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The Oncologist Dec 2016: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered... (Review)
Review
UNLABELLED
: High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m, is used to treat a range of adult and childhood cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI) in 2%-12% of patients. Nephrotoxicity results from crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. AKI and other toxicities of high-dose methotrexate can lead to significant morbidity, treatment delays, and diminished renal function. Risk factors for methotrexate-associated toxicity include a history of renal dysfunction, volume depletion, acidic urine, and drug interactions. Renal toxicity leads to impaired methotrexate clearance and prolonged exposure to toxic concentrations, which further worsen renal function and exacerbate nonrenal adverse events, including myelosuppression, mucositis, dermatologic toxicity, and hepatotoxicity. Serum creatinine, urine output, and serum methotrexate concentration are monitored to assess renal clearance, with concurrent hydration, urinary alkalinization, and leucovorin rescue to prevent and mitigate AKI and subsequent toxicity. When delayed methotrexate excretion or AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase are usually sufficient to allow renal recovery without the need for dialysis. Prompt recognition and effective treatment of AKI and associated toxicities mitigate further toxicity, facilitate renal recovery, and permit patients to receive other chemotherapy or resume HDMTX therapy when additional courses are indicated.
IMPLICATIONS FOR PRACTICE
High-dose methotrexate (HDMTX), defined as a dose higher than 500 mg/m, is used for a range of cancers. Although HDMTX is safely administered to most patients, it can cause significant toxicity, including acute kidney injury (AKI), attributable to crystallization of methotrexate in the renal tubular lumen, leading to tubular toxicity. When AKI occurs despite preventive strategies, increased hydration, high-dose leucovorin, and glucarpidase allow renal recovery without the need for dialysis. This article, based on a review of the current associated literature, provides comprehensive recommendations for prevention of toxicity and, when necessary, detailed treatment guidance to mitigate AKI and subsequent toxicity.
Topics: Acute Kidney Injury; Antimetabolites, Antineoplastic; Bone Marrow; Chemical and Drug Induced Liver Injury; Crystallization; Humans; Leucovorin; Methotrexate; Mucositis; gamma-Glutamyl Hydrolase
PubMed: 27496039
DOI: 10.1634/theoncologist.2015-0164 -
Cureus Sep 2022Methotrexate (MTX) is significantly more effective than and has a considerable advantage over placebo in patients with severe and persistent rheumatoid arthritis (RA).... (Review)
Review
Methotrexate (MTX) is significantly more effective than and has a considerable advantage over placebo in patients with severe and persistent rheumatoid arthritis (RA). The drug is used to treat a variety of malignant disorders (leukemia and cancer of the lung, breast, and uterus) and ectopic pregnancy. As its side effects are outweighed by its effectiveness, MTX is a first-line antirheumatic drug in many countries. MTX is found in extracellular compartments, such as the synovium, as well as other organs, such as the kidney and liver. To improve treatment, increase adherence, and decrease mortality in MTX therapy, it is essential to reduce its toxicity and understand its side effects. Therefore, this comprehensive review was conducted to assist physicians and researchers in better understanding the toxicity of MTX and how to deal with this toxicity. MTX is eliminated via the kidneys, which are capable of excretion and reabsorption within the renal tubules. Although higher doses of MTX (known as high-dose MTX (HD-MTX), defined as doses of 500 mg/m or greater) are often more beneficial, they can produce toxicity and side effects such as bone marrow suppression, pulmonary toxicity, nephrotoxicity, hematologic toxicity, and an increased risk of infections. Treatment of severe MTX toxicity has three main goals: clearance of MTX from the bloodstream, folinic acid therapy, and organ treatment. Leucovorin is highly beneficial in preventing myelosuppression, gastric toxicity, and neurotoxic effects after HD-MTX therapy. The preferred antidote for MTX poisoning is folinic acid. Glucarpidase has been licensed for the treatment of high plasma MTX levels of >1 μmol/L in patients with compromised renal function who have delayed MTX elimination. In patients with renal deficiency, a lower initial dose is considered with an estimated glomerular filtration rate (eGFR) between 30 and 59 mL/minute. These patients need to be monitored, and a more gradual dosage increase and a lower weekly maximum should be considered regarding their general health situation. MTX is contraindicated in patients with RA if the eGFR is <30 mL/minute.
PubMed: 36312688
DOI: 10.7759/cureus.29518 -
The Oncologist Jun 2006Methotrexate (MTX) is one of the most widely used anti-cancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an... (Review)
Review
Methotrexate (MTX) is one of the most widely used anti-cancer agents, and administration of high-dose methotrexate (HDMTX) followed by leucovorin (LV) rescue is an important component in the treatment of a variety of childhood and adult cancers. HDMTX can be safely administered to patients with normal renal function by the use of alkalinization, hydration, and pharmacokinetically guided LV rescue. Despite these measures, HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma treated on clinical trials. Prompt recognition and treatment of MTX-induced renal dysfunction are essential to prevent potentially life-threatening MTX-associated toxicities, especially myelosuppression, mucositis, and dermatitis. In addition to conventional treatment approaches, dialysis-based methods have been used to remove MTX with limited effectiveness. More recently carboxypeptidase-G(2) (CPDG(2)), a recombinant bacterial enzyme that rapidly hydrolyzes MTX to inactive metabolites, has become available for the treatment of HDMTX-induced renal dysfunction. CPDG(2) administration has been well tolerated and resulted in consistent and rapid reductions in plasma MTX concentrations by a median of 98.7% (range, 84%-99.5%). The early administration of CPDG(2) in addition to LV may be beneficial for patients with MTX-induced renal dysfunction and significantly elevated plasma MTX concentrations.
Topics: Antimetabolites, Antineoplastic; Humans; Leucovorin; Methotrexate; Neoplasms; Renal Insufficiency; gamma-Glutamyl Hydrolase
PubMed: 16794248
DOI: 10.1634/theoncologist.11-6-694 -
The Oncologist Jan 2018Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a...
UNLABELLED
Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a treatment approved by the Food and Drug Administration for high methotrexate concentrations in the context of kidney dysfunction, but the guidelines for when to use it are unclear. An expert panel was convened to provide specific, expert consensus guidelines for the use of glucarpidase in patients who develop HDMTX-induced nephrotoxicity and delayed methotrexate excretion. The guideline provides recommendations to identify the population of patients who would benefit from glucarpidase rescue by more precisely defining the absolute methotrexate concentrations associated with risk for severe or life-threatening toxicity at several time points after the start of an HDMTX infusion. For an HDMTX infusion ≤24 hours, if the 36-hour concentration is above 30 µM, 42-hour concentration is above 10 µM, or 48-hour concentration is above 5 µM and the serum creatinine is significantly elevated relative to the baseline measurement (indicative of HDMTX-induced acute kidney injury), glucarpidase may be indicated. After a 36- to 42-hour HDMTX infusion, glucarpidase may be indicated when the 48-hour methotrexate concentration is above 5 µM. Administration of glucarpidase should optimally occur within 48-60 hours from the start of the HDMTX infusion, because life-threatening toxicities may not be preventable beyond this time point.
IMPLICATIONS FOR PRACTICE
Glucarpidase is a rarely used medication that is less effective when given after more than 60 hours of exposure to high-dose methotrexate, so predicting early which patients will need it is imperative. There are no currently available consensus guidelines for the use of this medication. The indication on the label does not give specific methotrexate concentrations above which it should be used. An international group of experts was convened to develop a consensus guideline that was specific and evidence-based to identify the population of patients who would benefit from glucarpidase.
Topics: Acute Kidney Injury; Antimetabolites, Antineoplastic; Consensus; Dose-Response Relationship, Drug; Follow-Up Studies; Humans; Methotrexate; Neoplasms; Practice Guidelines as Topic; Recombinant Proteins; gamma-Glutamyl Hydrolase
PubMed: 29079637
DOI: 10.1634/theoncologist.2017-0243 -
Clinical Pharmacology in Drug... Mar 2022Glucarpidase rapidly decomposes methotrexate. A phase 1 study of glucarpidase in an open-label, randomized parallel group was conducted to evaluate the safety,...
Glucarpidase rapidly decomposes methotrexate. A phase 1 study of glucarpidase in an open-label, randomized parallel group was conducted to evaluate the safety, pharmacokinetics, and other pharmacologic effects in Japanese healthy volunteers without methotrexate treatment. A dose of 50 U/kg (n = 8) or 20 U/kg (n = 8) of glucarpidase was administered as an intravenous injection, with 1 repeated dose at 48 hours after the first dose. No dose-limiting toxicities, no significant clinical examination findings, and no clinically relevant differences between dose levels were observed. The pharmacokinetic parameters at a first dose of 20 or 50 U/kg were similar to those at a second dose and were as follows: half-life, 7.45 and 7.25 hours; area under the plasma concentration-time curve from time 0 to infinity, 8.25 and 19.05 μg·h/mL; total clearance, 4.85 and 5.47 mL/min; and volume of distribution during the elimination phase, 3.12 and 3.41 L, respectively. The area under the plasma concentration-time curve increased in a generally linear dose-proportional manner. An ethnicity specificity in the pharmacokinetic profile was not observed in Japanese volunteers. The serum folate concentration decreased after glucarpidase administration in all the volunteers. The production of anti-glucarpidase antibody was observed in many cases in both cohorts. Although the long-term effect of anti-glucarpidase antibody will need to be investigated in the future, the effects produced by the anti-glucarpidase antibody were not influenced by the pharmacokinetics of glucarpidase within 96 hours after the first dose. The observed safety and tolerability, pharmacokinetics, and pharmacodynamics support the continued evaluation of glucarpidase in the patients with lethal methotrexate toxicities.
Topics: Healthy Volunteers; Humans; Injections, Intravenous; Methotrexate; Recombinant Proteins; gamma-Glutamyl Hydrolase
PubMed: 34435467
DOI: 10.1002/cpdd.1010 -
BMC Cancer Jan 2022High-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration...
BACKGROUND
High-dose methotrexate (HD-MTX) has broad use in the treatment of central nervous system (CNS) malignancies but confers significant toxicity without inpatient hydration and monitoring. Glucarpidase is a bacterial recombinant enzyme dosed at 50 units (u)/kg, resulting in rapid systemic MTX clearance. The aim of this study was to demonstrate feasibility of low-dose glucarpidase to facilitate MTX clearance in patients with CNS lymphoma (CNSL).
METHODS
Eight CNSL patients received HD-MTX 3 or 6 g/m and glucarpidase 2000 or 1000u 24 h later. Treatments repeated every 2 weeks up to 8 cycles.
RESULTS
Fifty-five treatments were administered. Glucarpidase 2000u yielded > 95% reduction in plasma MTX within 15 min following 33/34 doses (97.1%) and glucarpidase 1000u yielded > 95% reduction following 15/20 doses (75%). Anti-glucarpidase antibodies developed in 4 patients and were associated with MTX rebound. In CSF, glucarpidase was not detected and MTX levels remained cytotoxic after 1 (3299.5 nmol/L, n = 8) and 6 h (1254.7 nmol/L, n = 7). Treatment was safe and well-tolerated. Radiographic responses in 6 of 8 patients (75%) were as expected following MTX-based therapy.
CONCLUSIONS
This study demonstrates feasibility of planned-use low-dose glucarpidase for MTX clearance and supports the hypothesis that glucarpidase does not impact MTX efficacy in the CNS.
CLINICAL TRIAL REGISTRATION
NCT03684980 (Registration date 26/09/2018).
Topics: Aged; Antineoplastic Agents; Central Nervous System Neoplasms; Female; Humans; Lymphoma; Male; Methotrexate; Middle Aged; Recombinant Proteins; gamma-Glutamyl Hydrolase
PubMed: 35027038
DOI: 10.1186/s12885-021-09164-x -
Journal of Clinical Oncology : Official... Sep 2010To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G(2)), leucovorin, and thymidine in the management and outcome of patients with...
PURPOSE
To assess the role of the recombinant bacterial enzyme, glucarpidase (carboxypeptidase-G(2)), leucovorin, and thymidine in the management and outcome of patients with high-dose methotrexate (HDMTX) -induced nephrotoxicity.
METHODS
Patients with HDMTX-induced nephrotoxicity received one to three doses of intravenous (IV) glucarpidase and leucovorin rescue. The initial cohort (n = 35) also received thymidine by continuous IV infusion. Subsequently, thymidine was restricted to patients with prolonged exposure (> 96 hours) to methotrexate (MTX) or with substantial MTX toxicity at study entry. Plasma MTX, leucovorin, and 5-methyltetrahydrofolate (5-mTHF) concentrations were measured pre- and postglucarpidase. Toxicities were monitored, and logistic regression analysis was used to assess the relationship of baseline characteristics to the development of severe toxicity and death.
RESULTS
Glucarpidase was administered at a median of 96 hours (receiving thymidine, n = 44) and 66 hours (not receiving thymidine, n = 56) after the start of the MTX infusion. Plasma MTX concentrations decreased within 15 minutes of glucarpidase by 98.7%. Plasma 5-mTHF concentrations also decreased more than 98% after administration of glucarpidase. Of 12 deaths, six were directly attributed to irreversible MTX toxicity. Presence of grade 4 toxicity before administration of glucarpidase, inadequate initial increase in leucovorin dosing, and administration of glucarpidase more than 96 hours after the start of the MTX infusion were associated with development of grade 4 and 5 toxicity.
CONCLUSION
Early intervention with the combination of leucovorin and glucarpidase is highly effective in patients who develop HDMTX-induced renal dysfunction. Severe toxicity and mortality occurred in patients in whom glucarpidase rescue was delayed and occurred despite thymidine administration.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Infant; Kidney Diseases; Leucovorin; Male; Methotrexate; Middle Aged; Thymidine; gamma-Glutamyl Hydrolase
PubMed: 20679598
DOI: 10.1200/JCO.2009.25.4540 -
The Netherlands Journal of Medicine Jan 2018High-dose methotrexate (MTX) induced acute kidney injury can lead to sustained high systemic MTX levels and severe toxicity. A 39-year-old man with lymphoblastic T-cell... (Review)
Review
High-dose methotrexate (MTX) induced acute kidney injury can lead to sustained high systemic MTX levels and severe toxicity. A 39-year-old man with lymphoblastic T-cell lymphoma was admitted to our intensive care unit with elevated serum creatinine and prolonged high serum MTX levels. Standard supportive care was complemented by the addition of a relatively novel agent, glucarpidase, which rapidly lowered the extracellular levels of MTX. Several case series support this effect of glucarpidase, but no randomised controlled trial has been performed to show this leads to better outcome. Furthermore, glucarpidase might negatively affect leucovorin rescue therapy. Lastly, glucarpidase carries a significant financial burden. Based on the current evidence we cannot recommend glucarpidase until further research elucidates its role in the treatment of MTX toxicity. There is no randomised clinical evidence to support its use in severe cases and theoretical evidence suggests that after prolonged exposure to high MTX levels glucarpidase administration is unable to reverse high intracellular MTX. We recommend that new randomised controlled studies be aimed at early administration of glucarpidase in patients with high MTX levels shortly after administration to prevent direct toxic effects of MTX on kidney function and further uptake into cells.
Topics: Acute Kidney Injury; Adult; Antimetabolites, Antineoplastic; Humans; Male; Methotrexate; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Recombinant Proteins; gamma-Glutamyl Hydrolase
PubMed: 29380731
DOI: No ID Found -
ClinicoEconomics and Outcomes Research... 2019Glucarpidase (Voraxaze) is used to treat methotrexate (Mtx) toxicity in patients with delayed Mtx clearance due to impaired renal function. We examine hospital length of...
PURPOSE
Glucarpidase (Voraxaze) is used to treat methotrexate (Mtx) toxicity in patients with delayed Mtx clearance due to impaired renal function. We examine hospital length of stay (LOS), mortality, and readmission rates for Medicare cancer patients with delayed clearance of Mtx treated with glucarpidase.
METHODS
Using 2010-2017 Medicare claims data, we identified glucarpidase patients as those hospitalized with indications of select lymphomas or leukemia, inpatient chemotherapy, and glucarpidase treatment. We assessed outcomes of glucarpidase patients relative to those experienced by patients treated for presumed Mtx toxicity using other therapies. These nonglucarpidase patients were identified with a diagnosis of primary central nervous system lymphoma, indications of cancer-chemotherapy toxicity, and acute kidney injury during hospitalization (not present on admission), and were divided into two groups: treated with dialysis (dialysis) and treated with or without dialysis (dialysis). Inverse-probability treatment weighting using propensity scores was used to adjust for differences between groups.
RESULTS
Patients treated with glucarpidase (n=30) had an average LOS of 14.7 days. They had inpatient, 30-day, and 90-day mortality rates of 3.3%, 13.3%, and 16.7%, respectively, and a 90-day all-cause unplanned readmission rate of 24.1%. The dialysis and dialysis groups, respectively, had higher average LOS (40.2, 21.9), higher inpatient mortality (50.6%, 20.8%), and higher 90-day mortality (58.6%, 37.6%). No statistically significant differences in 30-day mortality or 90-day readmission rates were detected between the glucarpidase group and either of the nonglucarpidase groups. Unobservable differences in patient severity may impact the interpretation of our findings.
CONCLUSION
Medicare cancer patients with presumed Mtx toxicity receiving conventional treatment experience long hospitalizations, high intensive-care unit use and high mortality. Glucarpidase patients had lower LOS, inpatient mortality, and 90-day mortality than the non-glucarpidase patients.
PubMed: 30799942
DOI: 10.2147/CEOR.S188786 -
Cancer Chemotherapy and Pharmacology Jan 2022High-dose methotrexate (HDMTX)-associated acute kidney injury with delayed MTX clearance has been linked to an excess in MTX-induced toxicities. Glucarpidase is a...
PURPOSE
High-dose methotrexate (HDMTX)-associated acute kidney injury with delayed MTX clearance has been linked to an excess in MTX-induced toxicities. Glucarpidase is a recombinant enzyme that rapidly hydrolyzes MTX into non-toxic metabolites. The recommended dose of glucarpidase is 50 U/kg, which has never been formally established in a dose finding study in humans. Few case reports, mostly in children, suggest that lower doses of glucarpidase might be equally effective in lowering MTX levels.
METHODS
Seven patients with toxic MTX plasma concentrations following HDMTX therapy were treated with half-dose glucarpidase (mean 25 U/kg, range 17-32 U/kg). MTX levels were measured immunologically as well as by liquid chromatography-mass spectrometry (LC-MS). Toxicities were assessed according to National Cancer Institute-Common Terminology Criteria for Adverse Events (CTCAE) v5.0.
RESULTS
All patients experienced HDMTX-associated kidney injury (median increase in creatinine levels within 48 h after HDMTX initiation compared to baseline of 251%, range 80-455%) and showed toxic MTX plasma concentrations (range 3.1-182.4 µmol/L) before glucarpidase injection. The drug was administered 42-70 h after HDMTX initiation. Within one day after glucarpidase injection, MTX plasma concentrations decreased by ≥ 97.7% translating into levels of 0.02-2.03 µmol/L. MTX rebound was detected in plasma 42-73 h after glucarpidase initiation, but concentrations remained consistent at < 10 µmol/L.
CONCLUSION
Half-dose glucarpidase seems to be effective in lowering MTX levels to concentrations manageable with continued intensified folinic acid rescue.
Topics: Acute Kidney Injury; Adult; Aged; Antimetabolites, Antineoplastic; Female; Humans; Male; Methotrexate; Middle Aged; Recombinant Proteins; Thrombocytopenia; gamma-Glutamyl Hydrolase
PubMed: 34669022
DOI: 10.1007/s00280-021-04361-8