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Therapeutic Targets in Myelodysplastic Neoplasms: Beyond Hypomethylating Agents

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Abstract

Purpose of Review

To discuss novel targeted therapies under investigation for treatment of myelodysplastic neoplasms (MDS).

Recent Findings

Over the last few years, results of phase 3 trials assessing novel therapies for high-risk MDS have been largely disappointing. Pevonedistat (NEDD-8 inhibitor) and APR-246 (TP53 reactivator) both did not meet trial endpoints. However, early phase trials of BCL-2, TIM3, and CD47 inhibitors have shown exciting data and are currently under phase 3 investigation. Moreover, combination of hypomethylating agents (HMA) with novel therapies targeting the mutational (IDH, FLT3, spliceosome complex) or immune (PD-1/PDL-1, TIM-3, IRAK-4) pathways are being investigated in early phase clinical trials and have shown adequate safety and promising efficacy.

Summary

Myelodysplastic neoplasms (MDS) are a group of hematopoietic neoplasms defined by cytopenias and morphological dysplasia. They are characterized by clonal proliferation of aberrant hematopoietic stem cells caused by recurrent genetic abnormalities. This leads to ineffective erythropoiesis, peripheral blood cytopenias, abnormal cell maturation, and a high risk of transformation into acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation is the only curative therapy; however, it is not a suitable option for majority patients due to their age, comorbidities, and the high rate of treatment-related complications. HMAs remain the only FDA-approved treatment option for high-risk MDS. Due to intolerance, primary, and secondary resistance to HMA, there is a large unmet need to develop new safe and effective therapies for patients with MDS. In this review, we focus on the current management strategies and novel therapies in development for treatment of high-risk MDS.

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Authors and Affiliations

  1. Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Prateek Pophali

  2. Department of Medicine, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Sudhamsh Reddy Desai

  3. Department of Oncology, Department of Developmental & Molecular Biology, Montefiore Medical Center & Albert Einstein College of Medicine, Chanin 302A, 1300 Morris Park Avenue, Bronx, NY, 10461, USA

    Aditi Shastri

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Pophali, P., Desai, S.R. & Shastri, A. Therapeutic Targets in Myelodysplastic Neoplasms: Beyond Hypomethylating Agents. Curr Hematol Malig Rep 18, 56–67 (2023). https://doi.org/10.1007/s11899-023-00693-9

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