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The prognostic value of serum methotrexate area under curve in elderly primary CNS lymphoma patients

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Abstract

Studies on pharmacokinetics and pharmacodynamics of high-dose methotrexate chemotherapy (HD-MTX) in elderly primary central nervous system lymphoma (PCNSL) patients are rare. MTX exposure time has recently been proposed as an outcome determining factor in PCNSL. We investigated 49 immunocompetent PCNSL patients (female N = 30, male N = 19, median age 73 years) who were treated according to HD-MTX-based protocols. A two-compartment pharmacokinetic model was used to describe the MTX clearance. Response to treatment was assessed by MRI. We used multivariable models to investigate the association between MTX exposure and tumor response as well as survival. Dose normalized MTX peak serum levels [C max, μmol/L g] and dose normalized area under the curve [AUCdn, μmol h/L g] were higher in females than in males, respectively [59.4 (f) vs. 48.1 (m), P < 0.001; 373.2 (f) vs. 271.9 (m), P = 0.008]. Increasing AUC was inversely correlated with tumor response. AUC values above 2,126 h μmol/L were independently associated with shorter overall and progression-free survival [hazard ratio (HR), 4.56, 95 % CI 1.74–11.94; HR 2.87, 95 % CI 1.18–7.00]. Exceedingly high MTX AUC levels can have a negative impact on progression-free and overall survivals in elderly PCNSL patients.

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Acknowledgments

We would also like to thank Vanessa Haug and Stefan Haug for their help and support in collecting the data. Special thanks to Juliane Schäfer and Hartmut Henss for fruitful discussions and valuable input to the manuscript.

Funding

The study was not supported by any external funding source.

Disclosure

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Hematology and Oncology, University Medical Center Freiburg, Hugstetterstrasse 5, 79106, Freiburg, Germany

    Benjamin Kasenda, Kristina Fritsch, Elisabeth Schorb, Jürgen Finke & Gerald Illerhaus

  2. Center for Systems Biology, Freiburg University, Freiburg, Germany

    Marcel Rehberg & Melanie Franzem

  3. Department of Clinical Pharmacology, Helios Clinics Wuppertal, Witten/Herdecke University, Wuppertal, Germany

    Petra Thürmann

  4. Basel Institute of Clinical Epidemiology and Biostatistics, Basel University Hospital, Basel, Switzerland

    Benjamin Kasenda

  5. Institute for Numerical Mathematics, University of Ulm, Ulm, Germany

    Dirk Lebiedz

  6. Department of Hematology, Leiden University Medical Center, Leiden, Netherlands

    Hendrik Veelken

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  1. Benjamin Kasenda
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  2. Marcel Rehberg
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  3. Petra Thürmann
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  10. Gerald Illerhaus
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Correspondence to Gerald Illerhaus.

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Kasenda, B., Rehberg, M., Thürmann, P. et al. The prognostic value of serum methotrexate area under curve in elderly primary CNS lymphoma patients. Ann Hematol 91, 1257–1264 (2012). https://doi.org/10.1007/s00277-012-1441-2

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  • DOI: https://doi.org/10.1007/s00277-012-1441-2

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