Multiple Doses of Intravenous Pegylated Asparaginase with a “Pediatric-like” Protocol in Adults with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL): Toxicity, Clinical Outcome and Low Rate of Anti Asparaginase Antibody Formation.

Abstract 3082 Poster Board III-19 Several, large randomized multi-agent trials, in pediatric ALL have shown that prolonged use of asparaginase (ASP) during remission resulted in better outcomes. Adequate serum asparagine depletion from ASP administration has been suggested to have a therapeutic impact. Historically, adult ALL regimens use less, shorter or no ASP compared to pediatrics, as the drug is considered more toxic. However, a recent Adult ALL study (Huguet et al, JCO 27:911, 2009), suggested an improved outcome (EFS 55%, OS 60%) using a “pediatric-inspired” protocol, which included longer duration and higher cumulative doses of E-coli ASP. PEG-asparaginase (PEG-ASP) is a modified E.coli ASP with a longer half life, resulting in sustained asparagine depletion. PEG-ASP is also considered to be less allergogenic, and in children causes fewer clinical hypersensitivity reactions and lower rate of anti-ASP neutralizing antibodies (“silent” hypersensitivity i.e. antibodies without clinical hypersensitivity) than the native E. coli ASP. We report, the use of multiple doses (up to 6) of PEG-ASP, given throughout the induction and the post-remission phases in a “pediatric-like” protocol, to newly diagnosed adult ALL. We also determined the rate of anti-ASP neutralizing antibody formation throughout our study; currently these rates are unknown in adults. Methods The backbone of our protocol is an augmented BFM pediatric ALL regimen consisting of 8 cycles of multi-agent chemotherapy, followed by two year maintenance. PEG-ASP (2000 U/m 2 /dose) is given intravenously (IV) once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Steroids are always given before and for at least 7 (dexamethasone) or 14 (prednisone) days after the PEG-ASP dose depending on the treatment cycle. Since December 2006 Ph+ patients receive imatinib 600mg/daily. Results 46 patients, aged 18-57 (median 33) years, precursor B cell - 41, T cell-5, Ph+ 11, were studied. Median WBC at diagnosis - 14,500/cumm (range 1,900-512,000). CR rate: 44(96%) pts (43 after induction phase I). So far the total number of PEG-ASP doses given was 160: 6-16 pts, 5- 3pts 3- 6 pts., 2-10 pts., 1-11 pts. Eighteen patients could not complete all doses of PEG-ASP: allogeneic SCT -8, refusal -1, pancreatitis -5 (one pt. had pancreatitis and SCT), anaphylaxis -2, DVT-1. Two additional patients died in CR from neutropenic sepsis. Patients with elevated liver enzymes, high bilirubin, DVT (except for one pt.) or hyperglycemia continued on the study. Number of pts. with PEG-ASP related grade 3/4 toxicities (at least once of each): anaphylaxis -2 (4%) (one additional patient a had grade 2 rash); pancreatitis 6 (13%) (one pt. after last dose); thrombosis- 5 (11%) with 4 of the 5 catheter-related in upper extremity; elevated liver enzymes -30 (64%); hyperbilrubinema - 11 (24%); hyperglycemia - 12 (26 %); hypertriglyceridemia -3 (7%); fatigue-5 (11%). All toxicities were reversible. Neutralizing antibodies were measured in 247 serum samples from 34 patients (33, 11 and 10 pts. after PEG-ASP doses # 1, 4, and 6 respectively). An antibody was detected in only ONE patient (after dose #1); he had PEG-ASP related rash. We confirmed the very long half life of PEG-ASP: 7 ±4.7 days after the fist dose increasing to 11.9±5.9 days after dose 4 and 6. Peak serum levels did not change significantly between the cycles. Four year EFS, OS and CIR were 59%, 64% and 32%, respectively. The 16 patients who received all 6 doses of PEG-ASP (no BMT) had a 4 year EFS of 85% (only 3 relapsed at 19, 28, 55 months). Conclusion This study suggests that multiple IV dosing with the long acting PEG-ASP is feasible in replacing the native E.coli asparaginase in the context of “pediatric-inspired” ALL protocols in adults (age Disclosures Douer: Enzon Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau.