ABSTRACT
OBJECTIVE To discuss the factors affecting the blood concentration of high-dose methotrexate （HD-MTX） and the occurrence of adverse drug reactions （ADR） when treating lymphoma with HD-MTX. METHODS From July 2020 to November 2021， the information of HD-MTX patients who had been monitored for HD-MTX blood drug concentration in the First Affiliated Hospital of Guangdong Pharmaceutical University was collected by retrospective analysis， such as medical record number， age， sex， height， body mass， chemotherapy plan， dosage； test indexes such as alanine transaminase， aspartate transaminase， total bilirubin， creatinine clearance （CrCl）， albumin （ALB） and other indexes were also collected before and after administration. The blood concentrations （c6 h， c24 h， c48 h） of HD-MTX were recorded， drug information of proton pump inhibitors （PPIs） was extracted and used， and ADR occurring within 48 h after administration were all evaluated. Single factor analysis， multiple linear regression and χ2 test were used to analyze the influential factors. RESULTS A total of 133 patients were included in this paper. The results of the single factor analysis of HD-MTX blood drug concentration showed that age， CrCl had an effect on c 6 h （P＜0.05）； age， CrCl and ALB had an effect on c24 h （P＜0.05）； age， body mass index （BMI）， CrCl， combined use of PPIs and ALB had an effect on c48 h （P＜0.05）. The results of multiple linear regression analysis showed that age and CrCl had no effect on c 6 h （P＞0.05）， age was the main influential factor of c 24 h （P＜0.05）， and CrCl and combined use of PPIs were the main influential factors of c48 h （P＜0.05）； the coefficient of variance expansion was between 1 and 3.5， indicating that the analysis results were acceptable. The overall incidence of adverse reactions was 51.13%， of which the blood and lymphatic system reactions were the most common. The results of the influential factors of ADR showed that age， BMI， liver function and CrCl had effect on the incidence of ADR （P＜0.05）. CONCLUSIONS During the process of HD-MTX in the treatment of lymphoma， the patient’s age， CrCl and combined use of PPIs should be considered， and the patient’s blood concentration should be monitored； at the same time， the age of patients， BMI， liver function and CrCl have an impact on the incidence of ADR.
ABSTRACT
Evidence-based Practice Guideline of Medication Therapy of High-dose Methotrexate in China was published in the British Journal of Clinical Pharmacology in February 2022. The guideline followed the latest definition of clinical practice guideline and the methodology specification for the guideline development of WHO. The Grading of Recommendations Assessment ， Development，and Evaluation （GRADE）approach was applied to rate the quality of evidence and determine the strength of recommendations. Finally ，this guideline presents 28 recommendations covering the whole process of clinical medication of high-dose methotrexate ，involving evaluation prior to administration （liver and renal function ，pleural effusion and ascites ， comedication，genetic testing ），pre-treatment and routine dosing regimen （pretreatment of hydration and alkalization ，urine alkalization，routine dosing regimen ），therapeutic drug monitoring （necessity，method，timing，target concentration ），leucovorin rescue（rescue timing ，rescue regimen ，rescue dose optimization ），and management of toxicities （liver and kidney function monitoring，supportive treatment ，blood purification treatment ）. This article aims to summarize and interpret the recommendations of this guideline ，so as to promote the better promotion and implementation of this guideline and provide comprehensive technical support and suggestions for whole-course individualized administration of high-dose methotrexate in China.
ABSTRACT
Objective: Primary central nervous system lymphoma (PCNSL) is a rare form of aggressive extranodal non-Hodgkin lymphoma. This study attempts to delineate the clinicopathological and radiological profile of PCNSL cases at our center. Materials and Methods: All the pathologically confirmed PCNSL cases between January 2007 and July 2016 were analyzed retrospectively. The influence of potential prognostic parameters and therapeutic strategies on survival was investigated by log-rank test and Cox regression analysis. Results: Of the 53 PCNSL patients, 34 (64%) patients were males. Median age at diagnosis was 44 years (range 22–65 years). The most common location in the brain was the cerebral hemispheres in 32 patients (60%), and 16 patients (30%) had multiple intracranial lesions. Histologically, all patients were diffuse large B-cell lymphomas, except one case of anaplastic large-cell lymphoma. The median survival of the patients received whole-brain radiation alone ( n = 6), standard CHOP chemotherapy + radiation ( n = 14), and DeAngelis protocol ( n = 31) was 8 months, 13 months, and 23 months, respectively. Among the 31 patients treated with DeAngelis protocol, Memorial Sloan Kettering Cancer Center Class 1 ( n = 23) and Class 2 ( n = 8) patients had a median overall survival (OS) of 25 months and 13 months, respectively. The incidence of treatment-related neurotoxicity was significantly higher with DeAngelis protocol, in comparison to CHOP + whole-brain radiation therapy (26% vs. 14%, P < 0.05). Conclusion: None of the potential prognostic factors had a statistically significant influence on OS in our patients. High-dose methotrexate-based chemotherapy combined with radiation was the only factor, which had a significant impact on survival (log-rank P = 0.000) but at the cost of increased neurotoxicity
ABSTRACT
To find the predictors of High Dose Methotrexate toxicities in childhood Acute Lymphoblastic Leukemia Patients. This study included 198 Childhood Acute Lymphoblastic Leukemia patients (303 infusions) who were treated with High Dose Methotrexate. Methotrexate levels at different time point were measured by modified enzyme multiplied immunoassay technique assay. The correlation between Methotrexate levels and toxicity was evaluated by Receiver Operating Characteristic curve. When the Methotrexate level at 42 h was lower than 0.76 µmol/L, the sensitivity for predicting thorough clearance at 66 h was 90.78%. When the Methotrexate level at 42 h was higher than1.5 µmol/L, the sensitivity for predicting delayed clearance was 82.17%. When the Methotrexate level at 66 h was higher than 0.5 µmol/L, the sensitivity for predicting Methotrexate toxicity was 89.09%. When the Methotrexate level at 66 h was lower than 0.1 µmol/L, the sensitivity for predicting Methotrexate nontoxicity was 92.73%. The Methotrexate level at 42 h could be predictor for delayed clearance. The Methotrexate level at 66 h could be predictor for toxicity.
Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Adolescent , Patients/classification , Methotrexate/administration & dosage , Methotrexate/analysis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Forecasting , ROC Curve , Enzyme Multiplied Immunoassay Technique/instrumentation , Dosage/adverse effectsABSTRACT
OBJECTIVE：To systematically evaluate the c orrelation of methylenetetra hydrofolate reductase （MTHFR）C677T and A 1298C gene polymorphisms with blood system adverse events induced by high-dose of methotrexate （HDMTX）. METHODS ： Retrieved from Medline ，Embase，Clinical Trials.gov ，CNKI，Wanfang database ，CBM，cohort studies about MTHFR gene polymorphism in hematological neoplasm treated by HDMTX were collected from inceptions to March 2018. After data extraction of included literatures ，quality evaluation with Newcastle Ottawa scale ，Meta-analysis was performed for adverse events of blood system induced by HDMTX in different genetic models with Rev Man 5.3 software. RESULTS ：Totally 25 cohort studies were included，23 studies of which were related to MTHFR C677T site （including 1 858 patients）and 16 studies related to MTHFR A1298C site （including 1 088 patients）. Results of Meta-analysis showed that MTHFR C677T mutation type significantly increased the risk of hematotoxicity [TT/CT vs. CC ：OR＝1.57，95％CI（1.12，2.20），P＝0.009；TT vs. CT/CC ：OR＝2.19，95％CI（1.49， 3.23），P＜0.001；T vs. C ：OR＝1.34，95％CI（1.03，1.74）， P＝0.03] and severe hematotoxicity [TT/CT vs. CC ：OR＝m 2.33，95％CI（1.43，3.81），P＜0.001]，including leukopenia [TT/CT vs. CC ：OR＝1.37，95％CI（1.02，1.82），P＝0.03]， severe leukopenia [TT/CT vs. CC ：OR＝1.63，95％CI（1.03， 010-82265810。E-mail：zhao_rongsheng@163.com 2.56），P＝0.04]，severe gra nulopenia [TT/CT vs. CC ：OR＝ ·2.26，95％CI（1.50，3.39），P＜0.001]. The mutation genotypes of MTHFR A1298C significantly decreased the risk of severe hematotoxicity [CC/AC vs. AA ：OR＝0.17，95％CI（0.04，0.76），P＝0.02]，including leukopenia [CC/AC vs. AA ：OR＝0.68， 95％CI（0.48，0.97），P＝0.03；CC vs. AC/AA ：OR＝0.28，95％CI（0.14，0.59），P＜0.001] and severe leukopenia [CC/AC vs. AA：OR＝0.43，95％CI（0.19，0.97），P＝0.04]. CONCLUSIONS ：Among patients with hematological neoplasms ，MTHFR C677T mutation may significantly increase the risk of hematotoxicity by HDMTX including the risk of leukopenia and granulopenia ；while MTHFR A1298C may reduce the risk of hematotoxicity by HDMTX ，including the risk of leukopenia.
ABSTRACT
OBJECTIVE： To systematically evaluate the effects of MTHFR， RFC1 and MDR1 gene polymorphisms on high- dose methotrexate-induced ADR in osteosarcoma patients， and to provide evidence-based reference for individual medication of high-dose of methotrexate. METHODS： Retrieved from Medline， Embase， clinical trials.gov， CNKI， Wanfang database and CBM， cohort studies about the association of MTHFR C677T/A1298C， RFC1 G80A， MDR1 C3435T gene polymorphisms with high-dose methotrexate-induced ADR were collected. After data extraction of clinical studies met inclusion criteria， and quality evaluation with the Newcastle-Ottawa Scale， Meta-analysis and descriptive analysis were performed for outcome indexes as the incidence of high-dose methotrexate-induced ADR （hematotoxicity and myelosuppression， hepatotoxicity， nephrotoxicity， oral mucositis， digestive tract toxicity and overall adverse events） with Rev Man 5.3 and Microsoft Excel 2016 software. RESULTS： Totally 8 cohort studies involving 608 patients were included； 6， 5， 4 and 2 studies reported outcome indexes related to MTHFR C677T/A1298C， RFC1 G80A and MDR1 C3435T gene polymorphisms respectively. Meta-analysis and descriptive analysis showed that MTHFR C677T gene polymorphism was significantly associated with the risk of G3-4 renal toxicity [TT/CT vs. CC： OR＝12.35， 95％CI＝（3.28，46.42）， P＜0.001]， G3-4 oral mucositis [T vs. C： OR＝2.04， 95％CI＝（1.06，3.93）， P＝0.03]， oral mucositis [（TT vs. CT/CC： OR＝2.27， 95％CI＝（1.20，4.27）， P＝0.01] and renal toxicity （P＜0.05）； MTHFR A1298C gene polymorphism was associated with G3-4 hepatotoxicity， G3-4 nephrotoxicity and G3-4 oral mucositis， without statistical significance （P＞0.05）. There was no significant correlation between RFC1 G80A polymorphism and hemotoxicity， hepatotoxicity， nephrotoxicity and digestive tract toxicity （P＞0.05）. MDR1 C3435T polymorphism was significantly correlated with oral mucositis （P＜0.05）， but not with hematotoxicity and hepatotoxicity （P＞0.05）. CONCLUSIONS： MTHFR C677T mutation can increase the risk of high-dose methotrexate-induced ADR. There is no significant association between MTHFR A1298C polymorphism and high-dose methotrexate-induced ADR. There are few studies on RFC1 G80A or MDR1 C3435T polymorphism and high-dose methotrexate-induced ADR， and their association is unclear.
ABSTRACT
Methotrexate ( MTX) is administered at a high dose for the treatment of diseases such as leukemia and malignant lymphoma. However, it will cause serious adverse reactions such as acute kidney injury,myelosuppression, and mucositis. On the basis of hydration alkalization and high-dose leucovorin rescue in children with high risk of MTX poisoning,blood purification should be performed as soon as possi-ble to clear MTX. The number and frequency of hemodialysis should be determined according to the general condition of the child,the degree of renal injury and the concentration of MTX,and high-throughput hemodi-alysis can be selected if available. Continuous renal replacement therapy is suitable for children with hemodynamic instability. When the MTX concentration is extremely high, it is recommended to combine hemoperfusion and hemodialysis to achieve better clearance.
ABSTRACT
Objective To analyze the safety of high dose methotrexate (HD-MTX) in the treatment of children with acute lymphoblastic leukemia (ALL) after 36 hours and 42 hours using leucovorin (CF) rescue. Methods A total of 137 childhood with acute lymploblastic leukemia(ALL) in our hospital from September 2012 to December 2015 were analysed in this study, 137 children with ALL were randomly divided into group A (n=69) and group B (n=68) according to the serial number (odd number and odd number). The total number of treatment times was 454 times. Among them, the rescue time of group A was 36 hours, there were 224 cases, and the rescue time of group B was 42 hours, 230 times.The plasma drug concentration, delayed excretion rate, the total dose of leucovorin, the total dose of methotrexate and the incidence of side effects were observed in group A and group B at 24, 48 and 96 hours. Results There was no significant difference in plasma concentration, delay of excretion and incidence of side effects between 2 groups of methotrexate, 24, 48 and 96 hours. The total dose of methotrexate/methotrexate in 2 groups was statistically significant (P＜0.05). Conclusion When the rescue time of leucovorin was 42h, the treatment of acute lymphoblastic leukemia with high-dose methotrexate was the best.
ABSTRACT
0.05) in incidence rate for bone marrow suppression,gastrointestinal reaction,hepatic damage and mucosa damage and infection between different therapic courses.Central nervous system leukemia(CNSL) occured in one high risk case followed up at 12 month after complete remission(CR);the incidence rate was 12.5%.Conclusions HD-MTX is practicable in basic-level hospitals,as long as there are perfect preparation,fitness hydration and alkalization and leucovorin rescue being used in time.
ABSTRACT
BACKGROUND: A primary central nervous system lymphoma (PCNSL) is a rare neoplasm with a poor prognosis. The treatment of PCNSL involves a combination of chemotherapy, intrathecal chemotherapy and radiotherapy. This study retrospectively evaluated the treatment outcomes and prognostic factors of Korean patients with PCNSL. METHODS: Between 1995 and 2003, 58 patients diagnosed with PCNSL from the multi-center hospitals were enrolled in this study. Among 56 patients who had received treatment, 16 patients were treated with radiotherapy alone, while 40 patients were treated with combined chemotherapy (CHOP; 9 cases, high-dose methotrexate; 31 cases) and radiotherapy. RESULTS: The median age of the patients was 58 years (range, 19-76). A diffuse large B-cell lymphoma was diagnosed in 56 cases (96.6%), while a peripheral T-cell lymphoma was diagnosed in 2 cases. Of the 47 patients who could be assessed for their response after treatment, a CR and PR was observed in 32 (68%) and 11 patients (23%), respectively, giving an overall response rate of 91% (95% CI, 82~100%). The estimated 3-year overall survival rate for all the patients was 67+/-7.9% and the 3-year disease free survival rate was 53+/-8.3%. The overall survival of the high-dose methotrexate group was superior to that of the CHOP group (77+/-10% versus 47+/-19%, p=0.05). Leukoencephalopathy was observed as a late complication in 9 patients (21%). No significant prognostic factors affecting survival were found by univariate analysis. CONCLUSIONS: Approximately half of the patients could have long-term survival after treatment in this study. High-dose methotrexate containing chemotherapy followed by radiotherapy was found to be an effective treatment.
Subject(s)
Humans , Central Nervous System , Disease-Free Survival , Drug Therapy , Leukoencephalopathies , Lymphoma , Lymphoma, B-Cell , Lymphoma, T-Cell, Peripheral , Methotrexate , Prognosis , Radiotherapy , Retrospective Studies , Survival RateABSTRACT
A 13 year-old girl with osteosarcoma and pulmonary tumor recurrence developed acute renal failure following high dose methotrexate (12 g/m2) therapy, she had previously tolerated high dose methotrexate and her renal and hepatic functions were normal. Briefly, 48 hours after beginning methotrexate infusion her methotrexate concentration and creatinine level were 1338.8microM/L and 5.8 mg/dl, respectively. Grade IV oral mucositis and neutropenia with fever developed at 144 hours after MTX infusion. Hydration and alkalinization were continued and leucovorin rescue was intensified based on the plasma MTX concentrations. Plasma exchange was performed twice and hemodialysis 3 times without problems, but methotraxate and creatinine levels remained high, 91.9 microM/L, and 2.5 mg/dl, respectively. After 3 courses of hemodialysis carboxypeptidase-G2 (CPDG2) was administered at 50 U/kg, intravenously over 5 minutes. After 15 minutes of CPDG2 (Voraxaze(TM)) infusion, her plasma MTX concentration was 0.91microM/L and no rebound elevation or side effects developed. Thirteen days post-MTX infusion her renal function had normalized. We report here our experience of a dramatic methotrexate level reduction caused by CPDG2 administration.
Subject(s)
Adolescent , Female , Humans , Acute Kidney Injury , Creatinine , Fever , Leucovorin , Methotrexate , Neutropenia , Osteosarcoma , Plasma , Plasma Exchange , Recurrence , Renal Dialysis , StomatitisABSTRACT
PURPOSE: Rat arthritis was induced by bovine type II collagen. To present the remedial effects on type II collagen arthritis and clinical efficacy, a high dose of methotrexate, of a level similar to that used in cancer patients was given to rats. MATERIALS AND METHODS: Healthy male Brown Norway rats were used, of mean weight; 300 g. There were 7 subgroups: a control group, given collagen only, an orally methotrexate treated (2.5mg/week), high methotrexate dose groups; 10 mg/kg, 30 mg/kg, 50 mg/kg, 100 mg/kg and a low dose methotrexate group (0.375 mg/kg/week, 4 times) were included in the present study. Type II collagen was injected for arthritis induction and a single intraperitoneal injection of methotrexate was administered after 15 days. Orally treated group was administered 4 times (2.5 mg/week). Histopathologic findings were evaluated. RESULTS: 50 mg/kg methotrexate was effectively reduced the arthritis index and significantly decreased inflammatory cell number between 2nd and 6 weeks. CONCLUSION: A high dose of methotrexate may be clinically effective in the short period treatment of rheumatoid arthritis patients.
Subject(s)
Animals , Humans , Male , Rats , Arthritis , Arthritis, Rheumatoid , Cell Count , Collagen , Collagen Type II , Injections, Intraperitoneal , Methotrexate , NorwayABSTRACT
PURPOSE: We had examined the effect of high dose MTX loaded acrylic cement in the treatment of type II collagen induced arthritis. MATERIALS AND METHODS: we used inbreed rat(16weeks - 20weeks) and divided into control group and experimental groups. inbreed rat was induced arthritis by prepared collagen through injection at the tail base. The control group was injected with collagen only. but the experimental groups were inserted intraperitoneally MTX-loaded acryl cement: 25mg, 20mg, 15mg, and 10mg MTX in acrylic cement (0.5gm) respectively. The histopathologic results were investigated to determine the effect of MTX on the 3rd, 7th, 14th, 28th, 42th, and 56th day after inserting high dose MTX loaded acrylic cement which was inserted intraperitoneally 2weeks later of collagenase injection RESULTS: The arthritis index of the MTX-loaded groups had reduced than arthritis index of the control group according to the dosage and In histopathological test, the experimental group injected with 15mg, 20mg, and 25mg of MTX had distinctive effects, compared to the control group, as dosage chronologically. CONCLUSION: The treatment of high-dose MTX loaded acrylic cement might be effective on rheumatoid arthritis managment.
Subject(s)
Animals , Rats , Arthritis , Arthritis, Rheumatoid , Collagen , Collagen Type II , Collagenases , Methotrexate , TailABSTRACT
A 16-year-old male patient was diagnosed as chondroid osteosarcoma of the left humeral shaft. He showed normal serum creatinine level and no complications following the first course of high-dose methotrexate (HD-MTX) chemotherapy with a total dose of 12g/m2. After the 2nd HD-MTX chemotherapy with the same dosage as in the 1st course, plasma MTX levels soared up to 72micromol/L and serum creatinine level increased to 1.39mg/dL. We failed to lower the plasma MTX levels and to recover the renal function by high-dose leucovorin rescue and plasmapheresis. Plasma MTX level was successfully lowered after three consecutive total plasma exchanges and the withdrawal of aceclofenac which was suspected as an aggravating agent. No rebound in plasma MTX level was observed. We report that total plasma exchanges were effective in a patient with renal failure and delayed MTX excretion which occurred after HD-MTX chemotherapy.
Subject(s)
Adolescent , Humans , Male , Acute Kidney Injury , Creatinine , Drug Therapy , Leucovorin , Methotrexate , Osteosarcoma , Plasma Exchange , Plasma , Plasmapheresis , Renal InsufficiencyABSTRACT
PURPOSE: We investigated serum levels of MTX and accompanying organic toxicities after administration of High-Dose Methotrexate (HDMTX). METHODS: We reviewed a total of 42 courses of HDMTX administration in 6 patients who were diagnosed with osteosarcoma in Hanyang University Hospital from 1993 to 1997. The HDMTX was infused at the doses of 8~12 g/m2, and serum levels were assessed. Leucovorin administration was started 20 hours from the beginning of MTX infusion, and continued until the serum MTX level is below 1x10-7 mol/L and toxicities are not detectable. RESULTS: Of 6 patients (4 males and 2 females), mean age at diagnosis was 11.6 years (8.5~15.6 years). Sites of origin included distal femur in 3, proximal tibia in 1, proximal fibula in 1 and proximal humerus in 1. Serum MTX levels were 1.87+/-0.69x10-4 mol/L at 12~23 hours, and 5.10+/-3.22x10-8 mol/L at 120 hrs after HDMTX infusion. Of 42 courses, hematologic toxicity greater than grade III was observed in 19(45.2%) resulting reduction of dose in 2 patients, and hepatic toxicity greater than grade III in 28(67%). The mean ALT levels was 680+/-563 U in 1st day, and mostly normalized in 10th day. Stomatitis was generally mild, except 1 patient with grade III toxicity. No renal or neurologic toxicity was observed, except 1 seizure episode due to SIADH. CONCLUSION: HDMTX with leucovorin in osteosarcoma was well tolerated, and in majority of courses, serum MTX levels returned to non-toxic level after 120 hours and leucovorin will be desirable to administer during at least 5 days.
Subject(s)
Child , Humans , Male , Diagnosis , Femur , Fibula , Humerus , Inappropriate ADH Syndrome , Leucovorin , Methotrexate , Osteosarcoma , Seizures , Stomatitis , TibiaABSTRACT
1.0 mmol/L).The clinical side effects after medication circa were compared between two groups.Results There was no significant difference in myelosuppression,liver functional lesion,gastrointestinal tract reaction and infection in 2 groups.But following the increase of MTX blood drug level,the incidence rate of skin mucosa contamination,electrocardiographic abnormality,the cardiac creatase abnormity and nervous system symptoms significantly increased.Conclusions In the course of child ALL treatment with HD-MTX+CF,the side effects are common and individual difference is obvious.Specific treatment on individuals is suggested.J Appl Clin Pediatr,2006,21(3):170-171
ABSTRACT
During the last decade, many clinical investigators at various cancer centers have reported the efficacy of various chemotherapeutic agents in the treatment of osteosarcoma. The regimens using high-dose methotrexate (HDMTX) with citrovorum factor rescue are now considered to be one of the most effective treatments of choice. From December 1989 to May 1991, sixteen patients with Enneking's stage (Enneking et al., 1980) IIB osteosarcoma of the extremities were treated with a high-dose methotrexate regimen. After two cycles of preoperative chemotherapy, an operation was performed; either limb salvage or amputation. The resected lesions were examined pathologically and classified according to Huvos' criteria. On pathological examination, 8 (50%) cases showed Grade IV; 1 (6.25%) Grade III; 4 (25%) Grade II; and 3 (18.75%) Grade I. The types of surgery performed were tumor prosthesis replacement (11); wide resection with or without reconstruction (2); resection and arthrodesis (1); and amputation (2).