Calquence (Acalabrutinib)
acalabrutinib
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| CLL or SLL | Adults | Monotherapy, or combination with obinutuzumab | FDA Approved |
| CLL or SLL — with venetoclax | Adults (previously untreated, no del(17p)/TP53 mutation) | Fixed-duration combination (up to 14 cycles) | FDA Approved (Feb 2026) |
| Previously untreated MCL — with BR | Adults ineligible for autologous HSCT | Combination with bendamustine + rituximab | FDA Approved |
| Previously treated MCL | Adults (≥1 prior therapy) | Monotherapy | Accelerated Approval |
Acalabrutinib is a second-generation, highly selective covalent BTK inhibitor that has become a preferred treatment option for CLL/SLL across all lines of therapy. Its greater selectivity for BTK compared with ibrutinib translates into a lower incidence of off-target cardiac and vascular toxicities, particularly atrial fibrillation and hypertension. In February 2026, acalabrutinib received approval in combination with venetoclax as the first all-oral, fixed-duration regimen for previously untreated CLL based on the AMPLIFY trial. The MCL monotherapy indication remains under accelerated approval, with continued approval contingent on confirmatory trial results.
Waldenström macroglobulinemia: Case series and retrospective data support activity in WM, particularly in patients intolerant of ibrutinib. Evidence quality: Low (retrospective/case series).
Ibrutinib-intolerant CLL/SLL: Phase 2 data demonstrate successful switch to acalabrutinib in patients who discontinued ibrutinib due to intolerance. Evidence quality: Moderate (prospective Phase 2).
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| CLL/SLL — monotherapy (any line) | 100 mg BID | 100 mg BID | 200 mg/day | Continue until progression or intolerance Take approximately every 12 hours; with or without food |
| CLL/SLL — with obinutuzumab (treatment-naïve) | 100 mg BID | 100 mg BID | 200 mg/day | Start acalabrutinib Cycle 1; start obinutuzumab Cycle 2 for 6 cycles Give acalabrutinib before obinutuzumab on same day |
| CLL/SLL — with venetoclax (treatment-naïve, fixed-duration) | 100 mg BID | 100 mg BID | 200 mg/day | Up to 14 cycles (28-day cycles); venetoclax starts Cycle 3 with 5-week ramp-up AMPLIFY trial-based; first all-oral fixed-duration CLL regimen |
| Previously untreated MCL — with BR (ineligible for auto-HSCT) | 100 mg BID | 100 mg BID | 200 mg/day | Start Cycle 1 Day 1; BR for 6 cycles; maintenance rituximab every other cycle up to Cycle 30 Acalabrutinib continues beyond BR until progression |
| Previously treated MCL — monotherapy | 100 mg BID | 100 mg BID | 200 mg/day | After ≥1 prior therapy; continue until progression or intolerance Accelerated approval indication |
Dose Modifications for Drug Interactions
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| With moderate CYP3A4 inhibitor | 100 mg once daily | 100 mg once daily | 100 mg/day | 50% frequency reduction Resume BID after inhibitor discontinued |
| With unavoidable strong CYP3A4 inducer | 200 mg BID | 200 mg BID | 400 mg/day | Doubled dose to compensate for reduced exposure Avoid strong inducers when possible |
The capsule formulation requires gastric acidity for optimal absorption. Avoid concomitant proton pump inhibitors (PPIs) with capsules. Take acalabrutinib capsules 2 hours before H2-receptor antagonists, and separate from antacids by at least 2 hours. The tablet formulation (acalabrutinib maleate) has pH-independent release and can be co-administered with PPIs without exposure reduction.
For Grade 3 or greater non-haematologic toxicities, Grade 3 thrombocytopenia with bleeding, or Grade 4 cytopenias lasting more than 7 days: interrupt acalabrutinib until recovery to Grade 1 or baseline. First and second occurrence: resume at 100 mg BID. Third occurrence: resume at 100 mg once daily. Fourth occurrence: discontinue permanently.
Pharmacology
Mechanism of Action
Acalabrutinib is a second-generation, highly selective, irreversible covalent inhibitor of Bruton tyrosine kinase (BTK). It binds to cysteine-481 in the BTK active site via a 2-butynamide warhead that exhibits lower non-specific reactivity than the acrylamide warheads used in first-generation BTK inhibitors. This selectivity profile means acalabrutinib has minimal inhibitory activity against off-target kinases including EGFR, ITK, TEC, and Src family kinases at clinically relevant concentrations, which contributes to a more favourable cardiovascular and bleeding safety profile compared with ibrutinib. By inhibiting BTK, acalabrutinib blocks B-cell receptor signalling, disrupting downstream NF-kB and PI3K/Akt activation, thereby reducing malignant B-cell proliferation, survival, adhesion, and tissue migration. Like ibrutinib, acalabrutinib produces a redistribution lymphocytosis early in treatment that is pharmacodynamic in nature and resolves over time. Twice-daily dosing achieves sustained near-complete BTK occupancy despite the short plasma half-life of the parent compound.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapid; median Tmax 0.5–1 h; absolute bioavailability 25%; food does not affect AUC but decreases Cmax by 54–73% | Can be taken with or without food; capsule absorption is pH-dependent—avoid PPIs with capsule formulation |
| Distribution | Vss ~101 L; protein binding 97.5% (parent), 98.6% (ACP-5862); blood-to-plasma ratio 0.8 | Moderate volume of distribution; no clinically significant displacement interactions expected |
| Metabolism | Hepatic via CYP3A4 (primary) to active metabolite ACP-5862 (pyrrolidine ring-opened); ACP-5862 has approximately half the potency of parent against BTK | CYP3A4 dependence creates significant interaction potential; ACP-5862 contributes to overall pharmacological activity with a longer half-life |
| Elimination | Parent t½ ~1–2 h; ACP-5862 t½ ~6.4 h; CL/F ~159 L/h; 84% faecal (<2% unchanged), 12% renal | Very short parent half-life but sustained BTK occupancy from irreversible binding and active metabolite; BID dosing essential; no renal dose adjustment needed |
Side Effects
Adverse reaction data below are derived from the pooled safety population of 1,764 patients with haematologic malignancies who received acalabrutinib 100 mg approximately every 12 hours in clinical trials (FDA PI, revised January 2025). Acalabrutinib was given as monotherapy (1,256 patients) or in combination (508 patients); 88% were exposed for at least 6 months and 80% for at least 1 year.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea | 37% | Usually Grade 1–2; self-limiting; loperamide for symptom control |
| Upper respiratory tract infection | 36% | Includes nasopharyngitis and sinusitis; Grade 3+ uncommon (≤3%) |
| Headache | 35% | Often Grade 1; characteristic of acalabrutinib; usually resolves within first months |
| Musculoskeletal pain | 33% | Includes back pain, myalgia, arthralgia; Grade 3+ in 1–5% |
| Lower respiratory tract infection | 32% | Includes pneumonia (9%), bronchitis; Grade 3+ in 6–17% (higher with combo) |
| Fatigue | 32% | Usually Grade 1–2; manageable with supportive care |
| Neutropenia (lab) | 23–53% | All grades; Grade 3/4 ANC decreased in 26% (monotherapy + obinutuzumab); Grade 4 in 14% |
| Anaemia (lab) | 47–53% | All grades; Grade 3+ in 10–15% |
| Thrombocytopenia (lab) | 32–51% | All grades; Grade 3/4 in 3–12%; monitor CBC regularly |
| Bruising | 10–31% | Includes contusion and ecchymosis; typically cosmetic; Grade 3+ very rare |
| Rash | 9–26% | Includes dermatitis and related terms; Grade 3+ in 0.6–2%; may require dose interruption in MCL combination setting (up to 12%) |
| Haemorrhage (any, excl. bruising) | 40% | Any-grade bleeding events excluding bruising/petechiae |
| Second primary malignancy | 18% | NMSC 10%; other solid tumours 9%; haematologic 1%; annual skin exam recommended |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Atrial fibrillation / flutter | 3.6–7% | All grades; Grade 3/4 in 2.6%; significantly lower than ibrutinib (9.4% vs 16% in ELEVATE-RR) |
| Hypertension | 3–5% | Lower incidence than ibrutinib; monitor BP at each visit |
| Arthralgia | 8–22% | Usually Grade 1–2; manageable with analgesics |
| Nausea | 19–22% | Grade 3 rare; usually transient |
| Urinary tract infection | 5–15% | Grade 3+ in 1–3% |
| Constipation | 15–25% | Grade 3 in ≤1% |
| Dizziness | 5–20% | Usually Grade 1; self-limiting |
| Peripheral oedema | 5–20% | Usually Grade 1–2 |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Serious / Grade 3+ infections | 32% | Throughout treatment | Evaluate promptly; respiratory tract infections most common (19%); pneumonia in 9%; consider PJP/antifungal prophylaxis; PML reported |
| Major haemorrhage (≥Grade 3 / serious / CNS) | 4.4% | Any time; cumulative risk | Hold acalabrutinib; fatal haemorrhage in 0.2%; withhold 3–7 days pre/post-surgery; caution with antithrombotics |
| Grade 3/4 atrial fibrillation / flutter | 2.6% | Variable; cumulative | ECG; cardiology referral; rate/rhythm control; evaluate benefit-risk of continuation |
| Ventricular arrhythmias (Grade 3+) | 0.6% | Variable | Fatal in 0.3%; urgent cardiology evaluation; consider permanent discontinuation |
| Grade 3/4 cytopenias | ANC 26%; ALC 23%; Plt 10%; Hb 10% | First months; monitor monthly | Hold acalabrutinib; G-CSF for neutropenia; transfuse as needed; resume per dose modification table |
| Drug-induced liver injury (DILI) | Rare (postmarketing) | Variable | Monitor LFTs; withhold if suspected; permanently discontinue if confirmed |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Infections (including COVID-19) | Most common in MCL+BR | COVID-19 and pneumonia were leading causes in ECHO trial (43% overall discontinuation with longer follow-up) |
| Second primary malignancies | Notable in ASCEND | NMSC and other solid tumours; 18% overall SPM rate |
| Atrial fibrillation | Lower than ibrutinib | Lower AF-driven discontinuation vs ibrutinib (14.7% vs 21.3% for all-AE discontinuation in ELEVATE-RR) |
Headache occurs in approximately 35% of patients receiving acalabrutinib, which is notably more frequent than with ibrutinib. It is typically Grade 1 in severity, occurs early in treatment, and usually resolves within the first few months without dose modification. Simple analgesics (paracetamol) are effective; if headache is severe or persistent, ensure adequate hydration and consider caffeine intake patterns.
Drug Interactions
Acalabrutinib is extensively metabolised by CYP3A4 and its capsule formulation requires gastric acidity for optimal absorption, creating two distinct axes of clinically significant interactions. Acalabrutinib is also an inducer of CYP1A2, CYP2B6, and CYP3A4, and an inhibitor of BCRP. Co-administration with itraconazole (strong CYP3A4 inhibitor) increased acalabrutinib exposure approximately 2–3-fold.
Monitoring
- Complete Blood CountRegularly during treatment
RoutineGrade 3/4 cytopenias: ANC decreased 26%, ALC decreased 23%, platelets 10%, Hb 10%, Grade 4 neutropenia 14%. Interrupt, reduce, or discontinue per dose modification guidelines. - Hepatic FunctionBaseline, then periodically
RoutineBilirubin and transaminases at baseline and throughout treatment. DILI has been reported with BTK inhibitors including acalabrutinib (postmarketing). Increase monitoring frequency if abnormal values develop. - Cardiac RhythmBaseline + as indicated
RoutineAF/flutter all grades in 7%, Grade 3/4 in 2.6%. Ventricular arrhythmias Grade 3+ in 0.6% (fatal in 0.3%). Evaluate symptoms of palpitations, syncope, or dyspnoea with ECG. Higher risk with cardiac comorbidities. - Bleeding SignsEach visit; ongoing
RoutineMajor haemorrhage in 4.4%, fatal in 0.2%. Assess bruising, petechiae, and signs of internal bleeding. Withhold 3–7 days pre/post-surgery depending on procedure type and bleeding risk. - Infection SurveillanceEach visit; ongoing
RoutineSerious/Grade 3+ infections in 32%. Respiratory tract infections most common (19%); neutropenic infection in 2.7%. Consider PJP and antifungal prophylaxis. Evaluate new neurological symptoms for PML. HBV reactivation can occur—screen before initiation. - Skin ExaminationBaseline, then annually
RoutineSecond primary malignancies in 18%, NMSC in 10%, other solid tumours in 9%. Advise sun protection. Annual dermatological review recommended. - Blood PressureEach visit
RoutineHypertension reported in 3–5% (lower than ibrutinib). Initiate antihypertensives as needed. - Pregnancy StatusBefore initiation
Trigger-basedVerify pregnancy status in females of reproductive potential. Advise contraception during treatment and for 1 week after last dose. May cause fetal harm and dystocia.
Contraindications & Cautions
Absolute Contraindications
- Pregnancy: Animal studies demonstrated fetal harm (reduced growth in rabbits) and dystocia (rats) at exposures 2 times the human dose. Must not be used in pregnant women.
- Severe hepatic impairment: PK data unavailable; markedly increased exposure expected. Use should be avoided.
Relative Contraindications (Specialist Input Recommended)
- Active severe bleeding or recent CNS haemorrhage: Major haemorrhage rate 4.4% with fatal events in 0.2%. Specialist risk-benefit assessment required.
- Concomitant strong CYP3A4 inhibitor therapy (chronic): 2–3-fold exposure increase with strong inhibitors. Avoid if possible; short-term use (≤7 days) requires acalabrutinib interruption.
- Pre-existing uncontrolled atrial fibrillation: Although AF risk is lower than ibrutinib, pre-existing arrhythmias warrant cardiology input before initiation.
Use with Caution
- Patients on anticoagulants or antiplatelet agents: Additive bleeding risk. Avoid warfarin; DOACs preferred if anticoagulation required.
- Patients on PPIs (capsule formulation): Switch to tablet formulation or alternative acid-reducing strategy to avoid absorption impairment.
- Elderly (≥65 years): 67% of the pooled safety population were ≥65. Grade 3 or higher adverse reactions were more common in older patients.
- Patients with cardiac risk factors: Higher susceptibility to arrhythmias; baseline cardiac evaluation recommended.
- Planned surgery within 3–7 days: Withhold acalabrutinib peri-operatively due to haemorrhagic risk.
- Patients at risk for HBV reactivation: Screen for hepatitis B before starting; reactivation has been reported.
Fatal and serious cardiac arrhythmias have occurred with acalabrutinib. Grade 3 or 4 atrial fibrillation or flutter was reported in 2.6% of 1,764 treated patients. All-grade AF/flutter occurred in 7%. Grade 3 or higher ventricular arrhythmia events were reported in 0.6%, including fatal cases in 0.3%. The risk may be increased in patients with cardiac risk factors, hypertension, prior arrhythmias, and acute infection.
Severe, life-threatening, and potentially fatal cases of DILI have been reported with BTK inhibitors, including acalabrutinib. Monitor bilirubin and transaminases at baseline and throughout treatment. Withhold if DILI is suspected; permanently discontinue if confirmed.
Patient Counselling
Purpose of Therapy
Acalabrutinib works by blocking a protein called BTK that cancer cells need to grow and survive. It is a targeted oral therapy—not traditional chemotherapy. Most patients take it twice daily as a continuous treatment to keep their disease under control. A temporary rise in white blood cell count or swelling of lymph nodes early in treatment is expected and is not a sign of treatment failure.
How to Take
Take one capsule or tablet twice daily, approximately 12 hours apart, with or without food. Swallow capsules whole—do not open, break, or chew them. Tablets should not be crushed or cut. If a dose is missed by more than 3 hours, skip it and take the next dose at the scheduled time. Never double up on doses.
Sources
- Calquence (acalabrutinib) capsules prescribing information. AstraZeneca Pharmaceuticals LP. Revised January 2025. FDA Label (Capsules)Primary source for all dosing, indications, adverse reactions, warnings, and pharmacokinetic data in this monograph.
- Calquence (acalabrutinib) tablets prescribing information. AstraZeneca Pharmaceuticals LP. 2025. FDA Label (Tablets)Tablet formulation PI with pH-independent PK data and additional clinical information.
- Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naïve chronic lymphocytic leukaemia (ELEVATE-TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278–1291. doi:10.1016/S0140-6736(20)30262-2Pivotal Phase 3 trial demonstrating superiority of acalabrutinib ± obinutuzumab over chlorambucil-obinutuzumab in treatment-naïve CLL.
- Ghia P, Pluta A, Wach M, et al. Acalabrutinib versus investigator’s choice in relapsed/refractory chronic lymphocytic leukemia: final ASCEND trial results. Hemasphere. 2022;6(12):e801. doi:10.1097/HS9.0000000000000801Final 4-year analysis of ASCEND trial confirming durable PFS benefit of acalabrutinib monotherapy in relapsed/refractory CLL.
- Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol. 2021;39(31):3441–3452. doi:10.1200/JCO.21.01210ELEVATE-RR trial; first head-to-head Phase 3 comparison of two BTK inhibitors, demonstrating noninferior PFS and lower AF with acalabrutinib.
- Wang M, Rule S, Zinzani PL, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018;391(10121):659–667. doi:10.1016/S0140-6736(17)33108-2Registration trial supporting accelerated approval in previously treated MCL; demonstrated 81% ORR.
- FDA Press Release: FDA approves acalabrutinib with venetoclax for chronic lymphocytic leukemia or small lymphocytic lymphoma. February 19, 2026. FDARegulatory announcement for the AMPLIFY trial-based approval of the first all-oral fixed-duration CLL regimen.
- National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Version 2.2026. NCCNPositions acalabrutinib as a preferred BTK inhibitor option for CLL/SLL across treatment lines.
- Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): a covalent Bruton tyrosine kinase inhibitor with a differentiated selectivity and in vivo potency profile. J Pharmacol Exp Ther. 2017;363(2):240–252. doi:10.1124/jpet.117.242909Preclinical characterisation of acalabrutinib demonstrating its selectivity advantage over ibrutinib across a kinase panel.
- Wu J, Zhang M, Liu D. Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor. J Hematol Oncol. 2016;9:21. doi:10.1186/s13045-016-0250-9Review of acalabrutinib’s mechanism of action, selectivity profile, and early clinical development.
- Podoll T, Pearson PG, Evarts J, et al. Bioavailability, biotransformation, and excretion of the covalent Bruton tyrosine kinase inhibitor acalabrutinib in rats, dogs, and humans. Drug Metab Dispos. 2019;47(2):145–154. doi:10.1124/dmd.118.084459Human mass balance and bioavailability study confirming 25% oral bioavailability and metabolic pathways.
- Edlund H, Melin J, Parra-Guillen ZP, et al. Population pharmacokinetics of the BTK inhibitor acalabrutinib and its active metabolite in healthy volunteers and patients with B-cell malignancies. Clin Pharmacokinet. 2019;58(5):659–672. doi:10.1007/s40262-018-0731-8Population PK model characterising acalabrutinib and ACP-5862 absorption, distribution, and elimination.
- Sharma S, Lau H, Engst S, et al. Bioequivalence and relative bioavailability studies to assess a new acalabrutinib formulation that enables coadministration with proton-pump inhibitors. Clin Pharmacol Drug Dev. 2023;12(1):78–89. doi:10.1002/cpdd.1153Bioequivalence data for the acalabrutinib maleate tablet demonstrating pH-independent release enabling PPI co-administration.
- Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib-obinutuzumab improves survival vs chemoimmunotherapy in treatment-naive CLL in the 6-year follow-up of ELEVATE-TN. Blood. 2025;146(11):1276–1288. doi:10.1182/blood.20240274686-year follow-up confirming sustained PFS benefit and consistent long-term safety profile of acalabrutinib in CLL.