Asparaginase premedication with hydrocortisone decreases hypersensitivity reactions

Background: While pegylated E. Coli asparaginase (PEG) is an integral component of leukemia and lymphoma treatment, hypersensitivity reactions (HSR) remain a common adverse event, often resulting in adjustments to the treatment regimen, increasing the burden on patients and families. HSR to asparaginase often indicates a transition to Erwinia asparaginase (ERW), which requires patients to return to the hospital six times for subcutaneous injections to replace one dose of IV PEG. Previous trials have demonstrated rates of HSR to pegylated E coli asparaginase (PEG) anywhere from 0.5% to 25%. At our institution, despite premedication with antihistamine medications such as diphenhydramine and famotidine, we have observed a similar range of patients develop treatment-limiting HSR to PEG. Additionally, nonallergic infusion reactions (IR) often overlap symptomatically with HSR, making it difficult to identify true HSR, thus leading to the conservative clinical decision to remove asparaginase from the treatment plan. There are reports of adding hydrocortisone to the premedication regimen for patients receiving PEG, but this has been reported mainly in the rechallenge setting. Methods: We conducted a retrospective analysis evaluating the benefits of adding hydrocortisone to a universal two-drug premedication regimen of famotidine and diphenhydramine. Data was gathered via chart audit comparing a group of patients with a 2-drug regimen (diphenhydramine and famotidine) to a group of patients with a three-drug regimen of diphenhydramine, famotidine, and hydrocortisone. Analysis included patients with any lymphoid malignancy treated with a frontline PEG-containing treatment regimen. A one-year time interval was used to collect data for the pre- and post-intervention groups. All patients who received IV PEG were reviewed. HSRs or infusion reactions were reviewed independently to confirm and grade using Common Terminology Criteria for Adverse Events (CTCAE), v5 of allergic reactions. Results: In 86 patients analyzed over a 2-year period, 51 were in Group 1 and given a 2-drug regimen of diphenhydramine and famotidine prior to PEG infusion. The rate of HSR in group 1 was 37.3% with 11.8% experiencing IRs. Group 2 contained 35 patients who received a 3-drug regimen with diphenhydramine, famotidine, and hydrocortisone. The rate of HSR in group 2 was 11.4% with another 11.4% experiencing IRs. Based on this data, rates of IR remained unchanged, while rates of HSR decreased significantly by more than 25% (p-value 0.0079) with the addition of hydrocortisone to the pre-medication regimen. Conclusions: Our retrospective cohort study provided preliminary evidence that the addition of hydrocortisone to a two-drug premedication regimen of diphenhydramine and famotidine can decrease the rates of hypersensitivity reactions to IV PEG.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, accounting for approximately 25% of all cancer diagnoses in patients younger than 15 years of age [1]. Survival rates for this population have significantly improved over the past fifty years, from 54% in the 1970s to greater than 90% today [1-3]. A contributor to this success has been the addition of asparaginase to standard chemotherapy regimens for ALL. A factor as to why asparaginase has been so instrumental in ALL therapy resides in the fact that lymphoblastic leukemia cells are unable to synthesize adequate levels of L-asparagine, a critical amino acid for protein synthesis, therefore impairing cell survival. Derived from Escherichia coli or Erwinia chrysathemi, asparaginase catalyzes the conversion of L-asparagine to aspartic acid and ammonia, thus depleting leukemic cells of this essential ingredient for cellular division and survival [4]. Asparaginase was initially added to large-scale clinical trials of ALL in the 1970s and continues to be used regularly today, demonstrating improved complete remission rates as well as survival [5-7]. Consequently, asparaginase has become one of the cornerstones of ALL treatment [8]. Unfortunately, hypersensitivity reactions (HSR) to this foreign bacterial protein remain some of the most common adverse events associated with administration of asparaginase products, where up to 30% of individuals may develop an allergic reaction to E. Coli -derived asparaginase [9-11]. HSR to E. Coli -derived asparaginase can quickly manifest as urticaria, bronchospasm, edema, and/or anaphylaxis [12]. A pegylated form of E. Coli asparaginase, pegaspargase (PEG), is commonly used in place of native E. Coli asparaginase, given it is less immunogenic than the native enzyme [13]. However, despite this change, clinical trials have continued to demonstrate high rates of HSR to PEG in the range of 10 to 25% [14]. At our institution, despite premedication with antihistamines such as diphenhydramine and famotidine, we continue to observe a similar range of patients developing treatment limiting HSR to PEG. Additionally, non-allergic infusion reactions (IR) are becoming more commonly recognized in addition to these hypersensitivity reactions, which can make the determination of HSR challenging. Non-allergic infusion reactions can occur minutes into the infusion and can manifest as flushing, tachycardia, tachypnea, nausea, rash and/or anxiety [15]. Given the overlap between the symptoms of HSR and IR, it can be very difficult to distinguish true HSR from non-allergic infusion reactions, thus leading to the conservative clinical decision to remove E. Coli asparaginase from the treatment plan and replace it with Erwinia -derived asparaginase (ERW). This transition requires patients to return to the hospital for six intramuscular injections to replace the one dose of PEG, resulting in a greater burden on patients and their families [16]. To combat these treatment-changing hypersensitivity reactions, some institutions have implemented universal premedication policies prior to the administration of PEG, including antihistamines and antipyretics. Corticosteroids have also been used successfully as a method to rechallenge patients with PEG [15,17]. Given the uncertainty as to the best premedication regimen, we set out to evaluate the benefits of adding hydrocortisone to our standard premedication regimen of famotidine and diphenhydramine for pediatric patients receiving PEG asparaginase for the treatment of their ALL.

Patients Our oncology section changed our standard-of-care premedication regimen for patients receiving asparaginase therapy in December 2021 from a 2-drug regimen to a 3-drug regimen. Prior to this time point, patients were receiving a two-drug combination, consisting of famotidine (0.5 mg/kg up to a maximum dose of 20 mg) and diphenhydramine (1 mg/kg up to a maximum dose of 50 mg). The change in 2021 involved the addition of hydrocortisone (1 mg/kg to a maximum dose of 100 mg) for all patients receiving asparaginase products from this time-point forward. This decision was based on literature demonstrating lower rates of HSR when rechallenged with a three-drug regimen that included hydrocortisone [15]. We conducted a retrospective analysis comparing the rates of HSR in two patient cohorts (2-drug versus 3-drug) to evaluate the benefits of adding hydrocortisone to our 2-drug premedication regimen. This analysis included all patients diagnosed with ALL, acute lymphoblastic lymphoma (LLy), or other lymphoid malignancies receiving an asparaginase containing treatment regimen. Group 1 (2-drug premedication) included 51 patients (ages 1-21 years) who received asparaginase between March 2020 to November 2021 before the inclusion of hydrocortisone as a premedication. Group 2 (3-drug premedication) included 35 patients (ages 2-22 years) who received asparaginase between December 2021 to December 2022 after the addition of hydrocortisone. Premedication Group 1 patients had been given a two-drug premedication regimen thirty to sixty minutes prior to their infusion with IV PEG. The two-drug regimen included diphenhydramine (1 mg/kg IV or oral, to a maximum dose of 50 mg) and famotidine (0.5 mg/kg IV or oral, to a maximum dose of 20 mg). Group 2 patients were given a three-drug regimen thirty minutes prior to infusion with PEG. The three-drug regimen included diphenhydramine (1 mg/kg IV or oral, to a maximum dose of 50 mg), famotidine (0.5 mg/kg IV or oral, to a maximum dose of 20 mg), and hydrocortisone (1 mg/kg IV, no maximum dose). Therapeutic drug monitoring (TDM) for serum asparaginase activity (SAA) levels was routinely sent for all patients receiving PEG around day 7 post-administration where SAA levels >0.1 IU/mL were identified as therapeutic. For patients who had an adverse reaction during the PEG infusion and received <10% of the dose, no TDM was sent given the low amount of drug delivered, otherwise all patients had TDM performed. Statistical Analysis and Hypersensitivity Grading Data was gathered via chart audit to compare the rates of hypersensitivity in patients in Group 1 to patients in Group 2. A one-year time interval was used to collect data in both groups. The symptoms of each hypersensitivity reaction (HSR) or infusion reaction (IR) had been documented in the electronic health record (EHR) by the medical providers. Hypersensitivity reactions were defined as reactions which included either urticaria or any respiratory symptoms, such as sneezing, cough, tachypnea, bronchospasm, and/or oxygen desaturations. The Common Terminology Criteria for Adverse Events (CTCAE), v5 of allergic reactions was used to grade the HSRs or IRs based on the documented symptoms. Other non-HSR symptoms reported were considered for IRs. Grade 2 HSR reactions included the use of intravenous diphenhydramine, while grade ≥3 reactions included intramuscular epinephrine. Statistical analysis between the two groups was then completed using Chi-Square analysis to calculate p-value.

Patient characteristics Patient characteristics are shown in Table 1. Our study involved a total of 86 pediatric patients who received asparaginase as part of their therapy for ALL, LLy, or other lymphoid malignancies between December 2020 and December 2022. The median age was 4.5 years (range, 1-22 years). Underlying diagnoses were B-ALL (n=74), T-ALL (n=7), LLy (n=2), or other lymphoid malignancies treated with PEG (n=3), including mixed phenotype acute leukemia (MPAL; n=2) and one case of plasma cell dendritic neoplasm. From December 2020 to December 2021, we reviewed the EHR of 51 patients (Group 1) who received the two-drug premedication for asparaginase. From December 2021 to December 2022, we reviewed the EHR of 35 patients (Group 2) who received the three-drug hydrocortisone-containing regimen for asparaginase. Rates of Asparaginase Hypersensitivity and Infusion Reactions The rates of HSR for the two groups are presented in Table 2. We identified significantly greater rates of hypersensitivity in Group 1 where nineteen patients (37.3%) developed HSR compared to only four in Group 2 (11.4%; p=0.0079). Similar rates of IRs were reported between the two groups. In Group 1, six patients developed IR (11.8%) compared to four (11.4%) in Group 2. As all HSR reactions for both groups occurred within 5 minutes of the PEG infusion with typically for these patients.

Hypersensitivity reactions to asparaginase products continue to be a challenge in the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LLy). Recent literature reports rates of hypersensitivity reactions to pegylated E. Coli asparaginase as high as 25%. Patients with hypersensitivity are no longer able to receive this frontline therapy and are transitioned to another more burdensome asparaginase product (typically Erwinia asparaginase) entailing additional hospital visits, six intramuscular injections for each dose of PEG, and a slightly different side effect profile. Consequently, efforts are underway to minimize the rates of these allergic reactions to pegylated asparaginase in ALL and LLy treatment. Many institutions have implemented different premedication regimens to reduce allergic reactions, including antipyretics or antihistamines with limited efficacy [15,17]. Corticosteroids have been used in premedication regimens in a rechallenge setting for patients who have previously reacted to pegylated E. Coli asparaginase [15]. Given these reports that corticosteroids successfully reduce hypersensitivity in drug rechallenges, our institution added hydrocortisone to our frontline premedication regimen for all patients receiving pegylated asparaginase. Prior to an institutional change implemented in 2021, patients received a two-drug regimen consisting of diphenhydramine and famotidine prior to treatment with PEG. This premedication regimen was updated in December 2021 to include a dose of hydrocortisone. The rates of HSR were analyzed before and after this change. From our study, the rate of hypersensitivity reactions to PEG decreased from 37.25% to 11.4%, a decrease of more than 25%, which we found to be statistically significant (p=0.0079). This finding suggests that hydrocortisone can be used in a three-drug regimen to assist in decreasing the rates of hypersensitivity to pegylated E. Coli asparaginase. To our knowledge, this is the first study comparing the rates of hypersensitivity reactions to PEG with the addition of hydrocortisone as a universal premedication. There are reports of corticosteroids being used to minimize hypersensitivity reactions to pegaspargase, but these reports are focused on the rechallenge setting, where a patient has already developed a hypersensitivity reaction to pegaspargase earlier in their therapy. Our study has several limitations. First, our study has a relatively small sample size of 86 patients, and thus the power is limited. Our study was not blinded, which may have introduced bias into the findings. Second, our study did not control for previous asparaginase exposures, which could have contributed to a Type 1 error as reactions are less likely after the fourth dose. Third, because the study was retrospective, we were reliant on documentation in the electronic medical record from multiple healthcare providers, which is subject to variability.

Our study provides preliminary evidence that the addition of hydrocortisone to a premedication regimen for asparaginase reduces the risk of hypersensitivity reactions for pediatric patients with leukemia or lymphoma. Further prospective and randomized studies comparing different premedication regimens and their effects on hypersensitivity reactions are needed.

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Premedication prior to PEG-asparaginase is cost-effective in pediatric patients with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2021 Aug;68(8):e29051 Table 1: Patient Characteristics | Number of patients | 51 | 35 | | Male (% of patients) | 26 (51.0%) | 17 (48.6%) | | Median Age (years, Range) | 4 (1-21) | 6 (2-22) | | B-ALL (%) | 44 (86.3%) | 30 (85.7%) | | T-ALL | 5 (9.8%) | 2 (5.7%) | | LLy | 1 (2.0%) | 1 (2.9%) | | Other | 1 (2.0%) | 2 (5.7%) | Characteristics of each patient population analyzed for this retrospective study. The pre-hydrocortisone group included patients from December 2020 to December 2021, and the post-hydrocortisone group included patients from December 2021 to December 2022. Other diagnoses included mixed phenotype leukemia and a case of plasma cell dendritic neoplasm. Table 2: Rates of hypersensitivity reactions between Groups 1 and 2 | Group 1 -hydrocortisone | 32 | 19 (37.25%) | | Group 2 +Hydrocortisone | 31 | 4 (11.4%) | | Comparison | p=0.0079 | Comparison of the different rates of HSR to pegylated E.Coli asparaginase products in groups 1 and 2. Group 2 demonstrated a significantly lower rate of HSR after the addition of hydrocortisone in a 3-drug premedication regimen. Statistical analysis was performed using Chi-square analysis, demonstrating a p-value of 0.0079. Information & Authors Information Version history Peer review timeline Published Journal of Pediatric Hematology/Oncology Version of Record10 Sep 2025Published Copyright This work is licensed under a Non Exclusive No Reuse License.

Authors Metrics & Citations Metrics Article Usage 256views 113downloads Citations Download citation Ryan Guerrettaz, Megan Wegter, Michael Burke. Asparaginase premedication with hydrocortisone decreases hypersensitivity reactions. Authorea. 05 March 2025. DOI: https://doi.org/10.22541/au.174115444.42476207/v1 DOI: https://doi.org/10.22541/au.174115444.42476207/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.