Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with &lt;i&gt;MLL&lt;/i&gt; rearrangement or &lt;i&gt;NPM1&lt;/i&gt;  mutation to venetoclax

Rausch, Johanna; Dzama, Margarita M.; Dolgikh, Nadezda; Stiller, Hanna L; Bohl, Stephan R; Lahrmann, Catharina; Kunz, Kerstin; Kessler, Linda; Echchannaoui, Hakim; Chen, Chun-Wei; Kindler, Thomas; Döhner, Konstanze; Burrows, Francis; Theobald, Matthias; Sasca, Daniel; Kühn, Michael W.M.

doi:10.3324/haematol.2022.282160

Cited by 15 publications

(5 citation statements)

References 15 publications

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“…Data from this study suggest that ziftomenib may induce apoptotic priming and resensitize AML cells to venetoclax. This finding may support further evaluation as a potential treatment option for AML patients with KMT2Ar or NPM1mut AML who have failed venetoclax-based regimens and have few other treatment options [ 10 , 35 , 36 ].…”

Section: Menin Inhibitors: Ongoing Clinical Trials In Amlmentioning

confidence: 72%

“…The investigation of mechanisms of resistance to venetoclax-based therapies in AML, which is the current standard of care for elderly patients or those unable to receive intensive chemotherapy, showed an important activation of a KMT2A-like signature. These mechanisms of resistance are mediated by the upregulation of HOX and MEIS1 [ 35 , 36 , 37 ].…”

Section: Menin Inhibitors: Ongoing Clinical Trials In Amlmentioning

confidence: 99%

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A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia

Candoni,

Coppola

2024

Hematology Reports

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Menin inhibitors are new and promising agents currently in clinical development that target the HOX/MEIS1 transcriptional program which is critical for leukemogenesis in histone-lysine N-methyltransferase 2A-rearranged (KMT2Ar) and in NPM1-mutated (NPM1mut) acute leukemias. The mechanism of action of this new class of agents is based on the disruption of the menin–KMT2A complex (consisting of chromatin remodeling proteins), leading to the differentiation and apoptosis of AML cells expressing KMT2A or with mutated NPM1. To date, this new class of drugs has been tested in phase I and II clinical trials, both alone and in combination with synergistic drugs showing promising results in terms of response rates and safety in heavily pre-treated acute leukemia patients. In this brief review, we summarize the key findings on menin inhibitors, focusing on the mechanism of action and preliminary clinical data on the treatment of acute myeloid leukemia with this promising new class of agents, particularly revumenib and ziftomenib.

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Section: Menin Inhibitors: Ongoing Clinical Trials In Amlmentioning

confidence: 72%

Section: Menin Inhibitors: Ongoing Clinical Trials In Amlmentioning

confidence: 99%

A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia

Candoni,

Coppola

2024

Hematology Reports

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“…Symptoms related to differentiation syndrome, including bone pain or arthralgia, pericardial and/or pleural effusion, pulmonary infiltrates, creatinine increase, rash, edema, and pyrexia, occurred in about 16% of patients with a median time of 18 days and were all of grade 2. 81 Ziftomenib (also known as KO-539), another menin inhibitor highly effective in vitro and in vivo 156 that also sensitizes AML blasts to venetoclax, 157 was tested in the COMET-001 (NCT04067336) trial enrolling heavily pretreated AML patients with MLL rearrangement or NPM1 mutations. Ziftomenib was well tolerated (600 mg recommended dose for phase II testing) 158 and the main dose-limiting toxicity was the differentiation syndrome.…”

Section: Menin Inhibitorsmentioning

confidence: 99%

NPM1‐mutated acute myeloid leukemia: New pathogenetic and therapeutic insights and open questions

Falini

2023

American J Hematol

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The nucleophosmin (NPM1) gene encodes for a multifunctional chaperone protein that is localized in the nucleolus but continuously shuttles between the nucleus and cytoplasm. NPM1 mutations occur in about one‐third of AML, are AML‐specific, usually involve exon 12 and are frequently associated with FLT3‐ITD, DNMT3A, TET2, and IDH1/2 mutations. Because of its unique molecular and clinico‐pathological features, NPM1‐mutated AML is regarded as a distinct leukemia entity in both the International Consensus Classification (ICC) and the 5th edition of the World Health Organization (WHO) classification of myeloid neoplasms. All NPM1 mutations generate leukemic mutants that are aberrantly exported in the cytoplasm of the leukemic cells and are relevant to the pathogenesis of the disease. Here, we focus on recently identified functions of the NPM1 mutant at chromatin level and its relevance in driving HOX/MEIS gene expression. We also discuss yet controversial issues of the ICC/WHO classifications, including the biological and clinical significance of therapy‐related NPM1‐mutated AML and the relevance of blasts percentage in defining NPM1‐mutated AML. Finally, we address the impact of new targeted therapies in NPM1‐mutated AML with focus on CAR T cells directed against NPM1/HLA neoepitopes, as well as XPO1 and menin inhibitors.

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“…Similarly, the combination of menin inhibitors with FLT3 inhibitors resulted in an enhanced inhibitory effect on the proliferation and stimulatory induction of apoptosis of primary FLT3-mut leukemic blasts [113] and of leukemia cells in a murine model of leukemia promoted by NPM1-mut and FLT3-ITD [114]. A recent study showed that menin inhibitors synergize with drugs targeting chromatin regulation and DNA damage, as well as with drugs targeting apoptosis and the cell cycle; particularly interesting was the observation of a synergistic interaction between menin inhibitors and ATRA [115].…”

Section: Therapy Of Npm1-mut Amlsmentioning

confidence: 99%

Genetic, Phenotypic, and Clinical Heterogeneity of NPM1-Mutant Acute Myeloid Leukemias

2023

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The current classification of acute myeloid leukemia (AML) relies largely on genomic alterations. AML with mutated nucleophosmin 1 (NPM1-mut) is the largest of the genetically defined groups, involving about 30% of adult AMLs and is currently recognized as a distinct entity in the actual AML classifications. NPM1-mut AML usually occurs in de novo AML and is associated predominantly with a normal karyotype and relatively favorable prognosis. However, NPM1-mut AMLs are genetically, transcriptionally, and phenotypically heterogeneous. Furthermore, NPM1-mut is a clinically heterogenous group. Recent studies have in part clarified the consistent heterogeneities of these AMLs and have strongly supported the need for an additional stratification aiming to improve the therapeutic response of the different subgroups of NPM1-mut AML patients.

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Menin inhibitor ziftomenib (KO-539) synergizes with drugs targeting chromatin regulation or apoptosis and sensitizes acute myeloid leukemia with <i>MLL</i> rearrangement or <i>NPM1</i> mutation to venetoclax

Abstract: Not available.

Cited by 15 publications

References 15 publications

A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia

A 2024 Update on Menin Inhibitors. A New Class of Target Agents against KMT2A-Rearranged and NPM1-Mutated Acute Myeloid Leukemia

NPM1‐mutated acute myeloid leukemia: New pathogenetic and therapeutic insights and open questions

Genetic, Phenotypic, and Clinical Heterogeneity of NPM1-Mutant Acute Myeloid Leukemias

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