Impact of Response to Hypomethylating Agent‐Based Therapy on Survival Outcomes in the Context of Baseline Clinical‐Molecular Risk and Transplant Status in Patients With Higher‐Risk Myelodysplastic Syndromes/Neoplasms: An analysis From the Internation

Baseline IPSS-M risk, response to hypomethylating agent (HMA) therapy, and receipt of allogeneic stem cell transplant (allo-HCT) have all been individually shown to impact overall survival (OS) in patients with myelodysplastic syndromes (MDS). However, the prognostic impact of response when adjusting for IPSS-M risk and treatment strategy remains unclear. Hence, we used the VALIDATE database of the International Consortium for MDS (icMDS) to evaluate the impact of International Working Group (IWG) 2023 best response on OS in 715 HMA-treated, higher-risk MDS patients stratified by baseline IPSS-M risk and their treatment strategy (subsequent allo-HCT vs. medical therapy alone) treating both best response and allo-HCT as time-dependent variables. Baseline IPSS-M risk (hazard ratio (HR): 0.5, p < 0.001) and receipt of allo-HCT (HR: 0.5, p < 0.001) were the strongest independent predictors of OS, whereas achievement of composite complete response (cCR) had a more modest impact on OS (HR: 0.8, p = 0.004). Among patients treated with medical therapy alone, achieving cCR improved OS significantly (HR: 0.7, p = 0.006). In contrast, among transplanted patients, cCR did not retain independent prognostic value for post-transplant survival after adjusting for baseline IPSS-M (HR: 0.9, p = 0.634). Achieving cCR did not fully overcome adverse disease biology as OS continued to segregate according to baseline IPSS-M risk. In summary, achieving cCR improves outcomes in non-transplanted patients, but it does not significantly impact post-transplant OS, suggesting that failure to achieve cCR with HMA may not warrant delay or preclude allo-HCT. Clinical trials should consider response in the context of IPSS-M risk distribution and treatment strategy (subsequent allo-HCT vs. medical therapy alone) to avoid overinterpretation of high response rates.

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Journal
American Journal of Hematology
Published
2026-08-27
DOI
https://doi.org/10.1002/ajh.70474
Primary Topic
Acute Myeloid Leukemia Research
Type
article
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0.00

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article

Impact of Response to Hypomethylating Agent‐Based Therapy on Survival Outcomes in the Context of Baseline Clinical‐Molecular Risk and Transplant Status in Patients With Higher‐Risk Myelodysplastic Syndromes/Neoplasms: An analysis From the Internation

Vasiliki Pappa, Samuel Urrutia, Aref Al‐Kali, Rami S. Komrokji et al.
American Journal of Hematology
Acute Myeloid Leukemia Research
article

Impact of Response to Hypomethylating Agent‐Based Therapy on Survival Outcomes in the Context of Baseline Clinical‐Molecular Risk and Transplant Status in Patients With Higher‐Risk Myelodysplastic Syndromes/Neoplasms: An analysis From the Internation

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

Abstract

Baseline IPSS-M risk, response to hypomethylating agent (HMA) therapy, and receipt of allogeneic stem cell transplant (allo-HCT) have all been individually shown to impact overall survival (OS) in patients with myelodysplastic syndromes (MDS). However, the prognostic impact of response when adjusting for IPSS-M risk and treatment strategy remains unclear. Hence, we used the VALIDATE database of the International Consortium for MDS (icMDS) to evaluate the impact of International Working Group (IWG) 2023 best response on OS in 715 HMA-treated, higher-risk MDS patients stratified by baseline IPSS-M risk and their treatment strategy (subsequent allo-HCT vs. medical therapy alone) treating both best response and allo-HCT as time-dependent variables. Baseline IPSS-M risk (hazard ratio (HR): 0.5, p < 0.001) and receipt of allo-HCT (HR: 0.5, p < 0.001) were the strongest independent predictors of OS, whereas achievement of composite complete response (cCR) had a more modest impact on OS (HR: 0.8, p = 0.004). Among patients treated with medical therapy alone, achieving cCR improved OS significantly (HR: 0.7, p = 0.006). In contrast, among transplanted patients, cCR did not retain independent prognostic value for post-transplant survival after adjusting for baseline IPSS-M (HR: 0.9, p = 0.634). Achieving cCR did not fully overcome adverse disease biology as OS continued to segregate according to baseline IPSS-M risk. In summary, achieving cCR improves outcomes in non-transplanted patients, but it does not significantly impact post-transplant OS, suggesting that failure to achieve cCR with HMA may not warrant delay or preclude allo-HCT. Clinical trials should consider response in the context of IPSS-M risk distribution and treatment strategy (subsequent allo-HCT vs. medical therapy alone) to avoid overinterpretation of high response rates.

American Journal of Hematology
University of North Carolina at Chapel Hill (US), Hebron University (PS), Roswell Park Comprehensive Cancer Center (US), Cleveland Clinic (US), Royal Adelaide Hospital (AU), Mayo Clinic (US), Memorial Sloan Kettering Cancer Center (US), 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), Yale University (US), Massachusetts General Hospital (US), Munich Leukemia Laboratory (Germany) (DE), Southwestern Medical Center (US), Azienda Ospedaliero-Universitaria Careggi (IT), Dana-Farber Cancer Institute (US), Yale New Haven Health System (US), Vall d'Hebron Hospital Universitari (ES), University General Hospital Attikon (GR), Mayo Clinic in Florida (US), Calvary Mater Newcastle Hospital (AU), Australasian Leukaemia and Lymphoma Group (AU), Austrian Breast & Colorectal Cancer Study Group (AT), Sylvester Comprehensive Cancer Center (US), IRCCS Humanitas Research Hospital (IT), Sidney Kimmel Comprehensive Cancer Center (US), Robert H. Lurie Comprehensive Cancer Center of Northwestern University, University of Florence (IT), The University of Texas Southwestern Medical Center (US), Vanderbilt University Medical Center (US), University of Colorado Denver (US)
Fondazione AIRC per la ricerca sul cancro ETS, Amgen, Bristol-Myers Squibb, Pfizer, AstraZeneca, GlaxoSmithKline, Gilead Sciences, Alexion Pharmaceuticals, Celgene, Karyopharm Therapeutics, Edward P. Evans Foundation, Moffitt Cancer Center, Regeneron Pharmaceuticals, Jazz Pharmaceuticals, TG Therapeutics, Astex Pharmaceuticals, BioCryst, Foghorn Therapeutics, Agios Pharmaceuticals, bluebird bio, CTI Biopharma, Incyte, Syndax Pharmaceuticals, Omeros Corporation, Astellas Pharma, Associazione Italiana per la Ricerca sul Cancro, Genesis Pharma, Deutsche Krebshilfe, Servier, Swedish Orphan Biovitrum, MorphoSys, Sierra Oncology, Genentech, Daiichi Sankyo Europe
Partnerships for the goals
Openalex Percentile: Top 11%
Acute Myeloid Leukemia Research
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