Dasatinib is a selective tyrosine kinase receptor inhibitor that is used in the therapy of chronic myelogenous leukemia (CML) positive for the Philadelphia chromosome. Dasatinib is commonly associated with transient elevations in serum aminotransferase levels during treatment, but with only rare instances of clinically apparent acute liver injury.
Dasatinib is an orally available, small molecule inhibitor of the unique BCR-ABL tyrosine kinase receptor, which is the product of a fusion gene resulting from the translocation between chromosomes 9 and 22 that underlies the Philadelphia chromosome of chronic myelogenous leukemia (CML). The abnormal tyrosine kinase receptor is constitutively expressed and causes abnormal cell growth and proliferation. Inhibition of the enzyme can lead to dramatic reversal of progression of leukemia and is highly effective, although limited by the development of tumor resistance caused by mutations in the kinase. Dasatinib is actually a multi-kinase inhibitor and also has activity against scr, c-Kit and ephrin receptors, among others. Dasatanib received approval for use in the United States in 2006 and is one of five such specific inhibitors of BCR-ABL approved for clinical use, the others being imatinib , nilotinib , bosutinib  and ponatinib . Dasatinib is available in tablets of 20, 50, 70, 80, 100 and 140 mg under the brand name Sprycel. Current indications are for treatment of Philadelphia chromosome-positive CML in the chronic, accelerated or blast phase usually after failure of a previous treatment. It is also approved for use in adutls with Philadelphia chromcsome-positive acute lymphoblastic leukemia. The typical dose is 100 to 140 mg daily. Common side effects include bone marrow suppression, fluid retention, diarrhea, headache, muscle cramps, arthralgias, fatigue, dyspnea, cough, pleural effusions and rash. Rare, but potentially severe side effects include bone marrow suppression, QTc prolongation, heart failure and pulmonary artery hypertension.
In large clinical trials, elevations in serum aminotransferase levels during dasatinib therapy occurred in up to 50% of patients, but were usually mild and self-limited. Elevations above 5 times the upper limit of normal (ULN) occurred in 1% to 9% of patients and generally responded to dose adjustment or temporary discontinuation and restarting at a lower dose, which is recommended if liver test results are markedly elevated (ALT or AST persistently greater than 5 times ULN or bilirubin more than 3 times ULN). While episodes of marked serum aminotransferase elevations with symptoms have been reported, there have been no published reports of clinically apparent liver injury with jaundice attributed to dasatinib therapy. Certainly other tyrosine kinase receptor inhibitors used in the therapy of CML such as imatinib, nilotinib and ponatinib have been associated with cases of acute liver injury with jaundice. With these agents, the liver injury typically arises after several months of therapy and the pattern of serum enzyme elevations is typically hepatocellular. Immunoallergic features (rash, fever and eosinophilia) and autoantibody formation are usually not present.
Reactivation of hepatitis B has been reported with dasatinib as well as imatinib and nilotinib therapy. Reactivation typically occurs in an HBsAg positive person treated with the tyrosine kinase inhibitor for 3 to 6 months, presenting with jaundice, marked serum aminotransferase elevations and an increase in HBV DNA levels. Reactivation of hepatitis B can be severe and fatal instances have been reported after imatinib and nilotinib therapy. Screening of patients for HBsAg and anti-HBc is sometimes recommended before starting cancer chemotherapy and those with HBsAg offered prophylaxis with oral antiviral agents, such as lamivudine, tenofovir or entecavir.
Likelihood score: D (possible cause of clinically apparent liver injury).
Mechanism of Injury
Dasatinib is metabolized in the liver largely through the CYP 3A4 pathway and liver injury may be related to production of a toxic intermediate. Because of this pathway of metabolism, dasatinib is susceptible to drug-drug interactions when used with agents that induce or inhibit CYP 3A4.
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 some situations, therapy can be restarted, particularly with concurrent prednisone (10 to 20 mg daily). In patients with clinically apparent liver injury and jaundice, restarting therapy should be done with caution. There does not appear to be cross reactivity with other tyrosine kinase inhibitors and switching to another tyrosine kinase receptor inhibitor may be the most appropriate approach. No cases of acute liver failure have occurred in patients receiving dasatinib, but instances have been reported with imatinib, nilotinib and ponatinib.
REPRESENTATIVE TRADE NAMES
Dasatinib – Sprycel®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 05 December 2017
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Dasatinib (Sprycel) for CML and Ph + ALL. Med Lett Drugs Ther 2007; 49 (1252): 6-7. PubMed Citation (Concise summary of the mechanism of action, efficacy and safety of dasatinib shortly after its approval in the US).
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Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, one case was attributed to imatinib, but none to other tyrosine kinase inhibitors).
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Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. PubMed Citation (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 49 [6%] were attributed to antineoplastic agents including 9 to kinase inhibitors such as imatinib, lapatinib and regorafinib).
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dysfunction. Clin Lymphoma Myeloma Leuk 2016; 16: 152-62. PubMed Citation (Among 215 patients with CML treated with nilotinib or dasatinib for an median of 49 months, the presence of mild liver dysfunction had no apparent effect on response rates or adverse events including liver toxicity; ALT and AST levels "remained generally unchanged" with elevations above 5 times ULN occurring only in the nilotinib treatment arm [11% vs 0%]).
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Dis 2017; 21: 115-34. PubMed Citation (Overview of hepatotoxicity of newer agents including tyrosine kinase inhibitors such as imatinib, bosutinib, nilotinib, ponatinib and dasatinib, all of which have been implicated in causing ALT and AST elevations [in 23-50% of patients] as well as clinically apparent liver injury).
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