High-dose methotrexate in ICU patients: a retrospective study

Background High-dose methotrexate (HD-MTX) is commonly used in the treatment of solid tumors and hematological malignancies. Severe toxicities are frequent, leading to organ dysfunction and death. Risk–benefit ratio of using HD-MTX in critically ill patients is unknown. This study aims to describe MTX-induced toxicities and to assess outcome in ICU patients. We conducted a retrospective single-center study conducted in a university hospital ICU between January 2002 and December 2018. Consecutive patients treated by HD-MTX were included. Results 33 patients (24 men and 9 women) aged 48 years [34–63], were included. B cell lymphoma had been diagnosed in 31 patients (Burkitt, n = 14; diffuse large B-cell lymphoma with CNS (central nervous system) involvement, n = 9; primary CNS lymphoma, n = 5) and T-cell lymphoma in two patients. Patients were mainly admitted for coma (n = 14; 42%) or acute kidney injury (n = 8; 24%). MTX was administered at a median dose of 6.1 g [5–14]. Fourteen patients had concomitant medication interacting with MTX. Median MTX clearance was 4 days [4–5]. Frequent MTX-related complication were mucositis (n = 21, 64%), diarrhea (n = 14, 44%) or hepatic failure (n = 15, 45%). During ICU stay, 11 patients experienced acute kidney injury (KDIGO stage 3 [2–3]). Two patients received carboxypeptidase and three underwent dialysis. Overall, 19 patients (57%) required mechanical ventilation, 10 (30%) vasopressors. Hospital mortality was 30% (n = 10). Cox model identified MTX concentration 24 h after administration higher than 4.6 µmol/L as associated with hospital mortality (HR 6.7; 95% CI 1.6–27.3). Conclusions To our knowledge, this is the first study assessing characteristics and outcome of critically ill patients receiving HD-MTX. MTX concentration at H24 was associated with hospital mortality. Despite underlying malignancy, ICU support of these patients was associated with a meaningful survival.


Background
Intravenous high-dose methotrexate (HD-MTX) is commonly used in the treatment of hematological malignancies, particularly in high-grade lymphomas [1]. MTX-related toxicities are common, leading to organ dysfunction that can be very severe, and rarely to death [1]. Acute kidney injury (AKI) is frequently reported, affecting up to 35% of adult patients, mostly in relation with intratubular crystal formation or endothelial injuries [1,2].
This drug requires a close monitoring and management of MTX-related toxicities relies mostly on preventing measures [1,3]. AKI is frequent in critically ill patients with newly diagnosed high-grade hematological malignancies [4] and is associated with a high level of frailty. Whether ICU patients may be considered eligible for HD-MTX and risk-benefit ratio in this setting has never been assessed.
This primary objective of this study was to assess outcome in critically ill patients requiring HD-MTX Open Access *Correspondence: sandrine.valade@aphp.fr 1 Medical ICU, APHP, Saint-Louis Hospital, Paris, France Full list of author information is available at the end of the article infusion. Secondary objectives were to describe toxicities and risk factors of poor outcome in this setting.

Patients and data collection
We retrospectively reviewed the medical charts of all consecutive adult patients admitted to the intensive care unit of one university hospital from January, 1st, 2002 to December 31th, 2018, and who received HD-MTX for hematological malignancy or solid tumor. There were no exclusion criteria.
HD-MTX was defined by a single intravenous infusion greater than 500 mg/m 2 . The different stages of toxicity were defined according to the CTCAE [5]. MTX complete elimination was considered when MTX concentration was lower than 0.1 µmol/L. This study was approved by a local ethic committee (Société de Réanimation de Langue Française, CE SRLF 19-01). According to French law, need for informed consent was waived.

Statistical analysis
Results are described as medians and interquartile ranges (IQR) for quantitative variables and numbers and percentages for qualitative variables. We used a non-parametric Wilcoxon tests and Fisher exact tests for baseline univariate comparisons between two groups.
Cox regression model were performed to identify factors associated with hospital mortality. Variable selection was performed on a stepwise fashion, backward conditional model according to P value with entry P value of 0.2 and critical removal P value of 0.1. Proportional hazard assumption was checked in the final model.
All tests were two-sided, and P values less than 0.05 were considered significant. Analyses were done using R software version 4.3.4 (R Project for Statistical Computing, Wien, Austria) and with 'Survival' packages.  (Table 1).

Discussion
To our knowledge, this is the first study assessing benefits and risk of HD-MTX in critically ill patients. This study underlines the high rate of risk factors for HD-MTX toxicity and the high rate of MTX-related toxicities. Our results also underline that 6-month survival may be obtained in 55% of the patients and that complete remission may be obtained in 83% of them.
In the literature, classically 2 to 12% of non-ICU patients are reported to develop renal failure following HD-MTX. In fact up to 35% of patients experienced AKI, with a large heterogeneity according to the studied population, HD-MTX protocols and AKI criteria [6]. In critically ill patients, AKI incidence also varies widely from 22 to 67%, discrepancies mainly relying on the definition applied [7]. In our study, we found a high rate of AKI as one in three patients experienced renal failure. This is in line with a previous study in which the authors showed that two-thirds of critically ill patients with newly diagnosed aggressive hematological malignancies developed AKI [4]. Our results highlight that MTX-induced renal toxicity is very frequent in ICU patients.
Survival of patients with hematological malignancies has improved over the past decades and an increasing number of patients may need ICU admission [8]. In previous studies in cancer patients receiving chemotherapy in the intensive care unit, hospital mortality is reported around 40% [9]. Our study, concurrently suggests the feasibility of HD-MTX in this setting, demonstrating that despite the high toxicity rate, a 6-month survival rate of 55% may be achieved, the majority of survivors achieving complete remission. Dose-toxicity relationship of MTX has been descried previously. The most commonly used threshold is a concentration greater than 10 µmol/L 24 h after MTX infusion or greater than 1 µmol/L at H48 [3]. Evans et al. [10]