Bortezomib is a proteasome inhibitor and antineoplastic agent that is used in treatment of refractory multiple myeloma and certain lymphomas. Bortezomib is associated with a low rate of serum enzyme elevations during treatment and to rare instances of clinically apparent, acute liver injury.
Bortezomib (bor tez’ oh mib) is an orally available, small molecule inhibitor of the 26S proteasome, the intracellular complex that degrades proteins involved in cell signaling and cell cycle regulation. Blocking proteasome activity prevents activation of factors involved in cell growth and resistance to chemotherapy induced apoptosis, leading to cancer cell death. Preclinical studies in vitro and in vivo suggested that bortezomib had activity against several hematologic malignancies. Clinical trials of bortezomib in patients with multiple myeloma showed improvements in progression free survival. Bortezomib received approval for use in the United States in 2003 for therapy of multiple myeloma and mantle cell lymphoma when given in combination with other chemotherapeutic agents. Bortezomib is available in powdered form in vials of 3.5 mg under the brand name Velcade. The typical starting dose is 1.3 mg/m2 intravenously or subcutaneously given once or twice weekly, usually in combination with other agents such as melphalan and prednisone. The recommended dosage and dose regimen varies by indication, tolerance and hepatic function. Common side effects include nausea, diarrhea, constipation, anorexia, fatigue, thrombocytopenia, neutropenia, anemia peripheral neuropathy, rash and fever. Uncommon, but potentially severe side effects include peripheral neuropathy, cardiac and pulmonary toxicity, bone marrow suppression and tumor lysis syndrome.
In large clinical trials of bortezomib, elevations in serum aminotransferase levels were common, occurring in ~10% of patients. However, values greater than 5 times the upper limit of normal (ULN) were rare, occurring in <1% of recipients. Cases of clinically apparent liver injury including acute liver failure have been reported in patients receiving bortezomib; however, in many instances multiple concomitant medications were being taken and the specific role of bortezomib in causing the liver injury was not always clear. The onset of injury was typically during the first cycle of therapy and usually, but not always recurred with retreatment. Cases characterized by acute hepatic necrosis and others by cholestatic hepatitis have been published, some of which were fatal. Hepatotoxici15ty is listed as a warning in the product label for bortezomib and monitoring of serum enzymes during treatment is recommended.
Bortezomib is typically given with other chemotherapeutic agents including cyclophosphamide and dexamethasone which can cause reactivation of hepatitis B. However, there have been no reports of reactivation of hepatitis B specifically attributable to bortezomib alone.
Likelihood score: C (probable cause of clinically apparent drug induced liver injury).
Mechanism of Injury
The mechanisms of liver injury accounting for serum enzyme elevations and hepatic toxicity during bortezomib therapy are not known. Bortezomib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic intermediate. Bortezomib is susceptible to drug-drug interactions with agents that inhibit or induce hepatic CYP 3A4 activity.
Outcome and Management
Serum aminotransferase elevations above 5 times the upper limit of normal (if confirmed) should lead to dose reduction or temporary cessation. Clinically apparent liver injury should prompt immediate interruption of bortezomib therapy. Cases of hepatic failure attributed to bortezomib have been described, but no instance of chronic hepatitis or vanishing bile duct syndrome. There is little information on cross reactivity in risk for hepatic injury between bortezomib and other cancer chemotherapeutic agents, including the tyrosine kinase inhibitors and other proteasome inhibitors such as carfilzomib, but, because of the differences in chemical structure, there is little reason to suggest that there might be.
REPRESENTATIVE TRADE NAMES
Bortezomib – Velcade®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 30 September 2017
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PubMed Citation (Retrospective review of outcome of bortezomib therapy in 25 HBsAg-positive patients with multiple myeloma [20 treated with nucleoside analogues for HBV] found no evidence of reactivation, ALT and HBV DNA levels remaining normal or negative).
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J Hematol Blood Transfus 2016; 32 (Suppl 1): 181-3. PubMed Citation (A 54 year old man with multiple myeloma developed jaundice a few days into a second 4-week cycle of cyclosphosphamide, dexamethasone and bortezomib [bilirubin 15.5 mg/dL, ALT 367 U/L, Alk P 2456 U/L], recovering in 4 weeks and later tolerating cyclophosphamide and thalidomide).
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