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Adverse effects of intrathecal methotrexate in children with acute leukemia in remission
Insights
A toxic syndrome affecting children with leukemia can be reduced. Using Elliott's B solution as a diluent for intrathecal methotrexate and appropriate dosing intervals helps prevent this neurotoxicity.
Area of Science:
- Pediatric Oncology
- Neuro-oncology
- Pharmacology
Background:
- Intrathecal methotrexate (IT Mtx) is crucial for central nervous system (CNS) prophylaxis in acute leukemia.
- A toxic syndrome has been observed in children undergoing this treatment.
- Concomitant cranial radiation may influence the incidence and severity of this syndrome.
Purpose of the Study:
- To investigate the incidence of a specific toxic syndrome in children with acute leukemia receiving CNS prophylaxis.
- To evaluate the impact of intrathecal methotrexate diluents and cranial radiation on the occurrence of this syndrome.
- To identify strategies for preventing this treatment-related toxicity.
Main Methods:
- Observational study comparing two groups of children with acute leukemia in complete remission.
- Group 1 received IT Mtx prophylaxis; Group 2 received IT Mtx plus cranial radiation.
- Analysis of toxic syndrome incidence, clinical symptoms, cerebrospinal fluid (CSF) findings (pleocytosis), and Mtx toxicity patterns.
Main Results:
- A toxic syndrome (fever, headache, vomiting) occurred in 61% of children receiving IT Mtx alone versus 14% with added cranial radiation.
- The syndrome was associated with pleocytosis and appeared cumulative, often after the third or fourth Mtx dose.
- Using Elliott's B solution as an Mtx diluent significantly reduced syndrome incidence compared to water or saline.
- Concomitant cranial radiation also significantly reduced the syndrome's occurrence and pleocytosis.
Conclusions:
- The toxic syndrome is a significant concern in pediatric leukemia CNS prophylaxis with IT Mtx.
- Elliott's B solution as an Mtx diluent and extended dosing intervals are effective preventive measures.
- Cranial radiation may mitigate this neurotoxicity, potentially due to its lympholytic effects.
Abstract:
A toxic syndrome characterized by fever, headache, and vomiting, lasting 2-5 days, occurred in 61% of 39 children with acute leukemia in complete remission, receiving central nervous system prophylaxis with intrathecal methotrexate, and in 14% of 34 children receiving the same plus cranial radiation. The syndrome was accompanied by pleocytosis with lymphocytes, monocytoid cells, and neutrophils. There was evidence of cumulative Mtx toxicity, since the toxic syndrome occurred mostly after the third and fourth dose and did not recur with longer intervals between doses. The incidence of the syndrome was significantly reduced by the use of Elliott's B solution as Mtx diluent, rather than water or normal saline. The occurrence of pleocytosis and toxic clinical syndrome was also significantly reduced in patients receiving concomitant cranial radiation, probably due to the lympholytic action of radiotherapy and the depressed cellular response of irradiated tissues. The use of Elliott's B solution as diluent for IT Mtx and an appropriate interval between Mtx doses are suggested for prevention of this toxic syndrome.