Risk factors for high‐dose methotrexate associated acute kidney injury in patients with hematological malignancies

Abstract

High dose methotrexate (HDMTX)-induced acute kidney injury (AKI) is a well-known adverse event in hemato-oncology patients. Our purpose was to define factors and setup cutoffs that may help better identify patients at-risk for developing AKI following HDMTX. All consecutive patients who received MTX dose ≥1 g were retrospectively reviewed. We compared patients with or without renal toxicity. We used a logistic regression model to define baseline variables associated with AKI. Overall survival (OS) was estimated by the Kaplan-Meier method employing log-rank test. Between 2012 and 2017, 160 patients were included with a total of 265 courses. Indications included: primary central nervous system (CNS) lymphoma, CNS prophylaxis in other lymphoma types, acute lymphatic leukemia and others. Median age at diagnosis was 58 years (range, 18-84), 54% were males, median MTX dose was 1941 mg/m 2 (range, 743-5442) and AKI developed in 9% of drug administrations (n = 24). In univariate analysis: age > 40, LDH > 380 units/L, eGFR < 112 mL/min, albumin <3.6 mg/dL at baseline and Charlson comorbidity index (CCI) were associated with AKI. In multivariable analysis, only LDH > 380 units/L (OR = 4.1, 95% confidence interval [CI] 1.04-20.9, P = .04) and albumin levels <3.6 g/dL (OR = 4.17, 95% CI 1.04-6.5, P = .04) remained significant. In patients with AKI, median drug elimination was longer (8 days vs 5 days). In 80% of cases, the creatinine levels returned to normal within 1 month. Yet, the median survival of patients who developed AKI was 37 months, compared to 145 months in patients without AKI (Log rank = 0.015). In conclusion, LDH > 380 units/L and albumin <3.6 g/dL were the strongest factors associated with AKI in patients receiving HDMTX. Although the rise in creatinine levels was almost uniformly reversible, AKI was associated with increased mortality rates.

Feasibility of high-dose methotrexate administered on day 1 of (R)CHOP in aggressive non-Hodgkin lymphomas

“…It is plausible that the risk of AKI when HDMTX is administered on day 1 of (R)CHOP is higher especially during the first treatment cycle when other risk factors for AKI (for example tumor lysis syndrome) or factors associated with higher risk for HDMTX-related nephrotoxicity (for example hypoalbuminemia) are more likely to be present. 29,30 Not only did patients in our HDMTX-P cohort receive more HDMTX cycles during the first treatment cycle (55% vs <40%), but they also received more HDMTX-containing cycles/patient overall. The definition of AKI was also different between the studies; we defined grade 2 AKI as creatinine increase >1.5-3.0 times the upper limit of normal per CTCAE V5.0 whereas Wilson et al defined it as creatinine 2-2.9 times baseline per KDIGO criteria.…”

Hypoalbuminemia and not undernutrition predicts high‐dose methotrexate‐induced nephrotoxicity in children with acute lymphoblastic leukemia in resource‐constrained centers

“…Some earlier studies have suggested the association of HMN or delayed MTX clearance with hypoalbuminemia. 7,16,19 While another study found low baseline serum protein and not low albumin levels as risk factor for HMN. 4 The cutoffs for low serum albumin were diverse (Supporting Information Table S1), and none of the study monitored CRP along with serum albumin, which may lead to falsely low albumin levels.…”

“…These studies are retrospective and heterogeneous with varying use of supportive measures. 4,7,8 Therefore, we decided to study factors affecting HMN prospectively in a center where serial MTX monitoring as per protocol is not feasible.…”

Advances in treatment of elderly primary central nervous system lymphoma

“…Simpler geriatric assessment tools have been developed to predict outcomes in NHL. An association of Charlson Comorbidity Index with risk of methotrexate (MTX)‐induced kidney injury in univariate analysis 34 and with OS has been demonstrated in a National Cancer Database US‐based study 35 …”

“…The PRIMAIN study evaluated R-MP in PCNSL patients >65 years. PRIMAIN is the largest prospective study specifically designed for elderly PCNSL patients, reporting one-and two-year PFS rates of 46Á3% (95% CI 36-55) and 37Á3% (95% CI [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] and OS rates of 56Á7% (95% CI 47-66) and 47% (95% CI 37-56) respectively. TRM rate was 8Á4% and 81Á3% of the patients experienced adverse events ≥grade 3.…”