An open-label, multicenter study of polyethylene glycol-L-asparaginase for the treatment of acute lymphoblastic leukemia
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L J Ettinger1, J Kurtzberg, P A Voûte
1Department of Pediatrics, UMDNJ, Robert Wood Johnson Medical School, New Brunswick 08903.
Insights
Polyethylene glycol-L-asparaginase (PEG-L-asparaginase) shows promise in treating relapsed acute lymphoblastic leukemia (ALL) with reduced hypersensitivity. This modified enzyme offers a safer alternative for pediatric ALL patients.
Area of Science:
- Oncology
- Hematology
- Pharmacology
Background:
- L-asparaginase is a critical component in pediatric acute lymphoblastic leukemia (ALL) treatment.
- Native L-asparaginase can cause severe hypersensitivity reactions due to its foreign protein nature.
- Polyethylene glycol (PEG) conjugation of L-asparaginase aims to mitigate these toxicities.
Purpose of the Study:
- To evaluate the safety and efficacy of PEG-L-asparaginase in children with relapsed ALL.
- To assess the immunogenicity and plasma half-life of PEG-L-asparaginase compared to the native enzyme.
Main Methods:
- A Phase II, open-label clinical trial (ASP-201A) was conducted.
- Patients received PEG-L-asparaginase (2000 IU/m2 every 2 weeks) as monotherapy initially, followed by combination therapy with vincristine and prednisone.
- Prior treatment with native L-asparaginase was permitted, including patients with prior hypersensitivity.
Main Results:
- Complete or partial remission was achieved by 22% of patients during monotherapy and 78% by the end of induction.
- No anaphylaxis was observed; mild allergic reactions occurred but did not necessitate treatment discontinuation.
- Hyperglycemia and pancreatitis incidence was lower than historical data for native L-asparaginase.
Conclusions:
- PEG-L-asparaginase can be administered safely in patients with relapsed ALL.
- The toxicity profile of PEG-L-asparaginase is comparable to native L-asparaginase.
- Single-agent activity of PEG-L-asparaginase was confirmed in pediatric ALL patients with bone marrow relapse.
Background:
L-asparaginase has been a mainstay of therapy along with vincristine and prednisone in the treatment of acute lymphoblastic leukemia (ALL) in children for almost 30 years. Because L-asparaginase is a foreign protein, the potential exists for severe, dose-limiting hypersensitivity reactions. To reduce this toxicity, L-asparaginase has been linked with polyethylene glycol (PEG).
Methods:
Patients with ALL in relapse were entered in a Phase II, open-label clinical trial (ASP-201A) to evaluate the toxicity and efficacy of PEG-L-asparaginase. PEG-L-asparaginase has demonstrated potential low immunogenicity and a prolonged plasma half-life relative to native enzyme. PEG-L-asparaginase (2000 IU/m2 every 2 weeks) was used as single-agent induction therapy during an initial 14-day investigational window. Thereafter, the regimen consisted of PEG-L-asparaginase, vincristine, and prednisone. Patients also were allowed to receive doxorubicin and intrathecal chemotherapy beginning on day 14. All patients had been treated previously with one or more courses of native L-asparaginase; one of these patients was hypersensitive to L-asparaginase at enrollment.
Results:
During the 14-day investigational window with PEG-L-asparaginase monotherapy, 22% of patients examined achieved a complete or partial remission. By completion of the 35-day induction period, 78% (or 14 of 18) of evaluated patients achieved complete or partial remission. Anaphylaxis did not occur during treatment. Mild urticaria and mild local allergic reactions occurred in five patients but did not cause discontinuation of treatment. The incidence of hyperglycemia and pancreatitis was less than expected from historic data published for previous studies with native L-asparaginase.
Conclusions:
As administered in this study, PEG-L-asparaginase can be given safely with a spectrum of toxicity similar to that of native L-asparaginase. Single-agent activity was documented in patients with ALL in bone marrow relapse.