Abstract 3636: Ethnic disparities in methotrexate neurotoxicity during pediatric acute lymphoblastic leukemia therapy: A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium

Abstract Introduction: Methotrexate (MTX) is a key component of curative chemotherapy for pediatric acute lymphoblastic leukemia (ALL). However, delivery of MTX is often interrupted by dose-limiting acute neurotoxicity, which manifests as seizures, stroke-like symptoms, or altered mental status. Because incidence and risk factors for MTX neurotoxicity are poorly defined, we evaluated clinical and demographic predictors of MTX neurotoxicity using the multi-ethnic REDIAL Consortium. Methods: The REDIAL cohort includes pediatric patients diagnosed with ALL at six treatment centers in the southwestern U.S. This interim analysis evaluated 756 patients age 1-21 years diagnosed with B-ALL (2005-2018). Electronic health records were reviewed to determine race/ethnicity (Latino, non-Latino White, non-Latino Black, or Other), body mass index, sex, age, and intravenous (IV) MTX dose. Applying Ponte di Legno criteria, acute MTX neurotoxicity was defined as neurologic episodes occurring <21 days from intrathecal or IV MTX, which resulted in MTX treatment modifications. The proportion of patients who experienced MTX neurotoxicity and corresponding 95% confidence interval (CI) was calculated overall and within the induction, post-induction, and maintenance treatment phases. Multivariable logistic regression was used to estimate adjusted odds ratios (aOR) for the association between clinical factors and MTX neurotoxicity. Results: The study population was 56.6% Latino, 52.8% male, 41.4% treated with >5g/m2 IV MTX, and diagnosed at a median age of 5 years. Overall, 15.5% (95% CI: 12.9-18.3%) of patients experienced neurotoxic events (n=117), including 1.9% (n=14, 95% CI: 1.0-3.1%) during induction, 13.0% (n=98, 95% CI: 10.7-15.6%) during post-induction, and 0.7% (n=5, 95% CI: 0.2-1.5%) during maintenance therapy. Ethnic differences were not statistically significant during induction or maintenance phases. Compared to non-Latinos, post-induction neurotoxicity was significantly more frequent among Latinos (aOR = 2.87, 95% CI: 1.68-5.10), with disparities observed during consolidation, interim maintenance and delayed intensification phases. Exposure to >5g/m2 IV MTX (aOR = 2.16, 95% CI: 1.08-3.24) and older age at diagnosis (aOR = 1.16, 95% CI: 1.08-1.24) were also associated with a significantly more post-induction neurotoxicity. No factors evaluated were significantly associated with neurotoxicity during induction and maintenance therapy. Conclusions: MTX neurotoxicity disproportionally affects Latino children during ALL post-induction therapy. Additional work is warranted to identify risk factors for neurotoxicity during induction and maintenance therapy as well as the specific clinical and host biological factors responsible for post-induction ethnic differences in MTX neurotoxicity. Citation Format: Austin L. Brown, Rachel D. Harris, Olga A. Taylor, Melanie B. Bernhardt, Juan C. Bernini, Rodrigo A. Erana, Timothy Griffin, Kenneth Heym, Van T. Huynh, Kathleen Ludwig, Avner Meoded, Sandi L. Pruitt, Philip J. Lupo, Karen R. Rabin, Michael E. Scheurer. Ethnic disparities in methotrexate neurotoxicity during pediatric acute lymphoblastic leukemia therapy: A report from the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3636.