Therapeutic Targets in Myelodysplastic Neoplasms: Beyond Hypomethylating Agents

by Selleckchem | Jun 24 2023

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. 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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Title: Novel Targeted Therapies for the Treatment of Myelodysplastic Neoplasms (MDS): A Review

Introduction: Myelodysplastic neoplasms (MDS) are hematopoietic disorders characterized by cytopenias and dysplastic changes in bone marrow cells. With a risk of progression to acute myeloid leukemia (AML), high-risk MDS requires effective treatment options. While allogeneic hematopoietic stem cell transplantation is curative, it is not suitable for most patients due to various factors. Currently, hypomethylating agents (HMAs) are the only FDA-approved therapy for high-risk MDS. However, the development of new therapies is crucial to address the unmet need for patients who are intolerant, resistant, or relapse after HMA treatment. This review explores the current management strategies and investigates novel targeted therapies under development for the treatment of high-risk MDS.

Recent Findings: Recent phase 3 trials investigating novel therapies for high-risk MDS have shown disappointing results for certain agents. Pevonedistat, a NEDD-8 inhibitor, and APR-246, a TP53 reactivator, did not meet their trial endpoints. However, there are promising early-phase trials for inhibitors targeting BCL-2, TIM3, and CD47, which are currently undergoing phase 3 investigations. These agents have shown exciting data in early studies, indicating potential efficacy for the treatment of high-risk MDS.

Additionally, combination therapies involving HMAs with novel agents targeting specific mutational or immune pathways have demonstrated promising safety profiles and efficacy in early-phase clinical trials. Targeting mutational pathways such as IDH, FLT3, and the spliceosome complex, as well as immune pathways involving PD-1/PDL-1, TIM-3, and IRAK-4, have shown potential as effective treatment strategies for high-risk MDS.

Discussion: High-risk MDS poses a significant challenge in terms of treatment options. Allogeneic hematopoietic stem cell transplantation remains the only curative therapy, but its limitations make it inaccessible to many patients. HMAs are the current standard of care; however, intolerance, primary, and secondary resistance to these agents necessitate the development of new therapies.

Despite the disappointing results of certain phase 3 trials, there is hope in the potential of targeted therapies for high-risk MDS. Early-phase trials of BCL-2, TIM3, and CD47 inhibitors have shown promising data, warranting further investigation in phase 3 trials. Additionally, combination therapies involving HMAs and agents targeting mutational or immune pathways have demonstrated adequate safety and promising efficacy in early-phase clinical trials.

Conclusion: The management of high-risk MDS is challenging, and the development of novel therapies is critical to address the unmet needs of patients who do not respond to or are intolerant of current treatments. While some phase 3 trials have yielded disappointing results, there are several promising agents under investigation, including inhibitors targeting BCL-2, TIM3, and CD47, as well as combination therapies involving HMAs and agents targeting mutational or immune pathways. Continued research and clinical trials are needed to further explore the potential of these novel targeted therapies for the treatment of high-risk MDS, ultimately improving outcomes for patients in need.