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CHRONIC MYELOGENOUS LEUKEMIA

Long-term treatment-free remission in patients with chronic myeloid leukemia after second-line nilotinib: ENESTop 5-year update

Leukemia volume 35, pages 1631–1642 (2021)Cite this article

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Abstract

The ENESTop study evaluated treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML) in chronic phase who had received ≥3 years of tyrosine kinase inhibitor therapy and achieved sustained deep molecular response only after switching from imatinib to nilotinib. After 1-year nilotinib consolidation, 126 patients attempted TFR. At 48 weeks (primary analysis), 57.9% (73/126) were in TFR. In the present analysis at 5 years, 42.9% (54/126) were in TFR. Since the 48-week analysis, among patients who left the TFR phase, 58% (11/19) did not have a loss of molecular response and discontinued for other reasons. Of the 59 patients who reinitiated nilotinib upon loss of major molecular response (MMR) or confirmed loss of MR4, 98.3% regained MMR, 94.9% regained MR4, and 93.2% regained MR4.5. Overall adverse event rates decreased over the 5 years of TFR. In patients reinitiating nilotinib, there was a cumulative increase in cardiovascular events with longer nilotinib exposure. No disease progression or CML-related deaths were reported. Overall, these results confirm the durability and safety of TFR for patients receiving second-line nilotinib. Cardiovascular risk should be carefully managed, particularly when reinitiating treatment after TFR.

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Fig. 1: Patient disposition at 5-year data cut-off.
Fig. 2: Kaplan–Meier estimate of TFS for patients who entered the TFR phase.
Fig. 3: Cumulative rates of MR4 and MR4.5 regained following treatment reinitiation.
Fig. 4: AEs in consolidation and TFR phases.

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References

  1. Sasaki K, Strom SS, O’Brien S, Jabbour E, Ravandi F, Konopleva M, et al. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials. Lancet Haematol. 2015;2:e186–93.

    Article  Google Scholar 

  2. Bower H, Bjorkholm M, Dickman PW, Hoglund M, Lambert PC, Andersson TM. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34:2851–7.

    Article  CAS  Google Scholar 

  3. Jabbour E. Chronic myeloid leukemia: first-line drug of choice. Am J Hematol. 2016;91:59–66.

    Article  Google Scholar 

  4. Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966–84.

    Article  CAS  Google Scholar 

  5. Hughes TP, Ross DM. Moving treatment-free remission into mainstream clinical practice in CML. Blood. 2016;128:17–23.

    Article  CAS  Google Scholar 

  6. Hochhaus A, Saussele S, Rosti G, Mahon FX, Janssen JJWM, Hjorth-Hansen H, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28:iv41–51.

    Article  CAS  Google Scholar 

  7. Mahon FX. Treatment-free remission in CML: who, how, and why? Hematol Am Soc Hematol Educ Program. 2017;2017:102–9.

    Article  Google Scholar 

  8. Cortes J, Rea D, Lipton JH. Treatment-free remission with first- and second-generation tyrosine kinase inhibitors. Am J Hematol. 2019;94:346–57.

    PubMed  Google Scholar 

  9. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology—Chronic Myeloid Leukemia (Version 2.2020). https://www.nccn.org/professionals/physician_gls/pdf/cml_blocks.pdf. Accessed 4 Dec 2020.

  10. Annunziata M, Bonifacio M, Breccia M, Castagnetti F, Gozzini A, Iurlo A, et al. Current strategies and future directions to achieve deep molecular response and treatment-free remission in chronic myeloid leukemia. Front Oncol. 2020;10:883.

    Article  Google Scholar 

  11. Jiang Q, Liu ZC, Zhang SX, Gale RP. Young age and high cost are associated with future preference for stopping tyrosine kinase inhibitor therapy in Chinese with chronic myeloid leukemia. J Cancer Res Clin Oncol. 2016;142:1539–47.

    Article  CAS  Google Scholar 

  12. 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. 2018;59:406–15.

    Article  Google Scholar 

  13. Mahon F-X, Réa D, Guilhot J, Guilhot F, Huguet F, Nicolini F, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029–35.

    Article  CAS  Google Scholar 

  14. 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;122:515–22.

    Article  CAS  Google Scholar 

  15. Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, 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;32:424–30.

    Article  CAS  Google Scholar 

  16. Imagawa J, Tanaka H, Okada M, Nakamae H, Hino M, Murai K, et al. Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. Lancet Haematol. 2015;2:e528–35.

    Article  Google Scholar 

  17. 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;35:298–305.

    Article  Google Scholar 

  18. 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;129:846–54.

    Article  CAS  Google Scholar 

  19. Okada M, Imagawa J, Tanaka H, Nakamae H, Hino M, Murai K, et al. Final 3-year results of the dasatinib discontinuation trial in patients with chronic myeloid leukemia who received dasatinib as a second-line treatment. Clin Lymphoma Myeloma Leuk. 2018;18:353–60.e1.

    Article  Google Scholar 

  20. Chen KK, Du TF, Xiong PS, Fan GH, Yang W. Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia with losing major molecular response as a definition for molecular relapse: a systematic review and meta-analysis. Front Oncol. 2019;9:372.

    Article  Google Scholar 

  21. Hughes TP, Leber B, Cervantes F, Spector N, Pasquini R, Clementino NCD, et al. Sustained deep molecular responses in patients switched to nilotinib due to persistent BCR-ABL1 on imatinib: final ENESTcmr randomized trial results. Leukemia. 2017;31:2529–31.

    Article  CAS  Google Scholar 

  22. Mahon FX, Boquimpani C, Kim DW, Benyamini N, Clementino NCD, Shuvaev V, et al. Treatment-free remission after second-line nilotinib treatment in patients with chronic myeloid leukemia in chronic phase: results from a single-group, phase 2, open-label study. Ann Intern Med. 2018;168:461–70.

    Article  Google Scholar 

  23. Shah NP, Garcia-Gutierrez V, Jimenez-Velasco A, Larson S, Saussele S, Rea D, et al. Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study. Leuk Lymphoma. 2020;61:650–9.

    Article  Google Scholar 

  24. Ross DM, Masszi T, Gomez Casares MT, Hellmann A, Stentoft J, Conneally E, et al. Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: 96-week update of the ENESTfreedom study. J Cancer Res Clin Oncol. 2018;144:945–54.

    Article  CAS  Google Scholar 

  25. Radich JP, Hochhaus A, Masszi T, Hellmann A, Stentoft J, Casares MTG, et al. Treatment-free remission following frontline nilotinib in patients with chronic phase chronic myeloid leukemia: 5-year update of the ENESTfreedom trial. Leukemia. 2021. https://doi.org/10.1038/s41375-021-01205-5.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Shanmuganathan N, Braley JA, Yong ASM, Hiwase DK, Yeung DT, Ross DM, et al. Modeling the safe minimum frequency of molecular monitoring for CML patients attempting treatment-free remission. Blood. 2019;134:85–9.

    Article  CAS  Google Scholar 

  27. Rousselot P, Loiseau C, Delord M, Cayuela JM, Spentchian M. Late molecular recurrences in patients with chronic myeloid leukemia experiencing treatment-free remission. Blood Adv. 2020;4:3034–40.

    Article  CAS  Google Scholar 

  28. Richter J, Söderlund S, Lübking A, Dreimane A, Lotfi K, Markevärn B, et al. Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome? J Clin Oncol. 2014;32:2821–3.

    Article  Google Scholar 

  29. Saussele S, Richter J, Hochhaus A, Mahon FX. The concept of treatment-free remission in chronic myeloid leukemia. Leukemia. 2016;30:1638–47.

    Article  CAS  Google Scholar 

  30. 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 chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044–54.

    Article  CAS  Google Scholar 

  31. Kantarjian HM, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre P, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021;35:440–53.

  32. Leong D, Aghel N, Hillis C, Siegal D, Karampatos S, Rangarajan S, et al. Tyrosine kinase inhibitors in chronic myeloid leukaemia and emergent cardiovascular disease. Heart. 2021;107:667–73.

  33. Aghel N, Delgado DH, Lipton JH. Cardiovascular toxicities of BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: preventive strategies and cardiovascular surveillance. Vasc Health Risk Manag. 2017;13:293–303.

    Article  CAS  Google Scholar 

  34. Ross DM, Arthur C, Burbury K, Ko BS, Mills AK, Shortt J, et al. Chronic myeloid leukaemia and tyrosine kinase inhibitor therapy: assessment and management of cardiovascular risk factors. Intern Med J. 2018;48:5–13.

    Article  CAS  Google Scholar 

  35. Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H, Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified interim analysis of a prospective, multicentre, non-randomised, trial. Lancet Oncol. 2018;19:747–57.

    Article  CAS  Google Scholar 

  36. Radich JP, Hochhaus A, Giles FJ, Ross DM, Saglio G, Hughes TP, et al. Analyses of predictors of durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline or second-line nilotinib. Blood. 2019;134 Supplement_1:2932.

    Article  Google Scholar 

  37. Ritchie EK, Catchatourian R, Klisovic RB, Pinilla-Ibarz J, Deininger MW, Erba HP, et al. Results from enestgoal: a phase 2 study of treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) who switched from imatinib to nilotinib. Blood. 2017;130 Supplement 1:2875.

    Google Scholar 

  38. Rea D, Kyrcz-krzemien S, Pungolino E, Falzetti F, Bogdanovic A, Medina Almeida A, et al. Molecular response by 24 months of nilotinib 300 mg bid treatment in patients with chronic myeloid leukemia (CML) who failed to achieve dmr with imatinib: Results from the enestpath study. HemaSphere. 2020;4:328–9.

    Article  Google Scholar 

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Acknowledgements

The authors would like to thank all study sites and participating countries, the study investigators, and all study participants and their families. The authors also thank Tim Harries of Novartis Pharmaceuticals UK Ltd, London, UK, for providing medical editorial assistance. This study was sponsored and funded by Novartis Pharmaceuticals.

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Authors and Affiliations

  1. South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, SA, Australia

    Timothy P. Hughes

  2. Hospital Das Clinicas Da UFMG, Belo Horizonte, Brazil

    Nelma Cristina D. Clementino

  3. Russian Research Institute of Hematology and Transfusiology, Saint Petersburg, Russian Federation

    Mikhail Fominykh

  4. Saint Petersburg State University, Saint Petersburg, Russian Federation

    Mikhail Fominykh

  5. Princess Margaret Cancer Centre, Toronto, ON, Canada

    Jeffrey H. Lipton

  6. National Research Center for Hematology, Moscow, Russian Federation

    Anna G. Turkina

  7. Hospital General De Agudos J. M. Ramos Mejia, Buenos Aires, Argentina

    Elena Beatriz Moiraghi

  8. Hematology Department, Centre Léon Berard, Lyon, France

    Franck E. Nicolini

  9. Department of Hematology, Nephrology and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan

    Naoto Takahashi

  10. Department of Hematology, Jagiellonian University Hospital, Krakow, Poland

    Tomasz Sacha

  11. Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, South Korea

    Dong-Wook Kim

  12. Novartis Pharma SAS, Rueil-Malmaison, Paris, France

    Rafik Fellague-Chebra & Catherine Bouard

  13. Novartis Healthcare Pvt. Ltd, Hyderabad, India

    Ranjan Tiwari

  14. Cancer Center of Bordeaux, Institut Bergonié, INSERM U1218, University of Bordeaux, Bordeaux, France

    Francois-Xavier Mahon

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Correspondence to Timothy P. Hughes.

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Conflict of interest

TPH has received honoraria and research funding from and is a member of a board of directors or advisory committee at Bristol-Myers Squibb and Novartis. NDC has received financial support for congresses from EMS. MF has received honoraria from and is a member of a speakers bureau for BMS, Novartis and Pfizer. JHL has received research funding from and provided consulting to Ariad, Bristol-Myers Squibb, Novartis and Pfizer. AGT has received honoraria from Bristol-Myers Squibb, Novartis, and Pfizer. BM is a member of a speakers bureau for Bristol-Myers Squibb and Novartis. FEN has received honoraria and research funding from Incyte Biosciences and Novartis, and provided consultancy to Analysis Group Inc. and Sun Pharma. NT has received honoraria from Bristol-Myers Squibb, Novartis Pharma KK and Pfizer Japan Inc., and research funding from Novartis Pharma KK and Pfizer Japan Inc. TS has provided consultancy to and received honoraria and research funding from Bristol-Myers Squibb, Incyte, Novartis and Pfizer, and provided consultancy to and received honoraria from Adamed. DWK has received honoraria and research funding from Bristol-Myers Squibb, ILYANG, Novartis and Pfizer, is a member of a speakers bureau for Bristol-Myers Squibb, Novartis and Pfizer, is a member of a board of directors or advisory committee at Bristol-Myers Squibb and Pfizer, and has provided consultancy for ILYANG and Novartis. RFC is employed by, is an equity holder in and has received research funding from Novartis. RT and CB are employed by Novartis. FXM h0as received honoraria from ARIAD, Bristol-Myers Squibb, Novartis and Pfizer, and has received research funding from Novartis. This study was sponsored and funded by Novartis Pharmaceuticals.

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Hughes, T.P., Clementino, N.C.D., Fominykh, M. et al. Long-term treatment-free remission in patients with chronic myeloid leukemia after second-line nilotinib: ENESTop 5-year update. Leukemia 35, 1631–1642 (2021). https://doi.org/10.1038/s41375-021-01260-y

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