What is the recommended use and dosage of Acalabrutinib (Calquence) for treating mantle cell lymphoma and chronic lymphocytic leukemia?

Acalabrutinib (Calquence) for Mantle Cell Lymphoma and Chronic Lymphocytic Leukemia

Acalabrutinib is dosed at 100 mg orally every 12 hours continuously until disease progression or unacceptable toxicity for both mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), with tablets swallowed whole with water, with or without food. 1

Approved Indications and Dosing

Mantle Cell Lymphoma

Previously Untreated MCL (Ineligible for Autologous HSCT):

• Acalabrutinib 100 mg orally every 12 hours in combination with bendamustine and rituximab 1
• Start acalabrutinib on Day 1 of Cycle 1 (28-day cycles) and continue until progression 1
• Administer bendamustine 90 mg/m² on Days 1 and 2, plus rituximab 375 mg/m² on Day 1 for 6 cycles 1
• Patients achieving partial or complete response may receive maintenance rituximab every other cycle for up to 12 additional doses (Cycles 8-30) 1
• This combination significantly improved progression-free survival to 66.4 months versus 49.6 months with placebo plus bendamustine-rituximab (HR 0.73, P=0.0160) 2

Previously Treated MCL (≥1 Prior Therapy):

• Acalabrutinib 100 mg orally every 12 hours as monotherapy until progression 1
• In relapsed/refractory MCL, acalabrutinib achieved 81% overall response rate with 40% complete response rate 3
• Median duration of response was not reached at 15.2 months median follow-up, with 12-month duration of response rate of 72% 3

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Treatment-Naive or Previously Treated CLL/SLL:

• Acalabrutinib 100 mg orally every 12 hours as monotherapy until progression 1
• For previously untreated CLL/SLL, acalabrutinib may be combined with obinutuzumab: start acalabrutinib at Cycle 1, add obinutuzumab at Cycle 2 for 6 cycles total 1
• Acalabrutinib is recommended as first-line therapy for relapsed CLL, particularly in patients with TP53 mutation or del(17p) 4
• In head-to-head comparison with ibrutinib, acalabrutinib demonstrated noninferior progression-free survival (median 38.4 months in both arms) with significantly lower atrial fibrillation rates (9.4% vs 16.0%, P=0.02) 5

Administration Instructions

Critical Dosing Details:

• 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 regularly scheduled time 1
• Do not take extra tablets to make up for missed doses 1

Dose Modifications for Drug Interactions

Strong CYP3A Inhibitors (e.g., clarithromycin, ketoconazole):

• Avoid co-administration 1
• If short-term use unavoidable (≤7 days for anti-infectives), interrupt acalabrutinib and resume 24 hours after inhibitor discontinuation 1

Moderate CYP3A Inhibitors:

• Reduce acalabrutinib dose from 100 mg every 12 hours to 100 mg once daily 1

Strong CYP3A Inducers:

• Avoid co-administration 1
• If unavoidable, increase acalabrutinib dose to 200 mg every 12 hours 1

Key Safety Considerations and Monitoring

Cardiovascular Advantages Over Ibrutinib:

• Acalabrutinib has significantly lower rates of atrial fibrillation (4-7% vs 16%) and hypertension (3-7% vs higher with ibrutinib) 6, 7, 5
• Preferred in patients with cardiovascular comorbidities 7
• Monitor for arrhythmias and manage appropriately; consider switching therapy if not medically controllable 1

Common Adverse Events:

• Headache occurs in 39-51% of patients, typically resolves within 1-2 months, managed with acetaminophen and caffeine supplements 6, 7, 8
• Diarrhea in 52-58% (grade ≥3 in 5%) 7, 8
• Musculoskeletal pain including back and leg pain in 21% 7
• Do not discontinue prematurely for headaches as they are self-limited 7

Bleeding Risk:

• Overall bleeding risk 26-39% for any grade, but only 2% for grade ≥3 6, 7
• Avoid concomitant warfarin use 6, 7
• Monitor patients requiring antiplatelet or anticoagulant therapies 6, 1

Hematologic Monitoring:

• Monitor complete blood counts regularly 1
• Grade ≥3 neutropenia in 14-19%, thrombocytopenia in 7-9%, anemia in 7-15% 7

Infections:

• Overall infection rate 65%, with grade ≥3 infections in 14% 6, 7
• Monitor for signs and symptoms of infection and treat promptly 1

Hepatotoxicity:

• Monitor hepatic function throughout treatment 1

Second Primary Malignancies:

• Other malignancies including skin cancers and solid tumors have occurred 1
• Advise patients to use sun protection 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

Clinical Context for Switching from Ibrutinib

For Patients Intolerant to Ibrutinib:

• Acalabrutinib is well-tolerated in patients who discontinued ibrutinib due to intolerance 8
• Of 61 ibrutinib-related adverse events, 72% did not recur and 13% recurred at lower grade with acalabrutinib 8
• Overall response rate was 76% with median progression-free survival not reached in this population 8