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Journal of Cancer Research and Clinical Oncology

, Volume 143, Issue 7, pp 1311–1318 | Cite as

Systematic review and meta-analysis of standard-dose imatinib vs. high-dose imatinib and second generation tyrosine kinase inhibitors for chronic myeloid leukemia

  • Verena S. HoffmannEmail author
  • Joerg Hasford
  • Michael Deininger
  • Jorge Cortes
  • Michele Baccarani
  • Rüdiger Hehlmann
Original Article – Clinical Oncology

Abstract

Purpose

Most randomized clinical trials evaluating second generation tyrosine kinase inhibitors (TKI) for the first-line treatment of Chronic Myeloid Leukemia used as comparator the ‘standard’ dose of 400 mg imatinib daily. Several studies showed higher rates of major molecular remission (MMR) at 12 months with 800 mg compared to 400 mg, suggesting that high-dose imatinib may be the appropriate comparator rather than 400 mg.

Methods

We systematically reviewed randomized trials comparing the two dosages, calculated a common estimator and compared the result to a common estimator of trials evaluating a second generation TKI in comparison with 400 mg imatinib daily.

Results

We identified three trials comparing 400–800 mg imatinib resulting in a common relative risk of 1.30 (1.13–1.49) and indicating a significantly higher rate of MMR in patients treated with 800 mg imatinib (p = 0.0003). We identified five trials comparing 400 mg imatinib daily to a second generation TKI. The common relative risk for MMR at 12 months was 1.69 (1.50–1.90, p < 0.0001). Differences in the prognostic profiles precluded a direct comparison of the common efficacy estimates.

Conclusions

We conclude that imatinib was probably not licensed at the optimal dose initially. We suggest that in the future, new TKIs are compared with a higher dose of imatinib. In addition, high-dose imatinib should be considered more often for routine clinical decisions based on the characteristics of the individual patient.

Keywords

Imatinib TKI Dosage Meta-analysis Systematic review 

Notes

Author contributions

VH and JH designed the work. VH extracted the data and performed the statistical analysis. All authors interpreted the results. VH wrote the manuscript draft; all authors participated in the revision. All authors approved the final version.

Compliance with ethical standards

Conflict of interest

VH received research funding form Novartis Oncology Europe and received honoraria from BMS. JH received research funding form Novartis Oncology Europe; MD researched research funding from BMS, Novartis, Celgene, Genzyme, and Gilead, and is on the advisory board and consultant for BMS, ARIAD, Novartis, Incyte, and Pfizer. JC has received research support from and has acted as a consultant for Ariad, Bristol-Myers Squibb, Novartis, and Pfizer; has received research support from Teva; and has been paid for travel expenses by Bristol-Myers Squibb, Novartis, and Pfizer. MB served on the speakers’ bureau of and received honoraria from ARIAD, Bristol-Myers Squibb, Novartis and Pfizer and acted as a consultant for ARIAD and Novartis. RH received research support from Novartis, consultation fees from BMS.

Ethical approval

All studies that were included in this systematic review stated to be in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

The studies included in this systematic review stated that informed consent was obtained from all individual participants included in the respective studies.

Supplementary material

432_2017_2385_MOESM1_ESM.docx (15 kb)
Supplementary material 1 (DOCX 15 KB)

References

  1. Baccarani M et al (2009) Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: a European LeukemiaNet Study. Blood 113:4497–4504. doi: 10.1182/blood-2008-12-191254 CrossRefPubMedGoogle Scholar
  2. Baccarani M et al (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 122:872–884. doi: 10.1182/blood-2013-05-501569 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Cortes JE et al (2009) High-dose imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: high rates of rapid cytogenetic and molecular responses. J Clin Oncol 27:4754–4759. doi: 10.1200/JCO.2008.20.3869 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Cortes JE et al (2010) Phase III, randomized, open-label study of daily imatinib mesylate 400 mg versus 800 mg in patients with newly diagnosed, previously untreated chronic myeloid leukemia in chronic phase using molecular end points: tyrosine kinase inhibitor optimization and selectivity study. J Clin Oncol 28:424–430. doi: 10.1200/JCO.2009.25.3724 CrossRefPubMedGoogle Scholar
  5. Cortes JE et al (2012) Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol 30:3486–3492. doi: 10.1200/JCO.2011.38.7522 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Deininger MW et al (2014) Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia. Br J Haematol 164:223–232. doi: 10.1111/bjh.12618 CrossRefPubMedGoogle Scholar
  7. Downs SH, Black N (1998) The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health 52:7CrossRefGoogle Scholar
  8. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et al (2001) Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 344(14):1031–1037. doi: 10.1056/NEJM200104053441401 CrossRefPubMedGoogle Scholar
  9. Egger M, Smith GD, Schneider M, Minder C (1997) Bias in metaanalysis detected by a simple, graphical test. Br Med J 315:6CrossRefGoogle Scholar
  10. Gafter-Gvili A et al (2011) High-dose imatinib for newly diagnosed chronic phase chronic myeloid leukemia patients—systematic review and meta-analysis. Am J Hematol 86:657–662. doi: 10.1002/ajh.22076 CrossRefPubMedGoogle Scholar
  11. Guidance for Industry—Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007) Center for Drug Evaluation and Research—Food and Drug Administration Rockville, MD, USAGoogle Scholar
  12. Hehlmann R et al (2011) Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol 29:1634–1642. doi: 10.1200/JCO.2010.32.0598 CrossRefPubMedGoogle Scholar
  13. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558. doi: 10.1002/sim.1186 CrossRefPubMedGoogle Scholar
  14. Higgins J, Thompson S, Deeks J, Altman DG (2003) Measuring inconsistency in meta-analyses. Br Med J 327:4CrossRefGoogle Scholar
  15. Hughes TP et al (2008) Impact of early dose intensity on cytogenetic and molecular responses in chronic- phase CML patients receiving 600 mg/day of imatinib as initial therapy. Blood 112:3965–3973. doi: 10.1182/blood-2008-06-161737 CrossRefPubMedGoogle Scholar
  16. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 17:1–12. doi: 10.1016/0197-2456(95)00134-4 CrossRefPubMedGoogle Scholar
  17. Jain P et al (2016) Analysis of 2013 European LeukaemiaNet (ELN) responses in chronic phase CML across four frontline TKI modalities and impact on clinical outcomes. Br J Haematol. doi: 10.1111/bjh.13936 PubMedCentralGoogle Scholar
  18. Kantarjian H et al (2010) Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 362:2260–2270. doi: 10.1056/NEJMoa1002315 CrossRefPubMedGoogle Scholar
  19. Kantarjian H et al (2011) Impact of treatment end point definitions on perceived differences in long-term outcome with tyrosine kinase inhibitor therapy in chronic myeloid leukemia. J Clin Oncol 29:3173–3178. doi: 10.1200/JCO.2010.33.4169 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Kwak J-Y et al (2015) Efficacy and safety of radotinib compared with imatinib in newly diagnosed chronic phase chronic myeloid leukemia patients: 12 months result of phase 3 clinical trial. Blood 126:476–476Google Scholar
  21. Liberati A et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62:e1–e34. doi: 10.1016/j.jclinepi.2009.06.006 CrossRefPubMedGoogle Scholar
  22. Malhotra H, Sharma P, Bhargava S, Rathore OS, Malhotra B, Kumar M (2014) Correlation of plasma trough levels of imatinib with molecular response in patients with chronic myeloid leukemia. Leuk Lymphoma 55:2614–2619. doi: 10.3109/10428194.2014.885515 CrossRefPubMedGoogle Scholar
  23. McDougall J, Ramsey SD, Radich J (2016) What happens when imatinib goes generic? JNCCN 14:128–131PubMedGoogle Scholar
  24. Mealing S, Barcena L, Hawkins N, Clark J, Eaton V, Hirji I, Davis C (2013) The relative efficacy of imatinib, dasatinib and nilotinib for newly diagnosed chronic myeloid leukemia: a systematic review and network meta-analysis. Exp Hematol Int Soc Cell 2:5–5. doi: 10.1186/2162-3619-2-5 Google Scholar
  25. O’Brien SG et al (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004. doi: 10.1056/NEJMoa022457 CrossRefPubMedGoogle Scholar
  26. Picard S et al (2007) Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 109:3496–3499. doi: 10.1182/blood-2006-07-036012 CrossRefPubMedGoogle Scholar
  27. Preudhomme C et al (2010) Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N Engl J Med 363:2511–2521. doi: 10.1056/NEJMoa1004095 CrossRefPubMedGoogle Scholar
  28. Radich JP et al (2012) A randomized trial of dasatinib 100 mg versus imatinib 400 mg in newly diagnosed chronic-phase chronic myeloid leukemia. Blood 120:3898–3905. doi: 10.1182/blood-2012-02-410688 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Rosmarakis ES, Soteriades ES, Vergidis PI, Kasiakou SK, Falagas ME (2005) From conference abstract to full paper: differences between data presented in conferences and journals. FASEB J 19:673–680. doi: 10.1096/fj.04-3140lfe CrossRefPubMedGoogle Scholar
  30. Saglio G et al (2010) Nilotinib versus Imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362:2251–2259. doi: 10.1056/NEJMoa0912614 CrossRefPubMedGoogle Scholar
  31. Wang J et al (2015) Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina. Blood 125:2771–2778. doi: 10.1182/blood-2014-09-601674 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Watkins DB, Hughes TP, White DL (2015) OCT1 and imatinib transport in CML: is it clinically relevant? Leukemia 29:1960–1969. doi: 10.1038/leu.2015.170 CrossRefPubMedGoogle Scholar
  33. Yeung DT et al (2015) TIDEL-II: first-line use of imatinib in CML with early switch to nilotinib for failure to achieve time-dependent molecular targets. Blood 125:915–923. doi: 10.1182/blood-2014-07-590315 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Verena S. Hoffmann
    • 1
    • 2
    Email author
  • Joerg Hasford
    • 1
  • Michael Deininger
    • 3
  • Jorge Cortes
    • 4
  • Michele Baccarani
    • 5
  • Rüdiger Hehlmann
    • 6
  1. 1.Institute for Medical Information Sciences, Biometry, and EpidemiologyLudwig-Maximilians-UniversitätMunichGermany
  2. 2.Division of Infectious Diseases and Tropical MedicineMedical Center of the University of Munich (LMU)MunichGermany
  3. 3.University of Utah Huntsman Cancer InstituteSalt Lake CityUSA
  4. 4.Department of LeukemiaThe University of Texas MD Anderson Cancer CenterHoustonUSA
  5. 5.Department of Hematology and Oncology L. and A. SeragnoliUniversity of BolognaBolognaItaly
  6. 6.Medizinische Fakultaet MannheimUniversität HeidelbergHeidelbergGermany

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