Managing Hypersensitivity Reactions after Asparaginase Treatment: A Systematic Literature Review

Introduction: L‐asparaginase (ASP) is an important component of multi‐agent treatment regimens for acute lymphoblastic leukemia/lymphoblastic lymphoma. However, hypersensitivity reactions (HSRs) to Escherichia coli (E. coli)‐derived ASPs are common. To avoid treatment discontinuation due to HSRs (associated with inferior clinical outcomes), guidelines recommend switching to an Erwinia chrysanthemi-derived ASP, which has minimal cross-reactivity. Historically, switching to an Erwinia ASP had been challenging due to global shortages of native Erwinia ASP from 2016-2021; practices such as administering premedication and rechallenging/desensitization with E. coli ASPs were explored to mitigate drug shortages and meet urgent patient needs. We conducted a systematic literature review (SLR) to evaluate the prevalence of HSRs with ASP formulations and summarized evidence on effectiveness of alternative HSR management practices.

Methods: PubMed, Embase, and the Cochrane library were searched in May 2023 to identify relevant studies reporting on HSRs and their management. The search strategy consisted of title/abstract key words and subject headings describing key concepts of “asparaginase” and “hypersensitivity”. The original search included congress abstracts published from 2010 to May 2023. Abstracts were screened independently by 2 researchers with discrepancies resolved by a project lead. As patients >1 month to <21.5 years old transitioned from pegaspargase (PEG) to calaspargase pegol (CAL-PEG) beginning December 2022, a limited search of recent congress abstracts was conducted after the original SLR was completed to capture recent data on CAL-PEG. HSR rates for different ASP formulations were extracted from studies and summarized descriptively, including ranges, calculated weighted averages of studies with ≥100 patients (based on study sample sizes), and data on premedication and rechallenge/desensitization.

Results: The original SLR identified 141 relevant publications, including 67 native E. coli ASP studies, 100 PEG studies, and 2 CAL-PEG studies. Publications reported a wide range of HSR rates across studies and formulations. In studies with >100 patients, native E. coli ASP and PEG studies reported the highest HSR rates of 5%-56% (mean 28%) and 1%-33% (mean 8%), respectively. For randomized trials with CAL-PEG, one trial reported a post-induction grade ≥2 allergy of 17% and another reported a grade 1-4 allergy of 27% during consolidation. Three congress abstracts reported grade ≥2 HSR rates with CAL-PEG at 4%, 9%, and 42%.

Five of 7 identified guidelines recommended use of premedication with (1 institutional, 1 national, ESMO and NCCN guidelines) or without (1 institutional) therapeutic drug monitoring (TDM) to prevent HSRs. Premedication (defined as ≥1 agent used to prevent HSRs in each study) has become common practice; we identified 25 studies on universal premedication from 2006 to 2022. Eight observational studies and 1 single-arm trial compared HSR rates with and without premedication (4 of 9 reported TDM): most (6/8) showed no impact on HSR rates whereas 2 studies showed a reduction in HSR rates including CALGB-10403. We identified 19 studies (mostly single center) employing variable methodologies, with desensitization protocols typically including ~12 steps and delivered over ~4 hours rechallenging patients with the same ASP as opposed to switching to an immunologically distinct ASP. Among 16 studies with ≥2 patients, 10 studies reported failure rates of ≥25%. Notably, 2 studies reported CAL-PEG desensitization, with success rates of 20% and 30%.

Conclusion: HSRs are common with ASP treatment. Including HSRs with the most recent frontline formulation, prevalence varies greatly across studies, reflecting differences in formulation, treatment plans, and HSR diagnosis/management. Consensus guidelines recommend switching patients with HSRs to Erwinia ASP, but historical drug shortages have increased rechallenge/desensitization with E. coli ASPs. This SLR demonstrated increasing use of premedication, although most published data demonstrate a lack of evidence on effectiveness. Likewise, reported usage of desensitization protocols is limited and standardization is lacking, demonstrating variable rates of success. A meta-analysis is being explored to further evaluate HSR rates and premedication effectiveness.

Maese:Jazz pharmaceuticals: Consultancy, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees. Orgel:Jazz Pharma: Consultancy. Bai:Jazz Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Nguyen:Jazz Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company. Martin:Crystallise Ltd: Current Employment. Gould:Crystallise Ltd: Current Employment. Stricherz:Jazz Pharmaceuticals: Current Employment, Current holder of stock options in a privately-held company.