Intramuscular (im) or Intravenous (iv): Impact of Erwinia Asparaginase Route of Administration on Asparaginase Activity.

10031 Background: Erwinia asparaginase (Erwinia) 25000 IU/m2 IM was approved in 2011 as a component of treatment for patients with acute lymphoblastic leukemia (ALL) with hypersensitivity to E. coli-derived asparaginase. In 2014, FDA approved the IV route of administration for Erwiniabased on the PK and safety findings described herein. Methods: Data from a single arm PK study in children (1 – 17 yrs) with ALL given Erwinia 25000 IU/m2 IV every Monday/Wednesday/Friday (M/W/F) were evaluated. The proportion of patients with 2-day and 3-day nadir serum asparaginase activity (NSAA) levels ≥ 0.1 IU/mL during the first 2 wks of IV Erwinia was compared to that of IM Erwinia. Population PK (PPK)-based simulations were used to determine IV Erwinia doses that would result in the same proportion of patients with 2-day and 3-day NSAA levels as that achieved with 25000 IU/m2 IM. The safety of IV and IM Erwinia administration was also compared. Results: IV dosing resulted in a mean (%CV) t½ of 7.5 h (24%) compared to 16 h (21%) for IM (PMID: 8355045). A smaller proportion of patients achieved 2-day or 3-day NSAA levels ≥ 0.1IU/mL while experiencing more adverse events with IV compared to IM administration (Table). PPK-based simulations showed that IV Erwinia doses of 35000 IU/m2 every M/W/F would be needed to attain NSAA levels of ≥ 0.1 IU/mL in 90% of the patients on Wednesday or Friday (2-day NSAA) and doses > 95000 IU/m2every M/W/F would be needed to achieve the same target on Monday (3-day NSAA). Conclusions: IV administration of Erwinia 25,000 IU/m2 every M/W/F, while clinically acceptable, led to a lower rate of target attainment (NSAA ≥ 0.1 IU/mL) and a higher rate of serious adverse events and discontinuations. Improving target attainment with higher IV doses would require clinical investigation. Efficacy and safety of Erwinia. Endpoint IM Study IV Study Proportion (n/N) and 95% CI Efficacy 2-day NSAA ≥ 0.1 IU/mL 100% (35/35) [90, 100] 83% (20/24) [63, 95] 3-day NSAA≥ 0.1 IU/mL 100% (13/13) [77, 100] 43% (9/21) [22, 66] Safety Serious Adverse Events 32.8% (19/58) 50% (15/30) All Grade Hypersensitivity 9% (5/58) 37% (11/30) Grade 3/4 Hypersensitivity 5% (3/58) 3% (1/30) Discontinuation rates 24% (14/58) 40% (12/30)