JZP458 closes the asparaginase allergy gap

In this issue of Blood, Maese et al¹ showed that intramuscular (IM) JZP458 at 25/25/50 mg/m² given thrice weekly was an effective and safe alternative for patients with hypersensitivity to Escherichia coli–derived asparaginases (ASPs).

ASPs are one of the cornerstones of acute lymphoblastic leukemia (ALL) therapy and are included in multiagent chemotherapeutic regimens for children, adolescents, and adults with ALL and lymphoblastic lymphoma (LBL).^2,3 Pegylated E coli–derived ASP (pegaspargase) administered every 2 weeks is typically used in frontline and salvage protocols, and the longer-acting calaspargase pegol was approved by the US Food and Drug Administration (FDA) in December 2018 as part of multiagent therapy for ALL in pediatric and young adult patients from 1 month to 21 years old.⁴ However, hypersensitivity reactions/silent inactivation (due to neutralizing anti-drug antibodies without allergy symptoms) limit the efficacy of both compounds. It has been hypothesized that the use of anti-CD20 monoclonal antibodies during the multidrug schedules could reduce the incidence of allergic reactions to E coli–derived ASP.⁵ When these reactions occur, a change to native Erwinia chrysanthemi–derived ASP is mandatory,⁶ but global shortages of this drug have resulted in poor availability. Recently, JZP458, a recombinant Erwinia ASP that utilizes a novel Pseudomonas fluorescent technology expression platform to produce an enzyme with no immunologic cross-reactivity to E coli–derived ASP was developed as a treatment for hypersensitivity reactions/silent inactivation due to E coli ASP. The results of a phase 1 study in healthy volunteers showed that a single IM dose of 25 mg/m² resulted in similar serum ASP activity (SAA) to 25 000 IU/m² of native Erwinia ASP.⁷ On the basis of the interim results of the AALL1931 study performed in patients with ALL and LBL, JZP458 was approved in June 2021 by the FDA for use as a component of a multiagent chemotherapeutic regimen for the treatment of ALL or LBL in pediatric and adult patients 1 month and older who develop hypersensitivity to E coli–derived ASP.⁸ 

The phase 2/3 of the AALL1931 study is an open-label, multicenter, dose confirmation, and pharmacokinetic (PK) study of JZP458 in patients of any age with ALL/LBL who were hypersensitive to E coli–derived ASP (allergic reactions or silent inactivation).¹ This study was designed to assess tolerability and efficacy by measuring SAA. The first part (part A) of the study investigated the IM route of administration, including a Monday-Wednesday-Friday (MWF) dosing schedule. PK modeling and simulations of data from the first 2 cohorts (cohorts 1a and 1b) were used to assess the best dosing schedule to ensure optimal 48- and 72-hour SAA levels ≥0.1 IU/mL (cohort 1c), which were found to be 25/25/50 mg/m² administered by IM route with a 2-week MWF course. This schedule is slightly different from the FDA-approved dosage of 25 mg/m² administered IM every 48 hours. Treatment-related adverse events of special interest included allergic reactions (5.4%), pancreatitis (6.0%), thrombosis (1.2%), hepatotoxicity (19.8%), and hypertriglyceridemia (7.2%), with the safety profile of this schedule being similar to that observed in other ASPs. However, some patients did not complete the treatment at the time of the analysis, and a complete safety follow-up will be required in the future. The second part (part B) of the AALL1931 study remains active to further confirm the dose and schedule for the intravenous route of administration.

The global shortage of native Erwinia ASP due to manufacturing issues is challenging and could negatively impact the efficacy of ALL therapy in patients who develop hypersensitivity reactions/silent inactivation to E coli–derived ASP. Omission of ASP in multidrug chemotherapy regimens can lead to a higher risk of relapse or poorer response to reinduction therapy in patients with relapsed ALL.⁹ Fortunately, JZP458 provides a reliable treatment option that closes the gap of Erwinia-derived ASP availability for patients who develop these adverse events (see figure). This feature, together with the adequate ASP management, especially in adult patients, will contribute to improve the contribution of this essential drug to the treatment of ALL.

Conflict-of-interest disclosure: The author declares no competing financial interests.