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

TY - JOUR

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 - 2015/5/1

Y1 - 2015/5/1

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

SN - 0943-9404

VL - 75

SP - 1089

EP - 1093

JO - Cancer Chemotherapy and Pharmacology, Supplement

JF - Cancer Chemotherapy and Pharmacology, Supplement

IS - 5

ER -