Early toxicity of high-dose methotrexate in the treatment of non-hodgkin lymphomas in children

   Background. Methotrexate (MTX), used in high doses (1000–5000 mg / m²), has proven to be one of the key components of successful therapy for non‑Hodgkin’s lymphomas. However, the flip side of high efficacy is its toxicity. Even adherence to modern guidelines for supportive care, including therapeutic drug monitoring, timely administration of the antidote (calcium folinate), maintaining alkaline blood and urine pH levels, and adequate hydration, does not always prevent the development of methotrexate‑induced organ toxicity. Therefore, further studies of the toxicity spectrum and the identification of potential prognostic factors for organ toxicity remains relevant.

   Aim. To analyze the spectrum of immediate toxic effects of non‑Hodgkin’s lymphomas therapy with high‑dose MTX and to identify possible predictors of toxic events.

   Materials and methods. From 2020 to 2024, 100 pediatric patients (under 18 years old) with primary diagnosed non‑Hodgkin’s lymphomas were enrolled the study and treated according to chemotherapy protocols (ALL IC‑bFM 2009, b‑NHL‑bFM 95, or ALCL‑NII dOG 2003) that included high‑dose MTX. The spectrum and severity of toxic events were analyzed with National Cancer Institute toxicity scales (uSA), and statistical analysis of feature distribution and correlation strength was performed.

   Results. Hepatotoxicity of grades 3–4 was noted in 49 % of patients, nephrotoxicity developed in 1 % and corresponded to grade 3. Hematologic toxicity of grades 1–2 was observed in 8 % of patients, and grades 3–4 – in 92 %. Neurotoxicity developed in 9 % of patients (grade 1 – in 2 %, grade 2 – in 1 %, grade 3 – in 3 %, and grade 4 – in 3 %). Mucositis of grades 3–4 occurred in 30 % of patients. Infectious complications of grades 3–4 developed in 74 % of patients. No cases of treatment timing violation or toxicity‑related death were noted. Delayed methotrexate elimination beyond 54 hours was observed in 30 % of patients. Analyzing the influence of MTx dose on drug elimination and the incidence of toxic effects found that the more MTX dose, the higher incidence of delayed MTX elimination and toxic events incidence.

   Conclusion. The study demonstrated the spectrum of methotrexate‑induced toxicity, including hematologic toxicity, mucositis, hepato‑, nephro‑, neurotoxicity, and infectious complications. delayed drug elimination correlates with increased MTx dose, which, in turn, associated with an increased risk of toxic events.

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