The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia

Issa, Ghayas C.; Aldoss, Ibrahim; DiPersio, John F.; Cuglievan, Branko; Stone, Richard; Arellano, Martha; Thirman, Michael J.; Patel, Manish R.; Dickens, David; Shenoy, Shalini; Shukla, Neerav; Kantarjian, Hagop M.; Armstrong, Scott A.; Perner, Florian; Perry, Jennifer A.; Rosen, Galit; Bagley, Rebecca G.; Meyers, Michael L.; Ordentlich, Peter; Gu, Yu; Kumar, V. S. Anil; Smith, Steven G.; McGeehan, Gerard M.; Stein, Eytan M.

doi:10.1038/s41586-023-05812-3

Cited by 166 publications

(155 citation statements)

References 32 publications

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“…Therefore, VTP maintained on-target transcriptional activity in resistant cells. This is consistent with the recently reported phase I clinical trial of revumenib (SNDX-5613), which saw downregulation of the key KMT2A target genes HOXA9, Meis1, FLT3, PBX3 and RUNX1 in nearly all patients, while the overall response and CR rates were much lower at 50% and 20% 14 .…”

Section: Resultssupporting

confidence: 91%

“…We suspect that the combination of multiple co-mutations in highly pretreated samples eventually renders the leukemia independently of the initiating genomic event ( KMT2A fusion), resulting in Menin-inhibitor resistance despite maintained on-target activity of the inhibitor on a transcriptional level ( Figure 2G ). KMT2A -fusion independence due to clonal evolution is one potential mechanism explaining resistance in the nearly 50% of patients who show a transcriptional response to revumenib without a clinical response 14 . Careful subset analysis in clinical trials will be required to precisely determine the influence of prior lines of therapy and the co-mutational landscape.…”

Section: Resultsmentioning

confidence: 99%

“…Preclinical and early studies of the Menin inhibitor VTP-60469 demonstrated impressive single agent activity in KMT2A-r ALL and AML 9,10,14 . Molecularly, Menin inhibitors suppress the expression of a subset of KMT2A-fusion target genes by interfering with the recruitment of the fusion to DNA [9][10][11]13 .…”

Section: % Of Acute Leukemias Carry Rearrangements Of the Kmt2a Gene ...mentioning

confidence: 99%

“…Recently, inhibition of the KMT2A-interacting protein Menin was identified as a promising therapeutic strategy [9][10][11][12][13][14] . Menin is essential for the oncogenic activity of KMT2A fusions 15 .…”

Section: Introductionmentioning

confidence: 99%

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Clonal evolution mediates Menin-inhibitor resistance inKMT2A-rearranged leukemias

Mahdavi

Lenard

Xie

et al. 2023

Preprint

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Inhibitors of the Menin-KMT2A interaction are emerging as promising agents for the treatment of KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Menin is required for the recruitment of the KMT2A-fusion to a subset of its target genes. We evaluated the efficacy of Menin-inhibition in KMT2A-r leukemias with high-risk features: high-risk KMT2A fusion partners in AML (MLLT10, MLLT4), infant ALL, and serial samples from patients with multiply relapsed ALL. We find that AML with high-risk fusion partners is sensitive to Menin-inhibition in xenografts. In contrast, highly pretreated samples from patients with KMT2A-AFF1 ALL are largely resistant. Menin inhibitor resistance in these patients is acquired, as Menin inhibition shows in vivo efficacy against leukemia samples obtained earlier in the disease course of the same patient. Transcriptomic analysis documents sustained on-target efficacy of the Menin inhibitor on a transcriptional level in resistant cells. However, genomic analysis documented the emergence of multiple co-mutations that may be sufficient to drive AML, and may mediate independence from the KMT2A-fusion induced transcription program. Our data suggest that it will be critical to use Menin-inhibitors upfront or in early lines of therapy before substantial clonal evolution has occurred.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: % Of Acute Leukemias Carry Rearrangements Of the Kmt2a Gene ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clonal evolution mediates Menin-inhibitor resistance inKMT2A-rearranged leukemias

Mahdavi

Lenard

Xie

et al. 2023

Preprint

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“…In particular, t‐ NPM1 AML should be now classified simply as NPM1 ‐mutated AML (adding “therapy‐related” or “post‐cytotoxic therapy” as qualifier), as is also now recommended in the ICC and 5th revision of WHO classifications 10,11 . Moreover, we predict that older t‐ NPM1 AML patients not eligible for intensive chemotherapy will show the same good response to venetoclax plus hypomethylating agents, as observed in dn‐ NPM1 AML 9,80 and that in the future, they could also benefit from menin 31 and/or XPO1 inhibitors, 15 that are currently under development for dn‐ NPM1 AML 81 …”

Section: Diagnosis Of Npm1‐mutated Amlmentioning

confidence: 86%

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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Contemporary Management of Acute Myeloid Leukemia

Venugopal,

Sekeres

2024

JAMA Oncol

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ImportanceAcute myeloid leukemia (AML) is a clonal hematopoietic cancer that disrupts normal hematopoiesis, ultimately leading to bone marrow failure and death. The annual incidence rate of AML is 4.1 per 100 000 people in the US and is higher in patients older than 65 years. Acute myeloid leukemia includes numerous subgroups with heterogeneous molecular profiles, treatment response, and prognosis. This review discusses the evidence supporting frontline therapies in AML, the major principles that guide therapy, and progress with molecularly targeted therapy.ObservationsAcute myeloid leukemia is a genetically complex, dynamic disease. The most commonly altered genes include FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53. The incidence of these alterations varies by patient age, history of antecedent hematologic cancer, and previous exposure to chemotherapy and/or radiotherapy for any cancer. Since 2010, molecular data have been incorporated into AML prognostication, gradually leading to incorporation of targeted therapies into the initial treatment approach of induction chemotherapy and subsequent management. The first molecularly targeted inhibitor, midostaurin, was approved to treat patients with AML with FLT3 variants in 2017. Since then, the understanding of the molecular pathogenesis of AML has expanded, allowing the identification of additional potential targets for drug therapy, treatment incorporation of molecularly targeted therapies (midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants, and enasidenib targeting IDH2), and identification of rational combination regimens. The approval of hypomethylating agents combined with venetoclax has revolutionized the therapy of AML in older adults, extending survival over monotherapy. Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis.Conclusions and RelevanceIn the era of genomic medicine, AML treatment is customized to the patient’s comorbidities and AML genomic profile.

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The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia

Cited by 166 publications

References 32 publications

Clonal evolution mediates Menin-inhibitor resistance inKMT2A-rearranged leukemias

Clonal evolution mediates Menin-inhibitor resistance inKMT2A-rearranged leukemias

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

Contemporary Management of Acute Myeloid Leukemia

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