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Therapy of high-risk myelodysplastic syndromes

Bone Marrow Transplantation (2026)Cite this article

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Abstract

Higher-risk myelodysplastic syndrome (HR-MDS) is a heterogeneous group of hematopoietic malignancies primarily affecting the elderly, characterized by ineffective hematopoiesis, cytopenias, and a risk of transformation to acute myeloblastic leukemia. This review outlines the current landscape of HR-MDS management, focusing on risk stratification, treatment options, and challenges. The International Prognostic Scoring Systems (IPSS-R and IPSS-M) classify patients into risk categories, integrating cytogenetics and molecular data to guide therapy. Hypomethylating agents remain the standard of care for non-transplant-eligible patients, though their efficacy varies, with median overall survival ranging from 13-19 months. Promising novel agents include anti-apoptotic drugs (e.g., venetoclax), mutation-targeted drugs (e.g., TP53, IDH1/2), signal transduction inhibitors, inflammation pathway inhibitors and immune checkpoint inhibitors. Combinations of hypomethylating agents and these novel agents have shown promise in early trials as initial or salvage therapy but have failed to improve survival in phase III studies. Allogeneic hematopoietic stem cell transplantation is the only potentially curative option, yet its applicability is limited by patient age, comorbidities, and donor availability. Post-transplant relapse monitoring via chimerism and measurable residual disease is critical, with preemptive donor lymphocyte infusion recommended for relapse prevention. Future research should focus on mutation-driven therapies and inclusive trial designs to optimize HR-MDS management.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (Key Program for International S&T Cooperation Projects of China) (2025YFE0151000) and the Fundamental Research Funds for the Zhejiang Provincial Universities (226-2025-00213).

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Authors and Affiliations

  1. Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yishan Ye

  2. Department of Hematology and Cell Therapy, Hospital Saint-Antoine, Sorbonne University, Paris, France

    Yishan Ye, Eolia Brissot & Mohamad Mohty

  3. Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon

    Ali Bazarbachi

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  1. Yishan Ye
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  2. Eolia Brissot
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  3. Ali Bazarbachi
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  4. Mohamad Mohty
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YY and MM conceptualized the work and drafted the initial manuscript. MM provided critical revision of the manuscript. EB and AB co-drafted sections of the manuscript, and provided key expert opinions and critical feedback.

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Correspondence to Mohamad Mohty.

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Ye, Y., Brissot, E., Bazarbachi, A. et al. Therapy of high-risk myelodysplastic syndromes. Bone Marrow Transplant (2026). https://doi.org/10.1038/s41409-026-02821-4

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