An open-label, multicenter study of polyethylene glycol-L-asparaginase for the treatment of acute lymphoblastic leukemia

Abstract

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. Cancer 1995;75:1176–81.

Toxicity, pharmacology and feasibility of administration of PEG-L-asparaginase as consolidation therapy in patients undergoing bone marrow transplantation for acute lymphoblastic leukemia

“…They were similar to those described previously for PEG-L-A. 31,34 Of the 24 patients treated with the drug, five developed allergic reactions. Two had both wheezing and skin rash, and the drug was discontinued after each had received three doses.…”

“…Although it is moderately immunosuppressive, [24][25][26] it is usually not myelosuppressive; 27 it has a unique mechanism of action among available agents, 28 and no evidence of cross-resistance to other anti-cancer drugs. Although almost all relapsing ALL patients will have received the drug previously, l-asparaginase can be used repeatedly as part of successful remission induction, [29][30][31] suggesting that past exposure does not preclude an antileukemic response.…”

Pharmacodynamics and safety of intravenous pegaspargase during remission induction in adults aged 55 years or younger with newly diagnosed acute lymphoblastic leukemia

“…The binding preserves the enzymatic function of the drug, but decreases the immunogenicity of the protein, thus potentially reducing the risk of hypersensitivity reactions. [1][2][35][36][37][38] Pegaspargase can be given safely to children with a history of allergic reaction to prior administration of E coli asparaginase, 2,39,40 and is indicated for patients who require asparaginase but have developed hypersensitivity to the native form or as part of front-line treatment of ALL. 41 Another advantage of pegaspargase is its prolonged half-life of elimination compared with the E coli or Erwinia forms, which may be important in improving the pharmacokinetic profile of the drug.…”

“…32 In addition, a single injection of pegaspargase can be given instead of the inconvenient administration of multiple doses of native asparaginase. Pegaspargase has shown antileukemic activity similar to that of E coli asparaginase in children with recurring ALL 39,[42][43][44] who have already been exposed to the native form, as well as in newly diagnosed patients. 19,35 In contrast to children, pharmacokinetic and toxicity data on pegaspargase in adults is very limited.…”

Evaluation of immunologic crossreaction of antiasparaginase antibodies in acute lymphoblastic leukemia (ALL) and lymphoma patients

“…24 Thus, PEG asparaginase has been used in patients who have prior allergy to E. coli or Erwinia asparaginase. 6,25 It is not clear whether antibodies to E. coli asparaginase also exhibit crossreactivity to Erwinia asparaginase or PEG asparaginase. To answer this question, we determined antiasparaginase antibody levels to E. coli, Erwinia, and PEG asparaginase preparations in 22 newly diagnosed childhood ALL and two newly diagnosed lymphoma patients who did and did not have hypersensitivity reactions during chemotherapy.…”