Venetoclax
Early studies of venetoclax (a B-cell lymphoma-2 [BCL-2] protein inhibitor) combined with azacitidine in patients with untreated or relapsed/refractory higher-risk MDS have shown promising results.[88]Wei AH, Garcia JS, Borate U, et al. A phase 1b study evaluating the safety and efficacy of venetoclax in combination with azacitidine in treatment-naïve patients with higher-risk myelodysplastic syndrome. Blood. 2019;134(1 suppl):568.
https://ashpublications.org/blood/article/134/Supplement_1/568/426368/A-Phase-1b-Study-Evaluating-the-Safety-and
[89]Zeidan AM, Borate U, Pollyea DA, et al. A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Am J Hematol. 2023 Feb;98(2):272-81.
https://www.doi.org/10.1002/ajh.26771
http://www.ncbi.nlm.nih.gov/pubmed/36309981?tool=bestpractice.com
The US Food and Drug Administration (FDA) has granted orphan drug designation and breakthrough therapy designation for venetoclax in combination with azacitidine for the treatment of patients with previously untreated higher-risk MDS.
Enasidenib
Enasidenib, an isocitrate dehydrogenase 2 (IDH2) inhibitor, is being investigated in MDS patients with IDH mutations. A phase 2 study is ongoing.[90]DiNardo CD, Venugopal S, Lachowiez C, et al. Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome. Blood Adv. 2023 Jun 13;7(11):2378-87.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10220255
http://www.ncbi.nlm.nih.gov/pubmed/35973199?tool=bestpractice.com
Eltanexor
Eltanexor (a second-generation, oral selective inhibitor of nuclear export) has shown promise in a phase 1/2 open-label study of patients with higher-risk MDS refractory to hypomethylating agents.[91]Lee S, Mohan S, Knupp J, et al. Oral eltanexor treatment of patients with higher-risk myelodysplastic syndrome refractory to hypomethylating agents. J Hematol Oncol. 2022 Aug;15(1):103.
https://jhoonline.biomedcentral.com/articles/10.1186/s13045-022-01319-y
http://www.ncbi.nlm.nih.gov/pubmed/35922861?tool=bestpractice.com
The FDA has granted orphan drug designation and fast-track designation for eltanexor as monotherapy for the treatment of patients with relapsed or refractory intermediate-, high-, or very-high-risk MDS. The European Medicines Agency (EMA) has granted orphan drug designation to eltanexor for the treatment of MDS.
Tamibarotene
Tamibarotene (an oral selective retinoic acid receptor alpha [RARA] agonist) has been granted orphan drug designation and fast-track designation by the FDA for the treatment of higher-risk MDS. The EMA has also granted orphan drug designation to tamibarotene for the treatment of MDS. Tamibarotene is currently being evaluated in a phase 3 clinical trial of patients with newly diagnosed RARA-positive higher-risk MDS (in combination with azacitidine).[92]ClinicalTrials.gov. Tamibarotene plus azacitidine in participants with newly diagnosed RARA-positive higher-risk myelodysplastic syndrome. Mar 2024 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04797780
[93]Dezern AE, Marconi G, Deeren D, et al. A randomized, double-blind, placebo-controlled study of tamibarotene/azacitidine versus placebo/azacitidine in newly diagnosed adult patients selected for RARA+ HR-MDS (SELECT-MDS-1). Paper presented at: 2022 American Society of Clinical Oncology Annual Meeting. 3-7 Jun 2022. Chicago, IL/virtual. Hematologic malignancies - leukemia, myelodysplastic syndromes, and allotransplant. Meeting abstract TPS7075. J Clin Oncol. 2022;40(16 Suppl):TPS7075.
https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.TPS7075
Magrolimab
Magrolimab (an anti-CD47 monoclonal antibody) has been granted orphan drug designation and breakthrough designation by the FDA for the treatment of newly diagnosed MDS. The EMA has also granted orphan drug designation to magrolimab for the treatment of MDS. Interim analysis of a phase 3 randomized clinical trial of magrolimab plus azacitidine versus azacitidine plus placebo in untreated higher-risk MDS demonstrated futility and increased risk of death.[94]ClinicalTrials.gov. Magrolimab + azacitidine versus azacitidine + placebo in untreated participants with myelodysplastic syndrome (MDS) (ENHANCE). Jun 2024 [internet publication].
https://clinicaltrials.gov/ct2/show/NCT04313881
[95]Garcia-Manero G, Daver NG, Xu J, et al. Magrolimab + azacitidine versus azacitidine + placebo in untreated higher risk (HR) myelodysplastic syndrome (MDS): the phase 3, randomized, ENHANCE study. Paper presented at: 2021 American Society of Clinical Oncology Annual Meeting. 4-8 Jun 2021. Virtual. Hematologic malignancies - leukemia, myelodysplastic syndromes, and allotransplant. Meeting abstract TPS7055. J Clin Oncol. 2021;39(15 Suppl):TPS7055.
https://ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.TPS7055
The trial has been discontinued, and the FDA has placed all magrolimab MDS and acute myeloid leukemia studies on hold.