Factors influencing delayed clearance of high dose methotrexate (HDMTX) in pediatric, adolescent, and young adult oncology patients

Abstract

PurposeTo identify modifiable risk factors associated with prolonged clearance of methotrexate in pediatric, adolescent, and young adult (AYA) oncology patients receiving high dose methotrexate (HDMTX).Design/MethodA single institution, retrospective chart review of patients receiving HDMTX between 2010-2017. Patients had a diagnosis of either leukemia or osteosarcoma. Data included demographics, concurrent intravenous (IV) medications, IV fluids (IVF) administered, urine output (UO), and rises in serum creatinine (RSC) reflective of renal toxicity (RT). Outcome measures included 1) delayed targeted MTX clearance (DC), 2) actual time to clearance (TTC) and 3) length of stay (LOS).ResultsData from 447 HDMTX administrations were analyzed. The sample consisted of 241 (54%) osteosarcoma encounters, and 206 (46%) leukemia encounters, with an average patient age of 12.7 years. Multivariate analysis showed that DC was associated with the diagnosis of leukemia (OR 7.64, p <.0001), and less UO on day 1 (OR 0.76, p=0.005). Increased TTC was associated with increasing age (RR 1.02, p<0.0001), higher 24-hour MTX levels (RR 1.001, p=0.012) and 48-hour MTX levels (RR 1.02, p<0.0001), RT (RR 1.004, p<0.0001), use of IV lorazepam (RR 1.08, p=0.001) and IV metoclopramide (RR 1.08, p<0.001) both on day 3. Like TTC, LOS was affected by MTX levels at 24 (RR 1.001, p=0.025) and 48 hours (RR 1.03, p<0.0001), RT (RR 1.006, p<0.0001), total IV medications on day 3 (RR 1.042, p<0.0001), and the use of leucovorin on day 2 (RR 0.93, p=0.002).ConclusionMultiple modifiable risk factors were identified which can be leveraged to improve HDMTX clearance. Subsequent efforts will assess whether acting on such risk factors can improve MTX clearance and shorten LOS.

Development of a novel nomogram for predicting delayed methotrexate excretion following high-dose methotrexate in adult patients with hematologic malignancies

“…Various risk factors for delayed MTX clearance have been reported, including older age, [5,6] sex, [5,7,8] impaired renal function, [5,6,9] hypoalbuminemia, [6, 10,11] uid retention, [12] and drug-drug interactions. [13,14] However, most identi ed predictors are presented as rough dichotomous values, such as creatinine clearance (CrCl) < 60 mL/min [5] and albumin (Alb) < 3.4 g/dL or < 3.7 g/dL. [10,11] These arbitrary cut-offs may preclude the more precise calculation of individual risk probabilities, which in turn could diminish their generalizability.…”

“…Moreover, previous studies on HDMTX have predominantly focused on pediatric and adolescent patients with acute lymphoblastic leukemia (ALL) or osteosarcoma. [8,9,[17][18][19] Even studies involving elderly cohorts often include a mix of lymphoma and solid tumors, [5,10,13,20,21] which compromises the direct application of ndings to these more vulnerable populations. For instance, con icting results have been reported regarding MTX concentration and renal function, with no relationship reported only in childhood ALL.…”