OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Dasatinib	863127-77-9	C22-H26-Cl-N7-O2-S.H2-O

ANNOTATED BIBLIOGRAPHY

References updated: 05 December 2017

• 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 dasatinib and the tyrosine kinase inhibitors).
• DeLeve LD. Cancer chemotherapy. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 541-67.

  (Review of hepatotoxicity of cancer chemotherapeutic agents; imatinib, gefitinib, erlotinib and crizotinib are discussed, but not dasatinib).
• Chabner BA, Barnes J, Neal J, Olson E, Mujagic H, Sequist L, Wilson W, et al. Targeted therapies: tyrosine kinase inhibitors, monoclonal antibodies, and cytokines. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1731-54.

  (Textbook of pharmacology and therapeutics).
• Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 2006; 354: 2531-41. [PubMed: 16775234]

  (Among 84 patients with CML resistant or intolerant of imatinib therapy who were treated with dasatinib, hematologic responses occurred in 68 [81%]; side effects included diarrhea, nausea, dyspnea, pleural effusion and myelosuppression; no mention of ALT elevations or hepatotoxicity).
• Guilhot F, Apperley J, Kim DW, Bullorsky EO, Baccarani M, Roboz GJ, Amadori S, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007; 109: 4143-50. [PubMed: 17264298]

  (Among 107 patients with CML in accelerated phase and resistant or intolerant of imatinib who were treated with dasatinib, common side effects were diarrhea [50%], nausea [22%], peripheral edema [22%], pleural effusions [23%] and fatigue [19%]; no mention of ALT elevations or hepatotoxicity).
• Dasatinib (Sprycel) for CML and Ph + ALL. Med Lett Drugs Ther 2007; 49 (1252): 6-7. [PubMed: 17220814]

  (Concise summary of the mechanism of action, efficacy and safety of dasatinib shortly after its approval in the US).
• Bonvin A, Mesnil A, Nicolini FE, Cotte L, Michallet M, Descotes J, Vial T. Dasatinib-induced acute hepatitis. Leuk Lymphoma 2008; 49: 1630-2. [PubMed: 18608866]

  (43 year old man with CML intolerant to imatinib therapy developed worsening fatigue and serum enzyme elevations 6 months after starting dasatinib therapy [bilirubin 1.5 mg/dL, ALT 758 U/L, Alk P 1432 U/L], which resolved within 3 weeks of stopping).
• 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. [PMC free article: PMC3654244] [PubMed: 18955056]

  (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).
• Apperley JF, Cortes JE, Kim DW, Roy L, Roboz GJ, Rosti G, Bullorsky EO, et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: the START a trial. J Clin Oncol 2009; 27: 3472-9. [PMC free article: PMC4979080] [PubMed: 19487385]

  (Among 174 patients with CML in accelerated phase who were resistant or intolerant of imatinib and were treated with dasatinib, hematologic responses occurred in 64%; common side effects were cytopenias and pleural effusions occurred in 27%; no mention of ALT elevations or hepatotoxicity).
• Shayani S. Dasatinib, a multikinase inhibitor: therapy, safety, and appropriate management of adverse events. Ther Drug Monit 2010; 32: 680-7. [PubMed: 20864900]

  (Review of efficacy and safety of dasatinib mentions that "liver abnormalities, which typically are associated with imatinib intolerance, rarely were reported in patients taking dasatinib").
• Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, Moiraghi B, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010; 362: 2260-70. [PubMed: 20525995]

  (Among 519 newly diagnosed patients with CML in chronic phase treated with either dasatinib or imatinib, cytogenetic responses were more frequent with dasatinib and safety profiles were similar, pleural effusions occurring only with dasatinib and ALT elevations causing discontinuation in 2 patients on imatinib, but none on dasatinib).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, none of which were attributed to tyrosine kinase inhibitors).
• Shah RR, Morganroth J, Shah DR. Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives. Drug Saf 2013; 36: 491-503. [PubMed: 23620168]

  (Review of the hepatotoxicity of 18 tyrosine kinase inhibitors approved for use in cancer in the US as of 2013; dasatinib is associated with ALT elevations in up to 50% of patients [above 5 times ULN in 1-9%], but has not been linked to cases of acute hepatitis or liver failure).
• Harbaum L, Marx A, Goekkurt E, Schafhausen P, Atanackovic D. Treatment with dasatinib for chronic myeloid leukemia following imatinib-induced hepatotoxicity. Int J Hematol 2014; 99: 91-4. [PubMed: 24264834]

  (32 year old woman with CML developed jaundice 6 months after starting imatinib [bilirubin 2.8 rising to 9 mg/dL, ALT 1638 U/L, Alk P 94 U/L, INR 1.33], recovered on prednisolone within 6 weeks of stopping imatinib and did not have a recurrence when subsequently treated successfully with dasatinib).
• 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. [PMC free article: PMC4446235] [PubMed: 25754159]

  (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).
• Sasaki K, Lahoti A, Jabbour E, Jain P, Pierce S, Borthakur G, Daver N, et al. Clinical safety and efficacy of nilotinib or dasatinib in patients with newly diagnosed chronic-phase chronic myelogenous leukemia and pre-existing liver and/or renal dysfunction. Clin Lymphoma Myeloma Leuk 2016; 16: 152-62. [PMC free article: PMC4769134] [PubMed: 26796981]

  (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%]).
• Bunchorntavakul C, Reddy KR. Drug hepatotoxicity: newer agents. Clin Liver Dis 2017; 21: 115-34. [PubMed: 27842767]

  (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).