Alternate Drug Less Toxic, Less Effective Than Standard Treatment for ALL
Key Words: asparaginase, childhood cancer, leukemia. (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Now two new studies suggest that, given at the same dose, the standard E. coli form of the drug asparaginase -- a mainstay for more than 30 years in the treatment of ALL -- appears to be more effective, though more toxic, than another form known as Erwinia asparaginase.
In 1978, the U.S. Food and Drug Administration (FDA) approved asparaginase derived from the E. coli bacterium for the treatment of ALL. However, a number of children with ALL are allergic to it (between 5 and 40 percent, depending on the study). Pegaspargase, a modified E. coli asparaginase with less potential as an allergen, was approved by the FDA in 1994 for use in patients allergic to standard E. coli asparaginase. Still, some hypersensitive children find any form of the E. coli-derived drug intolerable.
Possibly less toxic is asparaginase derived from the Erwinia bacterium, which has been around since the 1970s. Though it has never been approved by the FDA, it is available under a special exception for children allergic to the E. coli form. (Erwinia asparaginase is also available in some European countries.) But is it just as effective as the E. coli-derived drug? And if so, at what dose?
In the two most recent studies, patients treated with standard E. coli asparaginase survived for longer, and had fewer relapses, than patients treated with Erwinia asparaginase. However, patients treated with E. coli asparaginase were more likely to have an adverse reaction to the treatment, such as a blood-clotting abnormality or an allergic reaction.
"These two studies provide the most convincing evidence to date that the two forms of asparaginase are not equivalent when administered at the same dose," said Malcolm Smith, M.D., Ph.D., of the National Cancer Institute's Cancer Therapy Evaluation Program.
One study, published in the journal Blood on April 15, 2002 (see the journal abstract), involved 700 patients with ALL and lymphoblastic non-Hodgkin lymphoma who were treated at pediatric cancer centers in Belgium, France and Portugal. The second study, presented Monday, May 20, 2002, at the American Society of Clinical Oncology annual meeting in Orlando, Fla., involved 247 patients with ALL treated in the United States. In both studies, children with newly diagnosed disease were randomly assigned to receive either E. coli asparaginase or Erwinia asparaginase.
In the European study, after six years of follow-up, 73 percent of patients treated with E. coli asparaginase had survived with no disease recurrence, compared with 60 percent of those treated with Erwinia asparaginase. Thirty-six percent of patients in the Erwinia group relapsed, compared with 23 percent of those in the E. coli group. Blood-clotting abnormalities occurred in 30 percent of patients in the E. coli group and in 12 percent of those in the Erwinia group.
In the U.S. study, after an average of three years of follow-up, 92 percent of patients treated with E. coli asparaginase survived with no disease recurrence, compared with 81 percent of those treated with Erwinia asparaginase. Nineteen percent of patients in the Erwinia group relapsed, compared with 7 percent of those in the E. coli group. Allergic reactions to treatment occurred in 30 percent of patients in the E. coli group, compared with 9 percent of those in the Erwinia group. Overall, 24 percent of patients treated with E. coli asparaginase experienced at least one adverse reaction to the treatment, compared with 9 percent of patients treated with Erwinia asparaginase.
"We conclude that Erwinia asparaginase was less toxic but also less effective than E. coli asparaginase," say the authors of the U.S. study, who were led by Lewis B. Silverman, M.D., of the Dana Farber Cancer Institute in Boston. The fact that Erwinia asparaginase is active in the body for a shorter time than E. coli asparaginase may account for its lower effectiveness, the authors suggest.
E. coli asparaginase should be used for first-line (initial) therapy and Erwinia asparaginase reserved for patients who are allergic to the E. coli form of the drug, conclude the authors of the European study, who were led by Michel Duval of the Robert-Debre Hospital in Paris, France.
These studies represent the latest refinement of therapy for children with ALL, said NCI's Smith: "As a result of superior treatments identified through randomized clinical trials, deaths from ALL have steadily declined in children over the past two decades." More than 85 percent of children diagnosed with ALL now survive for at least five years. More research is underway to optimize asparaginase therapy for children with ALL and possibly increase survival rates even further, he added.
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