Update on a Phase 1/2 First-in-Human Study of the Menin-KMT2A (MLL) Inhibitor Ziftomenib (KO-539) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Erba, Harry P.; Fathi, Amir T.; Issa, Ghayas C.; Altman, Jessica K.; Montesinos, Pau; Patnaik, Mrinal M.; Foran, James M.; Botton, Stéphane de; Schiller, Gary J.; Walter, Roland B.; Kremyanskaya, Marina; Pettit, Kristen; Strickland, Stephen A.; Tomkinson, Blake; Tabachri, Marilyn; Leoni, Mollie; Dale, Stephen; Wang, Eunice S.

doi:10.1182/blood-2022-167412

Cited by 46 publications

(29 citation statements)

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“…Differentiation syndrome (DS) was a notable adverse event, with at least grade 3 severity occurring in 27% (8/29) of KMT2Ar patients including 1 death, although no grade 3 DS occurred in mNPM1 patients. However, DS was associated with improved response (75% of mNPM1 patients), and DS severity decreased with improved protocol guidance [4].…”

Section: Menin Inhibitors In Amlmentioning

confidence: 97%

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting

2023

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Developments in investigational agents and novel regimens in acute myeloid leukemia (AML) were reported in the 2022 American Society of Hematology (ASH) annual meeting. Encouraging efficacy data were presented from first-in-human studies of two investigational menin inhibitors, SNDX-5613 and KO-539, in relapsed and refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangement or mutant NPM1, with overall response rates (ORR) of 53% (32/60) and 40% (8/20), respectively. The addition of the novel drug pivekimab sunirine, a first-in-class antibody–drug conjugate targeting CD123, to azacitidine and venetoclax in R/R AML resulted in an ORR of 45% (41/91), which rose to 53% in those who were venetoclax naïve. Additional novel triplet treatment combinations included the addition of magrolimab, an anti-CD47 antibody, to azacitidine and venetoclax, with an ORR of 81% (35/43) in newly diagnosed AML, including an ORR of 74% (20/27) in TP53 mutated AML. The addition of the FLT3 inhibitor gilteritinib to azacitidine/venetoclax was also featured, with an ORR of 100% (27/27) in newly diagnosed AML and an ORR of 70% (14/20) in R/R AML.

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Section: Menin Inhibitors In Amlmentioning

confidence: 97%

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting

2023

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“…The ORR of ziftomenib (40%) was comparable to that of revumenib. However, the response was higher in NPM1 ‐mutated AML (CRc: 35%) as compared to MLL rearranged patients (11%) 158 . MRD‐negativity was achieved in 75% of patients with composite CR (33%).…”

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

confidence: 99%

“…Unlike revumenib, ziftomenib also resulted into more frequent episodes of differentiation syndrome that were of grade 3 in up to 30% of MLL rearranged patients while no grade 3 differentiation syndrome occurred in NPM1-mutated AML. 158 Notably, the differentiation syndrome was associated with improved response (75% of NPM1-mutated AML patients).…”

Section: Menin Inhibitorsmentioning

confidence: 99%

“…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. 159 The ORR of ziftomenib (40%) was comparable to that of revumenib.…”

Section: Menin Inhibitorsmentioning

confidence: 99%

“…However, the response was higher in NPM1-mutated AML (CRc: 35%) as compared to MLL rearranged patients (11%). 158 MRDnegativity was achieved in 75% of patients with composite CR (33%). Unlike revumenib, ziftomenib also resulted into more frequent episodes of differentiation syndrome that were of grade 3 in up to 30% of MLL rearranged patients while no grade 3 differentiation syndrome occurred in NPM1-mutated AML.…”

Section: Menin Inhibitorsmentioning

confidence: 99%

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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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Refractory/Relapsed AML in Children and Evolution of Novel Therapies

Juul-Dam,

Ishimaru,

Ceolin

et al. 2024

Pediatric Oncology

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Update on a Phase 1/2 First-in-Human Study of the Menin-KMT2A (MLL) Inhibitor Ziftomenib (KO-539) in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Cited by 46 publications

References 0 publications

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting

Novel agents and regimens in acute myeloid leukemia: latest updates from 2022 ASH Annual Meeting

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

Refractory/Relapsed AML in Children and Evolution of Novel Therapies

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