Journal of Clinical Oncology, Vol 12, 1667-1672, Copyright © 1994 by American Society of Clinical Oncology
Patient characteristics associated with high-risk methotrexate concentrations and toxicity
MV Relling, D Fairclough, D Ayers, WR Crom, JH Rodman, CH Pui and WE Evans
Pharmaceutical, Department, St Jude Children's Research Hospital, Memphis TN.
PURPOSE: 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.
PATIENTS AND 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). CONCLUSION: This study
identified several clinical variables that influence MTX disposition that,
when modified, can reduce the frequency of high-risk MTX concentrations and
toxicity.
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