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.