Dasatinib in second line treatment of chronic myeloid leukaemia in patients with imatinib resistance or intolerance treated at the Clinic of Haematology and Transfusiology
Bratislava between 2007 and 2011

Authors: M. Martišová ;  Z. Sninská ;  A. Hatalová ;  E. Demečková ;  M. Mistrík
Authors‘ workplace: Klinika hematológie a transfuziológie LFUK, SZU a UNB, Bratislava
Published in: Transfuze Hematol. dnes,18, 2012, No. 3, p. 105-111.
Category: Comprehensive Reports, Original Papers, Case Reports


Chronic myelogenous leukaemia is the first oncologic disease associated with a concrete chromosomal aberration termed the Philadelphia chromosome, which gives rise to the BCR-ABL1 fusion gene. The pathological protein arising from the transcription and translation of this gene has tyrosine kinase activity and is able to induce malignant transformation of the given cell. Bcr-Abl tyrosine kinase represents a pathogenetically relevant molecular target and disease remission can be achieved by its inhibition. Tyrosine kinase inhibitors have led to a revolution in the treatment of chronic myelogenous leukaemia and have improved patient prognosis. The initial success of imatinib – a representative of the first generation of tyrosine kinase inhibitors – however gave rise over time to several issues. Imatinib led to the selection of a group of patients who fail to respond optimally to treatment, lose the initially achieved treatment response or who do not tolerate imatinib. Aiming to offer a more optimal treatment alternative for these patients, researchers have tried to find a superior and more effective Bcr-Abl inhibitor. Thus, 2nd generation tyrosine kinase inhibitors were discovered, including dasatinib. Dasatinib improved patient overall survival as well as prognosis.

Study group and methodology:
The group included 14 patients with an initially demonstrated diagnosis of chronic myeloid leukaemia in chronic phase. Patients were treated at the Clinic of Haematology and Transfusiology, Medical Faculty of Comenius University, Slovak Medical University and University Hospital Bratislava. All patients underwent first line treatment with imatinib and experienced treatment failure because of resistance, suboptimal response or imatinib intolerance. Patients were then treated by the 2nd generation of tyrosine kinase inhibitor – dasatinib from January 1, 2007 until July 31, 2012. Efficacy of dasatinib was evaluated according to the achievement of cytogenetic and molecular response at certain time points (3, 6, 9 and 12 months). Tolerability and overall survival were evaluated throughout the whole treatment period.

To show the efficacy and tolerability of dasatinib in patients following imatinib failure.

Dasatinib is able to achieve good cytogenetic and molecular responses with an acceptable safety profile. Its efficacy and tolerability are lower in the progressive phases of the disease.

Key words:
2nd generation Bcr-Abl tyrosine kinase inhibitors, dasatinib, second line treatment, efficacy, tolerability


1. Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with Dasatinib 100 mg once daily preserves efficacy and improves tolerability in Imatinib-resistant and –intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol 2008; 26: 3204-3212.

2. 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-yl-amino)thiazole-5-carboxamide (BSM-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem 2004; 47: 6658-6661.

3. 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; 66: 5790-5797.

4. O Hare T, Walters DK, Stroffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relavant imatinib-resistant Abl kinase domain mutants. Cancer Res 2005; 65: 4500-4505.

5. Shah NP. Dasatinib. Drugs Today (Barc) 2007; 43: 5-12.

6. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in CP-CML after failure of imatinib therapy. Blood 2007; 109(6): 2303-2309.

7. Doubek M. Zvládání nežádoucích účinků dasatinibu (Sprycel) – spolupráce s hematologickou ambulancí v místě bydliště pacienta, Satelitné sympózium Sprycel: jediný tyrosinkinázový inhibitor 2. generace registrovaný pro všechny fáze CML a Ph+ ALL. Olomoucké hematologické dny 2008, oral presentation.

8. 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 2 trial. Blood 2007; 109: 5143-5150.

9. Shah NP, Tran C, Lee FY, et al. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305:399-401.

10. Copland M, Hamilton A, Elrick RJ, et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML, but does not eliminate the quiescent fraction. Blood 2006; 107(11): 4532-4539.

11. 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; 109: 4143-4150.

12. 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; 109: 3207-3213.

13. Ottmann O, Dombret H, Baccarani M, et al. Dasatinib (BMS-354825) induces rapid hematologic and cytogenetic responses in patients with imatinib-resistant or –intolerant Philadelphia chromosome-positive acute lymphoblastic leukemia: Interim results of a phase II study. Blood 2007; 110: 2309-2315.

14. National Comprehensive Cancer Network (NCCN): Clinical practise guidelines in Oncology™: Chronic myelogenous leukemia. V. 2.2007. http://www.nccn.org/professionals/physician-gls/PDF/ cml.pdf, accessed November 2007

15. Hochhaus A, Baccarani, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia 2008; 22: 1200-1206.

16. Talpaz M, Shah N, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome positive leukemias. N Engl J Med 2006; 354: 2531-2541.

17. Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanism of resistance to imatinib (STI571) therapy. Leukemia 2002; 16:2190-2196.

18. Thomas J, Wang L, Clark RE et al, Active transport of imatinib into and out of cells: implications of drug resistance. Blood 2004; 104: 3739-3745

19. Dai Y, Rahmani M, Corey SJ, et al. A Bcr/Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2. J Biol Chem 2004; 279: 34227-34239.

20. Kantarjian H, Pasquini R, Lévy V, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia resistant to imatinib at a dose of 400 to 600 milligrams daily (two-year follow-up of a randomized phase 2 study (START-R)). Cancer 2009; 115: 4136-4147.

21. Kantarjian HM, Cortes J. Second generation tyrosine kinase inhibitors: which and when? Hematology Education: education program for the annual congress of European Hematology Association. 2009; 3(1): 83-88.

22. Ten Hoeve J, Arlinghaus RB, Guo JQ, et al. Tyrosine phosphorylation of CRKL in Philadelphia+ leukemia. Blood 1994; 84: 1731-1736.

23. Oda T, Heaney C, Hagopian JR, et al. Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia. J Biol Chem 1994; 269: 22925-22928.

24. Nichols GL, Raines MA, Vera JC, et al. Identification of CRKL as the constitutively phosphorylated 39-kD tyrosine phosphoprotein in chronic myelogenous leukemia cells. Blood 1994; 84: 2912-2918.

25. Quintas-Cardama A, Kantarjian H, O Brien S, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol 2007; 25:3908-3914.

26. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia. An update of concepts and management recommendations of the EuropeanLeukemiaNet. J Clin Oncol 2009; 27 (35): 6041-6051.

27. Baccarani M, Saglio G, Goldman J, et al. Envolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the EuropeanLeukemiaNet. Blood 2006; 108:1809-1820.

28. Guidelines for mutation analysis of BCR/ABL kinase domain: Interpreting TKI-ressistance mutations in CML patients, West Midlands Regional Genetics Laboratory March 2007; Revised December 2007.

Haematology Internal medicine Clinical oncology
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