Generic Name

Calquence

Mechanism

• Selective covalent inhibition of BTK: Acalabrutinib binds irreversibly to the Cys481 residue in BTK, blocking phosphorylation of downstream signaling molecules.
• Suppression of B‑cell receptor (BCR) signalling: This leads to reduced proliferation, survival, and migration of malignant B cells.
• Minimal off‑target activity: Compared with ibrutinib, acalabrutinib has lower activity against EGFR, ITK, and other kinases, which translates to a more favorable safety profile.

Pharmacokinetics

• Absorption: Oral bioavailability ~50 %; food may modestly delay Tmax but not affect overall exposure.
• Distribution: Protein binding ~30 %; crosses the blood‑brain barrier minimally.
• Metabolism: Primarily via CYP3A4; minor glucuronidation contributes 5 %.
• Excretion: Fecal (≈80 %) and renal (≈15 %) routes.
• Half‑life: ~20 hours; steady state achieved in ~2 weeks with BID dosing.
• Drug interactions: Strong CYP3A4 inhibitors (ketoconazole, clarithromycin) ↑ plasma levels; strong inducers (rifampin, carbamazepine) ↓ levels.

Indications

• Chronic lymphocytic leukemia (CLL):
• With 17p deletion or TP53 mutation, or relapsed/refractory disease.
• Mantle‑cell lymphoma (MCL): Residual disease after prior therapy.
• Waldenström macroglobulinemia (WM): Relapsed or refractory disease.
• Other: Investigational use in diffuse large B‑cell lymphoma (DLBCL) and other B‑cell malignancies.

Contraindications

• Contraindications:
• Severe hepatic impairment (Child‑Pugh C).
• Active uncontrolled infections.
• Known hypersensitivity to acalabrutinib constituents.
• Warnings:
• Cardiac arrhythmias: Rare QT prolongation; consider baseline ECG.
• Bleeding risk: Particularly in patients on anticoagulants or antiplatelet agents.
• Immunosuppression: Increased risk of opportunistic infections.
• Pregnancy: Category C; avoid if possible.

Dosing

• Adults: 100 mg orally twice daily (BID).
• Children: 30 mg/m²/day divided BID (phase I studies).
• Administration: With or without food; avoid grapefruit juice.
• Rescue idea: If drug unavailable, temporary hold may be considered but not a substitute for therapy.

Adverse Effects

• Common (≥10 %):
• Anemia (≈10 %)
• Neutropenia (≈8 %)
• Fatigue (≈7 %)
• Diarrhea (≈6 %)
• Upper respiratory tract infections (≈6 %)
• Serious (≥1 %):
• Severe neutropenia or thrombocytopenia
• Pulmonary embolism
• Hemorrhagic events (intracranial, gastrointestinal)
• Embryo‑toxicity (observed in animal studies)
• Rare:
• Secondary malignancies, hepatotoxicity, arrhythmias.

Monitoring

• Baseline: CBC with differential, CMP, liver function tests, coagulation panel, ECG.
• During therapy:
• CBC weekly for first month, then monthly.
• CMP and LFTs monthly.
• Monitor for signs of bleeding or infection.
• Periodic ECG (every 3 months) if QT prolongation suspected.

Clinical Pearls

• Use with caution in patients on anticoagulants: Acalabrutinib can potentiate bleeding; consider platelet function tests or dose adjustment of anticoagulants.
• Dose adjustments for CYP3A4 interactions: Reduce dose to 50 mg BID if a moderate CYP3A4 inhibitor is co‑administered; hold therapy if strong inducers are used.
• Early neutropenia management: Consider growth factor support (filgrastim) if ANC falls below 0.5 × 10⁹/L.
• Phasing out therapy: In CLL, aural uptick “bridge” therapy with BTK inhibitors may help reduce marrow suppression during first 3 months.
• Pregnancy considerations: If a patient is pregnant or planning pregnancy, consider switching to a more favorable drug or postponing therapy until pregnancy is confirmed.

Key take‑away: Acalabrutinib offers a highly selective BTK inhibition without major off‑target effects, making it a preferred choice for mantle‑cell lymphoma and CLL with minimal cardiac toxicity compared to earlier agents.