PII-044 - UNDERSTANDING METHOTREXATE CONCENTRATIONS AND ASSOCIATED TOXICITIES TO GUIDE SUPPORTIVE CARE IN PATIENTS WITH NON-HODGKIN LYMPHOMA (NHL).

Z. Taylor¹, T. Miller², N. DeGroote³, L. Pommert¹, O. Awoniyi³, S. Board¹, E. Poweleit¹, N. Ugboh², V. Joshi³, N. Ambrosino¹, A. Chavana⁴, M. Bernhardt⁴, E. Schafer⁴, M. O'Brien¹, S. Castellino³, L. Ramsey¹; ¹Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, ²Emory University, Atlanta, GA, USA, ³Children's Healthcare of Atlanta, Atlanta, GA, USA, ⁴Baylor College of Medicine, Houston, TX, USA.

Background: High-dose methotrexate (HDMTX) is used to treat NHL. The current concentrations (CONC) that are associated with toxicities and govern glucarpidase (Glu) use are not optimal for HDMTX dosing of 3 grams infused over 3 hours (3/3) and 8 grams infused over 4 hours (8/4). The goal of this study was to identify serum MTX CONC associated with toxicity for these dosing strategies to inform supportive care and Glu use.

Methods: PK and toxicity data were collected for patients (ages 0.7-31.1) with NHL who received 3/3 or 8/4 of HDMTX at 3 children’s hospitals. PK data was analyzed in NONMEM using a 3 compartment model to simulate serum CONC at 24, 36, 42, 48, 60, and 72 hours after the start of infusion for each course. The mean and standard deviation (SD) were calculated at each time point. Toxicity grades were determined using Common Terminology Criteria for Adverse Events v5.0. The CONC cutoffs were set at two times the SD. The frequency above cutoffs were noted and the relative risk (RR) for toxicity was compared to the frequency below cutoffs.

Results: There were 503 HDMTX courses of 3/3 and 151 courses of 8/4. The cutoffs for the 24-hour timepoint are 2.57uM for 3/3 and 5.48uM for 8/4, which are substantially lower than the Glu guideline cutoff of 50uM. While only 13 (2.7%) 3/3 courses were above this cutoff, 7 courses experienced a Grade 2 creatinine increase (54%, RR=9.1) and 8 courses experienced Grade 3+ mucositis (62%, RR=3.6), with other timepoints demonstrating similar effects. For the 8/4 courses, only 5 (3.3%) were above this cutoff, with 2 courses experiencing a Grade 2 creatinine increase (40%, RR=9.7) and 2 courses experiencing Grade 3+ mucositis (40%, RR=1.3).

Conclusion: These data provide valuable cutoffs for HDMTX dosing strategies commonly used in NHL patients and could be useful for adjusting supportive care in patients above these CONC.