Methotrexate is an antifolate that has been an essential part of chemotherapy regimens for acute lymphoblastic leukemia (ALL) and specific subtypes of non-Hodgkin lymphoma (NHL), when it is used in high-dose (HD, ≥ 1 g/m2) to overcome the blood-brain barrier. Nephrotoxicity is the major toxicity of HDMTX, possibly inducing critical organ damage and death if not early treated. Although some factors for drug-induced acute kidney injury (AKI) have been pointed out, the reality is that in resource-poor settings, HDMTX is usually administered in an outpatient clinic and without drug monitoring. The exact incidence of AKI after MTX in these conditions was not reported in adults yet. In this study, we intend to summarize our toxicity data after outpatient administration of HDMTX without drug monitoring. We aim to find risk factors and describe their outcomes in a real-life setting.

This is a retrospective nested case-control study conducted at a large academic medical center in Sao Paulo, Brazil. Patients from 16 years old and above with ALL and NHL who received at least one outpatient infusion of HDMTX without drug level monitoring between Jan/2010 and Jun/2020 were included. Cases were those patients who developed AKI by KDIGO definition or with delayed MTX clearance (serum MTX level > 0.1 mM after 72h from drug infusion), when clinically suspected. A nested cohort of controls was composed of patients who did not develop the complication, sampling from a larger cohort of patients who received HDMTX. Cases and controls were randomly matched 1:2 for the employed protocol only. Conditional logistic regression was used to find baseline risk factors.

A total of 404 patients received at least one HDMTX, with 102 not fulfilling the inclusion criteria. Among 302 patients included, 840 infusions were performed (median 2 infusions/patient, range 1-10). Most patients had a diffuse large B-cell lymphoma (DLBCL) (37%), Burkitt lymphoma (BL) (19.5%), or ALL (18%) diagnosis. Most subjects received HDMTX within a course of Hyper-CVAD (HCVAD) or monotherapy (61%). Hospitalization occurred in 8.6% of infusions during the MTX nadir, with 4.6% needing intensive care, being febrile neutropenia the most common complication (63%). Twenty-five patients presented AKI after HDMTX administration, corresponding to 3% (95% CI 2-4.4) of MTX infusions and 8.3% (95% CI 5.5-12.1) of patients. Univariate analysis for finding pre-treatment factors related to AKI after HDMTX were age>44 y (OR 3.2 [95% CI 1 - 9.7], p = 0.045), body surface≥1.76 m2 (OR 3.4 [95% CI 1.2-9.9], p = 0.039), BMI≥23.8 kg/m2 (OR 3.5 [95% CI 1.2-9.9], p = 0.02), baseline creatinine clearance (OR 0.96 [95% CI 0.93-0.99], p = 0.012), thrombocytopenia (<150x109/L) (OR 4.7 [95% CI 1.7-13.1], p = 0.002). Multivariate analysis for adjusting such factors found that only BMI is independently related to AKI after HDMTX in our setting (OR 3.8 [95% CI 1.2-11.8], p = 0.06). Among these cases, 9/25 had their MTX serum level measured at the AKI, with delayed MTX clearance in 7/9. HIV-associated BL was more frequent in cases (18 vs. 6.8%, p = 0.03). 22/25 needed hospitalization, with infection diagnosed in 23/25 e need for dialysis in 5/25 cases. Death after AKI occurred in 56% (14/25).

Our data showed a similar rate of AKI after HDMTX to that reported in the literature, even without drug monitoring. However, patients who developed AKI in our cohort fare worse than expected, with more hospitalizations and death. Higher BMI was associated with MTX-induced AKI in our cohort, suggesting a differential drug clearance and the need for specific guidelines for obese patients.