Purpose: Because of the increasing awareness that Hispanics diagnosed with acute lymphoblastic leukemia (ALL) often experience worse outcomes, we sought to evaluate the risk of methotrexate (MTX)-related neurotoxicity (NT) by ethnic group and evaluate its effects on treatment outcomes in a multi-institutional prospective cohort of pediatric patients (2-17 years old).
Methods: Patients with ALL were prospectively recruited from 3 pediatric cancer centers in the United States for the period 2012-2017 and systematically followed for the development of treatment-related symptoms and toxicities. For this analysis, suspected NT cases were defined as patients with a neurologic event following intrathecal (IT) and/or intravenous (IV) MTX that led to a change in subsequent MTX therapy. Cumulative incidence of MTX NT was calculated by ethnic group. Multivariable linear regression models were generated to compare treatment differences between patients with and without MTX NT. The frequency of all-cause and central nervous system (CNS) relapse was compared between patients with and without MTX NT using the log-rank test and Cox regression models.
Results: Of the 280 patients enrolled, 39 (13.9%) experienced MTX NT (median follow-up = 22.6 months; range: 1.3 - 55.6 months). Cumulative incidence of MTX NT was 21.8% among Hispanic patients compared to 7.0% among non-Hispanic patients (p <0.001). After adjusting for relevant clinical characteristics, Hispanic patients were 2.74 times more likely to develop MTX NT compared to non-Hispanic white patients (95% CI: 1.21-6.19). Patients who experienced MTX NT received an average of 2.25 fewer doses of IT MTX (95% CI: 1.73-2.77), independent of treatment risk group, sex, or age. Six cases of MTX NT (15.4%) experienced all-cause relapse during the study period, compared to 13 (2.1%) patients without MTX NT (log-rank p = 0.0038). Similarly, CNS relapse was more frequent among patients with MTX NT (10.3%) than patients without NT (2.1%; log-rank p = 0.0014). In univariate Cox regression models, MTX NT was significantly associated with CNS relapse (HR: 3.80, 95% CI: 1.44-10.02), a trend which remained after individually accounting for treatment risk arm (HR: 2.92, 95% CI: 1.07-7.95), MRD status at day 29 (HR: 3.49, 95% CI: 1.32-9.24), race and ethnicity (HR: 3.15, 95% CI: 1.13-8.79), age at diagnosis (HR: 2.56, 95% CI: 0.91-7.21), and sex (HR: 3.82, 95% CI: 1.44-10.10).
Conclusion: We identified an increased risk of relapse, specifically in the CNS, among ALL patients following MTX NT, which was not fully explained by other clinical risk factors. Further, incidence of NT was higher among Hispanic patients in our clincs. This is particularly interesting given that Hispanic patients typically present with more favorable disease characterstics, yet often experience worse treatment outcomes.
Citation Format: Michael E. Scheurer, Olga A. Taylor, Austin L. Brown, Julienne Brackett, ZoAnne E. Dreyer, Ida (Ki) Moore, Pauline Mitby, Mary C. Hooke, Philip J. Lupo, Marilyn J. Hockenberry. Ethnic-specific risk of neurotoxocity and its impact on treatment outcomes among pediatric patients receiving acute lymphoblastic leukemia therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2967.