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Clinical Advances in Hematology & OncologyThe Development of Menin Inhibitors in AML and ALL

Emerging Role of Menin Inhibitors in Targeting Genetic Abnormalities in Acute Leukemia

Menin inhibitors represent a novel class of targeted therapies aimed at addressing specific genetic abnormalities in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). By disrupting the interaction between menin and KMT2A, these inhibitors reprogram leukemia cells and halt the gene expression programs that drive leukemia development. This article explores the mechanisms, clinical trial data, and practical implications of menin inhibitors, highlighting their potential as a promising therapeutic advancement.

Key Points:

  • Mechanism of Action: Menin inhibitors target epigenetic modifiers, disrupting the interaction between menin and KMT2A, essential for the transcription of leukemia-causing genes.
  • Genotype-Specific Targeting: These inhibitors are particularly effective in KMT2A-rearranged leukemias and NPM1-mutant AML, which depend on menin-KMT2A interaction.
  • Comparison to Other Therapies: Menin inhibitors differ from traditional chemotherapy and other targeted therapies by focusing on genetic abnormalities rather than cell division rates.
  • Role of Genotype Testing: Genotype testing is crucial to identify patients who would benefit from menin inhibition, particularly those with KMT2A rearrangements or NPM1 mutations.
  • Clinical Trial Data:
    • Revumenib: Phase 1 trials showed a 60% overall response rate (ORR) and 30% complete remission with partial hematologic recovery (CRh). Phase 2 trials reported an ORR of 63.2% and a CR/CRh rate of 22.8%.
    • Ziftomenib: Phase 1 trials showed a CR/CRh rate of 35% in NPM1-mutant AML.
    • JNJ-75276617: Phase 1 trials showed a 50% ORR and 25% CR/CRh rate.
  • Combination Therapy: Ongoing studies explore combining menin inhibitors with other therapies, such as decitabine/cedazuridine and venetoclax, showing promising preliminary results.
  • Side Effects Management:
    • Differentiation Syndrome: Commonly managed with corticosteroids; seen in 1% to 20% of patients.
    • QT Prolongation: Asymptomatic and manageable with dose adjustments.
    • Hematologic Toxicities: Potential for neutropenia and thrombocytopenia, though not fully characterized.
  • Effectiveness and Outcomes: Menin inhibitors have shown effectiveness in achieving remission, allowing patients to proceed to stem cell transplantation. MRD-negative remission is noted in several cases.
  • AML vs. ALL: No significant difference in response rates between AML and ALL in KMT2A-rearranged leukemia when treated with menin inhibitors.
  • Future Directions: Continued research on combination therapies and potential inclusion in frontline and maintenance therapies to enhance cure rates.

“Menin inhibitors work to reprogram leukemia cells back to a normal state by shutting down the gene expression programs responsible for causing leukemia.”
– Ghayas C. Issa, MD; Assistant Professor, The University of Texas, MD Anderson Cancer Center

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