PKP-012 Methotrexate levels in cerebrospinal fluid in children treated with high dose methotrexate

Abstract

BackgroundThe use of intrathecal (IT) methotrexate (MTX) in combination with systemic high dose MTX (HDMTX) is an established procedure for CNS prophylaxis in patients with acute lymphoblastic leukaemia (ALL), but the evidence for the necessity of this combination is not conclusive. An MTX concentration of 1 μM is assumed to be the lowest concentration for an antileukaemic effect.PurposeTo determine the rate of sufficient CSF MTX concentrations (1 μM) in paediatric patients with ALL who received HDMTX, to evaluate the suitability of IT MTX and to correlate MTX plasma and CSF concentrations.Material and methodsA retrospective observational study was conducted between April 2015 and September 2016. We included children up to 18 years with ALL who received 5000 mg/m² over 24 hours in accordance with LAL-SEHOP-PETHEMA-2013 protocols. CSF samples were obtained 18 hours (16–20 hours) after starting the HDMTX infusion and immediately before IT administration of MTX. Plasma samples were obtained at 2, 12, 23, 36, 42 and 60 hours after the start of infusion. CFS samples and plasma MTX at 12 hours were correlated by Spearman’s correlation. MTX was measured by architect chemiluminescence immunoassay.1 ResultsWe included 12 children, aged 2–16 years (7±3.6) who received 36 cycles of MTX. Patients received 5000 mg/m² over 24 hours; one child received 3000 mg/m² was included. MTX plasma levels at 12 hours and CSF concentrations were highly variable, ranging from 48.8 to 179.0 μM (median 72.2μM) and from 0.85 to 2.9 μM (median 1.4 μM), respectively. An MTX concentration above 1μM was found in 33 of 36 CSF samples (91.7%). The patient who received 3000 mg/m² (2 cycles) showed a lower CSF MTX concentration (0.83 and 1.08μM), corresponding to a lower plasma MTX concentration (54.37 and 60.88 μM). The correlation between plasma levels at 12 hours and CSF MTX concentrations was moderate–high (Spearman rank order correlation, r=0.71; p<0.01).ConclusionA potentially antileukaemic MTX concentration of 1 μM was obtained in CSF during the majority of MTX infusions (5000 mg/m2 over 24 hours).References and/or acknowledgements1. Montejano-Hervás P, et al. PKP-034. Determination of methotrexate in CSF by chemiluminescence using the architect. Eur J Hosp Pharm2016;23:A193–4.No conflict of interest