Ibrutinib (Imbruvica)

General information

Class/mechanism: Irreversible inhibitor of Bruton's tyrosine kinase (BTK), which is an enzyme that participates in the B-cell receptor (BCR) signal cascade and cytokine receptor pathways. BCR signaling is believed to promote cell proliferation, adhesion, and survival in B-cell malignancies. Inhibition of BTK interferes with the processes above, as well as B-cell chemotaxis and trafficking.
Route: PO
Extravasation: n/a

For conciseness and simplicity, HemOnc.org currently will focus on treatment regimens and not list information such as: renal/hepatic dose adjustments, metabolism (including CYP450), excretion, monitoring parameters (although this will be considered for checklists), or manufacturer. Instead, for the most current information, please refer to your preferred pharmacopeias such as Micromedex, Lexicomp, UpToDate (courtesy of Lexicomp), or the prescribing information.

Resistance mechanisms

1. Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, Xue L, Li DH, Steggerda SM, Versele M, Dave SS, Zhang J, Yilmaz AS, Jaglowski SM, Blum KA, Lozanski A, Lozanski G, James DF, Barrientos JC, Lichter P, Stilgenbauer S, Buggy JJ, Chang BY, Johnson AJ, Byrd JC. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014 Jun 12;370(24):2286-94. Epub 2014 May 28. link to original article PubMed

Significant side effects

1. Review: Leong DP, Caron F, Hillis C, Duan A, Healey JS, Fraser G, Siegal D. The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis. Blood. 2016 Jul 7;128(1):138-40. Epub 2016 May 31. link to original article PubMed
2. Review: Caron, F., Leong, D. P., Hillis, C., Fraser, G., & Siegal, D. (2017). Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis. Blood Advances, 1(12), 772-778. link to original article
3. Review: Tillman BF, Pauff JM, Satyanarayana G, Talbott M, Warner JL. Systematic review of infectious events with the Bruton tyrosine kinase inhibitor ibrutinib in the treatment of hematologic malignancies. Eur J Haematol. 2018 Apr;100(4):325-334. Epub 2018 Feb 6. link to original article PubMed
4. Ghez D, Calleja A, Protin C, Baron M, Ledoux MP, Damaj G, Dupont M, Dreyfus B, Ferrant E, Herbaux C, Laribi K, Le Calloch R, Malphettes M, Paul F, Souchet L, Truchan-Graczyk M, Delavigne K, Dartigeas C, Ysebaert L; on behalf on the French Innovative Leukemia Organization (FILO) CLL group. Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib. Blood. 2018 Apr 26;131(17):1955-1959. Epub 2018 Feb 1. link to original article PubMed

Diseases for which it is used

• Chronic lymphocytic leukemia (CLL/SLL)
• Diffuse large B-cell lymphoma
• Follicular lymphoma
• Graft versus host disease (GVHD)
• Mantle cell lymphoma
• Marginal zone lymphoma
• Waldenström macroglobulinemia

Patient drug information

• Ibrutinib (Imbruvica) package insert
• Ibrutinib (Imbruvica) patient drug information (Chemocare)
• Ibrutinib (Imbruvica) patient drug information (UpToDate)

History of changes in FDA indication

• 11/13/2013: FDA granted accelerated approval "for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy."
• 2/12/2014: FDA granted accelerated approval "for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy."
• 7/28/2014: FDA approval expanded to include patients with chronic lymphocytic leukemia (CLL) who carry a deletion in chromosome 17 (17p deletion).
• 1/29/2015: FDA approval expanded "for the treatment of patients with Waldenström’s macroglobulinemia (WM)."
• 3/4/2016: FDA approval expanded "for the treatment of patients with chronic lymphocytic leukemia (CLL)."
• 1/18/2017: FDA accelerated approval for treatment of patients with "marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy."
• 8/2/2017: FDA indication expanded "for the treatment of adult patients with chronic graft versus host disease (cGVHD) after failure of one or more lines of systemic therapy."

Also known as

• Code names: CRA-032765, PCI-32765
• Brand name: Imbruvica