Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia
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Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia. / Vang, Sophia Ingeborg; Schmiegelow, Kjeld; Frandsen, Thomas; Rosthøj, Susanne; Nersting, Jacob.
I: Cancer Chemotherapy and Pharmacology, Bind 75, Nr. 5, 05.2015, s. 1089-1093.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Mercaptopurine metabolite levels are predictors of bone marrow toxicity following high-dose methotrexate therapy of childhood acute lymphoblastic leukaemia
AU - Vang, Sophia Ingeborg
AU - Schmiegelow, Kjeld
AU - Frandsen, Thomas
AU - Rosthøj, Susanne
AU - Nersting, Jacob
PY - 2015/5
Y1 - 2015/5
N2 - 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.
AB - 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.
KW - 6-Mercaptopurine
KW - Adolescent
KW - Antineoplastic Combined Chemotherapy Protocols
KW - Bone Marrow
KW - Child
KW - Child, Preschool
KW - Dose-Response Relationship, Drug
KW - Drug Administration Schedule
KW - Erythrocytes
KW - Female
KW - Guanine Nucleotides
KW - Humans
KW - Infant
KW - Male
KW - Methotrexate
KW - Neutropenia
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma
KW - Thionucleotides
KW - Thrombocytopenia
U2 - 10.1007/s00280-015-2717-8
DO - 10.1007/s00280-015-2717-8
M3 - Journal article
C2 - 25788208
VL - 75
SP - 1089
EP - 1093
JO - Cancer Chemotherapy and Pharmacology, Supplement
JF - Cancer Chemotherapy and Pharmacology, Supplement
SN - 0943-9404
IS - 5
ER -
ID: 161270580