Skip to main content

Advertisement

SpringerLink
Log in

Effect of study-level factors on treatment-free remission rate in patients with chronic myeloid leukemia: a systematic review and meta-analysis

  • Original Article
  • Published:
International Journal of Hematology Aims and scope Submit manuscript

Abstract

As it is recommended that most assessments for treatment-free remission (TFR) in patients with chronic myeloid leukemia be conducted as prospective trials, we conducted a systematic review and meta-analysis to investigate which study-level factors affected the TFR rate. The MEDLINE, Embase, and Cochrane databases were systematically searched from inception to July 2018. A random effect model was used to estimate the overall mean TFR rate, subgroup differences, and regression coefficients with continuous variables. Overall, 12 tyrosine kinase inhibitor (TKI) stopping studies comprising 1699 chronic myeloid leukemia patients were included in this analysis. The overall mean TFR rate at 24 months after entering TFR phase was 55% [95% confidence interval (CI) 0.51–0.58]. Trials with molecular criteria of MR4.5 or better for stopping TKI reported higher TFR rates than those of MR4.0 (57.2% vs. 50.5%). Trials with eligible criteria for at least 24 months of deep molecular response (DMR) duration demonstrated higher TFR rates than those for 18 or 12 months (60.2% vs. 49.9%). Our results suggest that TKI stopping trials with sufficient duration of DMR and molecular criteria of MR4.5 or better may account for approximately 60% of the TFR rate at 24 months after stopping TKI.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344(14):1031–7.

    Article  CAS  Google Scholar 

  2. Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408–17.

    Article  CAS  Google Scholar 

  3. 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(24):2260–70.

    Article  CAS  Google Scholar 

  4. 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(24):2251–9.

    Article  CAS  Google Scholar 

  5. 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(24):2851–7.

    Article  CAS  Google Scholar 

  6. Huang X, Cortes J, Kantarjian H. Estimations of the increasing prevalence and plateau prevalence of chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy. Cancer. 2012;118(12):3123–7.

    Article  Google Scholar 

  7. Rousselot P, Huguet 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.

    Article  CAS  Google Scholar 

  8. Mahon FX, Rea 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(11):1029–35.

    Article  CAS  Google Scholar 

  9. National Comprehensive Cancer Network, 2018. NCCN clinical practice guidelines in oncology. Chronic Myeloid Leukemia. Version 1.2019 [WWW Document]. https://www.nccn.org/professionals/physician_gls/pdf/cml.pdf. Accessed Dec 2018.

  10. 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(5):424–30.

    Article  CAS  Google Scholar 

  11. Barendregt JJ, Doi SA, Lee YY, Norman RE, Vos T. Meta-analysis of prevalence. J Epidemiol Community Health. 2013;67(11):974–8.

    Article  Google Scholar 

  12. Koskenvesa P, Kreutzman A, Rohon P, Pihlman M, Vakkila E, Rasanen A, et al. Imatinib and pegylated IFN-alpha2b discontinuation in first-line chronic myeloid leukemia patients following a major molecular response. Eur J Haematol. 2014;92(5):413–20.

    Article  CAS  Google Scholar 

  13. 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(4):515–22.

    Article  CAS  Google Scholar 

  14. 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(12):e528–e535535.

    Article  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.

    Article  CAS  Google Scholar 

  16. Lee SE, Choi SY, Song HY, Kim SH, Choi MY, Park JS, et al. Imatinib withdrawal syndrome and longer duration of imatinib have a close association with a lower molecular relapse after treatment discontinuation: the KID study. Haematologica. 2016;101(6):717–23.

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  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(7):846–54.

    Article  CAS  Google Scholar 

  19. Kumagai T, Nakaseko C, Nishiwaki K, Yoshida C, Ohashi K, Takezako N, et al. Dasatinib cessation after deep molecular response exceeding 2 years and natural killer cell transition during dasatinib consolidation. Cancer Sci. 2018;109(1):182–92.

    Article  CAS  Google Scholar 

  20. 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(7):461–70.

    PubMed  Google Scholar 

  21. 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(6):747–57.

    Article  CAS  Google Scholar 

  22. Takahashi N, Nishiwaki K, Nakaseko C, Aotsuka N, Sano K, Ohwada C, et al. Treatment-free remission after two-year consolidation therapy with nilotinib in patients with chronic myeloid leukemia: STAT2 trial in Japan. Haematologica. 2018;103:1835–42.

    Article  CAS  Google Scholar 

  23. Takahashi N, Tauchi T, Kitamura K, Miyamura K, Saburi Y, Hatta Y, et al. Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study. Int J Hematol. 2018;107(2):185–93.

    Article  CAS  Google Scholar 

  24. Cross NC, White HE, Colomer D, Ehrencrona H, Foroni L, Gottardi E, et al. Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia. Leukemia. 2015;29(5):999–1003.

    Article  CAS  Google Scholar 

  25. Experts in Chronic Myeloid L. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood. 2013;121(22):4439–42.

    Article  Google Scholar 

  26. Hochhaus A, Saussele S, Rosti G, Mahon FX, Janssen J, Hjorth-Hansen H, et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv41–iv51.

    Article  CAS  Google Scholar 

  27. Kantarjian HM, Baccarani M, Jabbour E, Saglio G, Cortes JE. Second-generation tyrosine kinase inhibitors: the future of frontline CML therapy. Clin Cancer Res. 2011;17(7):1674–83.

    Article  CAS  Google Scholar 

  28. Talpaz M, Hehlmann R, Quintas-Cardama A, Mercer J, Cortes J. Re-emergence of interferon-alpha in the treatment of chronic myeloid leukemia. Leukemia. 2013;27(4):803–12.

    Article  CAS  Google Scholar 

  29. Campiotti L, Suter MB, Guasti L, Piazza R, Gambacorti-Passerini C, Grandi AM, et al. Imatinib discontinuation in chronic myeloid leukaemia patients with undetectable BCR-ABL transcript level: a systematic review and a meta-analysis. Eur J Cancer. 2017;77:48–56.

    Article  CAS  Google Scholar 

  30. 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 

Download references

Acknowledgements

This work was supported by INHA UNIVERSITY Research Grant. (no grant number)

Author information

Authors and Affiliations

  1. Department of Hematology-Oncology, Inha University College of Medicine and Hospital, 7-206 Third Street, Shinheung-dong Jung-gu, Incheon, Republic of Korea

    Jinchul Kim, Jisun Park, Joo Han Lim, Moon Hee Lee & Jinhyun Cho

  2. Department of Laboratory Medicine, Inha University College of Medicine and Hospital, Incheon, Republic of Korea

    Yeonsook Moon

  3. Department of Pathology, Inha University College of Medicine and Hospital, Incheon, Republic of Korea

    Suk Jin Choi

Authors
  1. Jinchul Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jisun Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yeonsook Moon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Suk Jin Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Joo Han Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Moon Hee Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jinhyun Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors had full access to all the study data and take responsibility for the integrity of the data and accuracy of the data analysis. Study concept and design: J.K. and J.C. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: J.K., J.P., and J.C. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: J.K. and J.H.L. Study supervision: Y.M., S.J.C., M.H.L., and J.C.

Corresponding author

Correspondence to Jinhyun Cho.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 479 kb)

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, J., Park, J., Moon, Y. et al. Effect of study-level factors on treatment-free remission rate in patients with chronic myeloid leukemia: a systematic review and meta-analysis. Int J Hematol 110, 683–689 (2019). https://doi.org/10.1007/s12185-019-02744-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12185-019-02744-5

Keywords

Search

Navigation