Clinical characteristics associated with terminal methotrexate clearance in patients with non-Hodgkin lymphomas receiving high-dose methotrexate

Introduction High-dose systemic methotrexate (HD-MTX) in doses ≥ 3 g/m 2 is the cornerstone of treatment for central nervous system (CNS) lymphomas and prophylaxis for patients with high-risk of CNS relapse. Its administration requires extensive supportive care until serum clearance is achieved. Risk factors for delayed methotrexate (MTX) clearance and renal injury are well-characterized and include baseline renal function, age, and hypoalbuminemia. Data assessing characteristics associated with slow terminal clearance are lacking. Methods We performed a single-center, retrospective cohort study between 1/2015 to 10/2023 to evaluate characteristics associated with the rate of MTX clearance in the 72 h after serum MTX levels decline to below 0.2 µmol/L in adult patients with lymphoma who received MTX at doses ≥ 3 g/m 2 . MTX administration was evaluated at the cycle level with slow terminal clearance (STC) defined as > 72 h to clear from < 0.2 µmol/L to < 0.05 µmol/L. Results Overall, 135 patients were included with a total of 462 cycles, median of 3 cycles, and 76 (56.3%) experienced at least one cycle of STC. Of 462 cycles, 138 (29.9%) were STC. Multivariable analysis, based on variables significant by univariable analysis, identified that age ≥ 80 years, BMI > 30 kg/m 2 , first MTX level > 10.0 µmol/L, and acute kidney injury (AKI) after MTX administration were significantly associated with STC. Conclusion Utilizing clinically and statistically significant variables from our analyses, we advocate for the development and validation of a model to inform supportive care management once MTX levels decline below 0.2 µmol/L.