MD
Submission received: 2026-08-14 / Accepted: 2026-08-25 / Published: 2026-09-28
Abstract
Background
Myelodysplastic syndromes (MDS) with TP53 mutations (mTP53) carry poor prognosis and limited response to hypomethylating agent (HMA) monotherapy. The phase 3 VERONA trial of azacitidine plus venetoclax (Ven) in higher-risk MDS did not meet its overall survival (OS) endpoint. The comparative impact of HMA-Ven versus HMA on response depth and OS in mTP53-MDS, stratified by TP53 allelic state and blast burden, remains unclear.
Methods
We conducted a multicenter retrospective study to compare clinico-genomic characteristics and outcomes between frontline HMA-Ven and HMA monotherapy in patients with mTP53-MDS. Treatment response was assessed by IWG 2006 and IWG 2023 criteria. Survival was evaluated by Kaplan-Meier methods and multivariable Cox regression.
Results
Our study included 454 patients with mTP53-MDS (HMA-Ven, n=65; HMA, n=389) treated at Vanderbilt University Medical Center and H. Lee Moffitt Cancer Center. Cohorts had comparable median age (71 vs. 70.9 years); HMA-Ven had higher baseline bone marrow blasts (13% vs. 6%, p<0.001) and more MDS/AML-mTP53 (ICC 2022; 47.7% vs. 26.7%, p<0.001). By IWG 2006, HMA-Ven yielded higher overall response rate (ORR; 56.9% vs. 42.2%, p=0.027), driven by marrow CR (43.1% vs. 12.9%, p<0.001). By IWG 2023, composite CR+CRh+CRL was numerically higher with HMA-Ven (51.9% vs. 39.8%, p=0.109). IWG 2006 ORR benefit was pronounced in patients with ≥5% blasts (62.3% vs. 44.9%, p=0.022), particularly in those with 10–19% blasts (70.0% vs. 43.4%, p=0.004), and MDS/AML-mTP53 (67.7% vs. 42.3%, p=0.013), with no advantage in <5% blasts. Overall, median OS (10.6 vs. 13.4 mo, p=0.179) and leukemia-free survival (6.3 vs. 10.7 mo, p=0.092) did not differ between HMA-Ven and HMA cohorts. Among transplanted patients (n=87), HMA-Ven trended toward improved OS (46.8 vs. 23.8 mo; p=0.482). On multivariable Cox analysis, allo-HSCT was the strongest predictor of OS (HR 0.447, p<0.001), with HMA-Ven having no independent favorable prognostic effect on OS (HR 1.193, p=0.280).
Conclusion
In mTP53-MDS, frontline HMA-Ven improves overall response rates primarily in patients with ≥5% blasts, but does not improve OS. Allo-HSCT remains the strongest driver of survival, with HMA-Ven as a potential disease-debulking bridge to transplant. Novel therapies for mTP53-MDS remain an area of serious unmet need.