GRASPALL 2005.01 Clinical Study: L-Asparaginase Loaded into Red Blood Cells Is Effective at Depleting Serum Asparagine in Children and Adults with Relapsed Acute Lymphoblastic Leukaemia (ALL)

L-asparaginase has been a mainstay of ALL treatment since decades and its efficacy has been demonstrated in a broad range of patient’s profiles. However its use has been hampered by frequent and/or significant toxicities, of which allergic reactions take a prominent place. In addition, loss of enzymatic efficacy, the so called “silent inactivation” may be observed as a consequence of the production of symptom-free serum antibodies directed to the asparaginase moiety and blocking its pharmacological activity. L-asparaginase loaded into homologous red blood cells (GRASPA) has been proposed as a new approach to maintain the complete activity of L-asparaginase while reducing its antibody mediated tolerability. In GRASPA, the red blood cells (RBC) act as a microbioreactor and protect the enzyme against circulating antibodies. Plasmatic asparagine diffuses through the RBC membrane to the intra cellular compartment where it is cleaved by the entrapped L-asparaginase. In addition encapsulation into RBC has been shown to extend the duration of action of drugs allowing a reduction in the number of injections.

GRASPALL 2005–01 is a randomized, active controlled, dose comparison study whose first objective is to assess the efficacy (defined as asparagine depletion ≤ 2μMol/L) of 3 doses of GRASPA given in double blind, during salvage therapy in children and adults with relapsed ALL. Patients who experienced severe allergy to L-asparaginase during the first line chemotherapy were excluded from the study.Twenty-four patients from 13 French centers, including 12 children (mean age, 8 years; range, 5–17) and 12 adults (mean age, 29 years; range, 19– 47) entered the trial from February 2006 to April 2008. Patients were randomized between either native E. Coli L-asparaginase (8 ×10 000 IU/m²/infusion) or GRASPA 50, 100 or 150 IU/kg (one single infusion).The backbone chemotherapy was based on the COPRALL protocol, a FRALLE and EORTC joint protocol for relapse.

The results regarding the efficacy and safety of GRASPA therapy are reported herein. The mean time of asparagine depletion ranged from 6 to 11.3 days, 6.2 to 11.9 days, and 14.6 to 22.5 days in the GRASPA 50, 100 and 150 IU/kg groups, respectively. For one patient receiving GRASPA 150UI/kg, the depletion exceeded 40 days. Overall, the mean duration of depletion and the proportion of patients with effective depletion over time with only one single infusion of GRASPA at a dose of 150 UI/kg was similar to what was observed with 8 infusions of native E. Coli asparaginase at a dose of 10 000 IU/ m². Treatment withdrawals during the study (defined as asparagine > 2μMol/L at D7 of the GRASPA infusion or any safety reason preventing study treatment reintroduction) occurred in 4/6 patients (67%) in the native E. Coli asparaginase group and 5/18 patients (28%) in the GRASPA groups. Out of these, two severe allergic reactions, including one life-threatening case, one non serious allergic reaction and one severe thrombosis were observed in the native E. Coli asparaginase group. Two asparagine > 2μMol/L at D7 , one pancreatitis, one transient elevation of pancreatic enzymes and one pulmonary aspergillosis were reported in the GRASPA group.

GRASPA is an effective therapy for depleting asparagine from the serum in children and adults with relapsed ALL. One single infusion of 150 IU/kg yielded to achieve a sustained depletion comparable with that observed with standard L-asparaginase therapy, but with a much better safety profile, especially regarding occurrence of allergic reactions, suggesting a better application of the therapeutic schedule. These results warrant future studies in allergic patients. [NCT00723346]