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

Acalabrutinib: Recommended Use and Dosage

Acalabrutinib (Calquence) is FDA-approved at 100 mg orally every 12 hours for chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL), with specific combination regimens available for treatment-naive MCL patients. 1

FDA-Approved Indications and Dosing

Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma

For CLL/SLL, acalabrutinib 100 mg orally every 12 hours is recommended as continuous therapy until disease progression or unacceptable toxicity. 1 This applies to both treatment-naive and relapsed/refractory disease. 2

• Combination option for treatment-naive CLL/SLL: Acalabrutinib 100 mg every 12 hours can be combined with obinutuzumab, starting acalabrutinib at Cycle 1 and adding obinutuzumab at Cycle 2 for 6 total cycles (28-day cycles). 1
• The ELEVATE-TN trial demonstrated 2-year progression-free survival rates of 93% with acalabrutinib plus obinutuzumab versus 47% with chlorambucil plus obinutuzumab. 2
• For relapsed CLL after prior chemoimmunotherapy or short remission (<36 months), acalabrutinib is a category 1 recommendation. 2

Mantle Cell Lymphoma

For previously untreated MCL in patients ineligible for autologous stem cell transplantation, acalabrutinib 100 mg every 12 hours is combined with bendamustine (90 mg/m² days 1-2) and rituximab (375 mg/m² day 1) for 6 cycles, followed by maintenance rituximab every other cycle for up to 12 additional doses. 1

• Start acalabrutinib on Day 1 of Cycle 1 and continue until disease progression or unacceptable toxicity. 1
• This combination achieved median progression-free survival of 66.4 months versus 49.6 months with bendamustine-rituximab alone (HR 0.73, p=0.0160). 3

For previously treated MCL (at least one prior therapy), acalabrutinib 100 mg every 12 hours as monotherapy is recommended. 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

Dose Modifications

Drug Interactions

Avoid strong CYP3A inhibitors; if unavoidable for short-term use (≤7 days), interrupt acalabrutinib and resume 24 hours after discontinuation. 1

• With moderate CYP3A inhibitors: Reduce dose to 100 mg once daily. 1
• With strong CYP3A inducers: Avoid co-administration; if unavoidable, increase dose to 200 mg every 12 hours. 1

Toxicity Management

For Grade 3+ non-hematologic toxicities, Grade 3 thrombocytopenia with bleeding, or Grade 4 neutropenia/thrombocytopenia lasting >7 days: 1

• First/second occurrence: Interrupt acalabrutinib until toxicity resolves to Grade 1 or baseline, then resume at 100 mg every 12 hours. 1
• Third occurrence: Interrupt until resolution, then resume at reduced frequency of 100 mg once daily. 1
• Fourth occurrence: Discontinue permanently. 1

Key Safety Considerations

Common Adverse Events

The most common adverse reactions (≥30%) are diarrhea (52-58%), upper respiratory tract infections, headache (22-51%), musculoskeletal pain (21%), and fatigue. 4, 5, 1

• Headaches typically resolve within 1-2 months and can be managed with acetaminophen and caffeine supplements—do not discontinue prematurely. 4, 5
• Diarrhea occurs in 58% of patients but is usually manageable. 4, 6

Cardiovascular Events

Acalabrutinib has a more favorable cardiovascular profile than ibrutinib, with atrial fibrillation occurring in 4-7% (Grade ≥3 in 1%) and hypertension in 3-7% (Grade ≥3 in 2-3%). 4, 5

• Monitor for arrhythmias and hypertension throughout treatment. 1
• Acalabrutinib is preferred over ibrutinib in patients with cardiovascular comorbidities. 5

Bleeding Risk

Overall bleeding risk is 26-39% for any grade but only 2% for Grade ≥3 bleeding. 4, 5

• Avoid concomitant warfarin use; monitor patients requiring antiplatelet or anticoagulant therapies closely. 4, 5

Infections and Cytopenias

Overall infection rate is 65% with Grade ≥3 infections in 14%; monitor for signs of infection and treat promptly. 4, 5, 1

• Grade ≥3 neutropenia occurs in 14-19%, thrombocytopenia in 7-9%, and anemia in 7-15%. 5
• Monitor complete blood counts regularly throughout treatment. 1

Other Warnings

Second primary malignancies, including skin cancers and solid tumors, have occurred—advise patients to use sun protection. 1

Hepatotoxicity including drug-induced liver injury can occur; monitor hepatic function throughout treatment. 1

Special Populations

Avoid acalabrutinib in patients with severe hepatic impairment. 1

Pregnancy: May cause fetal harm and dystocia. 1

Lactation: Advise patients not to breastfeed during treatment. 1

Clinical Context

The evidence strongly supports acalabrutinib as a highly effective BTK inhibitor with improved tolerability compared to ibrutinib. In treatment-naive CLL, acalabrutinib monotherapy achieved 97% overall response rate with 48-month duration of response rate of 97%. 7 For patients intolerant to ibrutinib, 72% of ibrutinib-related adverse events did not recur with acalabrutinib, and 13% recurred at lower grade. 6 The combination with bendamustine-rituximab in MCL represents a significant advance, providing superior progression-free survival with manageable toxicity across all risk subgroups. 3