title: Methotrexate polyglutamation may lack prognostic significance in children with B-cell precursor acute lymphoblastic leukemia treated with intensive oral methotrexate.
abstract: BACKGROUND
  The purpose of this study was to determine if a correlation exists between clinical outcome and accumulation and polyglutamation of methotrexate by lymphoblasts in vitro in children with B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
  
  
  METHODS
  The amount of accumulated methotrexate and of long-chain methotrexate polyglutamates (MTXPG(3-7)) by lymphoblasts was determined in 52 children newly diagnosed with BCP-ALL after incubation with 1 micromol/L [(3)H]MTX for 24 hours in vitro. All patients then received intensive multiagent chemotherapy that used divided-dose oral methotrexate during consolidation and intensive continuation and standard oral weekly methotrexate during maintenance.
  
  
  RESULTS
  Eight patients had a bone marrow relapse at a median of 40.4 months (range 18.5-48.3 months) after diagnosis. The median follow-up for the remaining 44 patients is 69.0 months (range 22-92.8 months). There was no significant difference in the amount of accumulated methotrexate (1450.0 +/- 896.3 vs. 640 +/- 472.5 pmol/10 cells) or of accumulated MTXPG (1450.0 +/- 919.4 vs. 617.4 +/- 482.7 pmol/10(9) cells) (median +/- semi-interquartile ranges) between patients who relapsed and those who remained in continuous complete remission. The estimated 5-year event-free survival rate for patients whose lymphoblasts accumulated more than 500 pmol MTXPG(3-7)/10(9) cells was 80.0% +/- 7.3% versus 90.5% +/- 6.4% for those whose lymphoblasts accumulated less than 500 pmol MTXPG(3-7)/10(9) cells.
  
  
  CONCLUSIONS
  In the context of effective prolonged divided-dose oral methotrexate-based therapy in the treatment of BCP-ALL, methotrexate accumulation and polyglutamation no longer seem to have prognostic significance.
authors.affiliation: Pediatric Hematology/Oncology Clinic, PEPAGNI University Hospital of Iraklio, Crete, Greece.
authors.forename: Elpis
authors.initials: E
authors.lastname: Mantadakis
authors.forename: Angela K
authors.initials: AK
authors.lastname: Smith
authors.forename: Linda
authors.initials: L
authors.lastname: Hynan
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Winick
authors.forename: Barton A
authors.initials: BA
authors.lastname: Kamen
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage; D001853:Bone Marrow / Q000473:pathology; D002648:Child; D003561:Cytarabine / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage; D007278:Injections, Spinal; D007621:Karyotyping; D002955:Leucovorin / Q000008:administration & dosage; D015993:Life Tables; D008214:Lymphocytes / Q000378:metabolism*; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage; D008727:Methotrexate / Q000008:administration & dosage / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D011099:Polyglutamic Acid / Q000378:metabolism; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000188:drug therapy / Q000401:mortality; D011241:Prednisone / Q000008:administration & dosage; D011379:Prognosis; D011624:Pteroylpolyglutamic Acids / Q000378:metabolism*; D012008:Recurrence; D012074:Remission Induction; D016019:Survival Analysis; D014407:Tumor Cells, Cultured / Q000378:metabolism; D014750:Vincristine / Q000008:administration & dosage
chemical_list: D011624:Pteroylpolyglutamic Acids; D003561:Cytarabine; D011099:Polyglutamic Acid; D014750:Vincristine; D003907:Dexamethasone; D015122:Mercaptopurine; D001215:Asparaginase; D002955:Leucovorin; D011241:Prednisone; D006854:Hydrocortisone; D008727:Methotrexate; D003630:Daunorubicin