Outcomes of patients with higher-risk myelodysplastic syndromes/neoplasms treated with hypomethylating agents + venetoclax—an analysis from the International Consortium for MDS (icMDS) VALIDATE database

Monotherapy with hypomethylating agents (HMA) remains the standard of care for patients with higher-risk myelodysplastic neoplasms (HR-MDS). Recently, the randomized phase III VERONA study evaluating azacitidine plus venetoclax (VEN) versus azacitidine plus placebo in newly diagnosed HR-MDS showed no difference in overall survival (OS) between the two arms. However, whether the addition of VEN to HMA improves outcomes among subsets of patients with HR-MDS remains debated. We analyzed 1907 patients with HR-MDS from 31 centers in 9 countries who were treated with HMA monotherapy or HMA/VEN in the frontline setting (HMA monotherapy: n = 1773; HMA/VEN: n = 134). Responses were assessed centrally by two investigators using the IWG 2023 response criteria. Addition of VEN improved composite complete remission (cCR) rates (48.8% vs. 27.7%; p < 0.001) but not CR rates (17.1% vs. 11.7%; p = 0.16). In multivariable logistic regression analysis, cCR remained favorable for HMA/VEN vs. HMA monotherapy (Odds Ratio [OR]: 2.49; 95% CI: 1.56-3.96; p < 0.001). However, we did not observe a statistically significant difference in OS for HMA/VEN vs. HMA monotherapy (Hazard Ratio [HR]: 0.83; 95% CI: 0.64-1.07; p = 0.15). In subgroup analyses, patients with TP53 wild-type disease (HR: 0.47; 95% CI: 0.29-0.74; p = 0.002) had a significant improvement in OS and those with ≥10% bone marrow blasts (HR: 0.73; 95% CI: 0.53-1.01; p = 0.06) had a trend towards OS benefit with HMA/VEN.

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Journal
Blood Cancer Journal
Published
2026-06-29
DOI
https://doi.org/10.1038/s41408-026-01543-6
Primary Topic
Acute Myeloid Leukemia Research
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article
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article

Outcomes of patients with higher-risk myelodysplastic syndromes/neoplasms treated with hypomethylating agents + venetoclax—an analysis from the International Consortium for MDS (icMDS) VALIDATE database

Vasiliki Pappa, Rami S. Komrokji, Yasmin Abaza, Gail J. Roboz et al.
Blood Cancer Journal
Acute Myeloid Leukemia Research
article

Outcomes of patients with higher-risk myelodysplastic syndromes/neoplasms treated with hypomethylating agents + venetoclax—an analysis from the International Consortium for MDS (icMDS) VALIDATE database

Vasiliki Pappa, Rami S. Komrokji, Yasmin Abaza, Gail J. Roboz, Ιoannis Kotsianidis, Anoop Kumar Enjeti, Hetty E. Carraway, David Valcárcel, Claudia Haferlach, David Andrew Sallman, Angela Consagra, Amy Elizabeth Dezern, Eunice S. Wang, Tariq Zuheir Kewan, Joshua F. Zeidner, Somedeb Ball, Seishi Ogawa, Maria L. Amaya, M. Sekeres, Jessica M. Stempel, Zhuoer Xie, Lisa Pleyer, Devendra Hiwase, Namrata S. Chandhok, Elizabeth A. Griffiths, Benjamin Rolles, María Díez‐Campelo, Khalid Halahleh, Yasuhito Nannya, Eytan M. Stein, Amer Methqal Zeidan, Hayley Hawkins, Talha Badar, Jan Philipp Bewersdorf, Luca Lanino, Yazan F. Madanat, Valeria Santini, Geoffrey L. Uy, Abi Harris, Najla H. Al Ali, Christine McMahon, Ted M. Getz, Aram Bidikian, P Desai, Aref Al-Kali, Kamal Al-Rabi, Maximilian Stahl, Jaroslaw P. Maciejewski, Tulika R. Gupta, Andrew M. Brunner, Michael R. Savona, Rory M. Shallis, Constantine N. Logothetis, Justin Grenet, Jaclynn Campos, Samuel Urrutia, Wei Wei, Matteo Giovanni Della Porta, Torsten Haferlach
article en

Abstract

Monotherapy with hypomethylating agents (HMA) remains the standard of care for patients with higher-risk myelodysplastic neoplasms (HR-MDS). Recently, the randomized phase III VERONA study evaluating azacitidine plus venetoclax (VEN) versus azacitidine plus placebo in newly diagnosed HR-MDS showed no difference in overall survival (OS) between the two arms. However, whether the addition of VEN to HMA improves outcomes among subsets of patients with HR-MDS remains debated. We analyzed 1907 patients with HR-MDS from 31 centers in 9 countries who were treated with HMA monotherapy or HMA/VEN in the frontline setting (HMA monotherapy: n = 1773; HMA/VEN: n = 134). Responses were assessed centrally by two investigators using the IWG 2023 response criteria. Addition of VEN improved composite complete remission (cCR) rates (48.8% vs. 27.7%; p < 0.001) but not CR rates (17.1% vs. 11.7%; p = 0.16). In multivariable logistic regression analysis, cCR remained favorable for HMA/VEN vs. HMA monotherapy (Odds Ratio [OR]: 2.49; 95% CI: 1.56-3.96; p < 0.001). However, we did not observe a statistically significant difference in OS for HMA/VEN vs. HMA monotherapy (Hazard Ratio [HR]: 0.83; 95% CI: 0.64-1.07; p = 0.15). In subgroup analyses, patients with TP53 wild-type disease (HR: 0.47; 95% CI: 0.29-0.74; p = 0.002) had a significant improvement in OS and those with ≥10% bone marrow blasts (HR: 0.73; 95% CI: 0.53-1.01; p = 0.06) had a trend towards OS benefit with HMA/VEN.

Blood Cancer Journal
Northwestern University (US), University of North Carolina at Chapel Hill (US), Hebron University (PS), Brigham and Women's Hospital (US), Roswell Park Comprehensive Cancer Center (US), Cleveland Clinic (US), Royal Adelaide Hospital (AU), Memorial Sloan Kettering Cancer Center (US), Humanitas University (IT), Harvard University (US), Johns Hopkins University (US), University of Miami (US), Democritus University of Thrace (GR), Universidad de Salamanca (ES), National and Kapodistrian University of Athens (GR), Washington University in St. Louis (US), Cornell University (US), Kyoto University (JP), Paracelsus Medical University (AT), King Hussein Cancer Center (JO), Yale Cancer Center (US), Moffitt Cancer Center (US), Massachusetts General Hospital (US), Munich Leukemia Laboratory (Germany) (DE), Southwestern Medical Center (US), Azienda Ospedaliero-Universitaria Careggi (IT), Dana-Farber Cancer Institute (US), Mayo Clinic in Arizona (US), Vall d'Hebron Hospital Universitari (ES), University General Hospital Attikon (GR), Mayo Clinic in Florida (US), Calvary Mater Newcastle Hospital (AU), Sylvester Comprehensive Cancer Center (US), IRCCS Humanitas Research Hospital (IT), Sidney Kimmel Comprehensive Cancer Center (US), Weill Cornell Medicine (US), Southwestern Medical Center (US), UNC Lineberger Comprehensive Cancer Center, University of Florence (IT), University of Colorado Anschutz Medical Campus (US), The University of Tokyo (JP), The University of Texas Southwestern Medical Center (US), Vanderbilt University Medical Center (US), Kindai University (JP), University of Colorado Denver (US)
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