What is the recommended use and dosing of Acalabrutinib (Acalabrutinib) for adult patients with mantle cell lymphoma or chronic lymphocytic leukemia who have received prior therapy?

Acalabrutinib for Previously Treated Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia

Recommended Dosing

Acalabrutinib is dosed at 100 mg orally approximately every 12 hours, taken continuously until disease progression or unacceptable toxicity. 1

Administration Instructions

• Swallow tablets whole with water; do not chew, crush, dissolve, or cut 1
• May be taken with or without food 1
• If a dose is missed by more than 3 hours, skip that dose and take the next dose at the regularly scheduled time—do not double up 1

Indications for Previously Treated Patients

Mantle Cell Lymphoma (MCL)

Acalabrutinib monotherapy is FDA-approved for adult patients with MCL who have received at least one prior therapy. 1

• The NCCN guidelines list acalabrutinib as an "Other Recommended Regimen" for previously treated Waldenström macroglobulinemia/lymphoplasmacytic lymphoma, demonstrating efficacy in lymphoid malignancies 2
• In a phase II trial of 106 patients with treatment-naïve or relapsed/refractory disease (39% had received ≥3 prior therapies, 31% had refractory disease), the 24-month progression-free survival was 82% in relapsed/refractory patients 2

Chronic Lymphocytic Leukemia (CLL) and Small Lymphocytic Lymphoma (SLL)

Acalabrutinib is FDA-approved and strongly recommended for adult patients with CLL/SLL, including those with prior therapy. 1

For Relapsed/Refractory CLL After Chemoimmunotherapy

• Acalabrutinib or zanubrutinib are preferred as continuous therapy (Level I, A evidence) 2
• Acalabrutinib is preferred over ibrutinib due to lower rates of atrial fibrillation and hypertension 2, 3

For Early Relapse After Venetoclax-Based Therapy (<36 months)

• BTK inhibitors (acalabrutinib, zanubrutinib, or ibrutinib) are preferred over venetoclax plus anti-CD20 antibody (Level II, B evidence) 2

For Late Relapse After Venetoclax-Based Therapy (≥36 months)

• Acalabrutinib or zanubrutinib as continuous therapy (Level I, A evidence) 2
• Venetoclax-rituximab for 24 months is an alternative option 2

For Relapse in Patients with TP53 Mutation or del(17p)

• Acalabrutinib, zanubrutinib, or ibrutinib (Level I, A evidence) 2
• Venetoclax-rituximab is an alternative 2

Drug Interactions Requiring Dose Modifications

CYP3A Inhibitors

• Strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin): Avoid co-administration. If short-term use is necessary (≤7 days), interrupt acalabrutinib and resume 24 hours after discontinuation 1
• Moderate CYP3A inhibitors: Reduce acalabrutinib dose to 100 mg once daily 1
• Azole antifungals significantly increase acalabrutinib levels through CYP3A4 inhibition, leading to potential toxicities 4

CYP3A Inducers

• Strong CYP3A inducers: Avoid co-administration. If unavoidable, increase acalabrutinib dose to 200 mg approximately every 12 hours 1

Common Adverse Events and Management

Headaches (22-51% incidence)

• Typically self-limited, resolving within 1-2 months of treatment initiation 3
• Manage with acetaminophen plus caffeine supplements 3, 5
• Critical pitfall: Do not discontinue acalabrutinib prematurely for headaches—counsel patients on expected resolution with conservative management 3

Diarrhea (52-58% incidence)

• Grade ≥3 occurs in only 5% of patients 3, 1
• Monitor and manage symptomatically 1

Musculoskeletal Pain/Arthralgia (21% incidence)

• Includes back and leg pain 3
• Most complaints are mild to moderate (grade 1-2) 3

Cardiovascular Events

• Atrial fibrillation: 4-7% overall (1% grade ≥3)—significantly lower than ibrutinib 3, 5
• Hypertension: 3-7% overall (2-3% grade ≥3)—significantly lower than ibrutinib 3, 5
• Monitor for symptoms of arrhythmias and manage appropriately 1
• Acalabrutinib is preferred over ibrutinib in patients with cardiovascular comorbidities 3

Bleeding Events (26-39% any grade, 2% grade ≥3)

• Avoid concomitant warfarin use—patients requiring anticoagulation need alternative agents 3, 5
• Monitor patients on antiplatelet or anticoagulant therapies 3, 5, 1

Infections (65% overall, 14% grade ≥3)

• Pneumonia occurs in 7% (grade 3-4 in 5%)—lower than ibrutinib 4, 1
• Routine antibiotic or antifungal prophylaxis is NOT recommended; instead, maintain high clinical suspicion and treat promptly 4
• For suspected pneumonia: Obtain chest CT, inflammatory markers, urinary antigens for Legionella and Pneumococcus, blood cultures, nasopharyngeal swab for respiratory viruses, and sputum culture 4
• Important drug interaction: Ciprofloxacin significantly increases acalabrutinib levels—avoid or adjust dose 4

Cytopenias

• Neutropenia (grade ≥3): 14-19% 3, 1
• Thrombocytopenia (grade ≥3): 7-9% 3, 1
• Anemia (grade ≥3): 7-15% 3, 1
• Monitor complete blood counts regularly 1

Second Primary Malignancies

• Skin cancers and other solid tumors have occurred 1
• Advise patients to use sun protection 1

Hepatotoxicity

• Monitor hepatic function throughout treatment 1

Special Populations

Hepatic Impairment

• Avoid acalabrutinib in patients with severe hepatic impairment 1

Pregnancy and Lactation

• May cause fetal harm and dystocia 1
• Advise not to breastfeed 1

Dose Modifications for Adverse Reactions

• Treatment interruption, dose reduction, or discontinuation may be necessary for toxicity management 1
• Refer to FDA prescribing information for specific grading and modification algorithms 1