Truong, Huong L.

Background: A summary of pharmacist-based practices and preferences regarding the prevention and management of high-dose methotrexate (HDMTX) toxicity in patients with lymphoma does not exist. The objective of the study was to describe current practices surrounding management of HDMTX therapy. This was done through a self-administered, web-based, cross-sectional survey of hematology/oncology pharmacists to ascertain practices and individual attitudes about HDMTX therapy management. Responses were summarized with descriptive statistics. Response comparisons were made using Chi-square or Fisher’s exact test for categorical data, and Kruskal-Wallis test for variables on the Likert scale. A total of 175 pharmacists provided 116 eligible surveys [68 (59%) complete responses and 48 (41%) partial responses] for analysis. The Cockcroft-Gault estimated creatinine clearance formula was the most preferred method (61%) to estimate kidney function and determine HDMTX dosing. Respondents would proceed with HDMTX therapy until the predicted risk of AKI, or AKI stage 2 or 3, exceeded 50% and 20%, respectively. Preferred treatment modifications for a high predicted AKI risk after HDMTX exposure included additional prehydration, HDMTX dose reduction, and increased kidney function monitoring, although levels and degrees of agreement varied. Respondents indicated that serum cystatin C-based GFR estimates lacked evidence, accuracy, and practicality in HDMTX therapy management. There was limited familiarity with cell cycle arrest biomarker use during HDMTX therapy. Glucarpidase was considered time-sensitive and highly effective; however, acquisition cost represented a barrier to use, and the optimal dose was felt to be unknown. In conclusion, there is significant heterogeneity in supportive practices and beliefs about the optimal management for patients with lymphoma receiving HDMTX therapy.

Abstract High-dose methotrexate (MTX) results in high rates of acute kidney injury (AKI), neutropenia, and hepatotoxicity. Glucarpidase is a recombinant enzyme that cleaves MTX, but clinical data supporting its use are scarce. We examined the association between glucarpidase administration and outcomes in adults with MTX-AKI from 28 cancer centers across the United States using a sequential target trial emulation framework. The primary end point was kidney recovery at hospital discharge, defined as survival to discharge with serum creatinine <1.5-fold baseline and without dialysis dependence. Key secondary end points were time to kidney recovery, neutropenia, and transaminitis on day 7, and time to death. Using multivariable logistic and Cox regression models, we compared outcomes in patients who received glucarpidase within 4 days following MTX initiation with those in patients who did not. Among 708 patients with MTX-AKI, 209 (29.5%) received glucarpidase. Overall, 183 (25.8%) had a primary end point event. Glucarpidase receipt was associated with a 2.70-fold higher adjusted odds of kidney recovery (95% confidence interval [CI], 1.69–4.31) compared with no glucarpidase receipt. Patients treated with glucarpidase also had faster time to kidney recovery (adjusted hazard ratio [aHR], 1.88; 95% CI, 1.18–3.33) and lower risks of grade ≥2 neutropenia (adjusted odds ratio [aOR], 0.50; 95% CI, 0.28–0.91) and grade ≥2 transaminitis (aOR, 0.50; 95% CI, 0.28–0.91) on day 7. There was no difference in time to death (aHR, 0.76; 95% CI, 0.49–1.18). These data suggest glucarpidase may improve both renal and extrarenal outcomes in patients with MTX-AKI.

PURPOSE Limited evidence exists regarding methotrexate (MTX) resumption after patients with lymphoma receive glucarpidase for toxic MTX levels and acute kidney injury (AKI). METHODS This retrospective review included adults with lymphoma treated with glucarpidase after MTX at Mayo Clinic between January 31, 2020, and October 10, 2022. Descriptive statistics summarize patient characteristics and clinical outcomes. RESULTS Of 11 patients treated with glucarpidase after MTX, seven (64%) were rechallenged with MTX. Indications for MTX rechallenge included confirmed CNS disease (n = 6, 86%) and intravascular lymphoma (n = 1, 14%). Compared with the nonrechallenged subgroup, before receiving MTX that required glucarpidase rescue, the rechallenged patients had lower median pretreatment serum creatinine (Scr; 0.7 v 1.2 mg/dL), and none had AKI with previous MTX doses, n = 0 (0%) versus n = 2 (50%). During the MTX dose requiring glucarpidase rescue, the rechallenged group had lower median peak Scr (1.26 v 3.32 mg/dL) and lower incidence of AKI stage III (n = 1 [14%] v n = 3 [75%]), and none of the rechallenged patients required renal replacement therapy (RRT; n = 0 [0%] v n = 1 [25%]). At the first rechallenge after glucarpidase administration, the median MTX dose reduction was 56% (range, 46%-75%), and the lowest used dose when prescribed according to each treatment protocol schedule was 1.5 g/m2. Two (29%) patients experienced AKI (n = 1 stage I, n = 1 stage II) after MTX rechallenge. Zero patients required RRT, and zero required another glucarpidase administration. Six (86%) patients completed all recommended MTX doses. CONCLUSION In selected adults with lymphoma who required glucarpidase for toxic MTX levels after administration of high-dose MTX, resumption of MTX therapy at lower doses is safe. Patients selected for MTX resumption had experienced less severe AKI during the previous cycle compared with those not selected for MTX resumption.

Introduction: Romiplostim is a thrombopoietin receptor agonist approved by the US FDA for chronic immune thrombocytopenia (ITP) in patients who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The recommended dose is 1 mcg/kg/week subcutaneously, escalated weekly by increments of 1 mcg/kg to achieve and maintain a platelet count of 50 x 10 9 /L g ( Kuter et al 2021). It has been postulated that starting at the maximum recommended dose of 10 mcg/kg/week in patients with severe bleeding may swiftly increase platelets and minimize bleeding ( Roumier et al 2021). However, this approach may also increase the risk of major thrombotic events (TE). It is unclear if the more aggressive dosing strategy results in more rapid, robust responses and a tolerable safety profile compared to the FDA approved approach. Methods: This retrospective chart review included adult patients who initiated romiplostim while admitted for ITP at a Mayo Clinic Enterprise site from May 2018 to May 2022. Outcomes included rate of TE at 30 days and 90 days and time to first TE in patients receiving initial romiplostim doses of < 5 mcg/kg (low dose, LD) and > 5 mcg/kg (high dose, HD), median time to platelet response (defined as platelets > 30 x10 9/L and > 50 x10 9/L on 2 separate checks) in LD vs HD, and cost to the institution comparing LD to HD. Outcomes were summarized using descriptive statistics. Statistical analysis was done using BlueSky. Fischer's exact test and chi-squared were performed for categorical data, and Wilcoxon rank sum test were done for continuous variables. Results: Forty-five patients met eligibility criteria: 33 (73%) received initial romiplostim doses < 5 mcg/kg and 12 (27%) received doses > 5 mcg/kg. The majority of patients (43/45 (96%)) presented with platelets < 50 x 10 9/L. The median age was 65 years (68 in LD vs 57 HD). There were 24 (73%) males in the LD group vs five (42%) in the HD group. At baseline, 64% (n = 21) of LD patients and 75% (n = 9) of HD patients presented with bleeding. Major bleeding (defined by 2019 ASH ITP guidelines) was present in 21% (n= 7) vs 17% (n = 2) of patients, LD versus HD, respectively ( Neunert et al 2019). The overall incidence of TE in this study was 24% (n = 11): LD 5 (15%) and HD 6 (50%) (p = 0.044) at 90 days. Median days to TE was 21 days, 12 days in LD group (range 5-21) vs 24.5 days (range 14-58) in HD group (p = 0.067). TE included deep vein thrombosis (DVT, n = 6), DVT with pulmonary embolism (n = 1), portal vein thrombus (n = 1), multiple brain infarcts (n = 1), splenic vein thrombus (n = 1), and left atrial appendage thrombus (n = 1). The median platelet count at the time of TE was 304 x 10 9/L, 415 x 10 9/L (range 58-900) in the LD group vs 323 x 10 8/L (range 33-1427) in the HD group (p = 0.79). Thirty-two (71%) out of 45 patients had a response to romiplostim: 22 in the LD group (71%) vs 10 (83.3%) in the HD group (p = 0.698). Of the patients that responded, the median time to response was 6 days in the LD group vs 11.5 days in the HD group (p = 0.09) The median dose at time of initial response was 2 mcg/kg in the LD group and 6 mcg/kg in the HD group. Wholesale Acquisition Cost (WAC) was used to determine the cost per dose, rounded to the nearest vial size. The average WAC for the initial dose in LD patients was $1806.80 compared to $6061.79 in HD patients. Conclusion:There was a significantly increased incidence of thrombosis in patients admitted with ITP that received initial romiplostim doses > 5 mcg/kg, with no differences in the time to platelet response. Careful consideration of risks versus benefits should be given prior to initiating romiplostim at doses higher than recommended doses.

AbstractStudy ObjectiveTo develop and validate a model for predicting acute kidney injury (AKI) after high‐dose methotrexate (HDMTX) exposure.DesignRetrospective analysis.SettingMultisite integrated health system throughout Minnesota and Wisconsin.PatientsAdult patients with lymphoma who received HDMTX as a 4‐h infusion.Measurements and Main ResultsLASSO methodology was used to identify factors available at the outset of therapy that predicted incident AKI within 7 days following HDMTX. The model was then validated in an independent cohort. The incidence of AKI within 7 days following HDMTX was 21.6% (95% confidence interval (CI) 18.4%‐24.8%) in the derivation cohort (435 unique patients who received a total of 1642 doses of HDMTX) and 15.6% (95% CI 5.3%‐24.8%) in the validation cohort (55 unique patients who received a total of 247 doses of HDMTX). Factors significantly associated with AKI after HDMTX in the multivariable model included age ≥ 55 years, male sex, and lower HDMTX dose number. Other factors that were not found to be significantly associated with AKI on multivariable analysis, but were included in the final model, were body surface area, Charlson Comorbidity Index, and estimated glomerular filtration rate. The c‐statistic of the model was 0.72 (95% CI 0.69‐0.75) in the derivation cohort and 0.72 (95% CI 0.60‐0.84) in the validation cohort.ConclusionThis model utilizing identified sociodemographic and clinical factors is predictive of AKI following HDMTX administration in adult patients with lymphoma.

PURPOSE:High-dose methotrexate (HDMTX; > 500 mg/m2) is an important component of lymphoma therapy. Serum MTX monitoring at 48 hours is the standard approach to identify those at increased risk of developing MTX toxicity. Our aim was to characterize the incidence of complications and their association with MTX levels.METHODS:A retrospective review of our institutional electronic medical record was conducted to identify patients with lymphoma who received HDMTX between January 1, 2002, and December 31, 2018. We characterized the incidence of acute kidney injury (AKI), intensive care unit (ICU) admission, length of hospital stay (LOS), and 30-day mortality across 48-hour MTX levels. To establish an association between 48-hour MTX levels and the complications listed, we performed chi-square analysis for dichotomous variables and Kruskal-Wallis for nonparametric data. Receiver operator characteristic curve analysis was performed to identify the MTX level where AKI grade ≥ 2 was more likely. Multivariate logistic regression analysis was performed to identify risk factors for this MTX level.RESULTS:We identified 642 patients with 2,804 cycles of HDMTX. The incidence of AKI was 19.1% with AKI grade ≥ 2 making up 21% of cases. Rates of AKI, ICU admission, and 30-day mortality are associated with elevated 48-hour MTX levels. There was a significant increase in median LOS with elevated MTX levels ( P < .001). Receiver operator characteristic curve analysis for AKI grade ≥ 2 demonstrated a 48-hour MTX level threshold of 1.28 μmol/L. Multivariate logistic regression analysis revealed age, male sex, elevated body surface area, higher MTX dose, monotherapy, and first cycle as independent factors.CONCLUSION:Elevated MTX levels are associated with a significant increased rate of AKI, ICU admission, prolonged LOS, and 30-day mortality. Elevated 48-hour MTX levels, particularly > 1.28 μmol/L, should alert clinicians for complications and to initiate measures to reduce MTX levels.

e20035 Background: HDMTX is a vital treatment of lymphoma secondary to central nervous system penetrance. MTX is nephrotoxic and may cause acute kidney injury (AKI). AKI results in delayed MTX elimination, increased hospital length of stay (LOS) and intensive care unit (ICU) stays. Our aim was to characterise the complications and associated 48-hour MTX levels in lymphoma patients undergoing HDMTX. Methods: A retrospective review of the electronic medical record was conducted to identify lymphoma patients who received HDMTX from 1/1/2002 to 12/31/18. We assessed the incidence of AKI using AKIN criteria, ICU admission, and LOS across 48 hour MTX levels per the table. Results: 2704 cycles of HDMTX were identified. The mean age was 64 years, 54% were male and 72.2% received high dose (≥8g/m2). A significant increase in AKI severity (p < 0.0001) and LOS (p < 0.01) occurred with increasing 48 hour MTX levels, (p < 0.001, Table). All 7 patients requiring dialysis had MTX levels > 10. ROC curve analysis for AKI grade ≥ 2 demonstrated a 48 hour MTX level threshold of 1.28 (AUC 0.79) with relative risk of 7.6 (95% CI 5.3-11) and odds ratio of 8.8 (95% CI 5.9-13.1). A significant increase occurred in LOS across escalating 48 hour MTX level subgroups (p < 0.01, Table). A significant rise in ICU admissions occurred with increasing MTX levels ( < 0.01% for MTX < 2 compared to 15% with MTX > 5). Conclusions: Complications of HDMTX are significantly increased with elevated 48 hour MTX levels, particularly with levels > 1 μmol/L. [Table: see text]

e20033 Background: HDMTX is an important component of lymphoma therapy due to its central nervous system penetration. Although HDMTX can be safely administered to most patients, it can cause significant toxicity with those who have prolonged exposure to high plasma concentrations of MTX due to delayed elimination. Therefore, serum MTX concentration monitoring is still a standard approach for identifying patients at high risk of developing MTX toxicity. A majority of MTX is excreted within the first 48 hours of infusion. Higher MTX plasma concentrations at 48 hrs increase the likelihood of delayed MTX elimination. This study will assess baseline characteristics associated with high 48-hour MTX levels (≥ 1µM) which has been associated with increased risk of complications. Methods: A retrospective review of the electronic medical record was conducted to identify lymphoma patients who received HDMTX from 1/1/2002 to 12/31/18. Baseline demographics including age, gender, comorbidities, body surface area, BMI, weight and baseline chronic kidney disease (CKD) were recorded. Demographics, HDMTX dosing per protocol (3.5g/m2 vs 8g/m2), HDMTX adjusted by renal function (CrCl < 100), and ratio of MTX dose to BSA (MTX/BSA) were compared to 48 hour MTX levels. Analysis was performed in JMP 15. Results: 2553 cycles were of HDMTX were identified. There was a significant association of increasing age, (p = 0.039), male patients (p < 0.001), 8g/m2 dosing (p < 0.001), higher MTX dose (p < 0.001), MTX/BSA (p < 0.001), GFR by CKD-EPI (p < 0.001) and lower number of comorbidities (p < 0.001) with 48-hour MTX levels ≥1. There was no significant association of 48-hour MTX levels ≥1 and GFR by Cockcroft-Gault (p = 0.73), baseline CKD (p = 0.78), and renal adjusted HDMTX (p = 0.52). Multivariate analysis revealed significance for MTX/BSA, gender, BSA, GFR by CKDEPI (p < 0.001), and age (P = 0.0002). Conclusions: Hematologists should be aware that age, gender, GFR by CKD-EPI, and ratio of MTX dose to BSA are associated with elevated 48-hour MTX levels ≥1.