OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Zanubrutinib – Brukinsa®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Zanubrutinib	1691249-45-2	C27-H29-N5-O3

ANNOTATED BIBLIOGRAPHY

References updated: 16 December 2019

• Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.

  (Review of hepatotoxicity published in 1999 before the availability of tyrosine kinase receptor inhibitors).
• DeLeve LD. Kinase inhibitors. Gefitinib. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, p. 556.

  (Review of hepatotoxicity of cancer chemotherapeutic agents, does not discuss the Bruton tyrosine kinase inhibitors).
• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2019/213217Orig1s000MultidisciplineR.pdf .

  (FDA website with product labels and initial medical review of the safety and efficacy of zanubrutinib; mentions on pages 116-117 that ALT elevations arose in 26% of patients but were above 5 times ULN in less than 1% and that no instance of severe hepatic injury was reported ).
• Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013;369:507–16. [PMC free article: PMC4513941] [PubMed: 23782157]

  (Among 111 patients with refractory mantle cell lymphoma treated with ibrutinib for 1-24 months, the objective response rate was 68% [complete in 21%]; listing of side effects does not include ALT elevations or hepatotoxicity).
• Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, Grant B, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32–42. [PMC free article: PMC3772525] [PubMed: 23782158]

  (Among 85 patients with refractory CLL treated with ibrutinib as a single agent, the overall response rate was 71%; side effects included diarrhea [49%], fatigue [32%], cough [31%], arthralgias [27%], rash [27%], fever [27%], peripheral edema [21%] and hypertension [18%]; ALT elevations and hepatotoxicity were not listed or mentioned).
• Ponader S, Burger JA. Bruton's tyrosine kinase: from X-linked agammaglobulinemia toward targeted therapy for B-cell malignancies. J Clin Oncol. 2014;32:1830–9. [PMC free article: PMC5073382] [PubMed: 24778403]

  (History of discovery of X-linked agammaglobulinemia, identification of BTK as its cause, elucidation of role of BTK in the pathway of B cell activation, and development of BTK inhibitors including ibrutinib).
• Ibrutinib (Imbruvica) for chronic lymphocytic leukemia. Med Lett Drugs Ther. 2014;56(1440):29–30. [PubMed: 24736247]

  (Concise review of mechanism of action, efficacy, safety and cost of ibrutinib shortly after its approval for use in the US, mentions that serious adverse events include cytopenias, bleeding and infections; no mention of ALT elevations or hepatotoxicity).
• de Jésus Ngoma P, Kabamba B, Dahlqvist G, Sempoux C, Lanthier N, Shindano T, Van Den Neste E, Horsmans Y. Occult HBV reactivation induced by ibrutinib treatment: a case report. Acta Gastroenterol Belg. 2015;78:424–6. [PubMed: 26712054]

  (80 year old man with refractory CLL had anti-HBc in serum without HBsAg but with low levels of HBV DNA [85 IU/mL] and developed reactivation of hepatitis B 5 months after starting ibrutinib [HBV DNA 23 million IU/mL, HBsAg positive, ALT 103 U/L], responding to entecavir with decline in HBV DNA and ALT levels but remaining HBsAg positive).
• Walter HS, Rule SA, Dyer MJ, Karlin L, Jones C, Cazin B, Quittet P, et al. A phase 1 clinical trial of the selective BTK inhibitor ONO/GS-4059 in relapsed and refractory mature B-cell malignancies. Blood. 2016;127:411–9. [PMC free article: PMC4731845] [PubMed: 26542378]

  (Among 90 patients with B-cell malignancies treated with zanubrutinib in escalating doses, response rates were highest in those with CLL [96%] and mantel cell lymphoma [92%], and adverse events included anemia [32%], thrombocytopenia [18%], diarrhea [18%], rash [18%], fever [13%], neutropenia [12%], nausea [12%] and cough [11%]; no mention of ALT elevations or hepatotoxicity).
• Nandikolla AG, Derman O, Nautsch D, Liu Q, Massoumi H, Venugopal S, Braunschweig I, Janakiram M. Ibrutinib-induced severe liver injury. Clin Case Rep. 2017;5:735–8. [PMC free article: PMC5458017] [PubMed: 28588800]

  (62 year old man with refractory CLL and hematopoietic cell transplant was started on ibrutinib and developed progressive liver injury [bilirubin 7.0 rising to 35.2 mg/dL, ALT 743 U/L, Alk P 486 U/L], which persisted despite stopping ibrutinib until he died of progressive disease 4 months later).
• Kahn A, Horsley-Silva JL, Lam-Himlin DM, Reeder CB, Douglas DD, Carey EJ. Ibrutinib-induced acute liver failure. Leuk Lymphoma. 2018;59:512–4. [PubMed: 28693376]

  (59 year old woman with Waldenström's macroglobulinemia developed fatigue 9 months after starting ibrutinib [bilirubin 2.5 rising to 13.6 mg/dL, ALT 441 U/L, AST 2707 U/L, Alk P 159 U/L, INR 7.7, lactate 9.4 mmol/L], with slow resolution after stopping).
• Wong J, Cher L, Griffiths J, Cohen A, Huang J, Wang L, Gregory G, et al. Efficacy of zanubrutinib in the treatment of Bing-Neel Syndrome. HemaSphere. 2018;2:e155. [PMC free article: PMC6745965] [PubMed: 31723793]

  (74 year old man with relapsed and refractory Waldenström macroglobulinemia and cervical and thoracic cord tumor infiltration had a clinical response to a 15 month course of zanubrutinib; no mention of adverse reactions or hepatotoxicity).
• Guo Y, Liu Y, Hu N, Yu D, Zhou C, Shi G, Zhang B, et al. Discovery of zanubrutinib (BGB-3111), a novel, potent, and selective covalent inhibitor of Bruton's tyrosine kinase. J Med Chem. 2019;62:7923–40. [PubMed: 31381333]

  (Description of development and characterization of zanubrutinib, a second generation and more selective inhibitor of Bruton’s tyrosine kinase than ibrutinib having less activity against other kinase families such as EGFR and Src).
• Tam CS, Trotman J, Opat S, Burger JA, Cull G, Gottlieb D, Harrup R, et al. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019;134:851–9. [PMC free article: PMC6742923] [PubMed: 31340982]

  (Among 89 patients with B cell malignancies treated with zanubrutinib [320 mg daily], the overall response rate was 96% and adverse events were common but generally mild-to-moderate; no mention of ALT elevations or hepatotoxicity and no liver related serious adverse events).