Introduction
Calquence (acalabrutinib) is a second-generation Bruton's tyrosine kinase (BTK) inhibitor developed by AstraZeneca. It is an oral targeted therapy approved for the treatment of various B-cell malignancies. As a selective BTK inhibitor, Calquence represents an important advancement in the treatment of hematologic cancers, offering improved specificity compared to earlier BTK inhibitors.
Mechanism of Action
Calquence covalently binds to cysteine 481 in the BTK active site, resulting in irreversible inhibition of BTK enzymatic activity. BTK is a key signaling molecule in the B-cell receptor signaling pathway, which is essential for B-cell proliferation, survival, and differentiation. By inhibiting BTK, Calquence blocks B-cell activation and downstream signaling pathways, ultimately leading to reduced tumor proliferation and promotion of apoptosis in malignant B-cells.
Indications
- Treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy
- Treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL)
- Treatment of adult patients with previously untreated CLL/SLL (based on ELEVATE-TN and ASCEND trials)
Dosage and Administration
Standard dosing: 100 mg orally approximately every 12 hours (total 200 mg per day) Administration:- Swallow whole with water
- Can be taken with or without food
- Do not crush, chew, or open capsules
- Severe hepatic impairment (Child-Pugh Class C): Reduce dose to 100 mg once daily
- Concomitant use with strong CYP3A inhibitors: Avoid concomitant use if possible; if necessary, reduce Calquence dose to 100 mg once daily
- Concomitant use with moderate CYP3A inhibitors: Monitor for toxicity
- Renal impairment: No dose adjustment required
- Hepatic impairment: Reduce dose in severe impairment
- Elderly: No dose adjustment required
- Pediatric: Safety and effectiveness not established
Pharmacokinetics
Absorption: Rapid absorption with median Tmax of 0.75 hours Distribution: Mean volume of distribution ~100 L; protein binding >99% Metabolism: Primarily via CYP3A4; also undergoes glutathione conjugation Elimination: Mean half-life ~1 hour; fecal excretion (84%) and renal excretion (12%) Bioavailability: ~25% (reduced by high-fat meal)Contraindications
- Hypersensitivity to acalabrutinib or any component of the formulation
- Concurrent use with strong CYP3A inducers
- Severe hepatic impairment (without appropriate dose reduction)
Warnings and Precautions
Serious infections: Increased risk of bacterial, viral, and fungal infections Hemorrhage: Serious and fatal hemorrhagic events reported; consider risks/benefits in patients requiring antiplatelet or anticoagulant therapy Cytopenias: Grade 3 or 4 neutropenia, thrombocytopenia, and anemia reported; monitor blood counts regularly Cardiac arrhythmias: Atrial fibrillation and flutter reported; monitor for symptoms and manage appropriately Second primary malignancies: Other malignancies, including skin cancers, reported Hypertension: New or worsening hypertension reported; monitor blood pressureDrug Interactions
Strong CYP3A inhibitors: Increased acalabrutinib exposure; avoid concomitant use or reduce Calquence dose Moderate CYP3A inhibitors: May increase acalabrutinib exposure; monitor for toxicity Strong CYP3A inducers: Decreased acalabrutinib exposure; contraindicated Gastric acid reducing agents: May decrease acalabrutinib absorption; avoid concomitant proton pump inhibitors Anticoagulants/antiplatelets: Increased bleeding risk; monitor closelyAdverse Effects
Most common (≥20%): Headache, diarrhea, musculoskeletal pain, bruising, fatigue, nausea, rash Serious adverse reactions:- Serious infections (pneumonia, sepsis)
- Major hemorrhage
- Atrial fibrillation/flutter
- Second primary malignancies
- Cytopenias
Monitoring Parameters
- Complete blood counts (baseline and periodically during treatment)
- Signs and symptoms of infection
- Bleeding manifestations
- Cardiac rhythm monitoring (especially in patients with cardiac risk factors)
- Blood pressure monitoring
- Liver function tests
- Signs of second primary malignancies
Patient Education
- Take exactly as prescribed, approximately every 12 hours
- Report signs of infection (fever, chills, persistent sore throat)
- Report unusual bleeding or bruising
- Monitor for heart palpitations, dizziness, or shortness of breath
- Use sun protection due to increased skin cancer risk
- Inform all healthcare providers about Calquence use before any procedures
- Avoid grapefruit products and St. John's wort
- Report new or worsening headaches
- Use effective contraception during treatment and for at least 1 week after final dose
References
1. FDA prescribing information: Calquence (acalabrutinib) 2. Byrd JC, et al. Acalabrutinib in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374(4):323-332 3. Wang M, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma. Lancet. 2018;391(10121):659-667 4. Sharman JP, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia. Lancet. 2020;395(10232):1278-1291 5. Ghia P, et al. ASCEND: Phase III, Randomized Trial of Acalabrutinib Versus Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. J Clin Oncol. 2020;38(25):2849-2861 6. National Comprehensive Cancer Network (NCCN) Guidelines