(191) Predictors of Delayed Methotrexate Clearance in Patients Receiving High-Dose Methotrexate Based Regimens for Primary Central Nervous System Lymphoma

Poster Abstract:

Background: Primary central nervous system lymphoma (PCNSL) is an extremely aggressive form of non-Hodgkin lymphoma. The National Comprehensive Cancer Network guidelines recommend a high-dose methotrexate (HD-MTX)- based induction regimen due to its ability to penetrate the blood brain barrier (1). Based on pharmacokinetic studies, HDMTX is defined as a dose greater than 1000 mg/m2 (2). At Weill Cornell Medical Center, HDMTX is administered at 3.5 mg/m2 over three hours intravenously, in combination with other first-line agents for PCNSL. However, delayed clearance of HDMTX poses substantial risk for adverse effects including but not limited to nephrotoxicity, hepatotoxicity, mucositis, and myelosuppression (2). Proper methotrexate clearance involves adequate hydration, urine alkalinization, and avoidance of substances that impede elimination. Following HDMTX administration, serum levels are obtained at 24, 48, and 72 hours after the start of HDMTX infusion, aiming for levels below < 10 micromol/L, < 1 micromol/L, and < 0.1 micromol/L respectively (3). Past retrospective studies have explored incidences and risk factors of delayed methotrexate levels primarily in pediatric and young adult populations diagnosed with lymphoma, leukemia, or osteosarcoma malignancies (3-5). Risk factors identified in these patient populations include female gender, elevated baseline serum creatinine, and prior instances of delayed methotrexate clearance (3-5). To our knowledge, this would be the first study exploring the incidence and risk factors of delayed methotrexate clearance in adult patients undergoing treatment with HDMTX for PCNSL.

Objectives: The primary aim of this study is to determine the incidence of delayed HDMTX clearance in the PCNSL population. The secondary aim is to identify clinical covariates associated with delayed HDMTX clearance.

Methods: This is a single-center retrospective cohort study based on electronic medical records of adult patients (>/= 18 years old) with PCNSL who received HDMTX (>/= 1000 mg/m2) at NewYork-Presbyterian Weill Cornell Medical Center from August 2019 to 2023. Patients were excluded if they had structural kidney disease, were on hemodialysis, or had a prior kidney or liver transplant. Delayed HD-MTX clearance is defined as patients not meeting pre-defined methotrexate level goals at either 24, 48, or 72 hours from initiating treatment. Statistical analysis will be performed using STATA. Chi-square testing will be utilized for the primary outcome, and linear regression for subgroup analysis. A p-value of =/ < 0.05 will be considered statistically significant.

Results/

Conclusions: Final results and conclusions are pending and will be presented at HOPA Annual Conference 2024.

References (must also be included in final poster): 1. Batchelor T, Carson K, O'Neill A, et al. Treatment of primary CNS lymphoma with methotrexate and deferred radiotherapy: a report of NABTT 96-07. J Clin Oncol. 2003;21(6):1044-1049.

2. Treon SP, Chabner BA. Concepts in use of high-dose methotrexate therapy. Clin Chem. 1996;42(8 Pt 2):1322-1329.

3. Misaka KO, Suga Y, Staub Y, et al. Risk factors for delayed elimination of methotrexate in children, adolescents and young adults with osteosarcoma. In Vivo. 2020;34(6):3459-3465.

4. Narita K, Kobayashi H, Abe Y, Takeuchi M, Matsue K, et al. Evaluation of risk factors and survival effect of delayed excretion of high-dose methotrexate in patients with leukemia and lymphoma. Blood. 2017;130:4132.

5. Nakano T, Kobayashi R, Matsushima S, et al. Risk factors for delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia and lymphoma. Int J Hematol. 2021;113(5):744-750.