Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase that is used in the therapy of refractory chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. Ibrutinib has not been associated with serum enzyme elevations during therapy but has been linked to rare cases of clinically apparent acute liver injury and to reactivation of hepatitis B.
Ibrutinib (eye broo’ ti nib) is an orally available, small molecule inhibitor of Bruton’s tyrosine kinase (BTK), which is an essential component in the B cell receptor signaling pathway. Inhibition of this pathway prevents B cell activation, differentiation and proliferation. Deficiency of BTK is the cause of X linked (Bruton’s) agammaglobulinemia, and B cell receptor signaling through BTK has been shown to be critical for proliferation and survival of malignant B lymphocytes in mantle cell lymphoma and CLL. Ibrutinib was approved for use in the United States as therapy for refractory mantle cell lymphoma in 2013 and for refractory CLL in 2014. Subsequently, it has been approved for use in Waldenstrom's macroglobulinemia, marginal zone lymphoma and chronic graft versus host disease after failure of standard therapy. Ibrutinib is available in capsules of 70 and 140 mg and as tablets of 140, 280, 420 and 560 mg under the brand name Imbruvica. The recommended dose is 420 (CLL) or 540 (lymphoma) mg orally, once daily. Side effects are common, but usually mild-to-moderate in severity; they include myelosuppression, fatigue, diarrhea, nausea, vomiting, anorexia, constipation, peripheral edema, dyspnea, arthralgia, myalgia, rash and fever. Uncommon, but potentially serious side effects include severe bone marrow suppression, infections, bleeding, cardiac arrhythmias, hypertension, tumor lysis syndrome and embryo-fetal toxicity.
In the pre-licensure clinical trials of ibrutinib in patients with CLL and mantle cell lymphoma, the rates of serum enzyme elevations during therapy were 20% to 30% but were similar to comparator arms, and elevations were generally mild (less than 5 times ULN) and self limited. In multiple controlled trials there were no reports of clinically apparent liver injury or need for early discontinuation because of hepatotoxicity. The major toxicities of ibrutinib resembled those of the tyrosine kinase receptor inhibitors and included hemorrhage and myelosuppression. While ibrutinib depressed peripheral lymphocyte counts and caused both lymphopenia and neutropenia, but it has little effect on serum immunoglobulin levels and was not associated with reactivation of tuberculosis or opportunitistic infections in pre-licensure studies. Nevertheless, with approval and more wide-spread use of ibrutinib, rare cases of acute liver injury including acute liver failure and severe instances of reactivation of hepatitis B have been reported. The latency to onset of liver injury varied from several weeks to 9 months. The pattern of injury was hepatocellular but the course was atypical of an acute hepatitis like injury and more similar to acute hepatic necrosis with early onset of hepatic failure.
Likelihood score: D (possible rare cause of clinically apparent liver injury).
Mechanism of Injury
The clinical features of reported cases of liver injury from ibrutinib suggested a direct hepatotoxicity, but the relationship of the injury to the kinase inhibitor was not entirely clear. Reactivation of hepatitis B is likely due to the profound inhibition of B cell activity as occurs with rituximab (anti-CD20) which appears to lead to increased viral replication due to immune suppression, followed by immune recovery and acute liver injury. Ibrutinib is metabolized in the liver via the cytochrome P450 system, largely CYP 3A4 and is susceptible to drug-drug interactions with agents that inhibit or induce this enzyme reactivity.
Outcome and Management
Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose reduction or temporary cessation. In patients with clinically apparent liver injury and jaundice, restarting therapy should be done with caution. Cross sensitivity to liver injury is uncommon among the tyrosine kinase inhibitors and, in many situations, switching to another tyrosine kinase inhibitor may be appropriate. Ibrutinib has also been linked to cases of reactivation of hepatitis B which can be severe. Importantly, patients who are to receive long term therapy with ibrutinib should be screened for hepatitis B (HBsAg and anti-HBc) and, if positive, given antiviral prophylaxis against reactivation (with an oral antiviral agent with potent activity against HBV such as entecavir or tenofovir) or monitored carefully for appearance or rises in HBV DNA levels with early initative of antiviral therapy.
REPRESENTATIVE TRADE NAMES
Ibrutinib – Imbruvica®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 13 April 2018
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PubMed Citation (59 year old woman with Waldenstrom'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).
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