Is hypoalbuminemia a risk factor for high-dose methotrexate toxicity in children with acute lymphoblastic leukemia?

Abstract

Background Repeated high-dose methotrexate (HDMTX) is a critical component of contemporary childhood acute lymphoblastic leukemia (ALL) treatment regimens. Serum albumin is considered a carrier of methotrexate (MTX) in the blood. Hypoalbuminemia is not a rare finding in children with leukemia. This study aimed to investigate the relationship between pre-infusion serum albumin and possible HDMTX toxicities. Methods Thirty Egyptian children with ALL were consecutively enrolled in the study between May 2018 and July 2020. They were prospectively followed up while receiving HDMTX during the consolidation phase of the TOTAL study XV protocol. HDMTX was administered intravenously as a 24-h infusion every 2 weeks. Doses of 2.5 g/m2 were used for low-risk patients and 5 g/m2 for standard/high-risk patients. The Common Terminology Criteria for Adverse Events (V.4.03) was used to report the observed toxicities after HDMTX cycles. Plasma MTX levels were estimated at 24 h (MTX24) from the beginning of HDMTX infusion in the first consolidation cycle. Serum albumin level was determined before HDMTX administration, and pre-infusion hypoalbuminemia was defined when serum albumin was <3.5 g/dL. Results The patients’ age ranged from 2.3 to 13.3 years at diagnosis, and most of them had B cell ALL (86.7%). Overall, 120 HDMTX cycles were analyzed, equally distributed between low and standard/high risk. Grade 3–4 anemia, grades 3–4 thrombocytopenia, febrile neutropenia, and oral mucositis were significantly more frequent in HDMTX cycles with pre-infusion hypoalbuminemia than those with normal pre-infusion albumin (p=0.003, p=0.007, p=0.006, and p=0.001, respectively). In addition, pre-infusion hypoalbuminemia was significantly associated with additional hospitalization due to HDMTX toxicity (p=0.031). Most HDMTX toxicities were comparable irrespective of the MTX dose. Oral mucositis was more frequently encountered in the 2.5 g/m2 than the 5 g/m2 HDMTX cycles (46.7 vs. 26.7%, p=0.023). A significantly longer hospitalization (due to HDMTX toxicity) was observed in the 5 g/m2 HDMTX cycles (median= 7 days vs. 4 days, p=0.012). Conclusions Serum albumin levels should be checked before starting HDMTX cycles, especially in resource-limited settings where malnutrition is common, and serum MTX monitoring may not be available. Optimizing serum albumin levels before HDMTX may help decrease the possibility of HDMTX toxicities.

The incidence and risk factors for acute kidney injury in patients treated with immune checkpoint inhibitors

“…The lower albumin levels were consistently associated with lower OS consistently across patients treated with chemotherapy, surgery and ICIs, similar to our findings [40–44]. Additionally, hypoalbuminemia was associated with a higher risk of chemotherapy toxicity in several studies [45–47]. Furthermore, baseline hypoalbuminemia was associated with increased AKI risk (OR, 2.34; 95% CI, 1.74–3.14) in the meta-analysis of 11 studies including 3917 patients [48].…”

“…Additionally, hypoalbuminemia was associated with a higher risk of chemotherapy toxicity in several studies [45][46][47]. Furthermore, baseline hypoalbuminemia was associated with increased AKI risk (OR, 2.34; 95% CI, 1.74-3.14) in the meta-analysis of 11 studies including 3917 patients [48].…”

Clinical covariates that improve the description of high dose methotrexate pharmacokinetics in a diverse population to inform MTXPK.org

“…Several reports have linked the effects of albumin and hypoalbuminemia to altered MTX PKs. 13,[18][19][20][21] Mainly, these reports support the reduction of MTX CL with decreasing albumin. Our parameterization for severe hypoalbuminemia on MTX CL resulted in an estimated ~2% reduction in MTX clearance (Table S1), and did not significantly improve the description of the data.…”

“…Circulating MTX is 50%–60% bound to albumin, 17 which suggests that a decrease in serum albumin would increase the amount of free (unbound) MTX. Several reports have linked the effects of albumin and hypoalbuminemia to altered MTX PKs 13,18–21 . Mainly, these reports support the reduction of MTX CL with decreasing albumin.…”

Effect of High Dose Methotrexate on Permeability Glycoprotein Serum Levels in Pediatric Patients with Acute Lymphocytic Leukemia

“…1 High-dose methotrexate (HDMTX) (>500 mg/m 2 ) has been widely employed for several years as a critical component in ALL treatment protocols. 2 P-glycoprotein (P-gp), which is encoded by the ABCB1 gene, is one of the ABC superfamily efflux transporters with widespread expression in diverse body organs as well as in many blood cells. 3 Methotrexate (MTX) had been recognized as a specific substrate of P-gp 4 interpreting the resistance of cancerous tissues towards MTX treatment with a subsequent suboptimal response.…”