Desensitization to calaspargase pegol appears to be less successful than pegaspargase

TO THE EDITOR:

Asparaginase is a critical component in the treatment of pediatric acute lymphoblastic leukemia (ALL), and children who are unable to complete their intended course of asparaginase therapy tend to have poorer outcomes.¹ This underscores the importance of optimizing the delivery of planned asparaginase therapy.

Pegaspargase, a pegylated asparaginase product, has been the preferred asparaginase formulation in the United States since the withdrawal of native L-asparaginase from the market in 2012.² As of 1 December 2022, pegaspargase became unavailable for patients aged one month to 21.5 years of age, leaving calaspargase pegol (CAL-PEG) as the only primary asparaginase option for pediatric patients in the United States. CAL-PEG was approved by the US Food and Drug Administration in 2018 for pediatric patients based on results from the Children's Oncology Group study AALL07P4 and Dana-Farber Cancer Institute (DFCI) trial 11-001.³ DFCI 11-001 protocol reported a postinduction CAL-PEG allergy rate (grade ≥ 2) of 15%, while the AALL07P4 study reported allergy rates up to 27.3% (grades 1-4).^4,5 

Although literature supports the effectiveness of desensitization following pegaspargase allergy, data on the feasibility or success of CAL-PEG desensitization remain limited, with only 2 cases reported to date.^6-12 Here, we describe our experience with CAL-PEG desensitization in both front-line and relapsed ALL therapy.

Patients desensitized to CAL-PEG from 1 December 2022 to 30 September 2024 at St. Jude Children’s Research Hospital were retrospectively reviewed. This research received approval from the St. Jude institutional review board.

A 12-step, 3-bag method was used for CAL-PEG desensitization (Table 1).⁶ Premedications given to all patients before desensitization included diphenhydramine, hydrocortisone, famotidine, and montelukast. The prepared CAL-PEG desensitization bags were infused within 4 hours when stored at room temperature and within 24 hours when refrigerated after preparation.¹³ Nurses were instructed to keep bag 3 refrigerated until step 6.

Desensitization was considered successful if the infusion was completed and serum asparaginase activity (SAA) was estimated to remain ≥0.1 IU/mL for at least 21 days. If the first desensitization was successful, subsequent desensitization doses were administered. Measurement of SAA levels was carried out by our Clinical Laboratory Improvement Amendments-certified pharmacokinetics laboratory using methods previously described.¹⁴ 

A linear 1-compartment model with Michaelis-Menten elimination (parameterized in terms of Vmax, Km, and V) was applied to the data using non-linear mixed-effects modeling with the stochastic approximation expectation-maximization approach (Monolix, 2023R1). The inter-individual variability and inter-occasion variability of the parameters were assumed to be log-normally distributed. Activity values below the lower limit of quantification (0.06 IU/mL) were treated as censored, and the M3 method was used for handling these values (as implemented in Monolix; Beal JPP, 2001). A proportional residual error model was used, assuming a normal distribution of the residuals. Individual post hoc estimates (the empirical Bayesian estimates) were used to estimate the duration that the SAA levels remained above the target threshold for each desensitization study.

Nine patients were desensitized to 11 doses of CAL-PEG (Table 2). Six patients received first-line ALL treatment, while the remaining 3 were treated for relapse. Of the 11 infusions, 8 (73%) were completed without signs of hypersensitivity reaction (HSR). In the 3 patients who were unable to complete the infusion, reported HSR symptoms included flushing, cough, rash, and angioedema (Table 2).

SAA results are presented in Table 2. Among the 8 completed infusions, 4 (50%) were estimated to maintain SAA ≥0.1 IU/mL for 21 days, yielding an overall success rate of 36.4% (4/11 infusions). The median duration of sustained activity was 26 days in patients with successful outcomes. Notably, 75% (3/4) of doses administered to relapsed patients maintained adequate SAA, while only 14.3% (1/7) of doses in front-line patients achieved this threshold. The median duration of SAA ≥0.1 IU/mL was 5 days for all doses given to front-line patients, compared to 26 days for relapsed patients. Relapsed patients had HSR to pegaspargase at least 1 to 3 years prior to desensitization, whereas front-line patients had a median interval of 21 days.

Two patients received a second desensitization dose and only 1 was able to maintain SAA ≥0.1 IU/mL with the second dose. Patient 4 (Table 2) maintained adequate SAA with the first desensitized dose, although the end of infusion activity was lower than that observed in relapsed patients due to a capped dose of 3750 units. The second desensitized dose for this patient could not be completed due to HSR during the infusion.

Our results demonstrate that 36.4% of the CAL-PEG doses administered via desensitization were successful, defined as both completion of the infusion and SAA predicted to remain ≥0.1 IU/mL for at least 21 days. Completion of the infusion does not guarantee adequate SAA, highlighting the importance of SAA monitoring in patients undergoing CAL-PEG desensitization. Additionally, patients receiving front-line therapy were less likely to either complete the infusion or maintain adequate SAA compared to relapsed patients who had never received CAL-PEG and had not recently been exposed to asparaginase.

There are several publications of successful pegaspargase desensitization using 1-, 2-, or 3-bag methods, but limited reports of CAL-PEG desensitization currently.^6-12 There are only 2 published case reports for CAL-PEG desensitization.^11,12 The first published report of CAL-PEG desensitization used a 1-bag method in a B-cell ALL patient that developed difficulty breathing and angioedema to the second CAL-PEG dose. During the CAL-PEG desensitization, the patient developed pruritis on step 10 of 12 that required a pause in the infusion and diphenhydramine administration before completing the infusion. The SAA was undetectable 14 days after the infusion.¹¹ The other experience of CAL-PEG desensitization was reported in a patient with relapsed B-cell ALL using a 13-step, 4-bag method. The patient had a HSR to pegaspargase during initial treatment and tolerated pegaspargase desensitization ∼4 years before relapse. The patient tolerated the infusion without reaction with SAA of 0.532 IU/mL 8 days following the infusion. No additional SAA were reported at later time points, but authors concluded success with CAL-PEG desensitization.¹² 

Because CAL-PEG is only stable at room temperature for 4 hours, this adds to the complexity of desensitization.¹³ Kuhn et al¹¹ used a 1-bag CAL-PEG desensitization method and reported that the infusion duration from start to finish was ∼5 hours. This administration time exceeds the stability data of 4 hours for diluted CAL-PEG at room temperature. If a patient requires a pause in infusion or rate reduction due to concern for HSR, the CAL-PEG infusion time could exceed 4 hours, potentially necessitating the preparation of an additional bag, thus increasing the cost of desensitization.

Our results with CAL-PEG desensitization in patients receiving front-line treatment were successful in 14.3% of doses administered, whereas patients with relapsed ALL had a 75% success rate and longer duration of sustained SAA. A limitation of our finding is that SAA levels were not checked consistently at the same time points across all patients.

In conclusion, our results, along with limited published reports on CAL-PEG desensitization, suggest that patients receiving front-line therapy with a recent HSR or evidence of silent inactivation are less likely to be successfully desensitized and may benefit from transitioning to an Erwinia asparaginase formulation for the remainder of their therapy. In contrast, relapsed patients without recent asparaginase exposure or prior exposure to CAL-PEG could be considered for CAL-PEG desensitization with monitoring of SAA to confirm sustained SAA of ≥0.1 IU/mL for at least 21 days. Further studies are needed to validate these results.

Acknowledgments: Supported in part by National Cancer Institute grants CA250418 and CA021765 and American Lebanese Syrian Associated Charities (ALSAC).

ALSAC had no role in the design and conduct of the study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Contribution: H.D.S., M.M., and J.C.P. analyzed the data; H.D.S. and M.M. drafted the manuscript; and all authors contributed to the study design, and reviewed and approved the final version of the manuscript.

Conflict-of-interest disclosure: H.D.S., S.E.K., and H.I. have served as consultants for Jazz Pharmaceuticals and Servier, Inc. The remaining authors declare no competing financial interests.

Correspondence: Hope Swanson, Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children’s Research Hospital, 262 Danny Thomas Pl, Mail stop 150, Memphis, TN 38105; email: hope.swanson@stjude.org.