Toxicity of reduced dose versus standard dose pegaspargase in adolescents and young adults with acute lymphoblastic leukemia Free

Introduction

Pediatric-inspired regimens have improved the survival of older adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL). Asparaginase products are a key component of these regimens; however, their use in adults is often limited by toxicities. Several studies have explored dose optimization strategies to reduce toxicities while preserving benefit, with one retrospective study finding lower grade 3-4 toxicity rates for pegaspargase (PEG-ASP) doses less than or equal to 1000 IU/m² without compromising relapse-free survival. Based on this data, in 2020 our institution initiated a practice change to empirically dose-reduce PEG-ASP to 1000 IU/m². This study aimed to examine the impact of this standard dose reduction on PEG-ASP-related toxicities and clinical outcomes.

Methods

This single-center retrospective cohort study included patients ages 18 to 49 years old with newly diagnosed ALL or lymphoblastic lymphoma treated with at least one dose of PEG-ASP at The Ohio State University Comprehensive Cancer Center between January 2014 and March 2025. Patients who received calaspargase were excluded. PEG-ASP doses of less than or equal to 1000 IU/m² were defined as reduced dose (RD), while greater than 1000 IU/m² was considered standard dose (SD). The primary endpoint was the composite incidence of grade 3 or higher PEG-ASP-related toxicities including hepatotoxicity, pancreatitis, hypertriglyceridemia and venous thromboembolism (VTE). Secondary endpoints included incidence of individual toxicities, combined rates of complete remission (CR), CR with incomplete count recovery (CRi), and CR with partial hematologic recovery (CRh), as well as event-free survival (EFS) and overall survival (OS). Primary and secondary endpoints were compared using chi-squared or Fisher's exact tests. EFS and OS were estimated by the Kaplan-Meier method.

Results

Seventy-seven patients were included, with 36 patients receiving RD-PEG-ASP and 41 patients receiving SD-PEG-ASP, with median follow-up of 1.97 years and 8.12 years, respectively. Baseline characteristics were similar between groups, except for age (27 vs 22 years, p=0.015) and BMI (27.7 vs 24.7 kg/m², p=0.026). Majority were male (59.7%) and white (83.1%). Disease was characterized by B-ALL (59.7%) and T-ALL (29.9%), including 8 (26.7%) early T-cell precursor (ETP) ALL and 15 patients (19.5%) having central nervous system involvement at diagnosis. Baseline comorbidities included obesity (29.9%), hepatic disease (18.2%), type II diabetes mellitus (6.5%), and VTE (2.6%). Most common dosing included 1000 IU/m² (94.4%) for RD-PEG-ASP and 2500 IU/m² (87.8%) for SD-PEG-ASP, with maximum dose capped at 3750 IU. Patients received a median of 3 doses of PEG-ASP (range 1 to 7 doses) throughout their treatment. A statistically significant difference was not seen in the composite primary endpoint of hepatotoxicity, pancreatitis, hypertriglyceridemia, and VTE between RD-PEG-ASP and SD-PEG-ASP (52.8% vs 65.9%, p=0.249). Similarly, significant differences were not noted for rates of transaminitis (25.0% vs 24.4%, p=1.000), hyperbilirubinemia (2.8% vs 9.8%, p=0.364), VTE (33.3% vs 31.7%, p=1.000) including cerebral venous thrombosis (5.6% vs 17.1%, p=0.162), pancreatic enzyme elevations (0 vs 4.9%, p=0.496), pancreatitis (0 vs 12.2%, p=0.057), or hypertriglyceridemia (16.7% vs 22.0%, p=0.767). In a logistic regression model, there were no baseline characteristics significantly associated with the primary outcome, including age, comorbidities, PEG-ASP dose, or number of doses. Comparing RD-and SD- cohorts, combined CR/CRi/CRh was achieved in 91.7 vs 95.1% (p=0.66), with a median time to response of 31 vs 29 days (p=0.549). Rates of allogeneic stem cell transplantation were similar between groups (44.4% vs 41.5%, p=0.974). Median EFS and OS were not reached in either group, with no significant differences in 3-year EFS (54% vs 70%, p=0.087) or 3-year OS (66% vs 80%, p=0.091).

Conclusions

In this single-center retrospective study, there were no significant differences in toxicity nor efficacy between reduced and standard PEG-ASP dosing. However, numerical differences seen in rates of pancreatitis and cerebral venous thrombosis may warrant further investigation. Future prospective studies are needed to determine the optimal PEG-ASP dosing for AYA patients, as well as which patients may benefit from empiric dose modifications.