Acalabrutinib
Overview
Acalabrutinib is an orally administered small‑molecule Bruton tyrosine kinase (BTK) inhibitor belonging to the class of targeted therapies used in certain B‑cell malignancies. BTK is a critical component of the B‑cell antigen receptor signalling pathway, which regulates proliferation, survival, and adhesion of malignant B cells. By forming a covalent bond with a cysteine residue in the active site of BTK, acalabrutinib inhibits its enzymatic activity, thereby blocking downstream signalling that drives malignant B‑cell growth and survival. This selective inhibition reduces off‑target effects compared with earlier BTK inhibitors while maintaining potent activity against malignant cells. Acalabrutinib’s mechanism supports its utility in conditions where aberrant BTK signalling contributes to disease progression, and it is administered orally, allowing for outpatient therapy with twice‑daily dosing. Its targeted action and improved tolerability profile have made acalabrutinib a significant option in managing mantle cell lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma, particularly in patients with relapsed or treatment‑naive disease where BTK inhibition is appropriate.
Background and Date of Approval
Acalabrutinib was developed as a second‑generation BTK inhibitor with enhanced selectivity and potency compared with earlier agents, aiming to improve tolerability while preserving efficacy. It first received regulatory approval from the United States Food and Drug Administration on 31 October 2017 for the treatment of adult patients with mantle cell lymphoma who have received at least one prior therapy. Subsequent regulatory actions expanded its use to include adult patients with chronic lymphocytic leukemia and small lymphocytic lymphoma. A tablet formulation enabling co‑administration with proton pump inhibitors was approved in August 2022. Acalabrutinib was approved for medical use in the European Union in November 2020, and additional regulatory updates in 2025 include expanded indications in combination with other agents for previously untreated mantle cell lymphoma. These approvals were supported by pivotal clinical trials demonstrating improvements in progression‑free survival and durable responses in BTK‑driven B‑cell malignancies.
Uses
Acalabrutinib is indicated for the treatment of adult patients with mantle cell lymphoma who have received at least one prior therapy. It is also indicated for the treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. In some regulatory jurisdictions, acalabrutinib is used in combination with bendamustine and rituximab for previously untreated mantle cell lymphoma in patients who are ineligible for autologous stem cell transplantation. These indications reflect its role in managing B‑cell malignancies where BTK signalling plays a central role in disease progression.
Administration
Acalabrutinib is administered orally, typically at a dose of 100 mg approximately every 12 hours. Tablets or capsules should be swallowed whole with water and may be taken with or without food. The twice‑daily schedule helps maintain near‑complete BTK occupancy over the treatment interval. Treatment is continued until disease progression or unacceptable toxicity, with routine monitoring guiding therapeutic decisions. Clinicians may adjust doses based on individual tolerability, organ function, and concurrent medications.
Side Effects
Common side effects observed with acalabrutinib include headache, diarrhea, fatigue, upper respiratory tract infections, bruising, anemia, thrombocytopenia, neutropenia, and muscle pain. Patients may also experience nausea and weight changes. These side effects vary among individuals and are generally manageable with supportive care, dose adjustments, or temporary interruption under medical supervision.
Warnings
Acalabrutinib carries warnings for serious adverse events including significant cytopenias such as neutropenia and thrombocytopenia, which can increase the risk of serious infections and bleeding. Cardiac events such as atrial fibrillation and hypertension have been reported, as well as severe hemorrhage and opportunistic infections. Use during pregnancy can cause fetal harm, and effective contraception is advised during treatment. Treatment should be interrupted or discontinued in cases of life‑threatening toxicities or severe organ dysfunction.
Precautions
Baseline assessments including complete blood counts, liver function tests, and evaluation of cardiovascular history are recommended before initiating acalabrutinib. Caution is required in patients with severe hepatic or renal impairment. Acalabrutinib is metabolised predominantly via hepatic pathways, and concomitant use of strong CYP3A4 inhibitors or inducers may alter drug exposure, necessitating dose adjustments or alternative therapy. Monitoring for signs of infection, bleeding, and organ dysfunction helps mitigate risks. Use during pregnancy or breastfeeding is not recommended due to potential harm to the fetus or infant.
Expert Tips
When prescribing acalabrutinib, assess patient comorbidities, blood counts, and concurrent medications to optimise safety. Counsel patients on correct administration timing and the importance of adherence to the twice‑daily schedule. Monitor complete blood counts frequently during the initial months of therapy and periodically thereafter, along with assessments of liver function and cardiovascular status. Educate patients to promptly report symptoms such as unusual bleeding, severe fatigue, or signs of infection. Coordination with supportive care and careful management of overlapping toxicities from combination regimens can enhance tolerability and therapeutic outcomes.