Acalabrutinib

Class & MOA

  • Second-generation Bruton’s tyrosine kinase (BTK) inhibitor.
  • Irreversibly binds BTK → blocks B-cell receptor (BCR) signaling → reduces malignant B-cell survival and proliferation.
  • Designed to be more selective than ibrutinib, with fewer off-target effects.

FDA-Approved Indications

  1. Chronic Lymphocytic Leukemia (CLL) / Small Lymphocytic Lymphoma (SLL) – first-line and relapsed/refractory.
  2. Mantle Cell Lymphoma (MCL) – for adults with relapsed/refractory disease.

Dosing

  • 100 mg PO twice daily (continuous, until progression or intolerance).
  • Swallow capsules whole, with or without food.
  • Avoid PPIs (reduce absorption); separate from H2RAs and antacids.

Adverse Effects

  • Hematologic: neutropenia, anemia, thrombocytopenia.
  • Infections: bacterial, viral, fungal (PJP, HBV reactivation).
  • Cardiac: atrial fibrillation (lower risk vs ibrutinib), hypertension.
  • Bleeding: bruising, major hemorrhage risk (esp. with anticoagulants/antiplatelets).
  • Headache: very common, often responsive to caffeine/acetaminophen.
  • Secondary malignancies: skin cancers.

Monitoring

  • CBC (baseline and regularly).
  • Signs of infection.
  • Cardiac rhythm if symptoms or history of AFib.
  • Bleeding risk (esp. if on anticoagulation).
  • Dermatology exam for skin cancers.

Drug Interactions

  • CYP3A substrate:
    • Avoid strong CYP3A inhibitors/inducers (e.g., ketoconazole, rifampin).
    • Adjust dose with moderate inhibitors.
  • Acid-reducing agents:
    • Avoid PPIs.
    • H2RAs: take acalabrutinib ≥2 hr before.
    • Antacids: separate by ≥2 hr.
  • Antiplatelets/anticoagulants: ↑ bleeding risk.

Ibrutinib vs Acalabrutinib

  • Acalabrutinib is more selective for BTK → lower rates of atrial fibrillation, hypertension, diarrhea.
  • Still effective in CLL/MCL, often preferred for patients with cardiac comorbidities.

Key Oncology Pearl

Acalabrutinib is a preferred BTK inhibitor in CLL/SLL, especially for patients who cannot tolerate ibrutinib due to cardiac or bleeding risk.

Supportive care includes infection prophylaxis (HBV, PJP in select cases), skin monitoring, and drug interaction review.