Monitoring of methotrexate and 7-hydroxymethotrexate in saliva from children with acute lymphoblastic leukemia receiving high-dose consolidation treatment: relation to oral mucositis.

Abstract

The purpose of the study was to find out if saliva concentrations of methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OHMTX), can predict oral mucositis in children with acute lymphoblastic leukemia (ALL) after treatment with high-dose consolidation therapy. We have also studied the relationship between the concentrations of MTX and 7-OHMTX in saliva and the unbound concentrations in plasma. Twelve patients (36 infusions) were studied during treatment with high-dose MTX as remission consolidation therapy (5-8 g/m2 by 24 h i.v. infusion followed by leucovorin rescue). Plasma and saliva concentrations of MTX and 7-OHMTX were determined concomitantly by HPLC at 20 h and at various times following infusion. Unbound plasma concentrations of MTX and 7-OHMTX were determined after ultrafiltration. Oral toxicity was graded according to the WHO criteria (grade 0-4). The concentrations of MTX and 7-OHMTX in saliva were not directly related to the development of mucositis. In patients with oral mucositis (WHO grade 1 or greater), the ratio to 7-OHMTX and MTX in saliva at 20 h was significantly lower than in patients without symptoms (p = 0.014, Mann Whitney rank sum test), but not at 42 and 66 h after starting the infusion. The salivary concentration of 7-OHMTX at 20 h ranged from undetectable (less than 1 nmol/l) to 1.6 micromol/l. No significant correlation was found between the unbound and total plasma concentrations of MTX and 7-OHMTX and the drug concentrations in saliva at different points in time. The concentrations of 7-OHMTX in saliva were 11, 23 and 13% of the unbound plasma concentrations at 20, 42 and 66 h, respectively, after starting the infusion. The respective median corresponding values for MTX were 1.6, 16.1 and 61.6%. The results suggest that determinations of saliva concentrations of MTX and 7-OHMTX may predict oral mucositis. This opens up the possibility of early identification of patients at high risk of developing oral mucositis in order to intensify topical or systemic treatment of these patients.