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Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia

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Abstract

High-dose methotrexate (HD-MTX) courses with concurrent oral low-dose MTX/6-mercaptopurine (6MP) for childhood acute lymphoblastic leukaemia (ALL) are often followed by neutro- and thrombocytopenia necessitating treatment interruptions. Plasma MTX during HD-MTX therapy guides folinic acid rescue to prevent toxicities, but myelosuppression can also be prevented by pre-HD-MTX 6MP dose reductions. Accordingly, we monitored pre-HD-MTX erythrocyte levels of methylated 6MP metabolites (Ery-MeMP) and of thioguanine nucleotides (Ery-6TGN) as well as DNA-incorporated thioguanine nucleotides (DNA-TGN) in circulating leucocytes to identify patients at highest risk of post-HD-MTX myelosuppression. In multiple linear regression analyses of neutrophil and thrombocyte nadir values (adjusted for gender, age, risk group and 6MP dose) after 48 HD-MTX courses in 17 childhood ALL patients on MTX/6MP maintenance therapy, the pre-HD-MTX DNA-TGN levels in neutrophils (P < 0.0001), Ery-MeMP (P < 0.0001) and Ery-6TGN (P = 0.01) levels were significant predictors of post-HD-MTX neutrophil nadirs, whereas Ery-MeMP (P < 0.0001) was the only predictor of post-HD-MTX thrombocyte nadir. In conclusion, pre-HD-MTX 6MP metabolite levels may be applicable for 6MP dose adjustments to prevent HD-MTX-induced myelosuppression.

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Acknowledgments

This work was supported by Grants from the Danish Cancer Society, the Nordic Cancer Union, the Danish childhood cancer foundation and the Swedish childhood cancer foundation.

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Paediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Sophia Ingeborg Vang, Kjeld Schmiegelow, Thomas Frandsen & Jacob Nersting

  2. Faculty of Medicine, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    Kjeld Schmiegelow

  3. Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark

    Susanne Rosthøj

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  1. Sophia Ingeborg Vang
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  2. Kjeld Schmiegelow
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  3. Thomas Frandsen
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  4. Susanne Rosthøj
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  5. Jacob Nersting
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Correspondence to Kjeld Schmiegelow.

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Vang, S.I., Schmiegelow, K., Frandsen, T. et al. Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia. Cancer Chemother Pharmacol 75, 1089–1093 (2015). https://doi.org/10.1007/s00280-015-2717-8

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  • DOI: https://doi.org/10.1007/s00280-015-2717-8

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