The development and clinical availability of second-generation tyrosine kinase inhibitors (TKIs) for the treatment of patients who discontinue imatinib therapy has further improved the outlook for patients with chronic phase chronic myeloid leukaemia (CP-CML). There is, however, uncertainty surrounding how best to treat patients after failing second-generation TKIs. A three-section questionnaire was devised by chronic myeloid leukaemia experts to address questions surrounding this issue. Responses were received from 14 out of 34 experts (41.2%). Generally, a reasonable consensus was found among the responses for most issues. There was a complete consensus that ponatinib was suitable for all patients carrying the T315I mutation regardless of the molecular response to prior treatment. There was also complete consensus that allografting is appropriate in any patient who has had blast crises and is back in a second chronic phase. More recommendations for third-line treatment of CP-CML patients are necessary.
Chronic phase chronic myeloid leukaemia, tyrosine kinase inhibitors, allogeneic haematopoietic stem cell transplantation
Tim Hughes has recevied research funding and honoraria from Novartis, BMS and Ariad. Giuseppe Saglio has received consulting fees from Novartis, BMS, Incyte, Ariad and Pfizer.
Compliance with Ethics: All procedures were followed in accordance with the responsible committee on human experimentation and with the Helsinki Declaration of 1975 and subsequent revisions, and informed consent was received from the patient involved in this case study; or This study involves a review of the literature and did not involve any studies with human or animal subjects. performed by any of the authors.
Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.
This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
October 08, 2016 Accepted
January 25, 2017
Tim Hughes, SAHMRI, North Terrace, Adelaide SA 5000 Australia, PO Box 11060, Adelaide SA 5001. E: firstname.lastname@example.org
The publication of this article was supported by Ariad. The views and opinions expressed are those of the authors and do not necessarily reflect those of Ariad. The authors provided Ariad with the opportunity to review the article for scientific accuracy before submission. Any resulting changes were made at the author’s discretion.
The treatment of patients with chronic phase chronic myeloid leukaemia (CP-CML) has changed dramatically with the advent of the first BCR-ABL tyrosine kinase inhibitor (TKI) imatinib (Gleevec®, Novartis Pharmaceutical Corporation, New Jersey, US) in the 1990s.1,2 Multiple studies demonstrated the efficacy and acceptable tolerability of imatinib 400 mg daily.3,4 Despite the good cytogenetic and molecular response rates, some patients show primary resistance (refractoriness) or relapse after an initial response (secondary or acquired resistance).5,6 Adverse events occurred mainly within the first 2 years of treatment initiation and symptoms appeared to be mild or moderate in most instances, but with other treatment options available even low-grade toxicities are less acceptable and lead to discontinuation. Definitions of haematological, cytogenetic and molecular response have been previously described.7 Resistance in this setting has been defined as treatment with imatinib ≥600 mg/d (for ≥3 months) with disease progression (≥50% increase in white blood cells), or no haematological response after 4 weeks, or patients receiving <600 mg/d with mutations at any of the following ABL amino acids: L248, G250, Q252, Y253, E255, T315, F317, H396.7 Dasatinib (Sprycel®; Bristol-Myers Squibb, New Jersey, US) and nilotinib (Tasigna®; Novartis, New Jersey, US), two second-generation TKIs initially launched for use as second-line therapies in 2006/2007, were approved for first line use in 2010. Treatment with dasatinib or nilotinib in recommended doses of 100 mg daily or 400 mg twice daily resulted in significantly higher cytogenetic and molecular response rates compared to imatinib 400 mg daily but there was no progression-free survival (PFS) or overall survival (OS) benefit. With the success of TKIs the earlier gold standard of allogeneic haematopoietic stem-cell transplantation (allo-HSCT) is reserved for later-line patients failing to achieve adequate responses.
In second-line, dasatinib and nilotinib have been recommended for treatment of CP-CML patients with resistance/intolerance to imatinib. In addition, bosutinib (Bosulif®; Pfizer, New York, US) received a conditional marketing authorisation in 2013 that is valid throughout the European Union (see Table 1),8–10 for the treatment of adult chronic myeloid leukaemia (CML) patients in all phases.11,12 Despite some good responses to second-line TKI therapy, approximately half of patients treated with dasatinib 100 mg daily or nilotinib 400 mg twice daily develop resistance or intolerance8,13,14 and discontinue therapy.
Third-line treatment Patients who fail to respond to second-line therapy generally receive third-line therapy with another TKI,10,15–20 and identifying patients most likely to benefit from third-line TKI therapy represents an important unmet need. A cohort of 26 patients with CP-CML who had failed imatinib and a second-line TKI was analysed to identify prognostic factors for response and outcomes.21 For the achievement of complete cytogenetic responses on third-line therapy, prior cytogenetic response with imatinib or a second-line therapy were the only independent predictors. For OS, younger age and the demonstration of a cytogenetic response on second-line therapy were the only independent predictors. The authors highlighted the need to be able to select more accurately
1. Okuda K, Matulonis U, Salgia R, et al., Factor independence of human myeloid leukemia cell lines is associated with increased phosphorylation of the proto-oncogene Raf-1, Experimental Hematology, 1994;22:1111–7.
2. Jemal A, Siegel R, Xu J, et al., Cancer statistics, 2010, CA: a cancer journal for clinicians, 2010;60:277-300.
3. de Lavallade H, Apperley JF, Khorashad JS, et al., Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis, J Clin Oncol, 2008;26:3358–63.
4. O’Brien SG, Deininger MW, Imatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia, Semin Hematol, 2003;40(2 Suppl 2):26–30.
5. Weisberg E, Manley PW, Cowan-Jacob SW, et al., Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia, Nat Rev Cancer, 2007;7:345–56.
6. Ramirez P, DiPersio JF, Therapy options in imatinib failures, The Oncologist, 2008;13:424–34.
7. Kantarjian HM, Giles F, Gattermann N, et al., Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance, Blood, 2007;110:3540–6.
8. Hochhaus A, Baccarani M, 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;22:1200–6.
9. Giles FJ, le Coutre PD, Pinilla-Ibarz J, et al., Nilotinib in imatinibresistant or imatinib-intolerant patients with chronic myeloid leukemia in chronic phase: 48-month follow-up results of a phase II study, Leukemia, 2013;27:107–12.
10. Khoury HJ, Cortes JE, Kantarjian HM, et al., Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure, Blood, 2012;119:3403– 12.
11. Hanaizi Z, Unkrig C, Enzmann H, et al., The European medicines agency review of bosutinib for the treatment of adult patients with chronic myelogenous leukemia: summary of the scientific assessment of the committee for medicinal products for human use, The Oncologist, 2014;19:421–5.
12. Jabbour E, Kantarjian HM, O’Brien S, et al., Front-line therapy with second-generation tyrosine kinase inhibitors in patients with early chronic phase chronic myeloid leukemia: what is the optimal response?, J Clin Oncol, 2011;29:4260–5.
13. Kantarjian HM, Giles FJ, Bhalla KN, et al., Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results, Blood, 2011;117:1141–5.
14. Kantarjian H, Pasquini R, Levy 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;115:4136–47.
15. Quintas-Cardama A, Kantarjian H, Jones D, et al., Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure, Blood, 2007;109:497–9.
16. Nicolini EE, Alimena G, Ali AJ, et al., Expanding nilotinib access iun clinical trials (ENACT) study in adult patients (PTS0 with imatinib-resistant or -intolerant chronic myeloid leukemia (CML): Subgroup analysis of patients who failed prior dasatinib therapy, Haematologica, 2009;94(S2):257.
17. Giles FJ, Abruzzese E, Rosti G, et al., Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy, Leukemia, 2010;24:1299–301.
18. Russo Rossi A, Breccia M, Abruzzese E, et al., Outcome of 82 chronic myeloid leukemia patients treated with nilotinib or dasatinib after failure of two prior tyrosine kinase inhibitors, Haematologica, 2013;98:399–403.
19. Ribeiro BF, Miranda EC, Albuquerque DM, et al., Treatment with dasatinib or nilotinib in chronic myeloid leukemia patients who failed to respond to two previously administered tyrosine kinase inhibitors--a single center experience, Clinics (Sao Paulo, Brazil), 2015;70:550–5.
20. Gambacorti-Passerini C, Khoury HJ, Kantarjian HM, et al., Bosutinib As Third-Line Therapy in Patients (Pts) with Chronic Phase Chronic Myeloid Leukemia (CP CML) Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 48-Month Update of a Phase 1/2 Study, Blood, 2014;124:4559.
21. Ibrahim AR, Paliompeis C, Bua M, et al., Efficacy of tyrosine kinase inhibitors (TKIs) as third-line therapy in patients with chronic myeloid leukemia in chronic phase who have failed 2 prior lines of TKI therapy, Blood, 2010;116:5497–500.
22. Garg RJ, Kantarjian H, O’Brien S, et al., The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: longterm follow-up, Blood, 2009;114:4361–8.
23. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Chronic Myelogenous Leukemia. Version 1.2016 2016. Available at: www.nccn. org/professionals/physician_gls/pdf/cml.pdf (accessed 2 September 2016).
24. Gratwohl A, Pfirrmann M, Zander A, et al., Long-term outcome of patients with newly diagnosed chronic myeloid leukemia: a randomized comparison of stem cell transplantation with drug treatment, Leukemia, 2016;30:562–9.
25. Pavlu J, Szydlo RM, Goldman JM, et al., Three decades of transplantation for chronic myeloid leukemia: what have we learned?, Blood, 2011;117:755–63.
26. Goldman JM, Ponatinib for chronic myeloid leukemia, New Eng J Med, 2012;367:2148–9.
27. Cortes JE, Kantarjian H, Shah NP, et al., Ponatinib in refractory Philadelphia chromosome-positive leukemias, New Engl J Med, 2012;367:2075–88.
28. O’Hare T, Shakespeare WC, Zhu X, et al., AP24534, a pan-BCRABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance, Cancer Cell, 2009;16:401–12.
29. Redaelli S, Piazza R, Rostagno R, et al., Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants, J Clin Oncol, 2009;27:469–71.
30. Hochhaus A, Cortes JE, Kim D-W, et al., Efficacy and Safety of Ponatinib in CP-CML Patients By Number of Prior Tyrosine Kinase Inhibitors: 4-Year Follow-up of the Phase 2 PACE Trial, Blood, 2015;126:4025.
31. Kantarjian HM, Kim D-W, Pinilla-Ibarz J et al., On behalf of the PACE Study Group. Ponatinib in Patients with Philadelphia Chromosome–Positive Leukemias Resistant or Intolerant to Dasatinib or Nilotinib, or With the T315I Mutation: Longer-term Follow-up of the PACE Trial. 50th American Society of Clinical Oncology (ASCO). Chicago, IL, USA, 2014.
32. European Medicines Agency. Assessment report: Ponatinib 2014. Available at: www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Assessment_Report_-_Variation/ human/002695/WC500183099.pdf (accessed 22 June 2016).
33. Ponatinib Full Prescribing Information. 2013. Available at: www. iclusigrems.com/packaged/pdf/PI.pdf (accessed 30 January 2017).
34. Lipton JH, Bryden P, Sidhu MK, et al., Comparative efficacy of tyrosine kinase inhibitor treatments in the third-line setting, for chronic-phase chronic myelogenous leukemia after failure of second-generation tyrosine kinase inhibitors, Leuk Res, 2014;39:58-64.
35. Baccarani M, Pileri S, Steegmann JL, et al., Chronic myeloid leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann Oncol, 2012;23 Suppl 7:vii72-7.
36. Baccarani M, Deininger MW, Rosti G, et al., European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013, Blood, 2013;122:872-84.
37. Soverini S, Branford S, Nicolini FE, et al., Implications of BCRABL1 kinase domain-mediated resistance in chronic myeloid leukemia, Leuk Res, 2014;38:10–20.
38. Cortes JE, Saglio G, Kantarjian HM, et al., Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naive Chronic Myeloid Leukemia Patients Trial, J Clin Oncol, 2016;34:2333–40.
39. Cortes JE, Kim DW, Pinilla-Ibarz J, et al., A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias, N Engl J Med, 2013;369:1783–96.
40. Quintas-Cardama A, Grgurevic S, Rozovski U, et al., Detection of dormant chronic myeloid leukemia clones in the bone marrow of patients in complete molecular remission, Clin Lymphoma Myeloma Leuk, 2013;13:681–5.
41. Parker WT, Yeoman AL, Jamison BA, et al., BCR-ABL1 kinase domain mutations may persist at very low levels for many years and lead to subsequent TKI resistance, Br J Cancer, 2013;109:1593–8.
42. Parker WT, Lawrence RM, Ho M, et al., Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy, J Clin Oncol, 2011;29:4250–9.
43. Shah NP, Kim DW, Kantarjian H, et al., Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib, Haematologica, 2010;95:232–40.
44. Shah NP, Cortes JE, Schiffer CA, Five-year follow-up of patients with imatinib-resistant or -intolerant chronic-phase chronic myeloid leukemia (CML-CP) receiving dasatinib, J Clin Oncol, 2011;29(Suppl 1):Abstract 65512.
45. Shah NP, Guilhot F, Cortes JE, et al., Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study, Blood, 2014;123:2317–24.
46. Cortes JE, Kantarjian HM, Brummendorf TH, et al., Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib, Blood, 2011;118:4567–76.
47. Khoury HJ, Bixby DL, Outcomes of chronic-phase chronic myeloid leukemia beyond first-line therapy, Leukemia & Lymphoma, 2014:1–9.
Chronic phase chronic myeloid leukaemia, tyrosine kinase inhibitors, allogeneic haematopoietic stem cell transplantation