Asparaginase-Associated Toxicities and Hypersensitivity Reactions in Pediatric and Adolescent Down Syndrome Patients with Acute Lymphoblastic Leukemia or Lymphoma
Authors: Huynh Van Thu , Lin Carol Hwang , Morales Sonia , Agrawal Anurag K. , Phillips Christine L , August Keith J. , Guest Erin M. , Apsel Winger Beth , Aftandilian Catherine , Long-Boyle Janel R. , Kasper Kirsten , Zabokrtsky Keri 
Published: December 2023

Children with Down syndrome acute lymphoblastic leukemia (DS-ALL) have worse prognosis compared to those with non-DS-ALL, largely due to higher treatment related mortality. Pegaspargase (PEG) is integral in protocols for the treatment of pediatric ALL and lymphoblastic lymphoma (LBL), and full exposure to all doses of PEG can be limited by toxicities, including hypersensitivity reactions (HSR) due to the production of anti-asparaginase antibodies rendering PEG therapy ineffective. To date, minimal data has been reported on the use of PEG in children with DS-ALL/LBL. We conducted a prospective, multicenter study to evaluate the efficacy of premedicating pediatric and adolescent ALL/LBL patients receiving PEG with antihistamines-H1 and -H2 blockers with subsequent therapeutic drug monitoring (TDM) to better identify patients with true HSR versus those with non-antibody mediated infusion reactions. Here, we report on the incidence of HSRs and PEG-associated toxicities in the cohort of children with DS-ALL/LBL.

Eligible patients from six centers received PEG, as per a Children's Oncology Group protocol, beginning in induction therapy. An H1 blocker (diphenhydramine) and H2 blocker (ranitidine, famotidine or cimetidine) were administered prior to PEG administration in consolidation and subsequent cycles. TDM was performed at 7 and 14 days post each PEG. PEG was administered at 2500 International units/m 2/dose that was capped for obesity or age &gt; 22 years. Patients were monitored for HSR and other PEG-related toxicities using CTCAE version 5 criteria. Therapeutic asparaginase activity (AA) was defined as ≥ 0.1 IU/mL (≥100 IU/L) at 7 days post infusion and greater than the lower level of quantification at 14 days. We observed for silent inactivation (subtherapeutic levels without symptoms) and accelerated clearance (levels below quantification at 14 days without symptoms). Descriptive statistics summarized patient characteristics and mixed effects modeling procedure assessed mean AA levels at 7 and 14 days with specification of repeat measures and compound symmetry covariance structure.

Out of 148 patients, 9 DS (8 B-ALL, 1 B-LBL) were enrolled between 10/2019 - 3/2022. The median age at diagnosis was 5.0 years [IQR: 4.3, 14.9], 4 were National Cancer Institute (NCI) High Risk (HR) at diagnosis, 4 were Hispanic and none were obese. ALL 9 DS patients received a total of 26 doses of PEG at the standard dose without dose capping required. The mean unadjusted AA levels at 7 and 14 days post PEG were 0.76 IU/ml (SE=0.11) and 0.54 IU/ml (SE=0.11), respectively, p&lt;.001. None of the DS patients experienced HSR or silent inactivation. Accelerated clearance was observed in 1 patient. Nineteen episodes of grade &gt;3 PEG-associated toxicity were observed in 5 DS-ALL patients (5/9; 55.6%). PEG-associated toxicity was observed more frequently in older patients whose mean age was 13 years (SD=6.2) versus 4.3 years in those without toxicity (SDE=0.9), p=.028. Four of the DS-ALL who experienced toxicities were NCI HR at diagnosis and &gt; 10 years of age. For the 19 episodes of toxicities: 6 occurred during induction, 9 during consolidation, and 4 during delayed intensification. The most common toxicity observed was hepatoxicity (increased alanine transaminase) which was experienced by 3 DS-ALL patients. There were no grade &gt; 3 hyperbilirubinemia. All 4 DS-ALL patients who experienced PEG toxicity during induction also had toxicity with subsequent cycles. One DS-ALL patient had a dose limiting toxicity (grade 3 pancreatic pseudocyst), requiring discontinuation of subsequent PEG therapy. There were no grade 4 or 5 toxicities observed. All 4 DS patients who did not experience toxicities were NCI Standard Risk patients. All DS patients had undetectable minimal residual disease (MRD) that was &lt; 0.01 at the end of induction therapy.

We noted that in this small DS-ALL/LBL cohort, none of the patients experienced HSR, and all achieved therapeutic AA at both time points of 7 and 10 days post PEG. Five (55.6%) of the DS-ALL patients experienced at least one grade &gt; 3 asparaginase toxicity, and they were older than those without toxicity. Most toxicity occurred during the consolidation phase and no grade 4 or 5 toxicities were observed. Given the PEG-associated toxicity observed in DS ALL/LBL, we are conducting pharmacokinetic analysis to propose a lower dose of PEG which may minimize toxicity while maintaining therapeutic efficacy.