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IV pegylated asparaginase shows promise for pediatric ALL
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IV pegylated asparaginase yielded similar efficacy as intramuscular native Escherichia coli L-asparaginase without increasing toxicity in pediatric patients with newly diagnosed acute lymphoblastic leukemia, according to the results of a phase 3 trial.
Further, IV pegylated asparaginase (PEG-asparaginase) appeared to decrease patient anxiety, which supported its use as a first-line asparaginase preparation in this patient population.
L-asparaginase — a universal treatment for childhood ALL — is usually administered intramuscularly. PEG-asparaginase has a longer half-life and is potentially less immunogenic than native Escherichia coli and can be administered via IV, according to study background.
Thus, Lewis B. Silverman, MD, associate professor of pediatrics at Harvard Medical School and clinical director of the Pediatric Hematologic Malignancies Center at Dana-Farber Cancer Institute, and colleagues sought to compare the relative toxicity and efficacy of these two regimens in children with newly diagnosed ALL.
Researchers enrolled 551 children from 11 treatment centers in the U.S. and Canada and assigned them to an initial risk group based on baseline characteristics. Patients then underwent 32 days of induction therapy.
Overall, 526 patients achieved complete remission after induction. The researchers randomly assigned 463 of these patients to IV PEG-asparaginase (15 doses of 2,500 IU/m2 every 2 weeks; n = 232) or intramuscular native E. coli L-asparaginase (30 doses of 25,000 IU/m2 every week; n = 231) 7 weeks after study entry.
Most patients were initially classified as having standard-risk disease based on Dana-Farber Cancer Institute criteria (native E. coli L-asparaginase, 60%; IV PEG-asparaginase, 56%) and were aged younger than 10 years (native E. coli L-asparaginase, 76%; IV PEG-asparaginase, 71%).
Overall frequency of asparaginase-related toxicity — including allergy, pancreatitis and thrombotic or bleeding complications — served as the primary endpoint. DFS, serum asparaginase activity and quality of life during therapy served as secondary endpoints.
Median follow-up was 6 years (interquartile range [IQR], 5-7.1)
The two arms did not significantly differ in the overall frequency of asparaginase-related toxicities (28% vs. 26%) or in the individual frequency of allergy, pancreatitis, or thrombotic or bleeding events. The most common grade 3 or higher adverse events included bacterial or fungal infections (PEG-asparaginase, 20%; native E. coli L-asparaginase, 22%) and asparaginase-related allergic reactions (PEG-asparaginase, 6%; native E. coli L-asparaginase, 3%).
A similar proportion of patients assigned PEG-asparaginase achieved 5-year DFS rate (90%; 95% CI, 86-94) as patients assigned native E. coli L-asparaginase (89%; 95% CI, 85-93).
Researchers measured serum asparaginase activity 4, 11, 18 and 25 days after dosing. The median nadir serum asparaginase activity, as well as the proportion of patients with nadir serum asparaginase activity of at least 0.1 IU/mL, appeared significantly higher in the PEG-asparaginase
cohort at each time point (P ˂ .0001 for all).
Two hundred and two patients completed the optional health-related quality-of-life assessment (native E. coli L-asparaginase, n = 97; PEG-asparaginase, n = 105). Emotional functioning, pain and hurt, general fatigue, and sleep or rest fatigue scores appeared comparable between the cohorts; however, children assigned native intramuscular L-asparaginase, as well as their parent-proxies, reported significantly higher anxiety levels.
“Future trials should focus on reducing toxicity and improving the cost-effectiveness of IV PEG-asparaginase,” Silverman and colleagues wrote. “The high nadir serum asparaginase activity noted with IV PEG-asparaginase suggests that a lower dose might provide similar efficacy at a lower cost. … We recommend the use of IV PEG-asparaginase in the front-line treatment of children and adolescents with ALL whenever feasible.”
In an accompanying editorial, Carmelo Rizzari, MD, PhD, of the pediatric hematology and oncology unit at University of Milano-Bicocca in Italy, asserted that mounting evidence has confirmed PEG-asparaginase as the preferred preparation of asparaginase treatment.
“This option reduces the number of hospital visits and the frequency of immunological reactions (either silent inactivation or hypersensitivity reaction) and product shifts, and thus, additional treatment costs,” Rizzari wrote. “Moreover, when administered by IV, this treatment results in less anxiety for patients and parents. Ongoing protocols from different cooperative groups, including the current AIEOP-BFM ALL 2009 study (NCT01117441), have adopted this approach. Hopefully soon, additional information will be available to enable us to finally choose not only the best asparaginase preparation but also the best schedule and treatment drug monitoring program.” – by Cameron Kelsall
Disclosure: The NCI and Enzon Pharmaceuticals provided funding for this study. Silverman reports advisory board positions with JAZZ Pharmaceuticals and Sigma-Tau Pharmaceuticals. Other study researchers report personal fees from and advisory board roles with with JAZZ Pharmaceuticals and Sigma-Tau Pharmaceuticals, as well as employment roles with and shareholder interests in Infinity Pharmaceuticals. Rizzari reports personal fees from JAZZ Pharmaceuticals outside of the submitted work.
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