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

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• 作者：Sophia Ingeborg Vang ; Kjeld Schmiegelow…
• 关键词：Bone marrow toxicity ; Childhood acute lymphoblastic leukaemia ; 6 ; Mercaptopurine ; High ; dose methotrexate ; Individualized medicine ; Therapeutic drug monitoring
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2015
• 出版时间：May 2015
• 年：2015
• 卷：75
• 期：5
• 页码：1089-1093
• 全文大小：400 KB
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• 作者单位：Sophia Ingeborg Vang (1)
  Kjeld Schmiegelow (1) (2)
  Thomas Frandsen (1)
  Susanne Rosth?j (3)
  Jacob Nersting (1)
  
  1. Department of Paediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark
  2. Faculty of Medicine, Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
  3. Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Cancer Research
  Pharmacology and Toxicology
  Oncology
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：1432-0843

文摘

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.