title: Myelotoxicity, pharmacokinetics, and relapse rate with methotrexate/6-mercaptopurine maintenance therapy of childhood acute lymphoblastic leukemia.
abstract: White blood cell and absolute neutrophil counts (WBC, ANC), aminotransferase (AT) levels, methotrexate (MTX) and 6-mercaptopurine (6MP) doses, metabolites in erythrocytes (E-MTX and E-6TGN), and the prognostic significance of these parameters were studied in 58 children receiving MTX/6MP maintenance therapy for acute lymphoblastic leukemia diagnosed from July 1986 to December 1991. At the end of follow-up July 1995, 13 patients had relapsed (pEFS = 0.77). Weighted means of AT, WBC, and ANC during and after maintenance therapy (mAT, mWBCON, mWBCOFF, mANCON, mANCOFF), E-MTX (mE-MTX), and E-6TGN (mE-6TGN) were calculated, as well as the product of mE-MTX and mE-6TGN (mE-MTX*6TGN), as MTX and 6MP probably act synergistically. Beyond higher MTX and 6MP doses to patients with high mWBCON, neither mWBCON, (median 3.5 x 10(9)/L), mANCON, nor mAT was correlated with the dose of MTX and 6MP, mE-MTX, mE-6TGN, or risk of relapse. Patients with mE-MTX*6TGN above or below 828 (nmol/mmol Hb)2 (median value) had pEFS values of 0.84 and 0.70, respectively (P = .16). All 5 patients who relapsed during therapy had mE-MTX*6TGN < 828 (nmol/mmol Hb)2 (P = .03). mWBCOFF and the degree of myelosuppression (= mWBCSHIFT = mWBCOFF - mWBCON; median: 2.5 x 10(9)/L) were related to age (rs = -0.50, P = .001 and rs = -0.40, P = .006, respectively). All eight relapses off therapy occurred in patients with mWBCSHIFT < 2.5 x 10(9)/L (P = .02). WBC levels during MTX/6MP therapy may underestimate the degree of MTX/6MP treatment intensity, especially in order children. Pharmacokinetic monitoring could be useful for optimizing MTX/6MP maintenance therapy.
authors.affiliation: Section of Pediatric Hematology and Oncology, Juliane Marie Centre, National University Hospital, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Schmiegelow
authors.forename: M
authors.initials: M
authors.lastname: Ifversen
mesh_terms: D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D001853:Bone Marrow / Q000473:pathology; D001855:Bone Marrow Diseases / Q000139:chemically induced*; D002490:Central Nervous System / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D017254:Leukemic Infiltration; D007958:Leukocyte Count / Q000187:drug effects; D015993:Life Tables; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology; D009504:Neutrophils; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000097:blood; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D013873:Thionucleotides / Q000097:blood; D016896:Treatment Outcome
chemical_list: D013873:Thionucleotides; D011099:Polyglutamic Acid; C014085:methotrexate polyglutamate; D015122:Mercaptopurine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D008727:Methotrexate