title: Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia.
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.
authors: Department of Paediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.
authors: Sophia Ingeborg
authors: SI
authors: Vang
authors: Kjeld
authors: K
authors: Schmiegelow
authors: Thomas
authors: T
authors: Frandsen
authors: Susanne
authors: S
authors: Rosthøj
authors: Jacob
authors: J
authors: Nersting
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D001853:Bone Marrow / Q000187:drug effects* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects*; D009503:Neutropenia / Q000139:chemically induced / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism*; D013873:Thionucleotides / Q000378:metabolism; D013921:Thrombocytopenia / Q000139:chemically induced / Q000378:metabolism
chemical_list: D006150:Guanine Nucleotides; D013873:Thionucleotides; D015122:Mercaptopurine; D008727:Methotrexate