A Systematic Review of Neuropsychological Studies Confirms that Adequate Folinic Acid Rescue Prevents Post Methotrexate Neurotoxicity

A comprehensive literature search was performed of all databases of the Web of Science Citation Index, during 1990-2020, for the terms: neuropsychological, neurocognitive, cognitive, acute lymphoblastic (and lymphocytic) leukemia, and osteogenic sarcoma, to see if there was evidence of a correlation between folinic acid (FA) rescue inadequacy and long-term cognitive damage. All English language, peer-reviewed articles of neuropsychological assessments of children who had been treated with high-dose methotrexate without irradiation, and which included details of methotrexate and FA schedules, were selected. Four groups of studies were found and analyzed, Those with no evidence of cognitive deterioration, Those with evidence of cognitive deterioration, studies with more than one protocol grouped together, preventing separate analysis of any protocols, and those with significant serious methodical problems. In all studies, protocols without evidence of cognitive deterioration reported adequate FA rescue, and those with evidence of cognitive deterioration reported inadequate FA rescue.

Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort

Purpose Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity. Methods We reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected. Results Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given. Conclusion A pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.