Methotrexate-induced toxicity in the front-line treatment of pediatric acute lymphoblastic leukemia: a single-center retrospective study

Introduction High-dose methotrexate (HD-MTX) is a cornerstone of pediatric acute lymphoblastic leukemia (pedALL) treatment, but it can be responsible for significant toxicity. Aim: To evaluate any HD-MTX-related toxicity in pedALL during front-line treatment. Materials and Methods Retrospective, single-center study including pediatric patients (0-18 years) with a new diagnosis of pedALL consecutively enrolled in the AIEOP ALL 2017 ad interim (Group 1, 06.2019-03.2021) and AIEOP-BFM ALL 2017 (Group 2, 08.2021-01.2024) protocols at the Pediatric Hematology, Oncology and Stem Cell Transplant Division, Maternal and Child Health Department, Padua University Hospital. HD-MTX level was assessed at standardized intervals as per therapeutic protocols. Severe impaired and delayed clearance were defined as a level ≥150.0 µmol/L at 24 hours and ≥0.5 µmol/L at 48 hours from infusion start, respectively. Results One hundred and six pediatric patients were included in the study, 52 (49.0%) of whom belonged to Group 1 and 54 (51.0%) to Group 2. No differences in clinical and leukemia characteristics at diagnosis and in risk group stratification were observed between the 2 groups, except for age (p = 0.044). Three patients with Down syndrome were comprised in our pedALL population - one in Group 1 and two in Group 2. The patients without Down syndrome received a total of 333 HD-MTX cycles. HD-MTX clearance was more frequently delayed in Group 2 patients [97 delays/153 cycles in Group 2 (63.4%) vs. 69 delays/180 cycles (38.3%) in Group 1, p < 0.001]. Among them, two patients showed a severe impaired HD-MTX clearance, both in Group 2. Several cases of delayed HD-MTX clearance were noticed. The delayed clearance was associated with treatment according to the AIEOP-BFM ALL 2017 protocol (OR = 2.450; 95% CI: 1.079 - 5.562, p = 0.032), a higher number of furosemide doses administered after HD-MTX infusion (OR = 1.629; 95% CI: 1.057 - 20.269, p = 0.042) and older age (>10 years) at diagnosis (OR = 9.802; 95% CI: 1.962 - 48.964, p = 0.005), while the administration of additional bicarbonate boluses before HD-MTX infusion (OR = 0.480; 95% CI: 0.239 - 0.966, p = 0.040) showed a protective effect in multivariable analysis. Although a slower clearance was associated with a poorer clinical status after HD-MTX cycle (Group 1, p = 0.027; Group 2, p = 0.020), clinical sequalae had been generally rare and manageable. Conclusions: As delayed HD-MTX clearance is relatively frequent in this patients’ population, our findings support the application of an individualized approach to HD-MTX administration and supportive care, integrating timely urine alkalinization and careful management of hydration to reduce toxicity and enhance patients’ therapeutic outcomes, especially in the oldest patients.