Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and safety of nilotinib therapy in patients with newly diagnosed chronic myeloid leukemia in the chronic phase

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

ABL1-tyrosine kinase inhibitors (TKIs) have led to dramatic changes in treatment strategies for chronic myeloid leukemia in the chronic phase (CML-CP). However, clinical studies have highlighted increasing numbers of adverse events (AE) with TKIs. Although TKI modification plays a key role in AE management, this process is poorly understood, particularly in terms of the TKI nilotinib. In the present study, we retrospectively analyzed the records of 70 patients with newly diagnosed (ND)-CML-CP who were treated with nilotinib to investigate the drug potency of nilotinib and treatment management. During a median observation period of 3.4 years, 76% of patients continued nilotinib as a first-line treatment. The 1-year and overall major molecular response (MMR) rates and the overall molecular response (MR) 4.5 rate for all patients receiving first-line nilotinib therapy were 70, 84.2, and 50%, respectively. No case progressed to the accelerated or blast phase during the study. To avoid AEs during the early phase, nilotinib doses were reduced to < 600 mg/day in a third of patients (Reduced group); these patients experienced better therapeutic efficacy and a lower rate of AEs relative to those in Standard group (300 mg twice daily). Ten patients who received < 600 mg/day of nilotinib throughout the study had a 1-year MMR rate and overall MR4.5 rate of 90 and 60%, respectively. In summary, our findings indicate that careful management, including dose reduction, can yield better outcomes in patients with ND-CML-CP.

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

Fig. 1

Similar content being viewed by others

References

  1. Steegmann JL, Baccarani M, Breccia M, Casado LF, García-Gutiérrez V, Hochhaus A, et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30:1648–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring. Am J Hematol. 2016;91:252–65.

    Article  CAS  PubMed  Google Scholar 

  3. Francis J, Dubashi B, Sundaram R, Pradhan SC, Chandrasekaran A. Influence of Sokal, Hasford, EUTOS scores and pharmacogenetic factors on the complete cytogenetic response at 1 year in chronic myeloid leukemia patients treated with imatinib. Med Oncol. 2015;32:213.

    Article  PubMed  Google Scholar 

  4. O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.

    Article  PubMed  Google Scholar 

  5. 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;376:917–27.

    Article  CAS  PubMed  Google Scholar 

  6. Tauchi T, Kizaki M, Okamoto S, Tanaka H, Tanimoto M, Inokuchi K, et al. Seven-year follow-up of patients receiving imatinib for the treatment of newly diagnosed chronic myelogenous leukemia by the TARGET system. Leuk Res. 2011;35:585–90.

    Article  CAS  PubMed  Google Scholar 

  7. Kizaki M, Okamoto S, Tauchi T, Tanaka H, Tanimoto M, Inokuchi K, et al. Current and future perspectives on the TARGET system: the registration system for Glivec established by the JSH. Int J Hematol. 2008;88:409–17.

    Article  PubMed  Google Scholar 

  8. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251–9.

    Article  CAS  PubMed  Google Scholar 

  9. 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  PubMed  PubMed Central  Google Scholar 

  10. Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260–70.

    Article  CAS  PubMed  Google Scholar 

  11. 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-naïve chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34:2333–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hochhaus A, Rosti G, Cross NC, Steegmann JL, le Coutre P, Ossenkoppele G, et al. Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study. Leukemia. 2016;30:57–64.

    Article  CAS  PubMed  Google Scholar 

  13. Castagnetti F, Breccia M, Gugliotta G, Martino B, D’Adda M, Stagno F, et al. Nilotinib 300 mg twice daily: an academic single-arm study of newly diagnosed chronic phase chronic myeloid leukemia patients. Haematologica. 2016;101:1200–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Di Bella NJ, Bhowmik D, Bhor M, Yap M, Middlebrook B, Rembert D, et al. The effectiveness of tyrosine kinase inhibitors and molecular monitoring patterns in newly diagnosed patients with chronic myeloid leukemia in the community setting. Clin Lymphoma Myeloma Leuk. 2015;15:599–605.

    Article  PubMed  Google Scholar 

  15. Henk HJ, Woloj M, Shapiro M, Whiteley J, et al. Real-world analysis of tyrosine kinase inhibitor treatment patterns among patients with chronic myeloid leukemia in the United States. Clin Ther. 2015;37:124–33.

    Article  PubMed  Google Scholar 

  16. Cortes JE, Jones D, O’Brien S, Jabbour E, Konopleva M, Ferrajoli A, et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol. 2010;28:392–7.

    Article  CAS  PubMed  Google Scholar 

  17. Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, Bua M, et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J Clin Oncol. 2010;28:2381–8.

    Article  CAS  PubMed  Google Scholar 

  18. Ibrahim AR, Eliasson L, Apperley JF, Milojkovic D, Bua M, Szydlo R, et al. Poor adherence is the main reason for loss of CCyR and imatinib failure for chronic myeloid leukemia patients on long-term therapy. Blood. 2011;117:3733–6.

    Article  CAS  PubMed  Google Scholar 

  19. Rychter A, Jerzmanowski P, Hołub A, Specht-Szwoch Z, Kalinowska V, Tęgowska U, et al. Treatment adherence in chronic myeloid leukaemia patients receiving tyrosine kinase inhibitors. Med Oncol. 2017;34:104.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Itamura H, Kubota Y, Shindo T, Ando T, Kojima K, Kimura S, et al. Elderly patients with chronic myeloid leukemia benefit from a dasatinib dose as low as 20 mg. Clin Lymphoma Myeloma Leuk. 2017;17:370–4.

    Article  PubMed  Google Scholar 

  21. Iriyama N, Tokuhira M, Takaku T, Sato E, Sugimoto K, Fujita H, et al. Incidences and outcomes of therapy-related chronic myeloid leukemia in the era of tyrosine kinase inhibitors: surveillance of the CML Cooperative Study Group. Leuk Res. 2017;54:55–8.

    Article  PubMed  Google Scholar 

  22. Sato E, Iriyama N, Tokuhira M, Takaku T, Ishikawa M, Nakazato T, et al. Introduction of second-generation tyrosine kinase inhibitors may reduce the prognostic impact of high-risk patients, according to the European Treatment and Outcome Study (EUTOS) score. Leuk Lymphoma. 2017;25:1–8.

    Article  Google Scholar 

  23. Baccarani M, Deininger MW, Rosti G, Cervantes F, Clark RE, Cortes JE, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122:872–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yagasaki F, Niwa T, Abe A, Ishikawa M, Kato C, Ogura K, et al. Correlation of quantification of major bcr-abl mRNA between TMA (transcription mediated amplification) method and real-time quantitative PCR. Rinsho Ketsueki. 2009;50:481–7.

    PubMed  Google Scholar 

  26. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.

    Article  CAS  PubMed  Google Scholar 

  27. Tanaka C, Yin OQ, Sethuraman V, Smith T, Wang X, Grouss K, et al. Clinical pharmacokinetics of the BCR-ABL tyrosine kinase inhibitor nilotinib. Clin Pharmacol Ther. 2010;87:197–203.

    Article  CAS  PubMed  Google Scholar 

  28. 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 leukaemia with stable major molecular response (DESTINY): an interim analysis of a non-randomised, phase 2 trial. Lancet Haematol. 2017;4:e310–6.

    Article  PubMed  Google Scholar 

  29. Rea D, Cayuela J-M, Dulucq S, Etienne G. Molecular responses after switching from a standard-dose twice-daily nilotinib regimen to a reduced-dose once-daily schedule in patients with chronic myeloid leukemia: a real life observational study (NILO-RED). In: 2017 ASH meeting, oral presentation, #380. 2017.

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama, 350-8550, Japan

    Michihide Tokuhira, Yuta Kimura & Masahiro Kizaki

  2. Department of Hematology, Juntendo University Urayasu Hospital, Urayasu, Japan

    Keiji Sugimoto

  3. Department of Hematology, Yokohama Municipal Citizen’s Hospital, Yokohama, Japan

    Tomonori Nakazato

  4. Department of Hemato-Oncology, Comprehensive Cancer Center, Saitama International Medical Center, Saitama Medical University, Saitama, Japan

    Maho Ishikawa & Norio Asou

  5. Department of Hematology, Juntendo University School of Medicine, Tokyo, Japan

    Isao Fujioka, Tomoiku Takaku & Norio Komatsu

  6. Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan

    Noriyoshi Iriyama & Yoshihiro Hatta

  7. Division of Hematology, Department of Medicine, Juntendo University Nerima Hospital, Tokyo, Japan

    Eriko Sato

  8. Department of Hematology, Saiseikai Yokohama Nanbu Hospital, Yokohama, Japan

    Hiroyuki Fujita

  9. Department of Hematology and Infectious Diseases, Kumamoto University Hospital, Kumamoto, Japan

    Tatsuya Kawaguchi

Authors
  1. Michihide Tokuhira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yuta Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keiji Sugimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tomonori Nakazato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maho Ishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Isao Fujioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomoiku Takaku
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Noriyoshi Iriyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eriko Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroyuki Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yoshihiro Hatta
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Norio Komatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Norio Asou
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Masahiro Kizaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Tatsuya Kawaguchi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michihide Tokuhira.

Ethics declarations

Conflict of interest

MT received honoraria from Pfizer Inc. and Bristol-Myers Squibb. TT, NI, YH, MK, and TK received honoraria from Bristol-Myers Squibb and Novartis Pharma K.K. The remaining authors declare no competing financial interests.

Ethical approval

All procedures performed in studies were in accordance with the ethical standards of each institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tokuhira, M., Kimura, Y., Sugimoto, K. et al. Efficacy and safety of nilotinib therapy in patients with newly diagnosed chronic myeloid leukemia in the chronic phase. Med Oncol 35, 38 (2018). https://doi.org/10.1007/s12032-018-1093-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-018-1093-8

Keywords

Search

Navigation