Subject(s)
Antibodies, Monoclonal/therapeutic use , Graft vs Host Disease/drug therapy , Immunosuppressive Agents/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/adverse effects , Clinical Trials, Phase III as Topic , Drug Resistance , Follow-Up Studies , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Kaplan-Meier Estimate , Multicenter Studies as Topic , Randomized Controlled Trials as Topic , Steroids/therapeutic use , Treatment OutcomeABSTRACT
PURPOSE: The GRASPALL/GRAALL-SA2-2008 Phase II trial evaluated the safety and efficacy of L-asparaginase encapsulated within erythrocytes (GRASPA®) in patients ≥ 55 years with Philadelphia chromosome-negative acute lymphoblastic leukemia. FINDINGS: Thirty patients received escalating doses of GRASPA® on Day 3 and 6 of induction Phases 1 and 2. The primary efficacy endpoint was asparagine depletion < 2 µmol/L for at least 7 days. This was reached in 85 and 71% of patients with 100 and 150 IU/kg respectively but not with 50 IU/kg. Grade 3/4 infection, hypertransaminasemia, hyperbilirubinemia and deep vein thrombosis occurred in 77, 20, 7, and 7% of patients, respectively. No allergic reaction or clinical pancreatitis was observed despite 17% of Grade 3/4 lipase elevation. Anti-asparaginase antibodies were detected in 50% of patients and related to a reduction in the duration of asparagine depletion during induction Phase 2 without decrease of encapsulated L-asparaginase activity. Complete remission rate was 70%. With a median follow-up of 42 months, median overall survival was 15.8 and 9.7 months, in the 100 and 150 IU/kg cohorts respectively. CONCLUSIONS: The addition of GRASPA®, especially at the 100 IU/kg dose level, is feasible in elderly patients without excessive toxicity and associated with durable asparagine depletion. (clinicaltrials.gov identifier NCT01523782).
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Asparaginase/therapeutic use , Gram-Negative Bacterial Infections/drug therapy , Gram-Positive Bacterial Infections/drug therapy , Mycoses/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Aged , Anti-Bacterial Agents/therapeutic use , Antifungal Agents/therapeutic use , Asparagine/metabolism , Drug Carriers , Drug Compounding , Erythrocytes/chemistry , Erythrocytes/cytology , Female , Gram-Negative Bacterial Infections/complications , Gram-Negative Bacterial Infections/mortality , Gram-Negative Bacterial Infections/pathology , Gram-Positive Bacterial Infections/complications , Gram-Positive Bacterial Infections/mortality , Gram-Positive Bacterial Infections/pathology , Humans , Male , Middle Aged , Mycoses/complications , Mycoses/mortality , Mycoses/pathology , Philadelphia Chromosome , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Remission Induction , Survival AnalysisABSTRACT
l-asparaginase encapsulated within erythrocytes (GRASPA(®) ) should allow serum asparagine depletion over a longer period than the native form of the enzyme, using lower doses and allowing better tolerance. The GRASPALL 2005-01 study, a multicentre randomized controlled trial, investigated three doses of GRASPA(®) for the duration of asparagine depletion in a phase I/II study in adults and children with acute lymphoblastic leukaemia (ALL) in first relapse. Between February 2006 and April 2008, 18 patients received GRASPA(®) (50 iu/kg: n = 6,100 iu/kg: n = 6, 150 iu/kg: n = 6) after randomization, and six patients were assigned to the Escherichia coli native l-asparaginase (E. colil-ASNase) control group. GRASPA(®) was effective at depleting l-asparagine. One single injection of 150 iu/kg of GRASPA(®) provided similar results to 8 × 10,000 iu/m(2) intravenous injections of E. colil-ASNase. The safety profile of GRASPA(®) showed a reduction in the number and severity of allergic reactions and a trend towards less coagulation disorders. Other expected adverse events were comparable to those observed with E. colil-ASNase and there was also no difference between the three doses of GRASPA(®) .
