LEUCOVORIN — Leucovorin is a biologically active form of folate that can enter the CNS even when folate transport is impaired. It has been used for many years to reduce the toxicity of folate antagonists such as methotrexate and to enhance the efficacy of 5-fluorouracil in the treatment of colorectal cancer and other malignancies.

CEREBRAL FOLATE DEFICIENCY — Cerebral folate deficiency (CFD) is characterized by low levels of folate in cerebrospinal fluid and normal folate levels outside the CNS. It can be caused by folate receptor alpha autoantibodies (FRAAs) that impair transport of folate across the blood-brain barrier, mitochondrial defects, genetic mutations, and other conditions that affect folate storage and metabolism. CFD typically presents in infants and young children; clinical symptoms include developmental delays in motor skills, cognition, speech, and language, movement disorders, and intractable epilepsy.1 Some children with CFD develop autism spectrum disorder (ASD).2 A diagnosis of CFD requires genetic testing and a lumbar puncture. A blood test for detection of FRAAs is commercially available, but it has not been approved by the FDA.

EFFICACY — Cerebral Folate Deficiency – No clinical trials of leucovorin have been conducted in patients with FOLR1 variants. FDA approval of the drug for FOLR1-CFTD was based on an analysis of case reports and case reviews (summarized in the package insert) that included 46 patients with the disorder who were treated with leucovorin via various routes of administration; information about the duration of leucovorin use was limited. Among the 27 patients 2-33 years old who received oral leucovorin, 24 had improvements in neurological symptoms, including a reduction in seizures and improvements in motor function, communication, and/or behavior. Three patients had either no change or no progression of symptoms. CSF folate levels were normalized in 5 of 7 patients whose levels were measured before and after starting leucovorin. One review of the literature found that the response to leucovorin treatment was greatest in patients who were diagnosed and treated soon after symptom onset.3

In a meta-analysis of case series/reports in children with both CFD and ASD who were treated with oral leucovorin, the response rate was 67% for improvement in overall ASD symptoms; improvements in irritability, ataxia, pyramidal signs, movement disorder, and epilepsy were reported.4

Autism Spectrum Disorder — In a few small randomized trials in children with ASD (not tested for CFD; ~60% had FRAAs), treatment with oral leucovorin for 12-24 weeks improved some ASD symptoms, including verbal communication and social interaction, compared to placebo, but the trials had methodological limitations5,6; the largest of these trials was recently retracted because of errors in results and concerns with statistical analyses.7

A double-blind trial in 55 children with ASD (not tested for CFD) who were receiving risperidone, which is FDA-approved for treatment of irritability associated with ASD, found that adjunctive treatment with oral leucovorin for 10 weeks improved speech and behavioral symptoms compared to placebo.8

ADVERSE EFFECTS — Leucovorin is generally well tolerated. Adverse effects have included pruritus, rash, urticaria, dyspnea, rigors, and impaired thermoregulation. Anaphylaxis and seizures have been reported in patients with cancer treated with the drug.

In a meta-analysis of adverse effects reported in studies in children with ASD, the most common in those treated with leucovorin alone were aggression, excitement or agitation, headache, insomnia, and increased tantrums.4

DRUG INTERACTIONS — Taken in large amounts, folate may reduce the efficacy of phenobarbital, phenytoin, and primidone, increasing the risk of seizures in susceptible patients. Leucovorin may decrease the efficacy of trimethoprim-sulfamethoxazole; concomitant use should be avoided.

DOSAGE, ADMINISTRATION, AND COST — Oral leucovorin is available in 5-, 10-, 15-, and 25-mg tablets. The FDA-approved initial dosage in patients with FOLR1-CFTD is 1-2 mg/kg/day given once daily or in divided doses up to 6 times per day (single doses ≤25 mg are preferred; maximum single dose is 75 mg). The maximum dosage is 8.5 mg/kg/day in patients weighing <40 kg and 330 mg/day in those weighing ≥40 kg. A 30-day supply of oral leucovorin (2 mg/kg/day for a patient weighing 25 kg) costs about $354.9

AAP GUIDANCE — Interim guidance from the American Academy of Pediatrics (AAP) states that, because evidence is limited, routine use of leucovorin in children with autism is not currently recommended; shared decision-making can be used with families that request leucovorin. Information on appropriate patient selection, optimal dosing and monitoring, and the long-term safety of the drug are lacking.10

CONCLUSION — The FDA has approved use of oral leucovorin (folinic acid) to treat folate receptor 1 (FOLR1)-related cerebral folate transport deficiency (CFTD) based on a small number of case reports showing that it can improve some neurological symptoms in patients with this rare genetic disorder. Treatment with leucovorin has also been reported to improve some autism symptoms in patients with both cerebral folate deficiency and autism. Whether the broader population of children with autism could benefit from leucovorin treatment remains to be determined.

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