Systematic review and meta-analysis of standard-dose imatinib vs. high-dose imatinib and second generation tyrosine kinase inhibitors for chronic myeloid leukemia
- 671 Downloads
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.
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.
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.
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.
KeywordsImatinib TKI Dosage Meta-analysis Systematic review
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.
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.
The studies included in this systematic review stated that informed consent was obtained from all individual participants included in the respective studies.
- 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
- 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
- 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
- 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
- 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