Randomized Comparison of IV PEG and IM E. Coli Asparaginase in Children and Adolescents with Acute Lymphoblastic Leukemia: Results of the DFCI ALL Consortium Protocol 05-01

Abstract

Abstract 874E. coli L-asparaginase (E. coli ASP) is an important component of treatment for childhood ALL, but is associated with multiple toxicities, including allergy, pancreatitis, and thrombosis. It is typically given intramuscularly (IM). Because most pediatric ALL patients have indwelling venous catheters, intravenous (IV) administration of asparaginase would be a more convenient and less painful option than IM injection. PEG-asparaginase (PEG), the polyethylene glycol conjugate of E. coli ASP, has a longer circulating half-life and so may be given less frequently. We have previously demonstrated that a single dose of PEG 2500 IU/m2 given IV is tolerable in children with ALL, with potentially therapeutic serum enzyme activity (≥ 0.1 IU/mL) maintained for at least 18 days in most patients.[Blood 2010;115:1351-3] On DFCI ALL Consortium Protocol 05-01, all patients (pts) with newly diagnosed ALL aged 1–18 years (yrs) who achieved complete remission were eligible to participate in a randomized comparison of IM E. coli ASP and IV PEG during the 30-week (wk) multi-agent post-induction Consolidation phase. Beginning at week 7 of therapy, pts received either IM E. Coli ASP 25000 IU/m2 weekly × 30 wks or IV PEG 2500 IU/m2 every 2 wks × 30 wks. Serum samples were obtained every 6 wks just prior to an ASP dose and were assayed for ASP enzyme activity by a validated biochemical assay. Between 2005–2010, 463 pts were enrolled in the randomized comparison. Median age was 5 yrs (range 1.2–17.9 yrs). There was no significant difference in presenting characteristics between the two arms, except that more pts on the E. coli ASP arm presented with a mediastinal mass (9% vs 3%, p=0.04). Median follow-up was 2.8 years. Median nadir serum ASP activity (NSAA) at each assayed timepoint during the Consolidation phase was significantly higher with IV PEG than with IM E. coli ASP (Table 1). An NSAA of ≥ 0.1 IU/mL was achieved in ≥ 95% of IV PEG pts compared with < 50% of IM E. coli ASP pts (p<0.01 at each timepoint). There was no significant difference in ASP-related toxicities (allergy, pancreatitis, thrombosis) between the two types of ASP (Table 2). Older pts (≥ 10 yrs old) had a significantly higher overall rate (p<0.01) of pancreatitis (18% vs 7%) and thrombosis (18% vs 4%), but not of allergy (p=0.49) or infection (p=0.21), compared to younger pts. There was no significant difference in the rates of ASP-related toxicities when comparing IM E. coli ASP vs IV PEG separately within the two age groups (≥10 yrs and < 10 yrs). We conclude that every 2-week IV PEG is no more toxic than weekly IM E. coli ASP in children and adolescents with ALL, and is associated with higher serum ASP activity. Longer follow-up is necessary to determine whether there is any difference in event-free survival between the two treatment arms.Table 1:Nadir Serum ASP activity (NSAA) during 30-week Consolidation phaseIV PEGIM ECOLISample Time (wks)*NMedian IU/mL% pts with NSAA ≧ 0.10 IU/mLNMedian IU/mL% pts with NSAA ≧ 0.10 IU/mL5840.6795%920.09448%11700.7197%740.09447%17730.7697%860.09247%23600.70100%760.09446%29680.70100%630.09544%*Number of weeks after start of Consolidation phaseTable 2:Toxicities by ASP type during 30-week Consolidation phaseToxicityIV PEG # of pts (%)IM E. COLI # of pts (%)p-valueNumber of Patients232231Asparaginase Toxicity59 (25)58 (25)>0.99Allergy26 (11)20 (9)0.44Pancreatitis25 (11)21 (9)0.64 Mild/Moderate13 (6)13 (6) Severe12 (5)8 (3)Thrombosis14 (6)21 (9)0.22Infection (bacteremia, invasive fungal disease)35 (15)46 (20)0.18 Disclosures:Silverman:Enzon Pharmaceuticals: Honoraria. Supko:Enzon Pharmaceuticals: Research Funding. Sallan:Enzon Pharmaceuticals: Honoraria.