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 International Consortium for MDS (icMDS)
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.
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Authors: Benjamin Rolles, Jan Philipp Bewersdorf, Tariq Kewan, Ondřej Bláha, Jessica M. Stempel, Luca Lanino, Najla H. Al Ali, Amy E. DeZern, Mikkael A. Sekeres, Geoffrey L. Uy, Samuel Urrutia, Hetty E. Carraway, Pinkal Desai, Elizabeth A. Griffiths, Eytan M. Stein, Andrew M. Brunner, Christine McMahon, Rory M. Shallis, Joshua F. Zeidner, Michael R. Savona, Shougat Barua, Namrata S. Chandhok, Constantine Logothetis, Aram Bidikian, Ted M. Getz, Gail J. Roboz, Eunice S. Wang, Amyah C. Harris, Maria L. Amaya, Hayley Hawkins, Somedeb Ball, Justin Grenet, Parisa Abedi, Shai Shimony, R. Coleman Lindsley, Zhuoer Xie, Yazan F. Madanat, Yasmin Abaza, Talha Badar, Torsten Haferlach, Jaroslaw P. Maciejewski, David A. Sallman, Anoop Enjeti, Kamal Al-Rabi, Khalid Halahleh, Devendra Hiwase, María Díez‐Campelo, David Valcárcel, Claudia Haferlach, Lisa Pleyer, Ιoannis Kotsianidis, Vasiliki Pappa, Valeria Santini, Angela Consagra, Aref Al‐Kali, Seishi Ogawa, Yasuhito Nannya, Matteo Giovanni Della Porta, Rami S. Komrokji, Amer M. Zeidan, Maximilian Stahl
Institutions: Robert H. Lurie Comprehensive Cancer Center of Northwestern University, University of Colorado Denver, Johns Hopkins University, Harvard University, University of North Carolina at Chapel Hill, Kyoto University, Royal Adelaide Hospital, Cornell University, Hebron University, University of Miami, Azienda Ospedaliero-Universitaria Careggi, Washington University in St. Louis, Yale University, Sidney Kimmel Comprehensive Cancer Center, Universidad de Salamanca, University of Florence, Vall d'Hebron Hospital Universitari, Southwestern Medical Center, The University of Texas Southwestern Medical Center, Dana-Farber Cancer Institute, Massachusetts General Hospital, IRCCS Humanitas Research Hospital, Memorial Sloan Kettering Cancer Center, Roswell Park Comprehensive Cancer Center, Mayo Clinic, Moffitt Cancer Center, Democritus University of Thrace, National and Kapodistrian University of Athens, University General Hospital Attikon, Vanderbilt University Medical Center, Cleveland Clinic, Paracelsus Medical University, Mayo Clinic in Florida, King Hussein Cancer Center, Yale Cancer Center, Sylvester Comprehensive Cancer Center, Yale New Haven Health System, Calvary Mater Newcastle Hospital, Munich Leukemia Laboratory (Germany), Australasian Leukaemia and Lymphoma Group, Austrian Breast & Colorectal Cancer Study Group