International Journal of Clinical Pharmacy

, Volume 39, Issue 4, pp 851–859 | Cite as

Use patterns of first-line inhibitors of tyrosine kinase and time to change to second-line therapy in chronic myeloid leukemia

  • Jorge Enrique Machado-AlbaEmail author
  • Manuel Enrique Machado-Duque
Research Article


Background Chronic myeloid leukemia (CML) has a low incidence but a high burden of disease, and is treated with high-cost tyrosine kinase inhibitors (TKI). Objective To determine the time from the start of a first-line TKI until it passes to second-line, and to establish the reasons for the change of therapy time. Setting Patients with Philadelphia-positive CML treated with some TKI. Methods Retrospective cohort study, between January 1 2007 and July 31 2015, with information obtained from medical records, the time to change initial drugs to secondline therapy, and the reasons for change, were identified. Kaplan–Meier survival analysis was carried out. Main outcome measure A change in therapy to the secondline TKI and the final reason for the change of therapy. Results A total of 247 patients treated were found in 22 cities in Colombia with a mean age of 53.2 ± 15.2 years. The drug most used as initial therapy was imatinib; 53.8% of cases had to change to another TKI. 50% of patients changed therapy in 42 months, men in 24 and women in 67 months (95% CI 14.314–33.686; p = 0.001). Being male (OR 2.23; 95% CI 1.291–3.854; p = 0.004) and receiving hydroxyurea (OR 3.65; 95% CI 1.601–8.326; p = 0.002) were associated with a higher probability of switching to nilotinib or dasatinib, while receiving a new-generation TKI (OR 0.15; 95% CI 0.071–0.341; p < 0.001) reduced this risk. Conclusions A high proportion of patients needed to change to a second line with nilotinib and dasatinib management. It is necessary to obtain more real world evidence, to improve the effectiveness, adherence and safety of the treatment.


BCR-ABL Positive Chronic Leukemia Myelogenous Pharmacoepidemiology Treatment failure 



The authors want to thank the Universidad Tecnológica de Pereira, Audifarma S.A. and Novartis Colombia for their support.


This study received funding from the Universidad Tecnológica de Pereira, Audifarma S.A. and Novartis of Colombia.

Conflicts of interest

The authors declare that Novartis of Colombia financed the data collection process. There was no intervention in the stages of processing, analysis or publication of that data. No non-financial conflicts of interest exist for any of the authors.


  1. 1.
    Instituto Nacional de Cancerología - ESE. INC. Colombia. Cáncer en cifras, Incidencias por tipo de cáncer 2002–2006 (internet). Cited 21 Feb 2017.
  2. 2.
    Hehlmann R, Hochhaus A, Baccarani M. European Leukemia Net: chronic myeloid leukaemia. Lancet. 2007;370(9584):342–50.CrossRefPubMedGoogle Scholar
  3. 3.
    Wetzler M, Marcucci G, Bloomfield CD. Acute and Chronic Myeloid Leukemia. Chapter 109. In: Longo DL, Kasper DL, Jameson JL, Fauci AS, Hauser SL, Loscalzo J, editors. Harrison’s principles of internal medicine. 18th ed. New York: McGraw-Hill, Medical Pub. Division; 2011. p. 905–18.Google Scholar
  4. 4.
    Apperley JF. Chronic myeloid leukaemia. Lancet. 2015;385(9976):1447–59.CrossRefPubMedGoogle Scholar
  5. 5.
    Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Druker BJ, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. IRIS Investigators. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–17.CrossRefPubMedGoogle Scholar
  7. 7.
    Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med. 2007;357(3):258–65.CrossRefPubMedGoogle Scholar
  8. 8.
    Balabanov S, Braig M, Brümmendorf TH. Current aspects in resistance against tyrosine kinase inhibitors in chronic myelogenous leukemia. Drug Discov Today Technol. 2014;11:89–99.CrossRefPubMedGoogle Scholar
  9. 9.
    Stenehjem DD, Albright F, Kuo KL, Raimundo K, Bauer H, Shami PJ, et al. Response monitoring, tolerability, and effectiveness of imatinib treatment for chronic myeloid leukemia in a retrospective research database. J Natl Compr Cancer Netw. 2014;12(8):1113–21.CrossRefGoogle Scholar
  10. 10.
    Weisberg E, Manley PW, Cowan-Jacob SW, Hochhaus A, Griffin JD. Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nat Rev Cancer. 2007;7(5):345–56.CrossRefPubMedGoogle Scholar
  11. 11.
    Goulden S, Sutcliffe F, Stevens A. NICE guidance on dasatinib, high-dose imatinib, and nilotinib for patients with CML who are resistant or intolerant to imatinib. Lancet Oncol. 2012;13(2):127–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Romero M, Chávez D, De Los Ríos M, Alvis-Guzmán N. Cost-effectiveness of nilotinib, dasatinib and imatinib as first-line treatment for chronic myeloid leukemia in Colombia, 2012. Biomedica. 2014;34(1):48–59.CrossRefPubMedGoogle Scholar
  13. 13.
    Guevara G, González JA, Lopera DE, González M, Saavedra JD, Lobaton JF, et al. Follow-up of the tumor load in patients with de novo chronic myeloid leukemia and in complete cytogenetic remission treated with imatinib in Colombia. Colomb Med (Cali). 2012;43(4):267–72.Google Scholar
  14. 14.
    Jabbour EJ, Cortes JE, Kantarjian HM. Resistance to tyrosine kinase inhibition therapy for chronic myelogenous leukemia: a clinical perspective and emerging treatment options. Clin Lymphoma Myeloma Leuk. 2013;13(5):515–29.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Jabbour E, Kantarjian HM, Jones D, Shan J, O’Brien S, Reddy N, et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood. 2009;113:2154–60.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Henk HJ, Woloj M, Shapiro M, Whiteley J. Real-world analysis of tyrosine kinase inhibitor treatment patterns among patients with chronic myeloid leukemia in the United States. Clin Ther. 2015;37(1):124–33.CrossRefPubMedGoogle Scholar
  17. 17.
    Mitra D, Trask PC, Iyer S, Candrilli SD, Kaye JA. Patient characteristics and treatment patterns in chronic myeloid leukemia: evidence from a multi-country retrospective medical record chart review study. Int J Hematol. 2012;95(3):263–73.CrossRefPubMedGoogle Scholar
  18. 18.
    Whiteley J, Iyer S, Candrilli SD, Kaye JA. Treatment patterns and prognostic indicators of response to therapy among patients with chronic myeloid leukemia in Australia, Canada, and South Korea. Curr Med Res Opin. 2015;31(2):299–314.CrossRefPubMedGoogle Scholar
  19. 19.
    Chen L, Guérin A, Xie J, Wu EQ, Yu AP, Ericson SG, et al. Monitoring and switching patterns of patients with chronic myeloid leukemia treated with imatinib in community settings: a chart review analysis. Curr Med Res Opin. 2012;28(11):1831–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Saleh MN, Haislip S, Sharpe J, Hess T, Gilmore J, Jackson J, et al. Assessment of treatment and monitoring patterns and subsequent outcomes among patients with chronic myeloid leukemia treated with imatinib in a community setting. Curr Med Res Opin. 2014;30(4):529–36.CrossRefPubMedGoogle Scholar
  21. 21.
    Kim TD, Schwarz M, Nogai H, Grille P, Westermann J, Plöckinger U. Thyroid dysfunction caused by second-generation tyrosine kinase inhibitors in Philadelphia chromosome-positive chronic myeloid leukemia. Thyroid. 2010;20(11):1209–14.CrossRefPubMedGoogle Scholar
  22. 22.
    Yoshizato T, Nannya Y, Yoshiki Y, Nakamura F, Imai Y, Ichikawa M, et al. Nilotinib-induced hypothyroidism in a patient with chronic myeloid leukemia. Int J Hematol. 2011;93(3):400–2.CrossRefPubMedGoogle Scholar
  23. 23.
    Edesa WA, Abdel-malek RR. Impact of imatinib interruption and duration of prior hydroxyurea on the treatment outcome in patients with chronic myeloid leukemia: single institution experience. J Egypt Natl Canc Inst. 2015;27(2):69–75.CrossRefPubMedGoogle Scholar
  24. 24.
    Payandeh M, Sadeghi M, Sadeghi E. Treatment and survival in patients with chronic myeloid leukemia in a chronic phase in West Iran. Asian Pac J Cancer Prev. 2015;16(17):7555–9.CrossRefPubMedGoogle Scholar
  25. 25.
    Pulte D, Barnes B, Jansen L, Eisemann N, Emrich K, Gondos A, GEKID Cancer Survival Working Group, et al. Population level survival of patients with chronic myelocytic leukemia in Germany compared to the US in the early 21st century. J Hematol Oncol. 2013;6(1):70.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    de Almeida MH, Fogliatto L, Couto D. Importance of adherence to BCR-ABL tyrosine-kinase inhibitors in the treatment of chronic myeloid leukemia. Rev Bras Hematol Hemoter. 2014;36(1):54–9.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Efficace F, Baccarani M, Rosti G, Cottone F, Castagnetti F, Breccia M, et al. Investigating factors associated with adherence behaviour in patients with chronic myeloid leukemia: an observational patient-centered outcome study. Br J Cancer. 2012;107(6):904–9.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Noens L, van Lierde MA, De Bock R, Verhoef G, Zachée P, Berneman Z, et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: the ADAGIO study. Blood. 2009;113(22):5401–11.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing 2017

Authors and Affiliations

  1. 1.Grupo de Investigación en Farmacoepidemiología y Farmacovigilancia, Facultad Ciencias de la Salud-Programa de MedicinaUniversidad Tecnológica de Pereira- Audifarma S.A.Pereira, RisaraldaColombia

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