MTX Dose Research Articles

High-dose methotrexate and rituximab induction regimen in immunocompetent patients with primary CNS lymphoma: a retrospective single-center study of survival predictors.

Primary Central Nervous System Lymphoma (PCNSL) is an aggressive tumor that is confined to the CNS. Although the provision of high-dose methotrexate (HD-MTX) has remarkably improved outcomes in PCNSL patients, the optimal treatment regimens and standard MTX dose for induction therapy have been largely controversial. Herein, we sought to explore the impact of adjuvant rituximab and different dosages of induction HD-MTX on survival outcomes of immunocompetent patients with PCNSL. In this study, we examined patients with PCNSL treated at a single NCI-designated comprehensive cancer center to evaluate their survival outcomes. We conducted a retrospective analysis of 51 immunocompetent patients with PCNSL who received their induction chemotherapy at the University of Alabama at Birmingham (UAB) between 2001 and 2019. Only adult patients with a confirmed diagnosis of PCNSL who had either HD-MTX alone or in combination with rituximab were included. Patients' demographics, clinical characteristics, and survival data were collected and analyzed. There is no significant difference in survival among patients who received MTX alone versus MTX plus rituximab (HR = 0.996 (95% CI: 0.398-2.493), p = 0.994). Lower doses of MTX were associated with worse survival outcomes (HR = 0.680 (95% CI: 0.530-0.872), p = 0.002); however, this difference in survival was not significant when adjusted to age (HR = 0.797 (95% CI: 0.584-1.088), p = 0.153). Our experience challenges the role of rituximab in PCNSL during induction therapy. Our study also highlights the shorter survival in elderly patients with PCNSL which can be related, to some extent, to the relatively lower doses of HD-MTX. There is an unmet need to establish a consensus on the most effective upfront regimen in PCNSL through prospective studies.

Protective Effect of Selenium against Methotrexate Induced Hepatotoxicity

Introduction: The liver is the largest internal organ by percent weight in the human body and has crucial functions, including cholesterol production, intermediary metabolism, hormone synthesis, bile and urea production and drug detoxification. Objectives: The main objective of the study is to analyse the Protective effect of selenium against methotrexate induced hepatotoxicity in mice. Material and methods: This descriptive study was conducted in Jinnah Hospital Lahore during 2020. Selenium and all chemical reagents of analytical grades were purchased from Sigma Chemical Co. (St. Louis, Mo, USA). The dose of MTX diluted in water (50% 1ml/kg of body weight of Mice were applied twice a week for six weeks to induced hepatocellular injury determined by liver function tests. The mice were maintained under pathogen-free conditions with air conditioning, a 12-hr light/12-hr dark cycle, and %55 humidity. Results: Results shows that a significant increase in serum enzymes (ALT, AST, ALP) and significant decrease in total protein was observed in all groups receiving MTX for the induction of hepatic injury. Mice receiving combination therapy of selenium along with MTX shows a time course recovery towards normalcy. The highest value of ALT (94.83 IU/L), AST (73.21 IU/L) and ALP (157 IU/L) were recorded in Mice receiving MTX for hepatic injury. The lowest values (63.67, 51.49 and 139.95 IU/L) was recorded in group treated with MTX+ Se (200mg/kg b.w) but both the groups differed non significantly and shows the same trend but a decreasing trend in serum enzymes (ALT 32.85%), (AST 29.67%) and (ALP 11.40%). Conclusion: It is concluded that selenium supplementation in MTX treated rats elicited a reduction in the toxic effects of the pesticide by improving the studied parameters, which was confirmed by the biochemical analysis of serum.

Using FibroScan to Assess for the Development of Liver Fibrosis in Patients With Arthritis on Methotrexate: A Single-center Experience.

Methotrexate (MTX) is often the primary medication to treat various rheumatic diseases (RDs) because of its low cost and its demonstrated efficacy in controlling disease activity. However, a concern has been the potential for hepatic fibrosis associated with long-term MTX usage. This study investigated the association between cumulative MTX intake and development of liver fibrosis by utilizing noninvasive transient elastography (FibroScan). All patients with inflammatory arthritis treated with MTX were offered screening with FibroScan. A certified technician measured liver stiffness after patients adhered to a fast. Relevant clinical information was obtained by patient survey and medical records review. The population was divided into quartiles based on participants' cumulative dosage of MTX. Five hundred twenty patients with RD were included in this study. The prevalence of stages F3 or F4 liver fibrosis was 13.3% in the control group and 12.7% in the entire sample. Compared with subgroup 1 (control with cumulative MTX exposure of ≤ 499 mg), MTX subgroups 2 to 4 were not significantly correlated with higher FibroScan scores (P = 0.82, 0.59, and 0.18, respectively). In multivariable linear regression analysis, statistically significant factors for liver stiffness were BMI, waist circumference, male sex, and age. No significant correlation between the cumulative MTX dosage and liver stiffness, even at high MTX doses, was observed. The analyses showed significant correlations between the FibroScan score and BMI. These findings were reassuring in that current rheumatology practice appears to be safe and effective in screening for liver fibrosis in patients on long-term low-dose MTX therapy.

40 Multidose methotrexate treatment of tubal ectopic pregnancies with high initial β-human chorionic gonadotropin over 5,000 mIU/mL

Introduction and aims of the study: To investigate the success, fertilization and side effect rates of individualized multidose methotrexate (MTX) regimen in patients with high initial serum hCG (>5000mIU/mL). Methods: 90 patients with tubal pregnancies were included to this prospective case-control study that consists of three groups: Single-dose (n=40), double-dose (n=10) and multi-dose (n=40) regimens. Patients were followed between 2014-2020 in a dedicated referral center for management ectopic pregnancies. Patients with serum βhCG>5,000 mIU/mL received individualized multiple doses of Mtx (1mg/kg) with tailored folinic acid rescue taking the patient's clinical course into consideration. Results: The success rate of single-, double- and multi-dose MTX regimens were 90%, 80% and 82.5%, respectively. Mean BhCG level was found as 11631.3±7577.3 mIU/mL (range:5042-31114). The changes in before and after MTX injections can be seen in Figure-1. Twelve patients were conceived after the multidose regimen; 10 of those have delivered healthy babies and remaining 2 have ongoing pregnancy. There was no recurrent ectopic pregnancy observed. In multidose protocol,10 patients (25%) had ectopic mass size larger than 30mm with mean size of 35.1±2.77mm and success rate of 80% (n=8/10; failures had 35 and 40 mm). Fetal pole was seen in 13 patients (32.5%) and success rate was 69.2% in patients with visible fetal pole. Free intraperitoneal fluid was observed in 17 patients (42.5%, mean: 28.59±14.45mm). Among those, the success rate was 82.35% (n=3). Side effects in multidose protocol were observed in 23 of 40 (57.5%); 20(50%) of them exhibited mild symptoms and all resolved spontaneously, whereas 3 patients (7.5%) had a severe symptom, where all were resolved under appropriate medical treatment. A second dose of MTX was needed in 12.5% of patients who underwent to single-dose protocol. Conclusions: Multiple-dose Mtx treatment for ectopic pregnancies with high initial hCG is safe and effective alternative to elective surgery.

Medical Management of Unruptured Ectopic Pregnancy with Methotrexate and its Outcome

Ectopic pregnancy (EP) is a classic gynecologic emergency and remains a major cause of maternal morbidity and mortality. The combination of serum beta hCG titre and transvaginal sonography have supplanted physical examination findings as the most accurate diagnostic tool for determining the site of ea rly gestation. Early diagnosis by transvaginal scan has facilitated the move towards medical therapy with methotrexate for most women with unruptured ectopic pregnancies. Our study aims to analyze the outcomes of medically managed unruptured ectopic pregnancies treated with methotrexate and to correlate them with serum β -hCG levels. Patients who fulfilled the inclusion criteria for medical management of unruptured ectopic pregnancy (β -hCG >1500 mIU/mL and <10000 mIU/mL) with transvaginal scan feature s suggestive of unruptured ectopic pregnancy were included in the study for either single or multiple dose methotrexate . Main outcomes analysed were the success rates of single & multiple dose MTX regimens. Secondarily the correlation between β hCG levels on D1, D4, D7 and the success rates of medical management was analyzed. Conclusion- Medical management of unruptured ectopic pregnancy with methotrexate has been successful in 80% of our study group, with least side effects and hence can be recommended as the first line of management in selected group of early unruptured ectopic pregnancies

Selection of treatment regimens based on shared decision-making in patients with rheumatoid arthritis on remission in the FREE-J study.

To compare the outcome of various treatment de-escalation regimens in patients with RA who achieved sustained remission. At period 1, 436 RA patients who were treated with MTX and bDMARDs and had maintained DAS28(ESR) at <2.6 were divided into five groups based on shared patient/physician decision-making; continuation, dose reduction and discontinuation of MTX or bDMARDs. At end of year 1, patients who achieved DAS28(ESR) <3.2 were allowed to enrol in period 2 for treatment using the de-escalation regimens for another year. The primary and secondary endpoints were the proportion of patients with DAS28(ESR) <2.6 at year 1 and 2, respectively. Based on shared decision-making, 81.4% elected de-escalation of treatment and 48.4% selected de-escalation of MTX. At end of period 1, similar proportions of patients maintained DAS28(ESR) <2.6 (continuation, 85.2%; MTX dose reduction, 79.0%; MTX-discontinuation, 80.0%; bDMARD dose reduction, 73.9%), although the rate was significantly different between the continuation and bDMARD-discontinuation. At end of period 2, similar proportions of patients of the MTX groups maintained DAS28(ESR) <2.6 (continuation or de-escalation), but the rates were significantly lower in the bDMARD-discontinuation group. However, half of the latter group satisfactorily discontinued bDMARDs. Adverse events were numerically lower in MTX and bDMARD-de-escalation groups during period 1 and 2, compared with the continuation group. After achieving sustained remission by combination treatment of MTX/bDMARDs, disease control was achieved comparably by continuation, dose reduction or discontinuation of MTX and dose reduction of bDMARDs at end of year 1. Subsequent de-escalation of MTX had no impacts on disease control but decreased adverse events in year 2.

Risk Factors for Hepatic Toxicity of High-dose Methotrexate in Patients With Osteosarcoma.

High-dose methotrexate (HD-MTX) is widely used to treat osteosarcoma. However, some patients develop hepatic toxicity, leading to dose modification and delays in the scheduled chemotherapy. The present study aimed to identify the risk factors of hepatotoxicity in patients with osteosarcoma. We conducted a retrospective study of patients with osteosarcoma treated with HD-MTX between January 2014 and June 2020 at the National Cancer Center Hospital, Japan. The risk factors for MTX-induced hepatotoxicity (≥grade 3) were identified using multivariate logistic regression analysis. The final analysis included 88 courses of 36 patients. Hepatotoxicity occurred in 51 (58.0%) of the 88 courses. Female sex, MTX dose (>10.2 g/m2), and serum calcium concentration (>9.3 mg/dl) were identified as risk factors for HD-MTX-induced hepatotoxicity. Identifying the risk factors of HD-MTX-induced hepatotoxicity may contribute to improvements in the safety and management of HD-MTX therapy.

Phase II Study of Gemcitabine, Peg-Asparaginase, Dexamethasone and Methotrexate Regimen for Newly Diagnosed Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: Final Analysis With Long-Term Follow-Up and Rational Research for the Combination.

Patients with extranodal natural killer/T-cell lymphoma (ENKTL), nasal type are benefit from peg-asparaginase, gemcitabine, and methotrexate. Therefore, we conducted a prospective phase II trial using a combination of these drugs as GAD-M regimen in naïve ENKTL patients, simultaneously, explored the combinational mechanism. The GAD-M regimen was administered for 6 cycles sandwiched by radiotherapy for stage I/II and 6 cycles for stage III/IV patients. After 6 cycles, the overall response rate of 36 patients was 91.6%, and the complete remission rate increased to 83.3%. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 74.8% and 77.8%, respectively. The 5-year PFS and OS were 68.3% and 77.8%. No patient suffered from the central nervous system (CNS) relapse. Most patients experienced recoverable liver dysfunction and anemia in this study. The plasma MTX concentration ratio at 12 to 24 hr during the first cycle could be an early predictor of outcomes in ENKTL (PFS, P=0.005; OS, P=0.002). Additionally, we found that high dose MTX (HD-MTX) and gemcitabine had the synergistic effect of ENKTL cell in vitro. Mechanistically, we demonstrated that the combination could lead to obviously apoptosis in ENKTL cell with extremely release of reactive oxygen spices (ROS), which mediated by endoplasmic reticulum stress. In conclusion, the GAD-M regimen could be a new choice to newly diagnosed ENKTL, especially for stage I/II patients. Furthermore, our results showed the synergy effect of HD-MTX with gemcitabine in ENKTL.Clinical Trial RegistrationThis trial was registered at www.clinicaltrials.gov as #NCT01991158.

Optimization of high-dose methotrexate prophylaxis for central nervous system relapse in diffuse large B-cell lymphoma: a multicenter analysis.

Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare but devastating event. Intravenous high-dose methotrexate (HD-MTX) is recommended as CNS prophylaxis, but the optimal timing and dose has not been elucidated. Here, we report a multicenter analysis of prophylactic HD-MTX administration for DLBCL. Two hundred eighty-four patients receiving HD-MTX either concurrent with each induction chemotherapy cycle (n = 221) or at the end of induction therapy (EOI, n = 63) were included. Patients with CNS-IPI scoring 4-6, and/or testicular involvement, and/or double/triple hit lymphoma, were stratified into the high-risk group and the others into the moderate-risk group. Concurrent HD-MTX was associated with increased risk of grade 3/4 treatment-related toxicity (OR,1.49; P = 0.006) and subsequent chemotherapy delays (OR, 1.87; P = 0.003) in multivariate analysis. With a median follow-up of 36.0months, no significant difference in CNS relapse rate was identified between the concurrent and EOI groups (3.2% vs 4.8%, P = 0.34), even in the high-risk group. Analysis on systemic MTX dose suggested that high-dose MTX (≥ 2g/m2) was associated with better CNS relapse control only in the high-risk group, but not in the moderate-risk group. This study may elucidate the superiority of EOI HD-MTX to some extent. High MTX dose (≥ 2g/m2) may not be necessary for the moderate-risk patients.

Study on success of methotrexate in single or two doses for medical management of ectopic pregnancy

Background: The treatment of ectopic pregnancy in conservative manner in order to preserve the subsequent fertility is important. Methotrexate can be effectively used in termination of ectopic pregnancy. This study compares the single dose versus double dose approach for the conservative management of pregnancy. Material and Methods: A prospective study was conducted in a tertiary care centre. About 70 women with ectopic pregnancy were administered with single or double dose of methotrexate were followed up. The second dose of MTX was administered when there was no 15% decrease in β-hCG levels between day 4 and 7. The data thus obtained was compiled and analysed. Results: The mean age was comparable in single and double dose groups. The mean gestational age in single dose group was 7.1 weeks and double dose group was 7.48 weeks. The termination of ectopic pregnancy was successful in 80.8% of the single and 33.3% of the two dose groups. The mean EP diameter in single dose group was 24.03 and double dose group was 33.7 mms. The length of stay was significantly lower in double dose groups. Conclusion: The single dose protocol of methotrexate was superior when compared with the double dose protocol.

Radical Improvement in Prognosis of CNS Ptlds Using Methotrexate Dose Alorithm Regardless of Renal Function

IntroductionWhile systemic post-transplant lymphoproliferations (PTLDs) have a good prognosis, with a median survival of more than 6 years, PTLD of the central nervous system (CNS-PTLD) have a very poor prognosis with a CR rate of 38% and overall survival (OS) of 43% at 3 years. The main prognostic criterion being the response to the first line (Evens AM et al. Am J Transpl 2013), we hypothesized that the majority of treatment failures were due to the absence or underuse of the major drug in CNS NHL treatment, namely methotrexate (Mtx), due to the high rate of renal failure in transplanted patients.Patients and methodsSince April 2017, CNS-PTLD treated at Pitie-Salpetriere Hospital, Paris, France, have been systematically treated with a combination of methotrexate on day 1, Cytarabine on days 2 and 3, every 15 days for 6 cures. Cytarabine is given at 2g/m 2/d when the creatinine clearance (cc) is > 50ml/min, 1g/m 2/d below. The dose of Mtx of the first treatment is 100 mg/m 2 in case of dialysis or cc <30 ml/min, between 100 and 500 mg/m 2 for cc between 30 and 50 ml/min, between 500 and 1000mg/m 2 between 50 and 60 ml/min and/or albuminemia <35g /L and/or> 65 years, 3000mg/m 2 in other cases. The dose of Mtx during the following treatments depends on the dosage of Mtx at 24h: below 1 microM the following dose is increased, above 5 microM it is reduced otherwise it remains the same. The results are compared to those of CNS-PTLDs treated in the same unit before April 2017ResultsOf the 182 PTLDs treated since 1990 at Pitie-Salpetriere hospital, 49 are CNS-PTLD, including 16 processed with the new algorithm. The median age is 58 years, 9 patients have kidney or kidney-pancreas transplants, 2 heart, 1 lung and 3 liver, all are EBV positive diffuse large B cell CNS-PTLDs. The diagnosis is made in median 88 months after the transplantation. The cc at the diagnosis is in median of 50 ml / min. Of these 16 patients, only 2 had a cc> 60 ml/min, and only two were able to receive 3000 mg/m 2 of Mtx. The other patients received between 100 and 1000 mg/m 2 at the first treatment, 6 had an increased dose during the next cycles following the algorithm. No worsening of renal function or overdose of Mtx have been rated. Of the 16 patients 14 achieved complete remission (93%), 1 a PR, 1 died of progression after the first cycle, 1 relapsed within 3 months and 1 after 1 year of CR. Median overall survival (OS) is not achieved (448 days +). In comparison, of the 33 CNS-PTLDs treated before April 2017, 10 obtained a CR (30%), 6 a PR and the median OS is 211 days, for the 9 CNS-PTLDs treated without Mtx, only one obtained a CR, 1 a PR and their OS is only 180 days (p=0.016) cf figureConclusionContrary to general belief, methotrexate can be used regardless of the renal function by adapting its dose to the cc then to the dosages at H24. This new simple algorithm increased the CR rate from 30% to more than 90% and improve OS. In case of confirmation on further series, this new attitude should revolutionize the management of CNS-PTLDs ... but also other CNS-NHLs in case of renal failure [Display omitted] DisclosuresLeblond: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Roche: Honoraria; Amgen: Honoraria; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Real-World Outcomes of Patients with Primary CNS Lymphoma (PCNSL): A Report from the Australasian Lymphoma Alliance (ALA)

Real-World Outcomes of Patients with Primary CNS Lymphoma (PCNSL): A Report from the Australasian Lymphoma Alliance (ALA)

Consideration of differences in drug usage between young-onset and elderly-onset rheumatoid arthritis with target of low disease activity

Objectives Elderly-onset rheumatoid arthritis (EORA) is reported to differ from young-onset rheumatoid arthritis (YORA) with regard to patient background and drug treatment. We examined the amount of drug administered to patients who achieved low disease activity (LDA) for rheumatoid arthritis at our hospital. Methods Demographics, clinical history, and treatments were compared between patients with EORA (n = 70) and YORA (n = 190). Results There was a significant difference in the average age (73.8 vs. 57.8 years), disease duration (6.66 vs. 14.7 years), and sex (62.9% males vs. 83.7% females), but no difference in rheumatoid factor positivity (85.3% vs. 80.7%), anti-citrullinated peptide antibody positivity (86.5% vs. 87.7%), simplified disease activity index (4.28 vs. 4.59), or disease activity score 28-CRP (1.99 vs. 2.04) in the EORA and YORA groups, respectively. There were also no significant differences in prednisolone use (37.1% vs. 36.3%), amount of methotrexate administered (MTX) (1.45 vs. 1.41 mg), and MTX use (55.7% vs. 65.3%). However, the MTX dose (2.89 vs. 4.09 mg/week, p = .011) and overall biologics use (32.9% vs. 56.3%, p = .0012) were significantly lower in patients with EORA than in those with YORA. Conclusion Patients with EORA may be able to achieve LDA with lower drug dosage than those with YORA.

Rituximab plus methotrexate combination as a salvage therapy in persistently active granulomatosis with polyangiitis.

The aim of this study was to describe the efficacy and safety of rituximab and MTX (RTX/MTX) combination therapy in ANCA-associated vasculitides (AAV). A retrospective French nationwide study was conducted in patients with AAV who received RTX/MTX combination therapy for persistently active disease. Seventeen patients were included. All patients had granulomatosis with polyangiitis (GPA), with positive ANCA in 76% of them, mainly with PR3-ANCA specificity. Sixteen patients (94%) had priorly failed to achieve remission with RTX and 11 (65%) with CYC. Patients had experienced a median of 3 (2-4) flares. Manifestations requiring RTX/MTX combination therapy were subglottic or bronchial stenosis in 6 patients (35%), orbital mass in 6 (35%), disabling ENT involvement in 2 (12%), and epiduritis and pachymeningitis in 1 case (6%) each. The median follow-up duration for the RTX/MTX combination therapy was 11 months (11-26 months). At 6 months, global response had been achieved in 15 patients (88%), including partial response in 11 (65%) and complete response in 4 (24%). At last evaluation, global response had been achieved in 16 patients (94%). Seven patients (41%) experienced severe adverse events (grade 3 or 4), including infections in 4 (24%) and hepatitis in 2 (12%). Combination therapy was withdrawn in 4 patients (24%), but never for safety concerns. In contrast, the MTX dose was decreased in 2 patients (12%) because of adverse events. One patient died of an unknown cause. RTX/MTX combination therapy could be an effective salvage therapy to treat persistently active GPA with granulomatous manifestations, with an acceptable safety profile.

OP01.04: Non‐surgical treatment of Caesarean scar pregnancy

Case 1 is of a 33-year-old woman with a history of one previous Caesarean section (CS) presented with spotting. Transvaginal sonography showed a 33mm gestation sac, 3mm live fetal pole with heart beat at lower segment of uterus at the location of previous CS scar. The first β-hcG titer of the patient was 58000 IU/L. Her second set of β-hcG increased to 110500 IU/L. Two doses of MTX with 48 hours' interval was prescribed for her. The fetus was reducted with KCL injection with sonography guidance transadominally. The patient was observed for one more week and then discharged with weekly checking of β-hcG titer. At the third week of follow-up, her β-hcG level was under 1000 IU/L. The level of β-HcG became negative after 4 weeks and pregnancy mass in Caesarean scar disappeared after 5 months. Case 2 is of a 34-year-old woman with a history of one previous CS who was presented with spotting. Transvaginal sonography showed an 18x20 mm gestation sac with fetal heart and yolk sac at lower segment of uterus at the location of the previous CS scar. The patient's first set of serum β-hcG titer was 14480IU/L. Two doses of MTX were prescribed for her. In follow up, the repeated transvaginal sonography showed similar findings with fetal heart activity. The patient did not experience any symptom of pain or bleeding at this point and was clinically stable. She was offered the option of Intra sac MTX injection with sonography guidance. In her follow-up after injection, the fetal heart was not detected. She was discharged with weekly checking of β-hcG titer. At the second month of follow-up, her β-hcG level was undetectable. Caesarean scar mass disappeared after 6 months and she became pregnant with normal implantation of pregnancy after 2 years.

Rate of hourly change in serum beta-human chorionic gonadotropin levels in ectopic pregnancy can predict the success of treatment with single-dose methotrexate: A retrospective observational study

ObjectiveTo determine whether the success of treatment with single-dose methotrexate (SD MTX) for ectopic pregnancy can be predicted using the rate of change in serum β-human chorionic gonadotropin (β-hCG) level. Study designThis was a retrospective observational study conducted at a tertiary referral centre. The study population included women who underwent treatment with SD-MTX for ectopic pregnancy. We analysed data of 119 women treated with SD-MTX for ectopic pregnancy at the Galilee Medical Centre between 2012 and 2016. Success was defined as a <15% decrease in β-hCG level between days 4 and 7, with no need for a second dose of MTX or surgical intervention.The dynamics of serum β-hCG levels before treatment were considered as the main outcomes. ResultsSD-MTX administration was successful in 77 (65%) patients. The average baseline β-hCG level was significantly lower in women with successful outcomes than in those without successful outcomes (763.1 vs. 1429.63 mIU/L, respectively, p < 0.0048). The hourly change in β-hCG level was significantly lower in those with successful outcomes than in those without successful outcomes (0.38 vs. 5.73 mIU/mL, respectively, p < 0.0023). The percentage change in β-hCG level was 13.1%, which was not significantly different between the groups (p < 0.133). At serum β-hCG level < 946 mIU/mL and sac size < 2.55 cm, the treatment was successful in 88% of women. ConclusionsWe propose a predictive model of hourly change in β-hCG to achieve successful treatment using SD-MTX in ectopic pregnancy based on objective and measurable criteria.

Improvement of outcomes of an escalated high-dose methotrexate-based regimen for patients with newly diagnosed primary central nervous system lymphoma: a real-world cohort study.

PurposeHigh‐dose methotrexate (HD‐MTX)-based chemotherapy regimen is the first-line treatment of primary central nervous system lymphoma (PCNSL). At present, doses of MTX in the range of 3.5–8 g/m2 are frequently used. However, the optimal dose of methotrexate for PCNSL remains controversial. The purpose of this real-world study was to compare the efficacy and toxicity of HD-MTX in patients with untreated PCNSL.MethodsImmunocompetent adults with newly diagnosed PCNSL between January 2015 and December 2018 were investigated and followed up to June 2019. All patients’ initial treatments were based on HD‐MTX chemotherapy regimens.ResultsA total of 73 patients were reviewed. For patients who received HD-MTX at 8 g/m2 vs.3.5 g/m2, the complete response (CR) rates were 68.29% vs 43.75% (p = 0.03), and the median PFS times were 17.7 months vs 9.05 months (HR=0.455, 95% CI 0.239–0.865, p=0.016). There was no significant difference in OS between the two groups. Serious adverse effects were uncommon and clinically manageable.ConclusionThere is a correlation of treatment response and clinical outcomes between the dosage of MTX in initial induction therapy in newly diagnosed PCNSL. MTX dose of 8 g/m2 provided a higher CR rate and PFS benefits with acceptable adverse effects.

Association of Nonalcoholic Hepatic Fibrosis with Body Composition in Female and Male Psoriasis Patients.

Psoriasis has been associated with increased frequency of hepatic diseases. Psoriasis severity, obesity, insulin resistance, aspartate aminotransferase level, platelet count, and alcohol use are significant predictors for advanced fibrosis in psoriasis patients. Although psoriasis patients also present body composition changes (e.g., higher overall body fat, visceral fat and sarcopenia), and these have recently been reported as risk factors for hepatic fibrosis, to date, body composition has not been prospectively investigated in psoriasis in the context of liver fibrosis. In this study anthropometric assessment (body weight and body mass index (BMI)), body composition analysis (body fat%, visceral fat scores and muscle mass%), and liver stiffness measurements (using transient elastography [TE]) were done in 52 psoriasis patients undergoing methotrexate therapy. Fourteen patients (26.9%) had advanced (F3–F4) liver fibrosis. There was no correlation between the patients’ liver stiffness values and the cumulative MTX doses. On the other hand, patients with higher BMI values, total body fat% and visceral fat scores were significantly more likely to present with higher hepatic stiffness values. BMI was a significant predictor of hepatic fibrosis in both genders. In males, body fat% (R = 0.578, p = 0.002) and, especially, visceral fat scores (R = 0.716, p < 0.001) had statistically significant correlation with stiffness scores, while in females only visceral fat scores were statistically significant predictors of the liver stiffness values (R = 0.452, p = 0.023), and body fat% was not (R = 0.187, p = 0.382). Our results suggest that anthropometric data should be assessed differently in female and male psoriasis patients when evaluating liver fibrosis risk.

Monitoring Of High-Dose Methotrexate (Mtx)-Related Toxicity and Mtx Levels in Children with Acute Lymphoblastic Leukemia: A Pilot-Study in Indonesia.

The administration of high-dose methotrexate (HD-MTX) requires an accurate monitoring of blood MTX levels to determine the regimen of leucovorin rescue and urine alkalinization to prevent toxicity. However, it is technically and logistically challenging to screen patients routinely in limited-resource settings. This study aimed to evaluate blood MTX levels at 24- and 48-hours from start of infusion in relation to clinical toxicity in childhood ALL. Methods: A prospective cohort study was conducted on 32 consecutive children with acute lymphoblastic leukemia (ALL) who had received at least one cycle of 1 g/m2 HD-MTX intravenous infusion as a part of consolidation treatment based on the 2013 Indonesian ALL Protocol. In total, 68 cycles were evaluated. Serum MTX concentrations were measured using enzyme immunoassay. MTX toxicity was categorized using common toxicity criteria (CTCAE) 3.0 version. The association between MTX level and clinical toxicity was assessed by non-parametric analysis. Results:The 24-hours MTX level was median 29.8 ng/mL (0.065 µmol/L) (IQR 8.1–390.6) with a modest decrease in 48-hours MTX serum level in all cycles (median 28.3 ng/mL and 0.062 µmol/L; IQR 0.35–28.7; p<0.05). The two most common toxicities were hepatotoxicity (32.2%) and neutropenia (30.9%). Nephrotoxicity and febrile neutropenia occurred in 8.8% and 5.8% of patients, respectively, with low percentage of mucositis (4.3%) and thrombocytopenia (5.6%) recorded. No statistically significant association was found between MTX levels and clinical toxicity, except for liver toxicity.Conclusion:Serum MTX levels at 24-hours and 48-hours are low, followed by only 4.4% grade III/IV hepatotoxicity and 26,4% grade III/IV neutropenia. There is no significant association between the clinical toxicity and MTX levels at the two points of measurement. An attempt to increase the MTX dose and/or to introduce a loading dose should be considered in subsequent ALL protocol as supported by further pharmacokinetic MTX studies in the Indonesian population.

Impact of the Duration of Methotrexate Administration and the Specific HLA Alleles on the Regressive Methotrexate-Induced Lymphoproliferative Disorders

[Background]Methotrexate-induced lymphoproliferative disorders (MTX-LPDs) are categorized as iatrogenic diseases and belong to the group of other iatrogenic immunodeficiency-associated LPDs, as defined in the 4th edition of the WHO classification manual for immunodeficiency-associated LPD. The phenomenon of LPD regression after MTX withdrawal is a specific event, directly suggesting an MTX influence on LPD development. Although previous data suggests this regressive phenomenon might be related to Epstein-Barr virus (EBV) infection, the precise pathogenesis still remains to be discovered. To investigate the factors involved in this phenomenon, we analyzed patients with regressive LPD after MTX withdrawal in this study.[Methods]Data were collected from 43 patients with autoimmune diseases (ADs) who developed LPD and were treated at our institutions. All diagnoses were confirmed by immunohistochemistry performed on paraffin-embedded tissue sections, along with EBV early RNAs (EBERs). All pathological samples were classified and diagnosed according to the WHO 2016 revision of classification (5th edition). HLA analysis was performed by the PCR-luminex method. The frequency of each HLA allele was determined by referring to the database of an HLA laboratory that has studied HLA alleles. The statistical analyses such as t-tests and the Kaplan-Meier method were performed using EZR software.[Results]Of 43 patients with MTX-LPD, the median age of patients at the time of LPD diagnosis was 64.7 years old (range: 41-83). Sixteen men and 27 women were included. The basal ADs were RA (N = 40), psoriasis vulgaris (N = 1), systemic lupus erythematosus (N = 1), and dermatomyositis (N = 1). The median durations of the basal ADs and MTX treatment were 10.5 (0.5-17.8) and 5.1 (0.2-16.3) years, respectively. Histopathological analysis of the LPDs revealed 14 cases of EBV + DLBCL, 6 DLBCL-NOS, 9 Hodgkin lymphoma (HL), 9 LPD, 3 follicular lymphoma (FL), 2 peripheral T-cell lymphoma (PTCL)-NOS, 1 extranodal marginal zone lymphoma of mucosal-associated lymphoid tissue (MALT), 1 plasmablastic lymphoma, and 3 with other LPDs. Regarding the clinical outcome, 32 patients (74%) were alive. After the LPD regression, 19 patients (44%) relapsed or experienced regrowth. Although patients with HL, FL, and other LPDs showed high relapse rates (100%, 67%, and 100%, respectively), the DLBCL-EBV+ and LPD cases had lower relapse rates (11% and 11%, respectively). In addition, patients with the PTCL-NOS and MALT subtypes were disease-free at the time of writing. Five and 10-year OS were 76.4% and 53.2%, respectively.To investigate any EBV influence, we compared the clinical parameters such as age, sex, clinical stages, serum LDH, serum CRP, serum soluble interleukin-2, MTX dose at the time of LDP development, the disease duration, MTX administration duration, and OS between the EBV+ and EBV - groups. Of 42 patients who underwent an EBER test, 20 patients (48%) were positive. Although for all parameters except MTX duration, significant differences were not detected, a strong association between EBV infection and the median MTX duration was observed (treatment durations in EBV + and EBV- patients were 7.4 years and 4.4 years, respectively; p = 0.0016).On the basis of the higher frequency seen in Japan, 18 patients with regressive LPD underwent HLA analysis. Ten alleles (A*2402, A*3101, A*1101, B*5101, B*5201, C*0303, DRB1*0405, DRB1*1502, DQB1*0401, and DQB1*0601) were significantly positive compared with the general frequency of these alleles in Japan.[Summary]In this study, we analyzed 43 patients with regressive MTX-LPD. After LPD regression, 19 patients (44%) experienced relapsed/regrowth, and their 5 and 10-year OS were 76.4% and 53.2%, respectively. Of 42 patients tested with EBER, 20 patients (48%) were positive. Although the clinical parameters were not significantly influenced by EBV infection, the MTX duration was strongly affected by EBV infection. In addition, 10 specific alleles including A*2402 as seen in Japanese and DRB1*0405 as seen in ADs were significantly positive compared with the general frequency of these alleles in Japan in this study.[Conclusions]Our data suggest that a longer period of MTX administration might activate EBV infection dependent on the presence of specific HLA alleles. DisclosuresTokuhira:Ezai: Honoraria. Mori:Pfizer Japan: Research Funding; Pfizer Japan: Honoraria; Bristol-Myers K.K: Research Funding; Chugai Pharmaceutical Co: Research Funding; Novartis: Research Funding. Amano:Pfizer Japan Inc: Honoraria. Okamoto:Bristol-Myers K.K: Research Funding; Pfizer: Research Funding; Bristol-Myers K.K: Honoraria; Astellas: Honoraria; Pfizer Japan: Speakers Bureau; Chugai Pharmaceutical Co.: Research Funding; Novartis: Research Funding; Alexion Pharma G.K.: Honoraria. Takeuchi:Eisai Co., Ltd: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Mitsubishi Tanabe Pharma Co.: Research Funding; Bristol-Myers K.K: Honoraria; Asahi Kasei Medical K.K: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Research Funding; Bristol-Myers K.K: Research Funding; Abbivie GK,: Research Funding; Asahi Kasei Medical K.K: Research Funding; Mitsubishi Tanabe Pharma Co: Honoraria; Abbivie GK: Honoraria; Astellas Pharma Inc: Honoraria. Tamaru:Chugai Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Nichirei Biosciences Inc.: Research Funding.