Asciminib

• Chronic Myeloid Leukemia (CML), Philadelphia chromosome-positive (Ph+), chronic phase (CP):
  Approved for adult patients who are resistant or intolerant to two or more tyrosine kinase inhibitors (TKIs).
• CML with T315I mutation:
  Specifically indicated for Ph+ CML-CP patients harboring the T315I mutation, which confers resistance to most other TKIs.
• Off-label/Investigational:
  Possible investigational use in accelerated or blast phases of CML and combination therapy settings.

• Adults:
• Standard dose: 40 mg orally twice daily.
• For patients with T315I mutation: 80 mg orally twice daily.
• Doses may be adjusted based on therapeutic response and tolerability.
• Pediatrics:
  Safety and efficacy not established.
• Elderly:
  No specific dosing adjustments recommended; monitor carefully.
• Hepatic Impairment:
  Use with caution in moderate to severe impairment; monitor liver function.
• Renal Impairment:
  No dose adjustment necessary in mild to moderate cases; data limited in severe impairment.
• Administration:
  Swallow tablets whole with water; may be taken with or without food.

Asciminib is a selective allosteric inhibitor targeting the BCR-ABL1 fusion protein responsible for CML. It binds to the myristoyl pocket of BCR-ABL1, stabilizing the protein in an inactive conformation, thereby inhibiting its tyrosine kinase activity. This inhibition blocks leukemic cell proliferation and promotes apoptosis, including in cells resistant to ATP-competitive TKIs and those harboring the T315I mutation.

• Absorption: Peak plasma concentration ~3 hours after oral dosing.
• Distribution: Approximately 98% plasma protein bound.
• Metabolism: Predominantly via hepatic CYP3A4 enzymes.
• Half-life: Approximately 40 hours, supporting twice-daily dosing.
• Excretion: Mainly fecal elimination; <10% renal.

• Pregnancy: Category C (FDA). Animal studies show embryo-fetal toxicity; use only if benefits outweigh risks.
• Lactation: Unknown if excreted in human milk; breastfeeding not recommended during treatment and for one week after last dose.

• Antineoplastic agent
• BCR-ABL1 allosteric tyrosine kinase inhibitor

• Hypersensitivity to asciminib or any excipients.
• Concurrent use with strong CYP3A4 inhibitors or inducers unless benefits outweigh risks.

• Monitor for QT interval prolongation via ECG.
• Hepatic toxicity: monitor liver function tests regularly.
• Risk of pancreatitis: monitor serum amylase and lipase.
• Myelosuppression: monitor complete blood counts.
• Drug interactions with CYP3A4 modulators require dose adjustments.

• Common: Fatigue, nausea, headache, rash, arthralgia, diarrhea, increased lipase.
• Serious: Myelosuppression (anemia, neutropenia, thrombocytopenia), hepatotoxicity, pancreatitis, QT prolongation.
• Most adverse effects occur within weeks to months of treatment.

• CYP3A4 inhibitors (e.g., ketoconazole) increase asciminib levels—risk of toxicity.
• CYP3A4 inducers (e.g., rifampin) decrease efficacy.
• Concomitant QT-prolonging agents increase arrhythmia risk.
• May alter metabolism of other CYP450 substrates.

• Approved by FDA in 2021 for Ph+ CML-CP patients resistant or intolerant to multiple TKIs and with T315I mutation.
• Incorporated into NCCN guidelines as a treatment option post-TKI failure.
• Ongoing trials for combination therapies and other CML phases.

• Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C.
• Protect from moisture and light; keep in original container.
• Do not freeze.
• Keep out of reach of children.