Intramuscular JZP458 for Patients With AML With Hypersensitivity to E. Coli-Derived Asparaginases

Results from the Phase 2/3 AALL1931 Trial

Intramuscular JZP458  (asparaginase erwinia chrysanthemi [recombinant]-rywn), a recombinant Erwinia asparaginase derived from a novel expression platform, yielded safe and effective results among patients with acute lymphoblastic leukemia (ALL) or lymphoblastic leukemia (LBL) with hypersensitivity/silent inactivation to E. coli-derived asparaginases, according to findings from the phase 2/3 AALL1931 trial recently published in Blood. 

Luke Maese, MD, Huntsman Cancer Institute, University of Utah, Primary Children’s Hospital, Salt Lake City, UT, and coauthors stated, “JZP458 is a recombinant Erwinia asparaginase with an identical amino acid sequence to native Erwinia asparaginase (Erwinaze/Erwinase) but is derived from a novel Pseudomonas fluorescens expression platform.” 

They explained, “JZP458 is expected to have minimal immunologic cross-reactivity to E coli–derived asparaginase preparations and has comparable in vitro activity to native Erwinia-derived asparaginase.” 

In order to study the efficacy and safety of JZP458, Dr Maese and coauthors aimed to reach a primary endpoint of measuring the proportion of patients maintaining adequate nadir serum asparaginase activity at 72 hours and at 48 hours during the first treatment course. They also aimed to measure the safety endpoint of incidence and severity of treatment-related adverse events (TRAEs). 

167 patients with ALL/LBL who had experienced hypersensitivity or silent inactivation to E. coli-derived asparaginases were enrolled in this multi-center, dose-confirmation study. 3 regimens of 6 doses of intramuscular JZP458 were evaluated. At 72 hours, the mean serum asparaginase activity levels were 0.16 in cohort 1a, 0.33 in cohort 1b, and 0.47 in cohort 1c. At 48 hours, the mean was 0.45 in cohort 1a, 0.88 in cohort 1b, and 0.66 in cohort 1c, respectively. The proportion of patients achieving adequate nadir serum asparaginase activity (NSAA ≥0.1 IU/mL) at 72 hours and 48 hours in cohort 1c was 90% (n=44) and 96% (n=47). A pharmacokinetic assessment matched this data. 

Regarding safety, grade 3/4 treatment-related adverse events occurred in 51% of patients (n=86), the most common being febrile neutropenia (9.0%), increased alanine aminotransferase (7.8%), and nausea (5.4%). TRAEs leading to discontinuation of treatment in 12.6% of patients (n=21) included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). 

Dr Maese et al concluded, “[Intramuscular] JZP458 using the dosing regimen of 25/25/50 mg/m2 [Monday/Wednesday/Friday] is efficacious, is tolerable, and achieves NSAA levels ≥0.1 IU/mL at both 48 and 72 hours in the vast majority of patients. The safety profile of JZP458 is consistent with what has been described for other asparaginase products.”

They added, “These dosing regimens optimize [serum asparaginase activity] coverage, provide flexibility, and bring alignment with many pediatric oncology protocols throughout the world. More importantly, with its reliable manufacturing process, and the efficacy and safety demonstrated in AALL1931, JZP458 addresses one of the most significant drug shortages impacting the care of patients with ALL/LBL.” 

Source: 

Maese LD, Loh ML, Choi MR, et al. Recombinant erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study. Blood. Published online September 15, 2022. doi.org/10.1182/blood.2022016923