P406: incidence of complications of high-dose methotrexate administration in adults and children with hematologic cancers: preliminary results from a european registry

Background: High-dose methotrexate (“HDMTX”) is used to treat a variety of cancer types in patients of all ages. Despite the longevity and ubiquity of HDMTX as a critical component of many cancer treatment protocols, supportive care practices vary widely. A registry of HDMTX was initiated in Europe to better understand supportive care practices and the incidence of complications. Aims: In this retrospective registry, variations in HDMTX administration and supportive care practices were analyzed to identify gaps in care, concordance with best practices, and opportunities for improvement in outcomes of patients receiving HDMTX. This study lays the groundwork for future studies to improve care in real-time, reduce various HDMTX-related toxicities, and improve long-term outcomes, including overall and event-free survival. Methods: Data collection is ongoing at 3 centers in Spain and 1 in Italy. Recruitment and onboarding of new sites is ongoing. Patient level data collected included baseline demographic information (excluding personal identifiers), cancer diagnosis details with disease specific information, and long-term follow-up. HDMTX course level details analyzed included concomitant medication data, chemistry and hematologic lab results, serum methotrexate levels, duration of hospital and intensive care unit stays, and other toxicity-related outcomes. Results: Data collected included 154 patients who received 514 courses of HDMTX and included 96 males (311 courses) and 58 females (203 courses). Patients ranged in age from 1 to 83 years at time of cancer diagnosis. Patients received HDMTX doses ranging from 500 to 12,000 mg/m2 and received 1 to 6 courses of HDMTX. 134 patients had acute lymphoblastic leukemia and received HDMTX as a 24-hour infusion, while 20 had non-Hodgkin lymphoma of which 11 received 4-hour infusions and 9 received 24-hour infusions. Patients experienced acute kidney injury (AKI) in 119 courses (23.2%), including 85 grade 1 (16.5%), 25 grade 2 (4.9%), and 9 grade 3 (1.8%). In courses where adequate urine alkalinization was maintained during the first 72 hours, AKI occurred in 107 courses (22.1%), including 76 grade 1 (15.7%), 22 grade 2 (4.5%), and 9 grade 3 (1.9%); whereas, in those where urine alkalinization was not maintained, AKI occurred 12 courses (40.0%), including 9 grade 1 (30.0%), 3 grade 2 (10.0%), and 0 grade 3 (0.0%), (p=0.03) (See Figure). Male patients were more likely to develop AKI (26.4% vs. 18.2%, p=0.04), and those who received a dose higher than 4,000 mg/m2 of body surface area (26.4% vs. 16.3%, p=0.01). Age and cancer type were not associated with differences in AKI. In multivariate analysis, urine alkalinization and dose remained statistically significant (p=0.03 and p=0.02). Although inadequate urine alkalinization is associated with a two-fold increase in AKI (from 22% to 40%), this risk factor only occurred in 30 courses (6% of the total), of which AKI occurred in 12 (40%). However, of 119 courses with AKI, 12 had inadequate alkalinization and 107 with AKI (of 484) had adequate urine alkalinization. Thus, 90% of AKI (107 of 119 courses) occurs despite adequate urine alkalinization, so new biomarkers are needed to predict or pre-emptively detect impending AKI after HDMTX. Summary/Conclusion: While AKI still occurs in patients with adequate urine alkalinization, inadequate urine alkalinization during HDMTX administration is associated with a nearly two-fold higher risk of AKI and may be preventable. Further research will focus on supportive care measures that maximize safety and facilitate dose-escalation in patients who need HDMTX.Keywords: High dose methotrexate, Methotrexate