Skip to main content

Advertisement

SpringerLink
Log in

Current Information and Recommendations on the Discontinuation of TKI Inhibitors in Chronic Myeloid Leukemia

  • Leukemia (A Aguayo, Section Editor)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Discontinuation of tyrosine kinase inhibitors (TKIs) in chronic phase chronic myeloid leukemia (CP-CML) patients has become a reality. Treatment-free remission (TFR) is the term that identifies success after discontinuation.

Recent Findings

Several trials have demonstrated that with imatinib about 40% of patients discontinuing treatment in deep and stable molecular response remain disease-free. Second-generation TKIs have improved the rate of deep molecular responses and allowed to increase the percentage of patients attempting treatment discontinuation.

Summary

We hereby review the current information based on the available published data and discuss the current suggestions on how to move TFR into the clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. •• Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376(10):917–27. https://doi.org/10.1056/NEJMoa1609324. This paper reported the long-term follow-up of IRIS study, the first that tested imatinib frontline.

    Article  CAS  PubMed  Google Scholar 

  2. Dulucq S, Mahon FX. Deep molecular responses for treatment-free remission in chronic myeloid leukemia. Cancer Med. 2016;5(9):2398–411. https://doi.org/10.1002/cam4.801.

    Article  PubMed  PubMed Central  Google Scholar 

  3. • Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chrnic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30(5):1044–54. https://doi.org/10.1038/leu.2016.5. This paper reported the long-term follow-up of ENESTnd trial that tested nilotinib 300 mg BID as frontline treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. • Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boqué C, 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(20):2333–40. https://doi.org/10.1200/JCO.2015.64.8899. This paper reported the long-term follow-up of DASISION trial that tested dasatinib 100 mg QD as frontline treatment.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. •• Cross NC, White HE, Muller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia. 2012;26(10):2172–5. https://doi.org/10.1038/leu.2012.104. This paper reported the standardization provided to classify deep molecular responses in CML.

    Article  CAS  PubMed  Google Scholar 

  6. Goldman J, Gordon M. Why do chronic myelogenous leukemia stem cells survive allogeneic stem cell transplantation or imatinib: does it really matter? Leuk Lymphoma. 2006;47(1):1–7. https://doi.org/10.1080/10428190500407996.

    Article  CAS  PubMed  Google Scholar 

  7. Caldemeyer L, Akard LP. Rationale and motivating factors for treatment-free remission in chronic myeloid leukemia. Leuk Lymphoma. 2016;57(12):2739–51. https://doi.org/10.1080/10428194.2016.1198959.

    Article  CAS  PubMed  Google Scholar 

  8. Rousselot P, Hughet F, Rea D, Legros L, Cayuela JM, Maarek O, et al. Imatinib mesylate discontinuation in patients with chronic myelogenous leukemia in complete molecular remission for more than 2 years. Blood. 2007;109(1):58–60. https://doi.org/10.1182/blood-2006-03-011239.

    Article  CAS  PubMed  Google Scholar 

  9. •• Etienne G, Guilhot J, Rea D, Rigal-Huguet F, Nicolini F, Charbonnier A, et al. Long-term follow-up of the French Stop Imatinib (STIM1) study in patients with chronic myeloid leukemia. J Clin Oncol. 2017;35(3):298–305. https://doi.org/10.1200/JCO.2016.68.2914. This paper reported the long-term follow-up of STIM1 trial that tested for the first time the discontinuation of imatinib.

    Article  PubMed  Google Scholar 

  10. Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122(2013):515–22. https://doi.org/10.1182/blood-2013-02-483750.

    Article  CAS  PubMed  Google Scholar 

  11. Lee SE, Choi SY, Bang JH, Kim SH, Jang EJ, Byeun JY, et al. Predictive factors for successful imatinib cessation in chronic myeloid leukemia patients treated with imatinib. Am J Hematol. 2013;88(6):449–54. https://doi.org/10.1002/ajh.23427.

    Article  CAS  PubMed  Google Scholar 

  12. • Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini F, Varet B, et al. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol. 2014;32(5):424–30. https://doi.org/10.1200/JCO.2012.48.5797. This paper reported the results of A-STIM trial that considered for the first time the threshold of loss of MMR as relapse.

    Article  CAS  PubMed  Google Scholar 

  13. Mahon FX, Nicolini FE, Noel MP, Escoffre M, Charbonnier A, Rea D, et al. Preliminary report of the STIM2 study: a multicentre stop imatinib trial for chronic phase chronic myeloid leukemia de novo patients on imatinib. Blood. 2013;122:abstract 654.

    Google Scholar 

  14. Takahashi N, Tauchi T, Kitamura K, Miyamura K, Saburi Y, Miyata Y, et al. Around 70% of Japanese CML patients could stop imatinib according to a-STIM criteria: the JALSG-STIM213 study. Blood. 2015;126:abstract 4035.

    Google Scholar 

  15. Mori S, Vagge E, le Coutre P, Abruzzese E, Martino B, Pungolino E, et al. Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study. Am J Hematol. 2015;90(10):910–4. https://doi.org/10.1002/ajh.24120.

    Article  CAS  PubMed  Google Scholar 

  16. Fava C, Rege-Cambrin G, Dogliotti I, Berchialla P, Abruzzese E, Annunziata M, et al. Tyrosine kinase inhibitors discontinuation in chronic myeloid leukemia: a retrospective analysis of 208 Italian patients. Haematologica. 2016;101(s1):abstract 235.

    Google Scholar 

  17. • Richter J, Mahon FX, Guilhot J, et al. Stopping tyrosine kinase inhibitors in a very large cohort of European chronic myeloid leukemia patients: results of the EURO-SKI trial. Haematologica. 2016;101(s1):abstract 145. This abstract reported the first analysis of EURO-SKI trial, a large trial that included more than 700 patients who discontinued the treatment in stable MR4.

    Google Scholar 

  18. Pfirmann M, Mahon FX, Guilhot J, Richter J, Almeida A, Janssen JJWM, et al. No differences in molecular relapse-free survival after stopping imatinib treatment of chronic myeloid leukemia between patients with prior 4.5 log reduction (MR4.5) but detectable and patients with undetectable disease in the EURO-SKI trial. Blood. 2016;128(22):abstract 789.

    Google Scholar 

  19. Pfirmann M, Hochhaus A, Almeida A, Mahon FX, Ehrencrona H, Hjorth-Hansen H, et al. Chronic myeloid leukemia patients were not different in molecular relapse after stopping imatinib in MR4 whether residual disease was detected or not-when adjusting for number of control transcripts. Haematologica. 2017;102(s2):abstract 426.

    Google Scholar 

  20. Rea D, Nicolini FE, Tulliez M, Guilhot F, Guilhot J, Guerci-Bresler A, et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 2017;129(7):846–54. https://doi.org/10.1182/blood-2016-09-742205.

    Article  CAS  PubMed  Google Scholar 

  21. Imagawa J, Tanaka H, Okada M, Nakamae H, Hino M, Murai K. Discontinuation of dasatinib in patients with chronic myeloid leukemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. Lancet Haematol. 2015;2(12):e528–35. https://doi.org/10.1016/S2352-3026(15)00196-9.

    Article  PubMed  Google Scholar 

  22. Clark RE, Polydoros F, Apperley JF, Milojkovic D, Pocock C, Smith G, et al. De-escalation of tyrosine kinase inhibitor dose in patients with chronic myeloid leukemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial. Lancet Hematol. 2017;4(7):e310–6. https://doi.org/10.1016/S2352-3026(17)30066-2.

    Article  Google Scholar 

  23. Clark R, Pocock C, Milojkovic D, Polydoros F, Smith G, de Lavallade H, et al. Initial reduction of therapy before complete withdrawal improves the chance of successful treatment discontinuation in chronic myeloid leukemia (CML): year 2 results in the British Destiny Trial. Haematologica. 2017;102(s2):abstract 423.

    Google Scholar 

  24. • Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gomez Casares MT, et al. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017;31(7):1525–31. https://doi.org/10.1038/leu.2017.63. This paper reported the first follow-up of ENESTFreedom trial, in which patients were treated with nilotinib 300 mg BID as frontline treatment and then after a stable MR4.5 entered in a discontinuation phase.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hughes TP, Turkina A, Moiraghi B, Boquimpani C, Kim DW, Nicolini FE, et al. Durable treatment-free remission (TFR) after stopping second-line nilotinib in patients with chronic myeloid leukemia in chronic phase (CML-CP): ENESTOP 96-wk update. Haematologica. 2017;102(s2):abstract 257.

    Google Scholar 

  26. Shah NP, Paquette R, Muller MC, Saussele S, Garcia-Gutierrez V, Jimenez-Velasco A, et al. Treatment-free remission (TFR) in patients with chronic phase chronic myeloid leukemia (CML-CP) and in stable deep molecular response (DMR) to dasatinib-the DASFREE study. Blood. 2016;128:abstract 1895.

    Google Scholar 

  27. Kumagai T, Nakaseko C, Nishiwaki K, Yoshida C, Ohashi K, Takezako N, et al. Discontinuation of dasatinib after deep molecular response for over 2 years in patients with chronic myelogenous leukemia and the unique profiles of lymphocyte subsets for successful discontinuation: a prospective, multicentre Japanese trial (D-STOP) trial. Blood 2016; 128. Abstract 791.

  28. • Legros L, Nicolini FE, Etienne G, Rousselot P, Rea D, Giraudier S, et al. Second tyrosine kinase inhibitor discontinuation attempt in patients with chronic myeloid leukemia. Cancer. 2017;123(22):4403–10. https://doi.org/10.1002/cncr.30885. This paper reported the first attempt of second discontinuation of imatinib (RE-STIM trial).

    Article  CAS  PubMed  Google Scholar 

  29. Matsuki E, Sakurai M, Karigane D, Kasahara H, Kikuchi T, Shimizu T, et al. Second attempt to discontinue TKI in CML patients who have sustained CMR for over 2 years is rarely successful even with the use of second generation TKIs. Blood. 2016;128:abstract 1887.

    Google Scholar 

  30. Rea D, Henry G, Khaznadar Z, Etienne G, Guilhot F, Nicolini F, et al. Natural killer-cell counts are associated with molecular relapse-free survival after imatinib discontinuation in chronic myeloid leukemia: the IMMUNOSTIM study. Haematologica. 2017;102(8):1368–77. https://doi.org/10.3324/haematol.2017.165001.

    Article  PubMed  Google Scholar 

  31. • Ilander M, Olsson-Strömberg U, Schlums H, Guilhot J, Brück O, Lähteenmäki H, et al. Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia. Leukemia. 2017;31(5):1108–16. https://doi.org/10.1038/leu.2016.360. This paper reported the results of a sub-analysis of EURO-SKI trial that analysed the immunological compartment in patients who discontinued the treatment.

    Article  CAS  PubMed  Google Scholar 

  32. Schutz C, Inselmann S, Saussele S, Dietz CT, Muller MC, Eigendorff E, et al. Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. Leukemia. 2017;31(4):829–36. https://doi.org/10.1038/leu.2017.9.

    Article  CAS  PubMed  Google Scholar 

  33. Rinaldetti S, Kiani A, Fabarius A, Burchert A, Spiess B, Janssen C, et al. Impact of ABCG2, OCT1 and ABCB1 (MDR1) on treatment free remission in an EUROSKI subtrial. Haematologica. 2017;102(s2):abstract 255.

    Google Scholar 

  34. Claudiani S, Apperley JF, Gale RP, Clark R, Szydlo R, Deplano S, et al. E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy. Haematologica. 2017;102(8):e297–9. https://doi.org/10.3324/haematol.2017.168740.

    Article  PubMed  PubMed Central  Google Scholar 

  35. •• Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122(6):872–4. https://doi.org/10.1182/blood-2013-05-501569. This paper reported the last update of European LeukemiaNet recommendations for the treatment and monitoring of CML patients.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. •• Hughes TP, Ross DM. Moving treatment-free remission into mainstream clinical practice in CML. Blood. 2016;128(1):17–23. https://doi.org/10.1182/blood-2016-01-694265. This paper reported the first attempt of suggested recommendations of discontinuation in clinical practice.

    Article  CAS  PubMed  Google Scholar 

  37. •• Pallera A, Altman JK, Berman E, Abboud CN, Bhatnagar B, Curtin P, et al. NCCN guidelines insights: chronic myeloid leukemia, version 1.2017. J Natl Compr Cancer Netw. 2016;14(12):1505–12. This paper reported the last edition of NCCN guidelines.

    Article  CAS  Google Scholar 

  38. Hochahus A, Saussele S, Rosti G, Mahon FX, Janssen JJWM, Hjorth-Hansen H, et al. Chronic myeloid leukemia: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv41–51. https://doi.org/10.1093/annonc/mdx219.

    Article  Google Scholar 

  39. Breccia M, Efficace F, Sica S, Abruzzese E, Cedrone M, Turri D, et al. Adherence and future discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia. A patient-based survey on 1133 patients. Leuk Res. 2015;39(10):1055–9. https://doi.org/10.1016/j.leukres.2015.07.004.

    Article  PubMed  Google Scholar 

  40. Boquimpani CM, Szczudlo T, Mendelson E, Benjamin K, Masszi T. Attitudes and perceptions of patients with chronic myeloid leukemia in chronic phase toward treatment-free remission (TFR). Blood. 2014;124:abstract 4547.

    Google Scholar 

  41. Goldberg S, Hamarman S. Patients with chronic myelogenous leukemia may not want to discontinue tyrosine kinase inhibitor therapy. Blood. 2015;126:abstract 1584.

    Google Scholar 

  42. Villemagne Sanchez LA, O'Callaghan C, Gough K, Hall K, Kashima Y, Seymour JF, et al. Patient perceptions of treatment-free remission in chronic myeloid leukemia. Leuk Lymphoma. 2017;59(2):406–15. https://doi.org/10.1080/10428194.2017.1337114.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hematology, Department of Cellular Biotechnologies and Hematology, Policlinico Umberto 1, ‘Sapienza’ University, Via Benevento 6, 00161, Rome, Italy

    Massimo Breccia & Robin Foà

Authors
  1. Massimo Breccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robin Foà
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Massimo Breccia.

Ethics declarations

Conflict of Interest

Massimo Breccia has received compensation from Pfizer, Bristol-Myers Squibb, Incyte, and Novartis for service as a consultant.

Robin Foà has received compensation from Janssen, Gilead, Roche, Celgene, Amgen, AbbVie, Novartis, and Sandoz for service on advisory boards and/or speaker’s bureaus.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Leukemia

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Breccia, M., Foà, R. Current Information and Recommendations on the Discontinuation of TKI Inhibitors in Chronic Myeloid Leukemia. Curr Oncol Rep 20, 23 (2018). https://doi.org/10.1007/s11912-018-0669-y

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-018-0669-y

Keywords

Search

Navigation