Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Spotlight Review
  • Published:

Choosing the best treatment strategy for chronic myeloid leukemia patients resistant to imatinib: weighing the efficacy and safety of individual drugs with BCR-ABL mutations and patient history

Leukemia volume 24, pages 6–12 (2010)Cite this article

Abstract

For patients with chronic myeloid leukemia who become or are inherently resistant to imatinib therapy, including dose escalation, several important factors must be considered when deciding which strategy to attempt next. The second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib offer improved potency and a high likelihood of success for these patients. Overall, the efficacy data are comparable for these two agents, and so physicians should consider the BCR-ABL mutation profile and the patient's history to make an educated decision on the best choice. Only a few BCR-ABL mutations seem to be less responsive to either nilotinib or dasatinib and it is recommended to choose the second-line TKI that has shown clinical activity against the specific mutation in these cases. For patients with all other mutations, and for patients with no mutations, it is recommended to choose the second-generation TKI based on the patient's disease history. It is important to choose an agent that minimizes the likelihood of exacerbating the patient's past tolerability issues to imatinib, or comorbid conditions. Here, we propose a treatment algorithm for imatinib-resistant patients based on BCR-ABL mutation status and patient history.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Rowley JD . Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 1973; 243: 290–293.

    Article  CAS  Google Scholar 

  2. Bartram CR, de Klein A, Hagemeijer A, van Agthoven T, Geurts van Kessel A, Bootsma D et al. Translocation of c-ab1 oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia. Nature 1983; 306: 277–280.

    Article  CAS  Google Scholar 

  3. Sawyers CL . Chronic myeloid leukemia. N Engl J Med 1999; 340: 1330–1340.

    Article  CAS  Google Scholar 

  4. Sessions J . Chronic myeloid leukemia in 2007. J Manag Care Pharm 2007; 13: 4–7.

    Google Scholar 

  5. Deininger MW, Goldman JM, Melo JV . The molecular biology of chronic myeloid leukemia. Blood 2000; 96: 3343–3356.

    CAS  Google Scholar 

  6. Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med 1996; 2: 561–566.

    Article  CAS  Google Scholar 

  7. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F et al. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108: 1809–1820.

    Article  CAS  Google Scholar 

  8. National Comprehensive Cancer Network. NCCN: clinical practice guidelines in oncology. Chronic Myelogenous Leukemia. Version (V.1.2010), 2009.

  9. Hochhaus A, O'Brien SG, Guilhot F, Druker BJ, Branford S, Foroni L et al. Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia. Leukemia 2009; 23: 1054–1061.

    Article  CAS  Google Scholar 

  10. O'Brien SG, Guilhot F, Goldman JM, Hochhaus A, Hughes T, Radich JP et al. International Randomized Study of Interferon and STI571 (IRIS) 7-year follow-up: sustained survival, low rate of transformation and increased rate of major molecular response (MMR) in patients (pts) with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib (IM). Blood 2008; 112: 76.

    Article  Google Scholar 

  11. Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002; 16: 2190–2196.

    Article  CAS  Google Scholar 

  12. Hochhaus A, La Rosée P . Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance. Leukemia 2004; 18: 1321–1331.

    Article  CAS  Google Scholar 

  13. Apperley JF . Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol 2007; 8: 1018–1029.

    Article  CAS  Google Scholar 

  14. Kantarjian HM, Larson RA, Guilhot F, O'Brien SG, Mone M, Rudoltz M et al. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 2009; 115: 551–560.

    Article  CAS  Google Scholar 

  15. Jabbour E, Kantarjian H, O'Brien S, Wierda W, Faderl S, Garcia-Manero G et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia post cytogenetic failure on standard-dose imatinib therapy. Blood 2008; 113: 2154–2160.

    Article  Google Scholar 

  16. Hughes T, Deininger M, Hochhaus A, Branford S, Radich J, Kaeda J et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors—review and recommendations for ‘harmonizing’ current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood 2006; 108: 28–37.

    Article  CAS  Google Scholar 

  17. Jabbour E, Cortes J, O'Brien S, Rios MB, Giles F, Kantarjian H . Management of patients with newly diagnosed chronic myeloid leukemia: opportunities and challenges. Clin Lymphoma Myeloma 2007; 7 (Suppl 2): S51–S57.

    Article  CAS  Google Scholar 

  18. Cortes JE, Baccarani M, Guilhot F, Druker BJ, Branford S, Kim D-W et al. A phase III, randomized, open-label study of 400 versus 800 mg of imatinib mesylate (IM) in patients (pts) with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase (CML-CP) using molecular endpoints: 1-year results of TOPS (Tyrosine Kinase Inhibitor Optimization and Selectivity) study. Blood 2008; 112: 130–131.

    Google Scholar 

  19. Baccarani M, Castagnetti F, Simonsson B, Porkka K, Haznedaroglu IC, Nagler A et al. Cytogenetic and molecular response to imatinib in high risk (Sokal) chronic myeloid leukemia (CML): results of a European LeukemiaNet prospective study comparing 400 and 800 mg front-line. Blood 2008; 112: 75.

    Google Scholar 

  20. Golemovic M, Verstovsek S, Giles F, Cortes J, Manshouri T, Manley PW et al. AMN107, a novel aminopyrimidine inhibitor of Bcr-Abl, has in vitro activity against imatinib-resistant chronic myeloid leukemia. Clin Cancer Res 2005; 11: 4941–4947.

    Article  CAS  Google Scholar 

  21. Weisberg E, Manley PW, Breitenstein W, Bruggen J, Cowan-Jacob SW, Ray A et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell 2005; 7: 129–141.

    Article  CAS  Google Scholar 

  22. Hantschel O, Rix U, Superti-Furga G . Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk Lymphoma 2008; 49: 615–619.

    Article  CAS  Google Scholar 

  23. Cortes J, O'Brien S, Jones D, Ferrajoli A, Konopleva M, Borthakur G et al. Efficacy of nilotinib (formerly AMN107) in patients (Pts) with newly diagnosed, previously untreated Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia in early chronic phase (CML-CP). Blood 2008; 112: 170.

    Google Scholar 

  24. Rosti G, Castagnetti F, Poerio A, Breccia M, Levato L, Capucci A et al. High and early rates of cytogenetic and molecular response with nilotinib 800 mg daily as first line treatment of Ph-positive chronic myeloid leukemia in chronic phase: results of a phase 2 trial of the GIMEMA CML Working Party. Blood 2008; 112: 73–74.

    Article  Google Scholar 

  25. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL . Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 2004; 305: 399–401.

    Article  CAS  Google Scholar 

  26. Cortes J, O'Brien S, Borthakur G, Jones D, Ravandi F, Koller C et al. Efficacy of dasatinib in patients (pts) with previously untreated chronic myelogenous leukemia (CML) in early chronic phase (CML-CP). Blood 2008; 112: 74.

    Google Scholar 

  27. Sprycel (dasatinib) [package insert]. Bristol-Myers Squibb Company: Princeton, NJ, 2007.

  28. Sprycel (dasatinib) [package insert]. Bristol-Myers Squibb Company: Princeton, NJ, 2009.

  29. Hochhaus A, Kantarjian HM, Baccarani M, Lipton JH, Apperley JF, Druker BJ et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood 2007; 109: 2303–2309.

    Article  CAS  Google Scholar 

  30. Cervantes F, Baccarani M, Lipton J, Matloub Y, Sinha R, Stone RM et al. Dasatinib long-term efficacy in patients with chronic myeloid leukemia in chronic phase (CML-CP) with resistance or intolerance to imatinib: A two-year update of the START-C study. Haematologica 2008; 93: 372.

    Article  Google Scholar 

  31. Rousselot P, Corm S, Paquette R, Bleickardt E, Dejardin D, Kantarjian H et al. Dasatinib compared with high-dose imatinib in patients with chronic myelogenous leukemia in chronic phase (CML-CP) after failure of standard-dose imatinib—a two-year update of the START-R study. Haematologica 2008; 93: 48.

    Article  Google Scholar 

  32. Shah NP, Kim DW, Kantarjian HMea . Dasatinib 50 or 70 mg BID compared to 100 or 140 mg QD in patients with CML in chronic phase (CP) who are resistant or intolerant to imatinib: one-year results of CA180034. J Clin Oncol 2007; 25: 358s.

    Article  Google Scholar 

  33. Tasigna (nilotinib) [package insert] Novartis Pharmaceuticals Corporation: East Hanover, NJ, 2007.

  34. Kantarjian HM, Giles F, Bhalla KN, Larson RA, Gattermann N, Ottmann OG et al. Nilotinib in chronic myeloid leukemia patients in chronic phase (CML-CP) with imatinib resistance or intolerance: 2-year follow-up results of a phase 2 study. Blood 2008; 112: 1112.

    Google Scholar 

  35. Jabbour E, Kantarjian HM, Baccarani M, le Coutre P, Haque A, Gallagher NJ et al. Minimal cross intolerance between nilotinib and imatinib in patients with imatinib-intolerant chronic myeloid leukemia in chronic phase (CML-CP) or accelerated phase (CML-AP). Blood 2008; 112: 1103.

    Google Scholar 

  36. Hochhaus A, Müller MC, Cortes JE, Kim DW, Matloub Y, Ploughman L et al. Dasatinib efficacy after imatinib failure by dosing schedule and baseline BCR-ABL mutation status in patients with chronic myeloid leukemia in chronic phase (CML-CP). Haematologica 2008; 93: 371–372.

    Google Scholar 

  37. Hughes T, Saglio G, Branford S, Soverini S, Kim D, Müller M et al. Impact of baseline BCR-ABL mutations on response to nilotinib in chronic myeloid leukemia patients in chronic phase (CML-CP). J Clin Oncol 2009; 27: 4204–4210.

    Article  CAS  Google Scholar 

  38. Bradeen HA, Eide CA, O'Hare T, Johnson KJ, Willis SG, Lee FY et al. Comparison of imatinib mesylate, dasatinib (BMS-354825), and nilotinib (AMN107) in an N-ethyl-N-nitrosourea (ENU)-based mutagenesis screen: high efficacy of drug combinations. Blood 2006; 108: 2332–2338.

    Article  CAS  Google Scholar 

  39. Tanaka R, Kimura S . Abl tyrosine kinase inhibitors for overriding Bcr-Abl/T315I: from the second to third generation. Expert Rev Anticancer Ther 2008; 8: 1387–1398.

    Article  CAS  Google Scholar 

  40. Cortes J, Khoury HJ, Corm S, Nicolini F, Lipton J, Jones D et al. Safety and efficacy of subcutaneous omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia patients with the T315I mutation—results of an ongoing multicenter phase 2/3 study. Blood 2008; 112: 1112–1113.

    Google Scholar 

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

    Article  CAS  Google Scholar 

  42. Lipton JH, Sriharsha L, Bogomilsky S, Casciaro L, Keating A, Messner H et al. Pleural effusions in patients treated with dasatinib: results from two institutions, risk factors and management. J Clin Oncol 2007; 25: 680s.

    Article  Google Scholar 

  43. Carpiuc KT, Stephens JM, Liou SY, Botteman MF . Incidence of grade 3/4 adverse events in imatinib resistant/intolerant chronic phase CML (CP-CML): a comparison of nilotinib and dasatinib. J Clin Oncol 2007; 25: 680s.

    Google Scholar 

  44. Hochhaus A, Neubauer A, Mueller MC, Napieralski S, Erben P, Bostel T et al. Sustained molecular responses with interferon alpha 2a maintenance therapy after imatinib plus IFN induction treatment for chronic phase chronic myelogenous leukemia. Blood 2007; 110: 16a–17a.

    Google Scholar 

  45. Mahon F, Huguet F, Guilhot F, Legros L, Nicolini FE, Charbonnier A et al. Is it possible to stop imatinib in patients with chronic myeloid leukemia? An update from a French pilot study and first results from the multicentre ‘Stop Imatinib’ (STIM) study. Blood 2008; 112: 76.

    Google Scholar 

  46. Jain N, Kantarjian HM, Garcia-Manero G, Borthakur G, Ebarb T, Cortes JE . Synthetic tumor-specific breakpoint peptide vaccine in patients (pts) with chronic myeloid leukemia (CML) and minimal residual disease: a phase II trial. J Clin Oncol 2008; 26: 386s.

    Article  Google Scholar 

Download references

Acknowledgements

The authors thank Michael Mandola, PhD (Articulate Science) for medical editorial assistance with this paper.

Author information

Authors and Affiliations

  1. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    E Jabbour, J Cortes & H M Kantarjian

  2. Department of Hematology/Oncology, University Medical Center, Jena, Germany

    A Hochhaus & P La Rosée

Authors
  1. E Jabbour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Hochhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J Cortes
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. P La Rosée
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H M Kantarjian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E Jabbour.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jabbour, E., Hochhaus, A., Cortes, J. et al. Choosing the best treatment strategy for chronic myeloid leukemia patients resistant to imatinib: weighing the efficacy and safety of individual drugs with BCR-ABL mutations and patient history. Leukemia 24, 6–12 (2010). https://doi.org/10.1038/leu.2009.193

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2009.193

Keywords

This article is cited by

Search

Advanced search

Quick links