Median Methotrexate Research Articles

Liver fibrosis in inflammatory arthritis patients treated with methotrexate and hydroxychloroquine: A FIB-4 index analysis.

To evaluate the risk of liver fibrosis and associated factors with the non-invasive fibrosis score-4 (FIB-4) index in patients with inflammatory arthritis using methotrexate (MTX). Patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who were followed up in the rheumatology outpatient clinic, who were on methotrexate only and for whom FIB-4 index was could be calculated at methotrexate initiation and follow-up were included. The FIB-4 index was calculated according to the following formula: age (years) × AST(IU/L)/(platelet count(10 (9)/L) × √ALT(IU/L)). The patients' demographics, comorbidities, other treatments, cumulative MTX dose, and reasons for MTX cessation were assessed. For the multivariate analysis, possible factors associated with intermediate-high risk FIB-4 index at last visit were determined. A total of 107 patients were enrolled in the study, of whom 82 (76.6%) had RA and 25 (23.4%) had PsA. At the initiation of MTX, 24 (22.4%) patients had intermediate-high risk FIB-4 index. Comorbidities and the rate of ≥3-4 Charlson comorbidity index were more common in patients with intermediate-high risk FIB-4 index. A total of 37 (34.5%) patients had intermediate-high risk FIB-4 index at the last visit after median 3.6 (0.3-22.06) years follow-up. The median cumulative MTX dose was 2550 mg (1050-13.991). Cumulative MTX dose [OR 1.18 (1.01-1.33), p = .03] and diabetes mellitus [OR 4.60 (1.74-12.50), p = .002] were associated factors with intermediate-high risk FIB-4 index. The concomitant use of hydroxychloroquine (HCQ) was found to be a low-risk factor for FIB-4 index [OR 0.28 (0.10-0.78) p = .015]. The FIB-4 index is a non-invasive method that can be used in daily rheumatology practice for the evaluation and follow-up of patients who will use methotrexate. Comorbidities and cumulative MTX dose seem to be related with the risk of liver fibrosis. Concomitant use of HCQ with MTX may reduce the risk of liver fibrosis.

Sexual dysfunction in male patients treated with methorexate for arthritis: Analysis of the IIEF5 questionnaire and hormonal status

ObjectiveThe aim of this study is to evaluate the impact of methotrexate (MTX) on erectile function in male patients through the International Index of Erectile Function (IIEF5) questionnaire and hormonal dosage. MethodsMale patients affected by inflammatory arthritis (rheumatoid arthritis [RA] or psoriatic arthritis [PsA]) with good disease control and treated with chronic MTX were enrolled. Age-matched patients affected by chronic arthritis not treated with MTX were enrolled as controls. Each patient had a complete sexual hormone evaluation. IIEF5 questionnaire was administered to each patient. ResultsOne hundred and nine patients were included, 77 in the MTX group and 32 as controls. The median weekly MTX dose was 10mg (IQR 7.5) with a median MTX duration therapy of 8 years (IQR 17). The total IIEF5 score was lower in patients MTX exposed compared to the control group without a significant result. The total IIEF5 score of patients treated with MTX≥5 years was statistically significantly lower when compared to those non-MTX exposed patients (17 [IQR 15] versus 20 [IQR 7.7]; P=0.04) and compared to those treated for<5 years (17 [IQR 15] versus 20 [IQR 7]; P=0.01). A negative correlation was identified between the total IIEF5 score and MTX time exposure (r=–0.20 CI [–0.38 to –0.04]; P=0.039). MTX exposure was still associated with a lower IIEF5 score when adjusted for age (β Estimate=–2.63; CI [–5.13 to –0.13]; P=0.039). Hormonal dosage was similar in both groups for all hormones evaluated. ConclusionMTX exposure was associated with a lower IIEF5 score in male patients adjusted for age. The preliminary results need to be confirmed in larger prospective studies.

Rechallenge With High-Dose Methotrexate After Treatment With Glucarpidase in Adult Patients With Lymphoma.

Limited evidence exists regarding methotrexate (MTX) resumption after patients with lymphoma receive glucarpidase for toxic MTX levels and acute kidney injury (AKI). 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. 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. 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.

Impact of Prophylactic Trimethoprim-Sulfamethoxazole on Clearance of High-Dose Methotrexate in Adult Patients.

High-dose methotrexate (HDMTX) is an antineoplastic dosing strategy used to treat various cancers including primary central nervous system lymphoma. Trimethoprim-sulfamethoxazole (TMP/SMX) is commonly used for antibiotic prophylaxis against Pneumocystis pneumonia infections in this patient population. Significant drug-drug interactions between TMP/SMX and methotrexate (MTX) leading to adverse outcomes have been documented, primarily in adult patients taking MTX for rheumatologic conditions. This study is a single-center, retrospective, cohort study comparing outcomes in patients where TMP/SMX was held during HDMTX and patients who received concurrent prophylactic TMP/SMX during treatment. The primary end point was mean MTX level at 24, 48, and 72 hours. Secondary end points included rate of nonhematologic toxicity, rate of hematologic toxicity, median days to MTX clearance, and frequency of glucarpidase utilization. In total, 248 cycles of HDMTX were analyzed from 221 individual patients. One hundred ninety-one cycles were administered without prophylactic TMP/SMX, and 57 were administered with TMP/SMX. The median MTX level at 24, 48, and 72 hours in those without versus with prophylactic TMP/SMX was 4.30 versus 4.30, 0.29 versus 0.30, and 0.14 versus 0.15, respectively. Similarly, rates of hematologic and nonhematologic toxicities did not differ significantly between groups with the exception of neutropenia; however, there was no corresponding increased rate of neutropenic fever. Only one patient received glucarpidase and had not received TMP/SMX. Prophylactic TMP/SMX had minimal interaction with HDMTX and does not lead to increased time to clearance or clinically relevant toxicities. Prophylactic TMP/SMX can be safely administered with HDMTX in adult patients.

Use of Methotrexate for More Than 4 Years Is Not Associated with Liver Fibrosis in Rheumatoid Arthritis Patients

Background. Methotrexate is an anchor drug in the management of rheumatoid arthritis (RA). However, the association between methotrexate and development of liver fibrosis remains a subject of controversy. Non-invasive methods to assess liver fibrosis, such as the FIB-4 score, have been developed. RA patients on methotrexate therapy should be monitored for any signs of liver fibrosis. This study aims to investigate the correlation between methotrexate cumulative dose and the FIB-4 score in rheumatoid arthritis patients who received methotrexate therapy to assess the hepatotoxic effects of methotrexate.&#x0D; Methods. This cross-sectional study involved rheumatoid arthritis patients who received methotrexate therapy at Dr. Hasan Sadikin General Hospital Bandung from September 2022 to November 2022. Clinical data, laboratory tests (including platelet values and liver function test), and cumulative methotrexate doses were extracted from medical records. Data were analyzed using the Spearman correlation test.&#x0D; Results. This study involved 100 subjects aged between 22-82 years, comprising 93% women and 7% men. The median FIB-4 score was 0.73 (0.24-6.80), while the median methotrexate cumulative dose was 2477.5 mg, with a range of 1005-10400 mg. The results showed that correlation coefficient between the FIB-4 score and methotrexate cumulative dose in rheumatoid arthritis patients was -0.089 (p=0.378).&#x0D; Conclusion. There is no significant correlation between FIB-4 score and cumulative dose of methotrexate in rheumatoid arthritis patients. The use of methotrexate in RA patients over 4 years is relatively safe as it does not increase the risk of liver fibrosis.

Early Post-Infusion Clearance of High-Dose Methotrexate Predicts Delayed Methotrexate Elimination and Acute Kidney Injury

Introduction High-dose methotrexate (HDMTX) is used for the treatment of hematologic malignancies but its use may be limited by delayed methotrexate elimination and acute kidney injury (AKI). Current guidelines for glucarpidase recommend administration between 48-60 hours following the start of a 24-hour HDMTX infusion based on methotrexate concentration at 36-, 42-, or 48-hours [Ramsey 2016]. However, this may be too late to prevent permanent toxicities in cases where significant AKI develops early during infusion. Recent evidence from pig models have shown that early methotrexate measurements can predict the development of AKI [Buddington 2023]. The aim of this study is to determine whether early elimination of methotrexate (soon after completion of the infusion) is a useful “early clearance biomarker” of delayed methotrexate elimination and AKI in humans. Methods Retrospective data from two sites in Spain that collected two or more early measurements of methotrexate levels from the end of HDMTX infusion were analyzed from a larger HDMTX registry. Methotrexate half-life was calculated employing exponential decay equations and the slope of a line connecting two out of three early time points; each combination was tested, and the best performing pair is reported. Early levels were tagged according to visual exploration and k-means cluster analysis (Figure 1). Delayed methotrexate elimination was defined as a concentration above 1 μmol/L after 42-hours from the start of infusion (micromolar criterion) or above 2 standard deviations (SD) from the population mean modeled using MTXPK.org at 42- or 48-hours from the start of infusion (SD criterion). Receiver operating characteristic (ROC) curves were fitted, with their respective area under the curve (AUC) and confidence intervals for delayed methotrexate elimination and AKI. Additionally, a logistic regression model was employed to predict AKI using a base model with covariates (age, sex, HDMTX dose, and first course) plus early methotrexate clearance. Results Data from 144 patients who received 453 HDMTX courses were included. Patient characteristics were as follows: 41% females, age ranged from 1.2 to 81.5 years at the time of HDMTX infusion; diagnoses included acute lymphoblastic leukemia, 79%; non-Hodgkin lymphoma, 21%. Median methotrexate dose was 4,856.9 mg/m 2 [IQR 2,871.7 - 4,985.0], with 88% of the courses infused over 24 hours and 12% over 4 hours. Delayed methotrexate elimination was found in 41% and 6.6% of the courses according to the micromolar criterion and SD criterion, respectively. AKI developed in 29.6% of courses. Median time for the first, second and third measurements were 0.25 [IQR 0.00 - 0.71], 6.32 [IQR 5.86 - 6.69] and 12 [IQR 11.68 - 12.50] hours, respectively. Half-life estimation between the second and third early time-points predicted delayed methotrexate elimination by the micromolar criterion with an ROC AUC of 0.81 [CI95 0.76 - 0.87] or SD criterion with an ROC AUC of 0.84 [CI95 0.68 - 1.00] (Fig. 2) and any grade AKI with an ROC AUC of 0.62 [CI95 0.55 - 0.69]. After adjusting for age, sex, HDMTX dose, and first course, half-life remained statistically significant in the logistic regression model, with an odds ratio of 1.4 [CI95 1.1 - 1.8] (p &amp;lt; 0.01). The addition of half-life to the base model improved the overall performance (ANOVA, p &amp;lt; 0.01). Conclusions The half-life of methotrexate elimination soon after completing the HDMTX infusion defines an early clearance biomarker that predicts delayed methotrexate elimination and AKI. It requires only the measurement of 2 early methotrexate levels soon after completing the infusion, and thus represents a practical and applicable method to identify patients at risk who may need pre-emptive interventions like increased hydration or glucarpidase.

Use of glucarpidase (carboxypeptidase-G2) in pediatric cancer patients: 11-year experience of a tertiary center.

Methotrexate is an essential drug in the treatment of childhood cancer that is not exempt from toxicities. Glucarpidase is a drug used to reduce the toxic concentration of plasma methotrexate in patients with delayed elimination or at risk of toxicity. We describe the characteristics of a cohort of pediatric patients that received glucarpidase and analyze its role in the treatment of toxicity induced by high doses of methotrexate (HDMTX). Retrospective observational study of all pediatric cancer patients who received glucarpidase between 2012 and 2022 at a single center. Fifteen patients were treated with a single dose of glucarpidase, eleven of them presented with acute lymphoblastic leukemia and received HDMTX at 5g/m2 in 24-hour infusion. In eight patients, glucarpidase was administered during the first cycle of HDMTX. The indication in thirteen cases was acute renal failure with delayed elimination of plasma methotrexate. The median maximum creatinine was 1.22mg/dl (0.682.01mg/dl), with a median increase over its baseline level of 313%. All patients normalized renal function after glucarpidase administration, with a median methotrexate excretion time of 193 hours (42-312hours). No grade ≥2 adverse events derived from carboxypeptidase administration. Eleven patients received new doses of HDMTX in subsequent cycles, without new episodes of serious toxicity. The use of glucarpidase is effective and safe in the treatment of acute renal failure and methotrexate elimination delay in pediatric cancer patients. Further HDMTX doses may be prescribed without additional toxicities.

A pooled subgroup analysis of glucarpidase treatment in 86 pediatric, adolescent, and young adult patients receiving high-dose methotrexate therapy in open-label trials.

Delayed methotrexate elimination can occur in patients undergoing high-dose methotrexate cancer treatment. Effectiveness of glucarpidase for rapidly reducing methotrexate concentrations was shown in compassionate-use trials in patients aged 0-84years. We performed post hoc analyses of infants (≥28days to <2years), children (≥2 to <12years), adolescents (≥12 to <15years), and young adults (≥15 to <25years) from four multicenter, open-label, single-arm, glucarpidase compassionate-use trials. Patients had toxic methotrexate levels due to delayed methotrexate elimination and/or renal dysfunction, and received glucarpidase (50U/kg). The primary endpoint was clinically important reduction (CIR) in plasma methotrexate (methotrexate ≤1μmol/L at all post-glucarpidase measurements) based on high-performance liquid chromatography. Among 86 patients included in efficacy analyses, CIR was achieved by zero of one infant (0.0%), five of 16 children (31.3%), seven of 24 adolescents (29.2%), and 26/45 young adults (57.8%). Median methotrexate reduction was 98.7% or higher in each group 15minutes post-glucarpidase. Patients with pre-glucarpidase methotrexate less than 50μmol/L (35/42, 83.3%) were more likely to achieve CIR than those with methotrexate 50μmol/L or higher (1/37, 2.7%). The most common treatment-related adverse event was paresthesia, occurring in three adolescents (4.5%) and six young adults (5.2%). No other treatment-related adverse event occurred in 5% or higher of any age group. After accounting for pre-glucarpidase methotrexate levels, glucarpidase efficacy at inducing CIR in pediatric/young adult patients was consistent, with efficacy observed in the overall study population (i.e., patients aged 0-84), and no unexpected safety findings were observed. These findings demonstrate glucarpidase (50U/kg) is an effective and well-tolerated dose for pediatric, adolescent, and young adult patients.

Safety and Effectiveness of a Pharmacist-Driven High-Dose Methotrexate Monitoring Protocol at an Academic Medical Center

Introduction: High-dose methotrexate (HD-MTX) requires extensive monitoring and implementation of supportive care strategies to prevent associated toxicities. Although monitoring protocols for MTX vary across institutions, standardized supportive care measures can improve treatment outcomes. The purpose of this study was to evaluate the impact of a pharmacist-driven monitoring protocol on management of patients with delayed MTX elimination.Methods: This was a single-center, retrospective analysis that included hospitalized adult cancer patients receiving HD-MTX therapy (≥ 1 g/m 2). The study consisted of a pre-protocol group (August 2014 to July 2017) and a post-protocol group (August 2017 to August 2020). Patients were included in the analysis more than once if they had a repeat but separate hospital encounter. The primary outcome measure was to compare the rate of appropriate leucovorin dosage adjustments, defined by adherence to institution-specific HD-MTX monitoring guidelines, before and after protocol implementation (Table 1). Secondary outcomes included MTX concentrations at 24, 48, and 72 hours; time to MTX elimination; evidence of delayed MTX clearance; urine pH; length of stay; drug-drug interactions; and incidence of toxicities. Group comparisons for continuous data were made using Mann-Whitney U test and Chi-square or Fisher's exact test was used for categorical data. A p-value of < 0.05 was used to indicate significance.Results: Of 272 hospital encounters initially identified, 82 pre-protocol encounters and 59 post-protocol encounters were included in the analysis. Thirty-five percent of patient encounters in the pre-protocol group were excluded as a result of inappropriately timed methotrexate levels compared to only 9% in the post-protocol group, indicating improved MTX monitoring after protocol implementation. Baseline characteristics are summarized in Table 2. The most common malignancy was primary CNS lymphoma (53.8%) followed by non-Hodgkin lymphoma (28.8%). HD-MTX monotherapy was the most common regimen used in the pre-protocol group (57.1%) whereas combination therapy with rituximab +/- procarbazine was the most common regimen used in the post-protocol group (62.5%). Twenty-one encounters in the pre-protocol group and 22 encounters in the post-protocol group required leucovorin dose escalations at 24, 48, or 72 hours (Table 3). Following the implementation of the pharmacist-driven protocol, the rate of appropriate leucovorin dose adjustments increased significantly from 61.9% to 90.9% (p = 0.034). The median methotrexate concentration at 48 and 72 hours was higher in the post-protocol group when compared to the pre-protocol group. [0.22 µM/L vs.0.18 µM/L (p = 0.019) and 0.1 µM/L vs. 0.07 µM/L (p < 0.001), respectively]. Median time to methotrexate elimination was slightly longer in patients managed according to the MTX protocol [73 hours vs. 72.4 hours, p = 0.022] with higher rates of delayed clearance noted in these patients [18 (30.5%) vs. 16 (19.5%), p < 0.001]. There were no statistically significant differences in length of stay, urine pH, or drug-drug interactions between the two groups during methotrexate therapy (Table 4). However, a lower percentage of concomitant drug interactions with methotrexate were identified after protocol implementation, suggesting improved drug interaction screening [29 (49.2%) vs. 53 (64.9%), p = 0.857]. Rates of toxicities are shown in Table 5. The post-protocol group experienced a higher incidence of any-grade hyperbilirubinemia [20 (33.9%) vs. 18 (22%), p = 0.019], encephalopathy [10 (17%) vs. 5 (6.1%), p = 0.043], and grade ≥ 3 neutropenia [4 (6.8%) vs. 4 (4.9%), p = 0.009]. These differences in toxicity rates may in part be due to more frequent use of multi-agent chemotherapy in the post-protocol group and greater number of MTX cycles administered to these patients. The incidence of nephrotoxicity was similar in both groups (6 (7.3%) vs. 5 (8.5%), p= 0.493) and in line with previous reports.Conclusion:The implementation of a pharmacist-driven HD-MTX monitoring protocol improved optimal timing of MTX serum concentrations, resulted in a statistically significant improvement in the rate of appropriate leucovorin dose escalations, and led to enhanced detection of drug interactions. These findings demonstrate the important role pharmacists can play in dosing and monitoring high-risk regimens. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Polymorphism in Gene for ABCC2 Transporter Predicts Methotrexate Drug Survival in Patients with Psoriasis.

Background and Objectives: Methotrexate is widely prescribed for the treatment of moderate-to-severe psoriasis. As drug survival encompasses efficacy, safety, and treatment satisfaction, such studies provide insights into successful drug treatments in the real-life scenario. The objective was to define methotrexate drug survival and reasons for discontinuation, along with factors associated with drug survival, in a cohort of adult patients with moderate-to-severe plaque psoriasis. Materials and Methods: Data on methotrexate treatment were extracted from our institutional registry. Drug survival was estimated by Kaplan–Meier analysis, and predictors of drug survival were analyzed by Cox proportional hazards regression. Results: We included 133 patients treated with methotrexate. Due to significant effects of the year of treatment initiation, drug survival analysis was performed for 117 patients who started methotrexate in 2010 or later. Median methotrexate drug survival was 11.0 months. Overall, 89% of patients discontinued treatment, with over half of these (51%) due to lack of efficacy. Significantly longer drug survival was seen for patients who discontinued treatment due to lack of efficacy versus drug safety (p = 0.049); when stratified by sex, this remained significant only for women (p = 0.002). The patient ABCC2 rs717620 genotype was significantly associated with drug survival in both univariate log-rank and multivariate Cox regression analyses, with variant T allele associated with longer drug survival (hazard ratio, 0.606; 95% confidence interval, 0.380–0.967; p = 0.036). Conclusions: We have identified the novel association of patient ABCC2 rs717620 genotype with methotrexate drug survival. This pharmacogenetic marker might thus help in the management of psoriasis patients in daily practice.

Single nucleotide polymorphisms associated with methotrexate-induced nausea in juvenile idiopathic arthritis

BackgroundContext: Methotrexate (MTX) is a cornerstone in the treatment of juvenile idiopathic arthritis (JIA). MTX treatment is commonly associated with nausea. Large inter-individual variation exists in the level of MTX-induced nausea, possibly due to genetic factors.Purpose: To investigate whether MTX-induced nausea was associated with single nucleotide polymorphisms (SNPs) in genes encoding MTX-transporter proteins, a MTX metabolizing enzyme and a nausea receptor.FindingsMethods: Children aged ≥9 years treated with MTX for JIA were eligible. MTX-induced nausea was registered by the children’s completion of a nausea diary (min. 7 days) and the parents’ completion of the MTX intolerance severity score (MISS). The selected SNPs were: SLCO1B1 (rs4149056; rs4149081), SLCO1B3 (rs2117032), SLC19A1 (rs1051266), ABCC2 (rs2273697; rs3740066; rs717620), ABCB1 (rs2032582; rs1045642), MTHFR (rs1801131, rs1801133), HTR3A (rs1062613; rs1985242; rs1176713) and HTR3B (rs1176744).Result: Enrolled were 121 JIA patients (82 girls: 39 boys) with a median age of 13.3 years (IQR: 11.3–15.1). The median MTX dose was 9.7 mg/m2/week (IQR: 9.0–10.9). The median MTX treatment duration prior to enrolment was 340 days (IQR: 142–766). The SNP analysis was available for 119 patients. MTX intolerance was associated with the genotype distribution of rs1801133 (MTHFR) (p = 0.02). There was no additive effect of the minor alleles for any of the selected SNPs, nor any significant haplotype associations.ConclusionSummary: MTX-induced nausea may be influenced by genetic polymorphisms in a MTX metabolizing enzyme (rs1801133; MTHFR).Implications: Further analyses involving inclusion of larger cohorts are needed to understand the impact of SNPs on MTX-induced nausea in JIA.

Primary and Secondary Central Nervous System Lymphoma: Outcomes from Houston Methodist Cancer Center

Introduction Primary Central Nervous System Lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin Lymphoma (NHL), with diffuse large B-cell Lymphoma (DLBCL) reported in 90% of cases. Secondary CNS lymphoma (SCNSL) may occur as an isolated recurrence of previously diagnosed NHL or occur simultaneously as a manifestation of systemic disease. Comparative data on survival in treated PCNSL and SCNSL in the real-world setting is lacking. We present a retrospective analysis of outcomes in PCNSL and SCNSL patients treated at the Houston Methodist Cancer Center. Methods We retrospectively identified patients with a diagnosis of PCNSL or SCNSL from 2015 to 2020. Data collected included age, race, sex, diagnosis (PCNSL, SCNSL), histology and immunohistochemistry, treatment type (chemotherapy, radiation), transplant rates as well as outcomes (alive/dead). Responses were classified as complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Survival was analyzed using Kaplan-Meier methodology, and log-rank tests were used to compare survival distributions. P &amp;lt; 0.05 was considered statistically significant. Results There were 50 patients with CNS lymphoma identified between 2015 and 2020; 68% were PCNSL. Out of 43 with available pathology, 2 patients were T-cell lymphomas and 41 DLBCL. Out of the DLBCL cases, 95% of cases expressed CD20 while close to 60% were positive for MUM1, bcl-2 and bcl-6. Less than 15% of cases were positive for CD10. CD30 was positive in 17% of cases. Cerebral hemispheres (76%) was the most common organ involved, followed by ocular (8%), intraventricular space (6%) and cerebellum (6%). Median age at diagnosis was 67 years; male to female ratio was 1.27. Caucasian (62%) and Hispanic (24%) were most common ethnicities. Epstein-Barr Virus was positive in 14% of patients (5 in PCNSL and 2 in SCNSL). One patient with SCNSL had human immunodeficiency virus. The median follow-up time was 9.1 months. Multiagent chemotherapy including high dose methotrexate (MTX), cytarabine and rituximab was given to 48% of the patients while 32% received high dose MTX alone plus rituximab. From the latter group, five out of sixteen patients received temozolomide. Other regimens were used in 6% of the cases. Median dose of MTX in a multiagent chemotherapy regimen was 2.5gr/m2 and 2.25gr/m2 when used alone or with temozolomide. Median number of cycles given was 3. Radiation therapy alone was given to 8% of cases. Three patients did not receive treatment. For patients with PCNSL, overall response rate (ORR) was 82.8% (CR 65.5%, PR 13.8%, SD 3.4%). ORRs were similar between multiagent chemotherapy and methotrexate alone (+/- temozolomide) with 86.7% and 83.3% respectively. ORR for SCNSL was 57.1% (CR 35.7%, PR 21.4%); only 1 patient was treated with MTX alone. Further lines of therapy were required in 9.3% of patients. Consolidation with whole brain radiation was given in 22% of the cases (29.4% for PCNSL and 6.3% for SCNSL). Autologous stem cell transplant was performed in 10% of the patients (2 PCNSL, 3 SCNSL). Overall survival for patients with PCNSL was 74.8 months and 10.1 months for SCNSL (p=0.0444) (Figure 1). Survival was not significant between patients receiving multiagent chemotherapy and MTX alone or in combination with temozolomide (3-year OS 57.3% vs 73.4%, p= 0.5652) (Figure 2). Conclusion Most patients diagnosed with PCNSL are non-germinal center DLBCL. Median MTX dose was lower than 3gr/m2 with excellent ORR of over 80% in PCNSL. Response rates were lower in SCNSL and in general, patients with PCNSL had better outcomes. Survival did not differ significantly between regimens, suggesting that a lower intensity therapy may perform similarly to multiagent chemotherapy. These results need to be confirmed by prospective studies. Disclosures No relevant conflicts of interest to declare.

Survival and Patient-Reported Outcomes of Older Adults with Primary Central Nervous System Lymphoma on Low-Dose Lenalidomide

Introduction: Management of primary CNS lymphoma (PCNSL) in patients age &amp;gt;70 represents a significant challenge. In most clinical series, median OS for PCNSL patients age &amp;gt;70 is &amp;lt;1 year (Mendez et al., Neuro-Oncology 2018). Since late 2011, our group has used low-dose lenalidomide as maintenance therapy in older patients with newly-diagnosed PCNSL who had &amp;gt;partial response (PR) to induction chemotherapy or salvage chemotherapy for relapsed disease. A preliminary report by our group supported the feasibility and efficacy of low-dose lenalidomide maintenance for 13 older patients with PCNSL, in lieu of consolidation with radiation or high-intensity chemotherapy (Vu et. al., BJH 2019).Here, we present the outcomes of 22 consecutive older patients with PCNSL (inclusive of updated outcomes on the original 13 patients) treated with low-dose lenalidomide after achieving &amp;gt;PR following induction chemotherapy. In addition, we provide a first report on the impact of maintenance low-dose lenalidomide on quality of life (QOL), overall functioning, and symptom burden. Methods: We performed a retrospective analysis of consecutive patients age &amp;gt;65 years with PCNSL, who achieved &amp;gt;PR to induction methotrexate/rituximab+temozolomide (MTR) chemotherapy and were subsequently treated with low-dose lenalidomide maintenance (5-10 mg/dose) in PR1/CR1. We determined their clinical characteristics, progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier. In addition, we obtained correlative data on QOL and symptom burden on a representative sample of older PCNSL patients who were treated with low-dose IMiDs over the course of &amp;gt; 2 months, via the European Organization of Research and Treatment of Cancer (EORTC) QOL questionnaire (QLQ)-C30. Our study was approved by the University of California San Francisco Institutional Review Board with patient informed consent. Results: The median age at diagnosis of the 22 consecutive older newly-diagnosed PCNSL patients was 77 (range 64 - 86). Median Karnofsky Performance Status was 70. Twenty patients received induction MTR (2 received M-R) without consolidative dose-intensive chemotherapy, autologous stem cell transplant, or whole brain irradiation. The median methotrexate dose was 2.5 gm/m2 (range 0.5 - 8). With median follow-up of 47 months, median time on low-dose lenalidomide maintenance was 14 months. Median PFS was 84 months, and median OS has not been reached. (Figure 1). At progression, patients received methotrexate followed by lenalidomide or pomalidomide. Thus far, there have been 3 deaths: one due to PCNSL, one by myocardial infarction, 4 years after discontinuation of lenalidomide, and one without definitive cause. To assess the tolerability of low-dose lenalidomide (and/or pomalidomide) in this population, we determined patient-reported outcomes with respect to quality of life, as measured by the EORTC QLQ-C30. We summarize our findings in Figure 2 on 8 consecutive PCNSL patients age &amp;gt;70 that received maintenance IMiD therapy for at least 2 months. Seven of the 8 patients were treated with maintenance low-dose lenalidomide for a median of 11 months, and one patient was on maintenance pomalidomide (1-2 mg/day) for a total of 76 months. Overall low-dose IMiDs were well-tolerated: mild-to-moderate fatigue and insomnia were the two most commonly reported symptoms. Conclusions: Our experience suggests that low-dose lenalidomide as maintenance therapy after induction chemotherapy in older patients with PCNSL may result in improved PFS and OS. Importantly, our data suggest that QOL and overall functioning as measured by the EORTC QLQ-C30 was comparable, if not better, than QOL as assessed for patients receiving high dose methotrexate-based therapy, autologous stem cell transplant, whole brain radiation therapy, and/or blood brain barrier disruption (Doolittle et. al., Neurology 2013). In conclusion, based on this preliminary assessment, maintenance low-dose lenalidomide (and pomalidomide) appear to be well-tolerated in older PCNSL, with patients reporting good quality of life, low symptom burden, and overall good level of functioning. Survival outcomes remain encouraging. A phase I trial in newly-diagnosed, non-transplant eligible PCNSL that evaluates combination nivolumab with lenalidomide, both as a component of induction therapy and as low-dose lenalidomide maintenance, is in development via Alliance (A051901). Disclosures Rubenstein: Kymera: Research Funding. OffLabel Disclosure: Low-Dose Lenalidomide as Maintenance in Older Patients with Primary CNS Lymphoma

Efficacy of methotrexate in polymyalgia rheumatica in routine rheumatology clinical care.

Current guidelines recommend methotrexate (MTX) as a glucocorticoid-sparing agent in patients with polymyalgia rheumatica (PMR) who relapse or suffer glucocorticoid adverse effects, although there is no level 1 evidence to support this recommendation. To review the effect of MTX in PMR on inflammation and glucocorticoid dose. Patients with PMR from rheumatology outpatient clinics at two tertiary centres were identified. A structured case note review was conducted for patient characteristics at diagnosis and medications including glucocorticoid and MTX use. There were 70 patients, 61% female; mean (range) age of 70 (51-87) years. At the time of diagnosis, median (±interquartile range) erythrocyte sedimentation rate (ESR) was 38.5 (26-74) mm/h and C-reactive protein (CRP) 34.5 (6-74 mg/L) with median initiating prednisolone dose of 15 mg (range 5-60 mg). MTX was prescribed in 22 (31%) patients. Mean disease duration at MTX initiation was 2.5 years (1-7 years), with median (range) MTX dose of 10 mg (5-20 mg). At MTX initiation, median (interquartile range) (±standard deviation) ESR was 33 (13-60 mm/h) and CRP 19 (8-42 mg/L). Reasons for commencing MTX were disease relapse (34%) or inability to wean prednisolone dose (66%). Six months after MTX initiation, there was significant reduction in ESR (P = 0.012), CRP (P = 0.0003) and prednisolone dose (P < 0.0001). Eleven (50%) patients stopped MTX, five due to controlled PMR, and six due to adverse effects. In this study of PMR patients in tertiary care, 31% were co-prescribed MTX, after prolonged disease duration. MTX was associated with improved inflammatory activity and reduced prednisolone dose, with a relatively high risk of adverse events.

Six-month flare risk after discontinuing long-term methotrexate treatment in patients having rheumatoid arthritis with low disease activity.

We investigated the disease flare rate in patients with rheumatoid arthritis (RA) who achieved low disease activity following long-term methotrexate (MTX) treatment and the factors related to flare. This retrospective longitudinal cohort study included patients with RA and low disease activity who were exposed to MTX for >10years. Disease flare was defined as an increase in Disease Activity Score of 28 joints (DAS28) of >1.2 within 6months of discontinuation of MTX. Logistic regression analysis was performed to identify the factors associated with flare. In total, 97 patients with RA were included in the study. The mean baseline DAS28 was 1.96±0.56. The median cumulative MTX dose was 11.7g; the median duration of exposure to MTX was 19years. Following MTX discontinuation, flare occurred in 43 (44.3%) patients; the median time to flare was 99 (28-168) days. According to univariate logistic regression analysis, C-reactive protein, erythrocyte sedimentation rate (ESR) at discontinuation, the average ESR in the 6months before discontinuation of MTX, a weekly dose of MTX before discontinuation, and use of other conventional synthetic disease-modifying antirheumatic drugs were associated with a higher risk of disease flare. In multivariable analysis, a weekly dose of MTX before discontinuation (odds ratio 1.014; 95% CI 1.014-1.342; P=.031) was significantly associated with flare risk. Among patients with RA who achieved low disease activity with long-term treatment with MTX, more than half remained flare free after MTX discontinuation. A higher MTX dose before discontinuation was associated with a high flare risk.

THU0190 METHOTREXATE THERAPY IS NOT ASSOCIATED WITH AN INCREASED RISK OF LIVER FIBROSIS ASSESSED BY THE FIBROSIS-4 INDEX

Background: Methotrexate (MTX) holds a unique place in the management of rheumatoid arthritis (RA) given its favorable balance between efficacy and safety. However, conflicting data still suggest a potential risk of MTX-induced long-term liver fibrosis. The fibrosis-4 (FIB-4) index was originally proposed as a simple and non-invasive marker of liver fibrosis in HIV/HCV co-infection. In patients with RA, FIB-4 values have been correlated to the amount of histologic liver lesions, suggesting that this index may be a valuable marker to diagnose liver disease in RA patients (1). Objectives: To estimate the amount of scarring in the liver with the FIB-4 index in RA patients on maintenance therapy with MTX. Methods: We performed a cross-sectional study including successive RA patients hospitalized in the Rheumatology department of Cochin Hospital for a 12-month period. Data on liver function, disease activity, hepatotoxic and cardiovascular risk factors were systematically collected. The FIB-4 index was calculated according the following formula: (age(years) × AST(U/L)/platelet (PLT) (109/L) × √ALT(U/L)). Using a lower cutoff value of 1.45, a FIB-4 score 3.25 had a 97% specificity and a positive predictive value of 65% for advanced fibrosis (2). Results: We included 170 patients with established RA: 141 (83%) were women, the mean age was 59+/-12 years and the mean disease duration was 15+/-11 years. Positive rheumatoid factors and anti-CCP antibodies were detected in 134 patients (79%). 102 patients (60%) were treated with methotrexate, with a mean dose of 10.0+/-8.4 mg/week, a mean treatment duration of 9.5+/-10.3 years and a cumulative dose of 5.3+/-5.1g. 23 patients (13.5%) received conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) other than MTX, 112 (66%) corticosteroids (99 with a dose 3.25. The FIB-4 was low and not significantly different between patients receiving MTX, patients previously treated with MTX and patients never treated with MTX (median 1.1, 1.25 and 1.18, respectively, p=0.709). This result was not modified after adjustment on treatments with other csDMARDs, corticosteroids, and bDMARDs. No correlation was observed between FIB-4 values and the cumulative dose of MTX (r=0.09, p=0.271). The FIB-4 index was low and similar between patients receiving cumulative MTX doses 1.45 (median cumulative MTX dose 5.5g vs. 3.5g, p=0.302). No association was detected between the FIB-4 index and parameters of disease activity (DAS28, ESR and CRP levels), the body mass index, traditional cardiovascular risk factors and metabolic syndrome. Conclusion: RA patients with long-term maintenance MTX therapy have low FIB-4 values suggesting that MTX is not associated with an increased risk of advanced liver fibrosis.

Evaluation of high-dose methotrexate serum concentration requirement for discharge.

e19204 Background: Methotrexate (MTX) is used in high doses for the treatment of ALL, lymphoma, and metastatic breast cancer with CNS involvement. To avoid drug accumulation and mitigate toxicities caused by delayed clearance, patients (pts) are usually admitted to the hospital and standard supportive care with IV hydration, urinary alkalization, and leucovorin is provided and adjusted based on daily levels. Historically, a serum methotrexate level ≤ 0.05 µmol/L has been used to declare clearance and an ideal level for discharge based on studies conducted in the 1970s. We conducted a retrospective review in 2018 to identify frequency of supportive dose escalations required with MTX levels &gt; 0.05 µmol/L. In 69 pts, 4 patients demonstrated delayed renal clearance and required supportive care escalations but all occurred at MTX levels &gt; 0.3 µmol/L. This led to a proposed pilot discharge process once MTX was &lt; 0.3 µmol/L to confirm the safety of earlier discharge. Methods: A retrospective chart review of pts with baseline CrCl ≥60 who received HD MTX between 07/2018 – 08/2019. Data collection included diagnosis, MTX discharge level, supportive care at discharge including PO Leucovorin and PO sodium bicarbonate and number of days supply, post-discharge complications (AKI, mucositis, fever, others). Primary outcome was the number of patients who required inpatient or outpatient supportive care for acute complications after being discharged with a methotrexate level ≥ 0.1 µmol/L. Descriptive statistics were used. Results: A total of 41 pts were included. Median age was 55 yrs (32-78), 25% were male. 73% were treated for DLBCL, median dose of MTX was 3500 mg/m2. Median MTX level at the time of discharge was 0.16 µmol/L (0.1-0.3 µmol/L). 12 pts were discharged with PO Leucovorin and 15 pts were discharged with both Leucovorin and PO Sodium bicarbonate with an average of 2 day’s supply. 1 acute complication of neutropenic fever requiring admission for inpatient antibiotics occurred which was felt to be unrelated to MTX level at discharge. Conclusions: This pilot suggests that pts can be safely discharged with MTX levels upto 0.3 µmol/L without acute complications. Results of this study will be used to a develop a standardized protocol outlining criteria for early discharge in select pts with MTX levels &lt; 0.3 µmol/L to reduce length of stay, cost of hospitalization and improve patient satisfaction. [Table: see text]

Outcome of methotrexate treatment for ectopic pregnancies among obese women

ObjectiveSingle dose administration of methotrexate (MTX) is considered the first line of treatment in selected patients with an ectopic pregnancy (EP). However, data regarding MTX efficacy among obese patients is limited. We sought to investigate the efficacy of MTX single dose regimen among obese patients Material and methodsA retrospective cohort study conducted at a gynecology department in a tertiary teaching hospital, between January 2010 and December 2018, including women diagnosed with an EP and treated by a single-dose regimen of MTX. We compared success rate and gestation characteristics between obese and non-obese women. ResultsOverall, 195 women were treated with single-dose intramuscular MTX for EP during the study period. Of those, 31 women (15.9%) were obese (BMI ≥ 30 kg/m2) and the rest 164 (84.1%) were of normal body weight. Median MTX dosage for the obese group was 95 milligrams (IQR 91-104) vs. 83 milligrams (IQR 78-87) for the non-obese group. Treatment success rate of the overall cohort was 66.6% (130/195) and treatment success rate of single-dose MTX was comparable between the obese and non-obese groups (64.5% vs. 67.0%, p = 0.78). Obese patients were older as compared to non-obese (median age 33 vs. 29, p = 0.03). In multivariate logistic regression analysis, percentage hCG change from day 1 to day 4 was the only factor associated with treatment success (aOR 1.02; 95%CI 1.01, 1.04, p < 0.001). ConclusionSingle-dose MTX treatment among obese patients diagnosed with ectopic pregnancy led to similar success rates as compared to non-obese patients.

Outcomes of older patients with primary central nervous system lymphoma treated in routine clinical practice in the UK: methotrexate dose intensity correlates with response and survival.

Data on older patients with primary central nervous system lymphoma (PCNSL) are scarce. Comorbidities and performance status frequently compromise outcomes in this group. Medical records for consecutive patients ≥65years (n=244) with PCNSL diagnosed 2012-2017 from 14 UK centres were retrospectively reviewed. Of these 192 patients received methotrexate (MTX)-based treatment. Patients were categorised based on clinician's treatment choice into 'palliative' (n=52), 'less intensive: MTX±rituximab±alkylators' (n=74) and 'intensive: MTX/cytarabine combinations' (n=118) groups. Complete remission (CR) rate, two-year progression-free survival (PFS) and overall survival (OS) rates were 49%, 11% and 24% for the less intensive and 69%, 40% and 50% for the intensive groups. Treatment-related mortality (TRM) was 6·8% for MTX-treated patients. Median MTX cumulative dose was 8·8g/m2 (range 1·5-21) over a median of three cycles. Higher relative dose intensity of MTX (MTX-RDI) was associated with improved PFS and OS in both groups adjusting for age, Eastern cooperative oncology group (ECOG) score and baseline parameters. Two-year PFS and OS for patients receiving four or more induction cycles followed by consolidation (n=36) were 65% and 70% respectively. Older patients completing MTX-based induction and consolidation had clinical outcomes similar to those in younger cohorts. These retrospective data suggest that maximising MTX-RDI and delivering consolidation in a subgroup of older patients may improve clinical outcomes.

Application of blood purification in acute lymphoblastic leukemia pediatric patients with hypermethotrexemia accompanied with acute kidney injury

Objective To investigate the efficacy of blood purification for acute lymphoblastic leukemia pediatric patients with high-dose methotrexate(MTX)-induced hypermethotrexemia and acute kidney injury (AKI). Methods The clinical data of 50 acute lymphoblastic leukemia pediatric patients with hypermethotrexemia (the 45th hour MTX blood concentration >20 μmol/L) and AKI who were admitted to Beijing Children's Hospital Capital Medical University from May 2010 to August 2018 were collected. After the treatment of blood purification, the declining rate of MTX concentration, the incidence of drug-related side effects and the clinical transition were analyzed retrospectively. Results The median MTX blood concentration at the 45th hour after high-dose MTX chemotherapy was 31.5 μmol/L (20.0-80.3 μmol/L). After blood purification treatment, 48 patients (96%) survived, 1 patient (2%) died, and 1 patient (2%) gave up treatment. It costed 10.0 days (7.0-15.0 days) to decline the MTX concentration to the normal level by using blood purification. The median time of purification was 32.5 hours (2.0-168.0 hours), and the days of dialysis were 3.0 days (1.0-9.0 days). The AKI occurred in approximately 96% (48/50) of patients, which was the main side effect. The time of declining the high MTX concentration to the normal was positively correlated with the increase times of serum creatinine (r = 0.371, P = 0.009) and urea nitrogen (r = 0.486, P = 0.001), and the value of the alanine aminotransferase (r = 0.364, P = 0.010) and gamma glutamyl transpeptidase (r = 0.344, P = 0.010), and the days of dialysis (r = 0.532, P < 0.01), but there was no relationship with the 45th hour MTX blood concentration (r=0.110, P = 0.248). The reduction of MTX blood concentration from the 45th hour to the 69th hour after high-dose MTX chemotherapy was negatively correlated with the increase times of urea nitrogen (r = -0.336, P = 0.009) and serum creatinine (r = -0.260, P = 0.035). Conclusion When the MTX blood concentration of patients with hypermethotrexemia and AKI couldn't be declined to the normal level by using high-dose leucovorin, hydration and alkalization, and without the effective detoxification drug (carboxypeptidase G2), they should be offered blood purification, especially continuous renal replacement therapy as soon as possible, which can reduce the blood concentration of MTX quickly and decrease the incidence of side effects effectively. Key words: Leukemia, lymphoblastic, acute; Methotrexate; Blood purification