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 DP, Hillis C, Fraser G, Siegal D. Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis. Blood Adv. 2017 May 9;1(12):772-778. eCollection 2017 May 9. Review. link to original article link to PMC article PubMed
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
5. Dickerson T, Wiczer T, Waller A, Philippon J, Porter K, Haddad D, Guha A, Rogers KA, Bhat S, Byrd JC, Woyach JA, Awan F, Addison D. Hypertension and incident cardiovascular events following ibrutinib initiation. Blood. 2019 Nov 28;134(22):1919-1928. link to original article PubMed

Diseases for which it is used

• Chronic lymphocytic leukemia
• Diffuse large B-cell lymphoma
• Follicular lymphoma
• Graft versus host disease
• Mantle cell lymphoma
• Marginal zone lymphoma
• T-cell prolymphocytic leukemia
• 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

Chronic graft versus host disease (cGVHD)

• 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. (Based on PCYC-1129-CA)

Chronic lymphocytic leukemia

• 2/12/2014: Granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. (Based on PCYC-1102, RESONATE, HELIOS)
• 7/28/2014: Converted to regular approval and approval expanded to include patients with chronic lymphocytic leukemia (CLL) who carry a deletion in chromosome 17 (17p deletion). (Based on RESONATE and iLLUMINATE)
• 3/4/2016: Approval expanded for the treatment of patients with chronic lymphocytic leukemia (CLL). (Based on RESONATE-2 and HELIOS)
• 4/21/2020: Approval expanded to include its combination with rituximab for the initial treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). (Based on ECOG E1912)

Mantle cell lymphoma

• 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. (Based on PCYC-1104-CA)

Marginal zone lymphoma

• 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. (Based on PCYC-1121-CA)

Waldenström macroglobulinemia

• 1/29/2015: FDA approval expanded for the treatment of patients with Waldenström’s macroglobulinemia (WM). (Based on DFCI 12-015 and iNNOVATE)

Also known as

• Code names: CRA-032765, PCI-32765
• Brand names: Ibrunib, Ibrutix, Imbruvica, Lucibru