Patient characteristics associated with high-risk methotrexate concentrations and toxicity.
OBJECTIVE
Following high-dose methotrexate (HD-MTX) treatment, delayed MTX elimination is an important problem because it necessitates increased leucovorin rescue and additional hospitalization for hydration and urinary alkalinization. Our purpose was to identify factors associated with high-risk MTX plasma concentrations (defined by plasma concentration > or = 1.0 mumol/L at 42 hours from the start of MTX) and with toxicity.


METHODS
Variables associated with MTX concentrations and toxicity were assessed in 134 children treated with one to five courses of HD-MTX (900 to 3,700 mg/m2 intravenously [i.v.] over 24 hours for a total of 481 courses) for acute lymphoblastic leukemia (ALL).


RESULTS
High-risk MTX concentrations, toxicity (usually mild mucositis), and delay in resuming continuation chemotherapy occurred in 106 (22%), 123 (26%), and 66 (14%) of 481 courses, respectively. Using a mixed effects model for repeated measures, high-risk MTX concentrations were significantly associated with a higher MTX area-under-the-concentration-time curve (AUC), low urine pH, emesis, low MTX clearance, low urine output relative to intake, use of antiemetics during the MTX infusion, and concurrent intrathecal therapy (all p values < .01). Clinical toxicities and delay in resumption of continuation chemotherapy due to myelosuppression were more common in those with high 42-hour MTX concentrations, despite increased leucovorin rescue for all patients with high-risk MTX concentrations. However, with individualized rescue, no patient developed life-threatening toxicity. A more aggressive hydration and alkalinization regimen for subsequent courses reduced the frequency of high-risk MTX concentrations to 7% of courses (13 of 183) (P = .0001), and the frequency of toxicity decreased to 11% of courses (P = .0074).


CONCLUSIONS
This study identified several clinical variables that influence MTX disposition that, when modified, can reduce the frequency of high-risk MTX concentrations and toxicity.
Relling
M V
MV
Pharmaceutical, Department, St Jude Children's Research Hospital, Memphis TN.
Fairclough
D
D
Ayers
D
D
Crom
W R
WR
Rodman
J H
JH
Pui
C H
CH
Evans
W E
WE
D002648:Child; D002675:Child, Preschool; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000188:drug therapy; D012307:Risk Factors; D014556:Urine; D014839:Vomiting / Q000097:blood
D002955:Leucovorin; D008727:Methotrexate