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Utility of Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib in Chronic Myeloid Leukemia: A Systematic Review and Meta-analysis

  • Manuel García-Ferrer
    Affiliations
    Department of Radiology, Hospital Universitario Virgen del Rocío, Seville, Spain
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  • Aneta Wojnicz
    Affiliations
    Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
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  • Gina Mejía
    Affiliations
    Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain

    UICEC Hospital Universitario de La Princesa, Plataforma Spanish Clinical Research Network, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
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  • Dora Koller
    Affiliations
    Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
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  • Pablo Zubiaur
    Affiliations
    Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
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  • Francisco Abad-Santos
    Correspondence
    Address correspondence to: Francisco Abad-Santos, Department of Clinical Pharmacology, Hospital Universitario de la Princesa, C/ Diego de León 62, 28006, Madrid, Spain.
    Affiliations
    Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain

    UICEC Hospital Universitario de La Princesa, Plataforma Spanish Clinical Research Network, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain

    Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain
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      Abstract

      Purpose

      This study examined the utility of therapeutic drug monitoring (TDM) of imatinib, nilotinib, and dasatinib in adult patients with chronic-phase chronic myeloid leukemia (CML). TDM in CML entails the measurement of plasma tyrosine kinase inhibitor (TKI) concentration to predict efficacy and tolerability outcomes and to aid in clinical decision making. TDM was to be deemed useful if it could be used for predicting the effectiveness of a drug and/or the occurrence of adverse reactions. It was expected that the findings from the present study would allow for the definition of a therapeutic range of each TKI.

      Methods

      A systematic review of studies reporting trough TKI levels (Cmin) and clinical outcomes was performed. We included randomized clinical trials, nonrandomized controlled studies, interrupted time series studies, and case series studies that provided information about plasma levels of imatinib, nilotinib, or dasatinib and relevant clinical end points in adult patients with chronic-phase CML treated with the corresponding TKI as the single antiproliferative therapy. Meta-analyses, Student t tests, and receiver operating characteristic analyses were performed to detect mean differences between groups of patients with or without: (1) the achievement of major molecular response and (2) adverse reactions.

      Findings

      A total of 38 studies (28 for imatinib, 7 for nilotinib, and 3 for dasatinib) were included in the systematic review. TDM was found useful in predicting the efficacy of imatinib, with a Cmin cutoff value of 1000 ng/mL, consistent with guideline recommendations. We suggest a therapeutic range of imatinib at a Cmin of 1000–1500 ng/mL because higher concentrations did not increase efficacy. The findings from the rest of the comparisons were inconclusive.

      Implications

      TDM is useful in predicting the efficacy of imatinib in CML. Further research is needed to determine its validity with nilotinib and dasatinib.

      Keywords

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