037: Understanding Methotrexate Concentrations & Associated Toxicities to Guide Supportive Care in Patients With Osteosarcoma

Statement of Purpose: High-dose methotrexate (HDMTX) is intravenously administered at 12 g/m² over 4 hours (12/4) to treat patients with osteosarcoma. The dose is capped at 20 g for patients larger than 1.67m², making their dose closer to 10 g/m² (10/4). Unfortunately, some patients will experience delayed elimination of HDMTX, which increases the risks for severe toxicities. Glucarpidase is a life-saving therapeutic agent for use in these cases. To facilitate optimal glucarpidase use, a consensus guideline outlines concentrations that are associated with toxicities, but these concentrations were determined based on low-quality evidence. The goal of this study was to identify and compare the methotrexate concentrations associated with toxicity for the 12/4 and 10/4 dosing strategies to inform supportive care and glucarpidase use.

Description of Methods & Materials: PK and toxicity data were collected for patients (ages 1.3-29.7) with osteosarcoma who received either 12/4 or 10/4 HDMTX at Cincinnati Children’s Hosp Medical Ctr, Children’s Healthcare of Atlanta or Texas Children’s Hosp. PK data was analyzed in NONMEM using a 3-compartment model to simulate concentrations at 4, 24, 36, 42, 48, 60 and 72 hours after the start of infusion for each administration. The mean and standard deviation (SD) were calculated at each time point. The concentration cutoffs were set at two times the SD. Toxicity grades were determined for serum creatinine increase and mucositis using Common Terminology Criteria for Adverse Events v5.0. The frequency above cutoffs were noted and the relative risk (RR) for toxicity was compared to the frequency below cutoffs.

Data & Results: There were 1,128 administrations of 12/4 and 180 administrations of 10/4. Four 12/4 administrations received glucarpidase during HDMTX treatment compared to zero 10/4 administrations (Table). The concentration cutoffs for the 24- (13.3uM, 18.8uM), 36- (3.77uM, 4.82uM), 42- (2.23uM, 2.61uM) and 48-hour (1.41uM, 1.48uM) timepoints for both the 12/4 and 10/4, respectively, are substantially lower than the glucarpidase consensus guideline cutoffs of 50uM, 30uM, 10uM and 5uM at corresponding time points. Additionally, the 10/4 administrations were found to have higher concentration cutoffs despite receiving a lower dose per meter squared and experienced higher proportions of administrations with either Grade 2+ serum creatinine increase (7% vs 5%) or Grade 2+ mucositis (16% vs 13%) compared to the 12/4 cohort. Regardless of administration amount, the RR for Grade 2+ serum creatinine increase is higher for later time points, with the 72-hour concentration cutoffs yielding the largest RR of 7.3 for 12/4 and 7.0 for 10/4. Concentration cutoffs were not associated with Grade 2+ mucositis for either the 12/4 or 10/4 dosing strategies. Age ( > 20 years) and obesity ( > 30 kg/m²) were not associated with either Grade 2 serum creatinine increase or Grade 2+ mucositis for 12/4 and 10/4.

Interpretation, Conclusion or Significance: These data provide valuable cutoffs for HDMTX dosing strategies commonly used in osteosarcoma patients and could be useful for adjusting supportive care in patients above these concentrations. Using a clinical decision support tool that can forecast the 72-hour concentration earlier in the treatment period could potentially enable proactive risk mitigation of nephrotoxicity.

Disclosures: