Erythrocyte encapsulated l-asparaginase (GRASPA) in acute leukemia

Abstract

l-asparaginase, an enzyme originally derived from Escherichia coli, represents a major drug in the treatment of acute lymphoblastic leukemia. However, the occurrence of major adverse effects often leads to early withdrawal of the enzyme. Main side effects include immune-allergic reactions, coagulopathy, pancreatitis and hepatic disorders. Novel asparaginase formulations and alternative sources have been developed to address this issue, but the results were not totally satisfactory. l-asparaginase loaded red blood cells (RBCs; GRASPA) represent a new asparaginase presentation with reduced immunological adverse reactions. RBCs protect l-asparaginase, enhance its half-life and reduce the occurrence of adverse events. We reviewed the history, biology and clinical experiences with l-asparaginase, and the characteristics and first clinical experiences with GRASPA in the treatment of acute leukemia.

Keywords: -asparaginase; acute leukemia; chemotherapy; erythrocyte encapsuled -asparaginase; safety profile; targeted therapy.

Figure 1.. l-asparaginase converts plasmatic l-asparagine into l-aspartate plus ammonia.

Leukemia cells are deficient in asparagine synthetase. l-asparagine deprivation, due tol-asparaginase activity, leads to asparagine starvation impairing protein biosynthesis in leukemia cells and then leading to apoptosis through cellular dysfunction.

Figure 2.. Mechanism of action of GRASPA.

Figure 3.. Schema of the GRASPALL 2009-06 Phase 2/3 randomized trial testing GRASPA versus native l-asparaginase in combination with standard polychemotherapy (COOPRALL regimen) in patients with first recurrence of Ph chromosome-negative acute lymphoblastic leukemia in adults and children with or without known hypersensitivity to l-asparaginase.

Patients with no prior history of allergy were randomized between GRASPA (150 IU/kg) and native l-asparaginase (10,000 IU/m²), while patients with a prior history of allergy received systematically GRASPA. ^†GRASPA-S: Single cohort in allergic patients. 6-MP: 6-mercaptopurine; ALL: Acute lymphoblastic leukemia; ASP: Asparaginase; mo: Month; MTX: Methotrexate; PS: Performance status.

Figure 4.. The GRASPA-AML 2012-01 study schedule.

Randomization was 2:1 with a combination of low-dose cytarabine (40 mg daily per day from day 1 to day 10) with GRASPA (100 IU/kg on day 11) in the experimental arm, and LDC (40 mg daily per day from day 1 to day 10) alone in the control arm. AML: Acute myeloid leukemia; C: Cycle; LDC: Low-dose cytarabine; RANDO: Randomization.