Abstract
▴ Dasatinib is a small-molecule inhibitor of multiple tyrosine kinases,including BCR-ABL,SRC,c-KIT,ephrin A receptor and platelet-derived growth factor-β receptor kinases,at nanomolar concentrations. In vitro, dasatinib is 325-fold more potent than imatinib against cells expressing wild-type BCR-ABL.
▴ The efficacy and tolerability of oral dasatinib has been established in the START phase II trials in adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who were intolerant or resistant to imatinib, and optimal dasatinib dosage regimens were identified in phase III randomized trials.
▴ In patients with chronic phase CML, the major cytogenetic response rate in the START-C trial (median follow-up 15.2 months) was 59% with dasatinib, and in the randomized START-R trial (median follow-up 15 months), was greater with dasatinib than with high-dose imatinib (52% vs 33%). Major hematologic response rates with dasatinib were 63% in patients with accelerated phase CML (follow-up ≥9 months; START-A trial), 34% in patients with myeloid blast phase CML and 35% in those with lymphoid blast phase CML (follow-up ≥12 months; START-B and START-L trials), and 41% in patients with Ph-positive ALL (follow-up ≥12 months; START-L trial).
▴ Based on phase III results, a once-daily dasatinib regimen is considered optimal in chronic phase CML (starting dosage 100 mg once daily), while a twice-daily regimen continues to be recommended in accelerated phase, myeloid blast phase or lymphoid blast phase CML and Ph-positive ALL (starting dosage 70 mg twice daily).
▴ Adverse events were frequent in patients treated with dasatinib, but most were mild to moderate in severity. Grade 3/4 adverse events were uncommon and were clinically manageable.
Similar content being viewed by others
Notes
The use of trade names is for product identification purposes only and does not imply endorsement.
References
National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology: chronic myelogenous leukemia v.2.2007 [online]. Available from URL: http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf [Accessed 2007 Mar 30]
Jabbour E, Cortes JE, Giles FJ, et al. Current and emerging treatment options in chronic myeloid leukemia. Cancer 2007 Jun; 109(11): 2171–81
Hochhaus A. Dasatinib for the treatment of Philadelphia chromosome-positive chronic myelogenous leukaemia after imatinib failure. Expert Opin Pharmacother 2007 Dec; 8(18): 3257–64
Kantarjian H, O’Brien S, Talpaz M, et al. Outcome of patients with Philadelphia chromosome-positive chronic myelogenous leukemia post-imatinib mesylate failure. Cancer 2007 Apr; 109(8): 1556–60
Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006 Sep 15; 108(6): 1809–20
Bocchia M, Forconi F, Lauria F. Emerging drugs in chronic myelogenous leukemia. Expert Opin Emerg Drugs 2006 Nov; 11(4): 651–64
Kantarjian HM, Giles F, Quintas-Cardama A, et al. Important therapeutic targets in chronic myelogenous leukemia. Clin Cancer Res 2007 Feb 15; 13(4): 1089–97
Jabbour E, Cortes J, Kantarjian H. Dasatinib for the treatment of Philadelphia chromosome-positive leukemias. Expert Opin Investig Drugs 2007 May; 16(5): 679–87
Shah NP. Medical management of CML. Hematol Am Soc Hematol Educ Program 2007; 2007: 371–5
Goldman JM. How I treat chronic myeloid leukemia in the imatinib era. Blood 2007 Jul 12; 110(8): 2828–37
Hochhaus A. Management of Bcr-Abl-positive leukemias with dasatinib. Expert Rev Anticancer Ther 2007 Nov; 7(11): 1529–36
Glivec (imatinib mesylate). Summary of product characteristics. Horsham: Novartis Europharm Ltd, 2007 Nov 27
Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 2006 Dec 7; 355(23): 2408–17
Moen MD, McKeage K, Plosker GL, et al. Imatinib: a review of its use in chronic myeloid leukemia. Drugs 2007; 67(2): 299–320
Shah NP. Loss of response to imatinib: mechanisms and management. Hematol Am Soc Hematol Educ Program 2005; 2005: 183–7
Jabbour E, Cortes J, O’Brien S, et al. New targeted therapies for chronic myelogenous leukemia: opportunities to overcome imatinib resistance. Semin Hematol 2007 Jan; 44(1 Suppl. 1): S25–31
O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005 Jun 1; 65(11): 4500–5
O’Hare T, Walters DK, Stoffregen EP, et al. Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib. Clin Cancer Res 2005 Oct 1; 11 (19 Pt 1): 6987–93
Schittenhelm MM, Shiraga S, Schroeder A, et al. Dasatinib (BMS-354825), a dual SRC/ABL kinase inhibitor, inhibits the kinase activity of wild-type, juxtamembrane, and activation loop mutant KIT isoforms associated with human malignancies. Cancer Res 2006 Jan 1; 66(1): 473–81
Tokarski JS, Newitt JA, Chang CY, et al. The structure of dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res 2006 Jun 1; 66(11): 5790–7
Jabbour E, Cortes J, Giles F, et al. The clinical challenge of imatinib resistance in chronic myeloid leukemia: emerging strategies with new targeted agents. Targ Oncol 2006; 4: 186–96
Nam S, Williams A, Vultur A, et al. Dasatinib (BMS-354825) inhibits Stat5 signaling associated with apoptosis in chronic myelogenous leukemia cells. Mol Cancer Ther 2007 Apr; 6(4): 1400–5
La Rosee P, Hartel N, Klag T, et al. MAPK-activation in response to BCR-ABL inhibition is cytokine-dependent and can be overcome by dasatinib [abstract no. 0535]. Haematologica 2007 Jun; 92Suppl. 1: 199
Copland M, Hamilton A, Elrick LJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006 Jun 1; 107(11): 4532–9
Dasatinib: summary of product characteristics. Uxbridge: Bristol-Myers Squibb Pharma EEIG, 2007
Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylami-no)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004; 47(27): 6658–61
Donate NJ, Wu J, Kong LY, et al. The SRC/ABL inhibitor BMS-354825 overcomes resistance to imatinib mesylate in chronic myelogenous leukemia cells through multiple mechanisms [abstract no. 1989]. Blood 2004 Nov; 104 (11 Pt 1): 549a
Lee FY, Lombardo L, Camuso A, et al. BMS-354825 potently inhibits multiple selected oncogenic tyrosine kinases and possesses broad-spectrum antitumor activities in vitro and in vivo [abstract no. 675]. Proceedings of the 96th Annual Meeting of the American Association for Cancer Research; 2005 Apr 17; Anaheim (CA). 159
Wild R, Castaneda S, Flefleh C, et al. BMS-354825, a dual SRC/ABL kinase inhibitor, displays potent anti-tumor activity in a model of intracranial CML growth [abstract no. 1988]. Blood 2004 Nov 16; 104 (11 Pt 1): 549a
Luo FR, Yang Z, Camuso A, et al. Dasatinib (BMS-354825) pharmacokinetics and pharmacodynamic biomarkers in animal models predict optimal clinical exposure. Clin Cancer Res 2006 Dec 1; 12(23): 7180–6
Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305(5682): 399–401
Li S, Hu Y, Swerdlow S, et al. Targeting BCR-ABL kinase activity-independent signalling pathways and leukemia stem cells is essential for curative therapy of Philadelphia chromosome positive (Ph+) leukemia [abstract no. 1990]. Blood 2005; 106(11): 563a
Kaul S, Wu C, Mayfield S, et al. Dasatinib can be administered orally with or without a meal [abstract no. 4569]. Blood 2007 Nov; 110 (11)
Wu CY, Callegari F, McCann B, et al. Mass balance, pharmacokinetics and metabolism of [14C] BMS-354825 in healthy male subjects [abstract no. 155]. EJC Supplements 2006 Nov; 4(12): 50
Wu CY, Callegari F, Williams K, et al. Effects of dasatinib on the pharmacokinetics of simvastatin, a cytochrome P450 3A4 substrate, in healthy subjects [abstract no. 150]. EJC Supplements 2006 Nov; 4(12): 48–9
Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med2006 Jun 15; 354(24): 2531–41
Cortes J, Sawyers CL, Kantarjian HM, et al. Long-term efficacy of dasatinib in chronic-phase CML: results from the phase I trial (CA180002) [abstract no. 1026]. Blood 2007 Nov 16; 110 (11)
Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase-II trial. Blood 2007 Jun 15; 109(12): 5143–50
Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007 Mar 15; 109(6): 2303–9
Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a Phase II study. Blood 2007 Oct 1; 110(7): 2309–15
Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood 2007 May 15; 109(10): 4143–50
Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood 2007 Apr 15; 109(8): 3207–13
Hochhaus A, Kim DW, Rousselot P, et al. Dasatinib dose and schedule optimization in chronic-phase CML resistant or intolerant to imatinib: results from a randomized phase-III trial (CA180034) [abstract no. 0359]. Haematologica 2007 Jun; 92Suppl. 1: 128–9
Pasquini R, Ottmann OG, Goh YT, et al. Dasatinib 140 mg QD compared to 70 mg BID in advanced-phase CML or Ph(+) ALL resistant or intolerant to imatinib: one-year results of CA180-035 [abstract no. 7025]. J Clin Oncol 2007 Jun 1; 25 (18 Suppl. Pt 1): 363s
Sprycel-H-709-II-02. Scientific discussion (after authorisation) [online]. Available from URL: http://www.emea.europa.eu [Accessed 2007 Nov 13]
Stone RM, Kantarjian HM, Baccarani M, et al. Efficacy of dasatinib in patients with chronic-phase chronic myelogenous leukemia with resistance or intolerance to imatinib: 2-year follow-up data from START-C (CA180-013) [abstract no. 734]. Blood 2007; 110 (11)
Gambacorti C, Cortes J, Kim D-W, et al. Efficacy and safety of dasatinib in patients with chronic myeloid leukemia in blast phase whose disease is resistant or intolerant to imatinib: 2-year follow-up data from the START program [abstract no. 472]. Blood 2007 Nov; 110 (11)
Guilhot F, Apperley JF, Kim D-W, et al. Efficacy of dasatinib in patients with accelerated-phase chronic myelogenous leukemia with resistance or intolerance to imatinib: 2-year follow-up data from START-A (CA180-005) [abstract no 470]. Blood 2007 Nov; 110 (11)
Porkka K, Simonsson B, Dombret H, et al. Efficacy of dasatinib in patients with Philadelphia-Chromosome-positive acute lymphoblastic leukemia who are resistant or intolerant to imatinib: 2-year follow-up data from START-L (CA180-015) [abstract no. 2810]. Blood 2007 Nov; 110 (11)
Dasatinib. Scientific discussion [online]. Available from URL: http://www.emea.europa.eu [Accessed 2007 Nov 1]
Baccarani M, Kantarjian HM, Apperley JF, et al. Efficacy of dasatinib (Sprycel®) in patients with chronic phase chronic myelogenous leukemia resistant to or intolerant of imatinib: updated results of the CA180013 START-C Phase II Study [abstract no. 164]. Blood 2006 Nov; 108 (11 Pt 1): 53
Guilhot F, Apperley J, Facon T, et al. Dasatinib induces durable cytogenetic responses in patients with chronic-phase CML with resistance or intolerance to imatinib: updated results of the CA180013 (START-C) trial [abstract no. 0358]. Haematologica 2007 Jun; 92Suppl. 1: 128
Cortes J, Kim DW, Guilhot F, et al. Dasatinib (Sprycel®) in patients with chronic myelogenous leukemia in accelerated phase that is imatinib-resistant or —intolerant: updated results of the CA180-005 ’sTART-A’ phase II study [abstract no. 2160]. Blood 2006 Nov; 108 (11 Pt 1): 613
Bergeron A, Rea D, Levy V, et al. Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series. Am J Respir Crit Care Med 2007 Oct 15; 176(8): 814–8
Lipton JH, Sriharsha L, Bogomilsky S, et al. Pleural effusions in patients treated with dasatinib: results from two institutions, risk factors and management [abstract no. 17503]. J Clin Oncol 2007 Jun; 25 (18 Suppl. Pt 1): 680s
Punnialingam S, de Lavallade H, Milojkovic D, et al. Pleural effusions associated with use of dasatinib in chronic myeloid leukemia may have an auto-immune pathogenesis [abstract no. 2945]. Blood 2007 Nov; 110 (11)
Sprycel™ (dasatinib) tablets: US prescribing information. Princeton (NJ): Bristol-Myers Squibb Company, 2007 Nov
Acknowledgments and Disclosures
The manuscript was reviewed by: J.M. Goldman, Department of Haematology, Imperial College at Hammersmith Hospital, London, England; N. Hamerschlak, Hospital Israelita Albert Einstein, Sao Paulo, Brazil; J.H. Lipton, Princess Margaret Hospital, Toronto, Ontario, Canada.
The preparation of this review was not supported by any external funding. During the peer review process, the marketing authorization holder of the agent under review was also offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Keam, S.J. Dasatinib. BioDrugs 22, 59–69 (2008). https://doi.org/10.2165/00063030-200822010-00007
Published:
Issue Date:
DOI: https://doi.org/10.2165/00063030-200822010-00007