BACKGROUND / OBJECTIVES: Acute methotrexate-induced neurotoxicity (MTX-NT) among pediatric patients with acute lymphoblastic leukemia (ALL) often results in treatment interruption, potentially reducing treatment efficacy. Despite its clinical significance, the effects of MTX-NT on subsequent treatment have not been well-described. Therefore, we evaluated the impact of acute MTX-NT on delays and modifications to MTX treatment among pediatric patients with ALL.
DESIGN/ METHODS: We identified patients treated on ALL protocols who had reached maintenance therapy at Texas Children’s Hospital and University of Arizona in 2012-2017 (n=158). MTX-NT was defined as the occurrence of NT-related symptoms (e.g., seizure, aphasia) after receiving MTX and led to a change in MTX therapy. Difference in time from diagnosis to start of maintenance, cumulative intravenous MTX dose, and number of intrathecal MTX courses between end of induction and start of maintenance were compared by MTX-NT status using multiple linear regression and adjusting for age at diagnosis, sex, ethnicity, and ALL risk stratification.
RESULTS: On average, patients were 8.3 years of age at diagnosis (range: 2.5-18.0). The majority was male (57%), Hispanic (58%), and assigned to high or very high risk treatment arms (56%). A total of 25 patients (16%) experienced acute MTX-NT, of which three (12%) subsequently relapsed or died during follow-up. After adjusting for demographics and risk group, those who experienced acute MTX-NT received a 2.7 g/m2 lower dose of intravenous MTX (95% confidence interval [CI]: 0.4-5.0; p=0.024) and 2.4 fewer intrathecal MTX courses (95% CI: 1.6-3.3; p<0.001) by the start of maintenance therapy compared to those without MTX-NT. The occurrence of MTX-NT did not significantly delay the start of maintenance therapy (p=0.680).
CONCLUSIONS: MTX-NT during post-induction chemotherapy for pediatric ALL results in patients receiving significantly less intravenous and intrathecal MTX. Future work is needed to determine whether modifications to therapy following acute MTX-NT compromise treatment efficacy or outcomes, including relapse and survival.
