Glucarpidase for Oncologic Emergency of Methotrexate Toxicity

Zosia Chustecka

June 14, 2012

June 14, 2012 (Chicago, Illinois) — Some cancer patients being treated with high doses of methotrexate, despite optimal supportive care, can develop renal impairment, which can cause blood levels of methotrexate to soar and create an oncologic emergency.

There is now an immediate rescue treatment that usually requires only 1 intravenous dose.

The product, glucarpidase (Voraxaze, BTG International), was approved by the US Food and Drug Administration (FDA) earlier this year. The agency described it as "an important new treatment option."

Glucarpidase consistently reduces methotrexate blood levels by approximately 99% within 15 minutes, said Brigitte Widemann, MD, from the National Cancer Institute, Bethesda, Maryland. For some patients, this can be lifesaving, she told Medscape Medical News.

Dr. Widemann was discussing data on glucarpidase at a poster presentation here at the 2012 Annual Meeting of the American Society of Clinical Oncology.

Rare Event, But an Emergency

High-dose methotrexate is a standard chemotherapy used to treat a variety of adult and pediatric cancers, Dr. Widemann explained, but it causes kidney toxicity in about 2% to 10% of patients.

Kidney toxicity is thought to be the result of the precipitation of methotrexate and its metabolites in the renal tubules, she explained. Because the drug is primarily eliminated through renal excretion, the development of renal dysfunction results in sustained elevated methotrexate levels in the blood, which can markedly enhance methotrexate toxicities such as myelosuppression, mucositis, skin and liver toxicity, and encephalopathy.

The standard treatment for this oncologic emergency includes the administration of high doses of leucovorin and continued alkalinization and hydration, if feasible, Dr. Widemann explained. Methotrexate can be removed mechanically (e.g., with dialysis), but such methods are invasive, time-consuming, and have been shown to have limited effectiveness, she added.

Compassionate-Use Data

Dr. Widemann presented data on the use of glucarpidase in this clinical situation. They were gathered from compassionate-use clinical trials of glucarpidase conducted after 1993, when it first became available for investigational use.

By June 2009, glucarpidase had been given to 429 patients experiencing renal toxicity and delayed elimination of methotrexate.

These patients were being treated with high-dose methotrexate for osteosarcoma (30%), acute lymphoblastic leukemia (23%), non-Hodgkin's lymphoma (40%), or other cancers.

The majority (76%) received only 1 dose of glucarpidase (50 U/kg administered intravenously over 5 minutes). Another 22% of patients received 2 doses of glucarpidase, and 2% received 3 doses.

The median time between the administration of high-dose methotrexate and glucarpidase was 3 days. When patients were experiencing acute methotrexate toxicity and renal problems, median methotrexate blood level was 17 µmol/L, although some patients had levels as high as 1000 µmol/L, Dr. Widemann reported.

After the administration of glucarpidase, the blood levels of methotrexate fell dramatically and rapidly; they were reduced by 99% within 15 minutes. In many patients this decrease was sustained, Dr. Widemann added.

The FDA labeling for the product notes a "rapid and sustained" clinically important reduction in plasma methotrexate levels (1 µmol/L or below at 15 minutes) after glucarpidase administration that is sustained for 8 days.

In addition to glucarpidase, all patients received intravenous hydration, urinary alkalization, and leucovorin rescue.

Glucarpidase was well tolerated, Dr. Widemann and colleagues report. Adverse events included paresthesia (reported by 2% of patients), flushing (1.8%), and headache (1%).

Of the 429 patients who received the drug on a compassionate-use basis, 34 (8%) died within 30 days of glucarpidase administration, but the treating physician in these cases judged the cause of death to be unrelated to glucarpidase.

"Glucarpidase provides a therapeutic option for clinicians treating patients with methotrexate toxicity," Dr. Widemann and her colleagues conclude.

In her discussion of the poster presentation, Jane Liesveld, MD, from the University of Rochester, New York, said that the data show that the use of glucarpidase to reduce methotrexate toxicity is feasible, and noted that it does not have an effect on overall disease outcome.

The oncology community is happy that it is available.

It is an advance in therapy, she told Medscape Medical News; it can save patients from having to undergo dialysis and can prevent severe toxicity, which can lead to renal failure, painful mouth sores, and liver toxicity.

"I don't expect that it will be widely used," Dr. Liesveld said, but "the oncology community is happy that it is available."

Useful to Stock in Pharmacies

Dr. Widemann noted that it will be useful to have the product in pharmacies at cancer centers that administer high-dose methotrexate. "If you give it as soon as you recognize acute renal impairment and elevated methotrexate concentrations, there is a good chance that you will prevent toxicity," she said.

"It is important to continue with leucovorin because glucarpidase does not enter into cells, whereas leucovorin does," she emphasized.

Glucarpidase works by cleaving the methotrexate into 2 parts that are no longer toxic, she explained. The product is a recombinant form of the bacterial enzyme carboxypeptidase G2, and works by rapidly hydrolyzing methotrexate into inactive noncytotoxic metabolites. These are not eliminated by the kidney, providing an alternative clearance route in patients who have acute kidney injury and delayed renal elimination.

2012 Annual Meeting of the American Society of Clinical Oncology: Abstract 6530. Presented June 1, 2012.

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