The Menin Inhibitor Ziftomenib (KO-539) Synergizes with Agents Targeting Chromatin Regulation or Apoptosis and Sensitizes AML with MLL Rearrangement or NPM1 Mutation to Venetoclax

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

doi:10.1182/blood-2022-167566

Cited by 4 publications

(5 citation statements)

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“…88,89 Ziftomenib treated AML cell lines displayed reduced mRNA and protein levels of BCL2 and FLT3, so phase 1 combination therapies of zifotmenib with VEN, VEN + AZA, and gilteritinib are ongoing. [90][91][92][93] With such promising results from these early phase trials, menin inhibitors will likely further transform therapy for eligible patients, particularly those with KMT2Ar which historically have experienced particularly poor prognosis.…”

Section: Flt3 Mutationsmentioning

confidence: 99%

“…While we await published results of revumenib and ziftomenib in the frontline setting, press releases from the drug companies are reporting 100% CRc rates in the frontline setting with combination AZA + VEN + revumenib and 7 + 3 + ziftomenib 88,89 . Ziftomenib treated AML cell lines displayed reduced mRNA and protein levels of BCL2 and FLT3, so phase 1 combination therapies of zifotmenib with VEN, VEN + AZA, and gilteritinib are ongoing 90–93 . With such promising results from these early phase trials, menin inhibitors will likely further transform therapy for eligible patients, particularly those with KMT2Ar which historically have experienced particularly poor prognosis.…”

Section: Investigational Lower Intensity Treatmentmentioning

confidence: 99%

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Frontline therapy of acute myeloid leukemia with lower intensity regimens: Where are we now and where can we go?

Marvin‐Peek,

Gilbert,

Pollyea

et al. 2024

American J Hematol

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The advent of molecularly targeted therapeutics has transformed the management of patients with acute myeloid leukemia (AML). Particularly for individuals unfit for intensive chemotherapy, lower intensity therapies (LIT) incorporating small molecules have significantly improved patient outcomes. With BCL2, IDH1, IDH2, and FLT3 inhibitors widely used for relapsed AML, combination regimens are now utilized in the frontline. Expansion of these targeted LIT combinations, along with development of novel agents including menin inhibitors, exemplifies the promise of precision medicine. Further understanding of molecular drivers of leukemic transformation and mechanisms of relapse will continue to advance frontline treatment options for patients with AML.

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Section: Flt3 Mutationsmentioning

confidence: 99%

Section: Investigational Lower Intensity Treatmentmentioning

confidence: 99%

Frontline therapy of acute myeloid leukemia with lower intensity regimens: Where are we now and where can we go?

Marvin‐Peek,

Gilbert,

Pollyea

et al. 2024

American J Hematol

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“…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 159 .…”

Section: Any Hope For Targeted Therapy In Npm1‐mutated Aml?mentioning

confidence: 99%

“…The finding that MN1 mutations confer resistance across multiple menin inhibitors 160 points to the need of designing second‐generation menin inhibitors, to overcome this problem. Another, possible option is to combine menin inhibitors with other synergistic drugs, such as FLT3 inhibitors, 162,163 venetoclax 156,157,164 and XPO1 inhibitors 32 …”

Section: Conclusion and Futurementioning

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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“…Targeting other epigenetic co-dependencies such as the bromodomain (BET), the lysine specific histone demethylase 1 (LSD1) or the transcriptional coactivator CBP/p300 in combination with Menin inhibition has shown potential preclinical results [50,53 ▪ ]. Furthermore, the CDK6 inhibitor abemaciclib and the BCL2 inhibitor venetoclax were shown to have synergistic effects with Menin inhibition [54,55 ▪ ]. Interestingly, venetoclax resistant AML cells upregulate MEIS1 and HOXA genes [56], which makes Menin inhibition a promising therapeutic approach for these patients.…”

Section: Preventing and Overcoming Resistance To Menin Inhibition Wit...mentioning

confidence: 99%

The future of HOXA-expressing leukemias: Menin inhibitor response and resistance

Wenge,

Armstrong

2023

Current Opinion in Hematology

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Purpose of review We provide an update on the successes and ongoing challenges of Menin inhibition as a novel approach for the treatment of patients with acute leukemias that express HOXA cluster genes including leukemias with KMT2A-rearrangements, NPM1 mutations or NUP98-rearrangements. Initial clinical trials show promising response rates in heavily pretreated patients suggesting these inhibitors may have a significant impact on patient outcome. Furthermore, the development of resistance mutations that decrease drug binding affinity, validates Menin as a therapeutic target in human cancers. Therapeutic strategies aiming at overcoming and preventing resistance, are of high clinical relevance. Recent findings Several Menin inhibitor chemotypes have entered clinical trials. Acquired point mutations have recently been described as a mechanism of resistance towards Menin inhibitors. However, resistance can develop in absence of these mutations. Combination therapies are currently being investigated in preclinical models and in early phase clinical trials. Summary Given the remarkable overall response rates, shedding light on treatment options for patients whose leukemias develop resistance to Menin inhibitors is an imminent clinical need. Studying the underlying mechanisms to inform clinical decision making, and to potentially prevent the development of resistance is of outmost importance.

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The Menin Inhibitor Ziftomenib (KO-539) Synergizes with Agents Targeting Chromatin Regulation or Apoptosis and Sensitizes AML with MLL Rearrangement or NPM1 Mutation to Venetoclax

Cited by 4 publications

References 0 publications

Frontline therapy of acute myeloid leukemia with lower intensity regimens: Where are we now and where can we go?

Frontline therapy of acute myeloid leukemia with lower intensity regimens: Where are we now and where can we go?

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

The future of HOXA-expressing leukemias: Menin inhibitor response and resistance

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