Ibrutinib — Drug Monograph

Brand names: Imbruvica

Drug class: Tyrosine Kinase Inhibitor

Mechanism of Action

First-in-class, orally bioavailable, covalent inhibitor of Bruton's tyrosine kinase (BTK). Ibrutinib irreversibly forms a covalent bond with a cysteine residue (Cys481) in the BTK active site, permanently inhibiting BTK signaling. BTK is essential for B-cell receptor (BCR) signaling, proliferation, trafficking, and survival. Ibrutinib also inhibits EGFR and ITK, contributing to both efficacy and toxicity (especially atrial fibrillation).

FDA Indications

• CLL/SLL — first-line and relapsed/refractory
• Mantle cell lymphoma (MCL) — relapsed/refractory
• Waldenström macroglobulinemia
• Marginal zone lymphoma — relapsed/refractory (with or without CD20)
• Chronic graft-versus-host disease (cGVHD) — after failure of ≥1 prior therapy
• Marginal zone lymphoma — first-line (with obinutuzumab)

Common Side Effects

• Diarrhea
• Fatigue
• Musculoskeletal pain
• Bruising
• Nausea
• Atrial fibrillation/flutter
• Rash
• Hypertension

Clinical Pearl

The newer BTK inhibitors acalabrutinib (Calquence) and zanubrutinib (Brukinsa) have greater BTK selectivity (less off-target inhibition of EGFR, ITK, TEC) resulting in lower rates of atrial fibrillation, bleeding, and rash compared to ibrutinib. They are preferred in patients with cardiac risk factors or those requiring anticoagulation.

Related Therapies & Mechanisms

• Methotrexate (Trexall) — Leukemia
• Rituximab (Rituxan) — Lymphoma
• Idelalisib (Zydelig) — Tyrosine Kinase Inhibitor · Leukemia
• Acalabrutinib (Calquence) — Lymphoma