A Retrospective Cohort Study Evaluating Outcomes of Higher Risk MDS Treated with Hypomethylating Agents with or without Venetoclax Using International Working Group 2023 Response Criteria
Authors: Shukla Mihir , Okpara Chinyere , Xiang Elaine , Abdul Hay Maher , Saint Fleur-Lominy Shella , Choi Jun Han 
Published: December 2024

Background: Myelodysplastic syndrome (MDS) is a disease of the hematopoietic stem cell that ultimately leads to ineffective hematopoiesis. Hypomethylating agents (HMA) are the current standard first-line treatment for patients with higher-risk MDS (HR-MDS). However, the response rates for these agents are relatively low. Phase 1 data have shown promising results using venetoclax (VEN) together with HMA in high-risk MDS (Bazinet, Lancet Haematol. 2022). Response criteria for MDS have recently been updated to better reflect patient-centered and clinically relevant outcomes in HR-MDS (Zeidan, Blood, 2023). In this single institution retrospective study, we aimed to provide outcomes for HMA plus VEN therapy compared with HMA alone in the treatment of higher-risk MDS using the International Working Group 2023 (IWG 2023) response criteria.
Methods: The study population consists of patients diagnosed with MDS between January 1, 2018 and October 30, 2023 with an inclusion criteria requirement of having HMA as first-line therapy, with subsequent lines of HMA also considered. Response rates, event-free survival (EFS), and overall survival (OS) were measured from the start of MDS treatment. Primary response measures (overall response rate (ORR) = CR + PR + CRL + CRh + HI) were assessed using criteria established by the IWG 2023 response criteria. Additional characteristics included patient demographics, disease risk groups, cytogenetics, and molecular profiles. Univariate comparisons were performed using the Kruskal-Wallis Rank Sum test, Fisher's exact test, and Chi-Squared tests. Given the longitudinal, heterogeneous, and high-dimensional nature of our data, we are currently exploring various non-parametric and parametric statistical and machine learning survival models for ongoing model comparison.
Results: This study includes 188 patients diagnosed with MDS, with 122 receiving HMA alone and 66 receiving HMA + VEN as either a first-line (N = 51) or second-line (N = 15). Median age at treatment initiation was 78 years for those receiving HMA alone and 70 years for those receiving any HMA+VEN treatment (p &lt; 0.001) with no statistically significant differences in sex or race. Baseline bone marrow blast count in the HMA +VEN group was 9% versus 4% in HMA only (p &lt; 0.001). Additionally, baseline neutrophil count were lower in in HMA + VEN group compared to HMA alone (1.2 K/uL vs 2 K/uL, p = 0.03) with no statistically significant differences in baseline hemoglobin or platelets. In the HMA + VEN group, 77% (49) of patients had high or very high IPSS-R score, compared to 45% (55) of HMA only (p &lt; 0.001). IPSS-M scores were available in 60% (113) of patient, of which 46% and 25% were in the high or very high risk range in the HMA + VEN and HMA only group, respectively (p=0.02). Among those with available mutation data (185), 30% (19) of patients who received HMA + VEN had TP53 mutation, compared to 12% (15) in HMA alone (p = 0.003). HMA + VEN group demonstrated a significantly higher ORR of 61% compared to 33% for HMA alone (p &lt; 0.001; CR/CRh/CRL rates of 49% versus 18%, respectively). Among the HMA + VEN group, those receiving at first-line had higher response rates (ORR 69%) compared to second line or beyond (ORR 33%). In patients with IPSS-R &gt;5, median EFS time was 14 months in HMA only compared to 27 months in HMA + VEN (p=0.04). Additionally, median OS time for patients with IPSS-R &gt; 5 was 26 months in HMA alone and 35 months in the HMA + VEN (p=0.16). In the HMA + VEN cohort 38% underwent allogeneic bone marrow transplant (allo-ASCT) compared to 1.6% of patients in the HMA only cohort (p &lt; 0.001).
Conclusion: This real world, single center retrospective cohort study demonstrates significantly higher ORR, including composite CR rates, in higher risk MDS patients when treated with HMA + VEN compared to HMA alone, despite more patients with &gt;5 IPSS-R in the combination cohort. Significantly more patients were able to undergo allo-ASCT after HMA + VEN treatment. The strength of our study comes from utilization of the updated IWG 2023 response criteria to better reflect clinically relevant outcomes for patients receiving treatment for MDS. Limitations include short follow up, retrospective analysis, and small sample size, which likely contribute to a lack of statistically significant OS benefit for the HMA + VEN group despite EFS that nearly doubles when compared to the HMA group in patients with IPSS-R &gt; 5.