Clinical trial and compassionate use experience with glucarpidase for methotrexate toxicity.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6530-6530 ◽  
Author(s):  
Brigitte C. Widemann ◽  
Nalini Jayaprakash ◽  
Scott C. Howard ◽  
Claire Daugherty ◽  
Nikhil Chauhan ◽  
...  
Keyword(s):  
Renal Impairment ◽  
Renal Toxicity ◽  
Lymphoblastic Leukemia ◽  
Osteogenic Sarcoma ◽  
High Dose ◽  
Compassionate Use ◽  
Non Hodgkin Lymphoma ◽  
Carboxypeptidase G2 ◽  
Dose Methotrexate ◽  
The Us

6530 Background: High dose methotrexate (MTX) is used to treat acute lymphoblastic leukemia (ALL), osteogenic sarcoma, non-Hodgkin lymphoma (NHL), and other cancers. MTX-associated renal impairment with delayed MTX elimination develops after 2 to 10% of treatment cycles, exposing patients to elevated MTX concentrations with potential for enhanced MTX toxicity and prolonged hospitalization. Glucarpidase, a recombinant form of carboxypeptidase G2, rapidly hydrolyzes MTX into inactive metabolites and provides an alternate way of clearance in patients with delayed MTX elimination. Methods: From November 1993 to June 2009, 492 patients experiencing renal toxicity and delayed elimination of MTX were treated with glucarpidase (50 U/kg intravenously) in compassionate use trials conducted in the US and EU. Their outcomes are presented here. Results: The median age of the 492 patients was 18 yrs (range: 5 wks to 85 yrs). Sixty-three percent were male. Forty-one percent had NHL, 30% osteogenic sarcoma, 23% ALL, and 7% other malignancies. The median pre-glucarpidase MTX concentration was 17 µmol/L. Seventy-six percent of patients received 1 dose of glucarpidase, 22% received 2 doses, and 2% received 3 doses. The first dose of glucarpidase was given at a median of 3 days after MTX administration. One-hundred and fifty-six patients had MTX concentrations determined by HPLC. At the first measurement (median 15 minutes post-glucarpidase) MTX was reduced by a median of 99% relative to the pre-glucarpidase baseline. At the last measurement (median 40 hrs post-glucarpidase) median MTX reduction remained at 99% compared with baseline. In 410 patients with pre-glucarpidase renal impairment measured as CTCAE Grade 2 or higher, 64% recovered to Grade 0 or 1 after a median of 12.5 days post-glucarpidase. Glucarpidase was well-tolerated overall; adverse events included paresthesia (2.0%), flushing (1.8%) and headache (1.0%). Eight percent of patients died within 30 days of glucarpidase administration of causes unrelated to glucarpidase, as judged by the treating physician. Conclusions: Glucarpidase is well-tolerated and reduces MTX concentrations by 99% within 15 min of administration in patients with impaired renal clearance of MTX.

scholarly journals Pretreatment Plasma Folate Modulates the Pharmacodynamic Effect of High-Dose Methotrexate in Children with Acute Lymphoblastic Leukemia and Non-Hodgkin Lymphoma: “Folate Overrescue” Concept Revisited

2006 ◽  
Vol 52 (4) ◽  
pp. 692-700 ◽  
Author(s):  
Jaroslav Sterba ◽  
Ladislav Dusek ◽  
Regina Demlova ◽  
Dalibor Valik
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hodgkin Lymphoma ◽  
Lymphoblastic Leukemia ◽  
Plasma Homocysteine ◽  
Whole Body ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Plasma Folate ◽  
Non Hodgkin Lymphoma ◽  
Dose Methotrexate

Abstract Background: To evaluate the influence of pretreatment plasma folate concentrations on methotrexate exposure in children with acute lymphoblastic leukemia/non-Hodgkin lymphoma treated with high-dose methotrexate, we assessed time profiles of plasma homocysteine, folate, and vitamin B12 concentrations in children treated with high-dose methotrexate with leucovorin rescue. Methods: We analyzed 98 treatment courses. The study endpoints were to determine how methotrexate exposure is related to homocysteine accumulation and whether it is influenced by pretreatment plasma folate. Results: Peak concentrations of homocysteine increased from the start of the intravenous infusion through cessation of methotrexate therapy up to time point t42, when this trend was reversed by administration of folinic acid. The area under the curve (AUC) for plasma homocysteine showed decreasing course-to-course tendencies with a statistically significant decrease only between courses 1 and 2 (P ≤0.05), indicating decreased whole-body homocysteine accumulation in response to administration of consecutive methotrexate courses. Therapeutic courses with low initial folate concentrations (≤10 nmol/L) gave significantly higher responses in homocysteine accumulation expressed both as hcysAUC0–66 h and the peak t42 homocysteine concentrations than did courses with initial folate >10 nmol/L. Correspondingly, in the courses with low initial folate, peak plasma concentrations of methotrexate were significantly higher than in courses with high precourse concentrations of plasma folate. Conclusion: Endogenous pretreatment plasma folate modulates the magnitude of the methotrexate effect, providing support for a “folate overrescue” concept.

scholarly journals Renal function as a predicting model for plasma methotrexate concentration after high-dose methotrexate chemotherapy in pediatric malignancy

2017 ◽  
Vol 7 (2) ◽  
pp. 74-79 ◽  
Author(s):  
Kaveh Jaseb ◽  
Ehsan Ghaedi ◽  
Mohadeseh Shahin ◽  
Majid Mirmohamadkhani ◽  
Parisa Javadian ◽  
...  
Keyword(s):  
Renal Function ◽  
Renal Toxicity ◽  
Lymphoblastic Leukemia ◽  
Developed Countries ◽  
High Dose ◽  
Cross Sectional ◽  
Non Hodgkin Lymphoma ◽  
Major Route ◽  
High Doses ◽  
Methotrexate Chemotherapy

Introduction: Methotrexate (MTX) is the most generally administered antimetabolite in pediatric cancers. Renal excretion is the major route of elimination of MTX. However, renal toxicity and delayed MTX elimination is a particular concern and direct serum MTX concentration is a gold standard for renal toxicity monitoring. However, checking plasma MTX concentrations in most oncology institutions is not always possible especially in less developed countries. Objectives: The purpose of this study was to further assess the renal function after administration of high-dose MTX by parameters such as serum creatinine and Cr clearance rate. Patients and Methods: This is a cross-sectional descriptive analytic study. The study was conducted on children with acute lymphoblastic leukemia, non-Hodgkin lymphoma and osteosarcoma receiving high doses MTX. Patients’ age was ranged from 5 to 16 years. Serum MTX concentration and serum Cr were measured at 24, 48 and 96 hours after receiving MTX and then Cr clearance calculated based on available formulas. All the statistical analyses were done by SPSS 20.0 statistical software Results: This study was performed on 4 patients with osteosarcoma, 3 patients with leukemia and one patient with lymphoma. MTX concentration reduced significantly during 96 hours (P<0.001). A significant correlation between Cr clearance at 48 hours and the average of serum MTX concentration (P=0.001) were observed. Furthermore there were significant correlations between Cr at 24 hours (P=0.003), 48 hours (P=0.009) and 96 hours (P=0.044), with the average of serum MTX concentration. Conclusion: Our findings indicated that serum Cr and Cr clearance can be used to estimate the average of serum MTX concentrations.

scholarly journals Methotrexate Associated Renal Impairment Is Related to Delayed Elimination of High-Dose Methotrexate

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Shi-Long Yang ◽  
Fen-Ying Zhao ◽  
Hua Song ◽  
Di-Ying Shen ◽  
Xiao-Jun Xu
Keyword(s):  
Renal Function ◽  
Renal Impairment ◽  
Serum Creatinine ◽  
Lymphoblastic Leukemia ◽  
Serum Creatinine Concentration ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Creatinine Ratio ◽  
Creatinine Concentration ◽  
Dose Methotrexate

Although Methotrexate (MTX) is an effective drug for the treatment of acute lymphoblastic leukemia (ALL), the toxicity remains a significant problem. In this prospective study, fifty-four patients with ALL were enrolled. 3 g or 5 g MTX/m2was administered over 24 hours. Serum MTX concentrations were determined in 24, 48, and 96 hours after MTX infusion. Serum creatinine concentrations and creatinine clearance rate (CCR) were determined before and 24 and 48 hours after MTX infusion. A total of 173 courses of MTX infusion were administered. The serum creatinine concentrations did not change much after MTX infusion while the CCR was gradually decreased. MTX clearance status was independently related to CCR decrease, with the risk of 8.07 to develop renal impairment in patients with delayed MTX elimination. Serum creatinine concentration, serum creatinine ratio, CCR, and CCR ratio at 24 hours were all related to MTX elimination delay. Patients with serum creatinine level >35.0 μmol/L, creatinine ratio >1.129, or CCR <100.0 mL/min were more likely to undergo MTX elimination delay. In conclusion, MTX could induce transient renal impairment and compromised renal function will delay MTX clearance. The serum creatinine concentration and the ratio and CCR are useful tools for evaluating MTX elimination status.

scholarly journals Reduced dose folinic acid rescue after rapid high-dose methotrexate clearance is not associated with increased toxicity in a pediatric cohort

2021 ◽  
Author(s):  
Riitta Niinimäki ◽  
Henri Aarnivala ◽  
Joanna Banerjee ◽  
Tytti Pokka ◽  
Kaisa Vepsäläinen ◽  
...  
Keyword(s):  
Folinic Acid ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Optimal Dosage ◽  
High Dose Methotrexate ◽  
Reduced Dose ◽  
Dose Methotrexate ◽  
Antileukemic Effect ◽  
Folinic Acid Rescue ◽  
High Doses

Abstract Purpose Low doses of folinic acid (FA) rescue after high-dose methotrexate (HD-MTX) have been associated with increased toxicity, whereas high doses may be related to a decreased antileukemic effect. The optimal dosage and duration of FA rescue remain controversial. This study was designed to investigate, whether a shorter duration of FA rescue in the setting of rapid HD-MTX clearance is associated with increased toxicity. Methods We reviewed the files of 44 children receiving a total of 350 HD-MTX courses during treatment for acute lymphoblastic leukemia according to the NOPHO ALL-2000 protocol. Following a 5 g/m2 HD-MTX infusion, pharmacokinetically guided FA rescue commenced at hour 42. As per local guidelines, the patients received only one or two 15 mg/m2 doses of FA in the case of rapid MTX clearance (serum MTX ≤ 0.2 μmol/L at hour 42 or hour 48, respectively). Data on MTX clearance, FA dosing, inpatient time, and toxicities were collected. Results Rapid MTX clearance was observed in 181 courses (51.7%). There was no difference in the steady-state MTX concentration, nephrotoxicity, hepatotoxicity, neutropenic fever, or neurotoxicity between courses followed by rapid MTX clearance and those without. One or two doses of FA after rapid MTX clearance resulted in a 7.8-h shorter inpatient time than if a minimum of three doses of FA would have been given. Conclusion A pharmacokinetically guided FA rescue of one or two 15 mg/m2 doses of FA following HD-MTX courses with rapid MTX clearance results in a shorter hospitalization without an increase in toxic effects.

scholarly journals High-dose methotrexate vs. Capizzi methotrexate for the treatment of childhood T-cell acute lymphoblastic leukemia

2018 ◽  
Vol 10 ◽  
pp. 44-51 ◽  
Author(s):  
Wasil Jastaniah ◽  
Naglla Elimam ◽  
Khalid Abdalla ◽  
Aeshah A. AlAzmi ◽  
Mohammed Aseeri ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Dose Methotrexate ◽  
Cell Acute Lymphoblastic Leukemia
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