Current Information and Recommendations on the Discontinuation of TKI Inhibitors in Chronic Myeloid Leukemia
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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.
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.
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.
KeywordsChronic myeloid leukemia Tyrosine kinase inhibitors Discontinuation Treatment-free remission
Compliance with Ethical Standards
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.
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. CrossRefPubMedGoogle 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. CrossRefPubMedPubMedCentralGoogle 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. CrossRefPubMedPubMedCentralGoogle 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. CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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. CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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. CrossRefPubMedGoogle 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
- 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
- 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.CrossRefPubMedGoogle 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.CrossRefGoogle 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. CrossRefPubMedPubMedCentralGoogle 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.Google Scholar
- 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). CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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. CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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. CrossRefPubMedPubMedCentralGoogle 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. CrossRefPubMedPubMedCentralGoogle 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. CrossRefPubMedGoogle 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.CrossRefPubMedGoogle 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