Toxicity of Very Prolonged Pegasparaginase and Erwinia Asparaginase Courses in Relation to Asparaginase Activity Levels with a Special Focus on Dyslipidemia
Authors: Tong Wing H. , Pieters Rob , de Groot-Kruseman Hester A. , Hop Wim C.J. , Boos Joachim , Tissing Wim J , van der Sluis Inge M. 
Published: October 2019

Abstract

Purpose
We prospectively studied the incidence and clinical course of hypertriglyceridemia and hypercholesterolemia during very prolonged use of PEGasparaginase or Erwinia asparaginase in relation to asparaginase activity levels in children with acute lymphoblastic leukemia (ALL). Also, the incidence of pancreatitis, thrombosis, hyperammonemia and central neurotoxicity and their association with asparaginase activity levels were evaluated.
Patients and Methods
Patients were treated according to Dutch Childhood Oncology Group (DCOG) ALL-10 medium risk intensification protocol, which includes 15 doses of PEGasparaginase (2,500 IU/m2) for 30 weeks. Erwinia asparaginase (20,000 IU/m2) was administered when an allergy to or silent inactivation of PEGasparaginase occurred. Definitions of silent inactivation of PEGasparaginase and Erwinia asparaginase were previously described (Tong et al., Blood, 2014 Mar;123(13):2026-33). Hypertriglyceridemia, hypercholesterolemia, hyperammonemia, pancreatitis, thrombosis and central neurotoxicity were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Changes over time of triglyceride, cholesterol, and ammonia levels were evaluated using mixed models analysis of variance (ANOVA). Changes related to age and gender were also investigated using mixed models ANOVA. The incidence of toxicities (pancreatitis, thrombosis, central neurotoxicity) related to treatment (PEGasparaginase or Erwinia asparaginase) was investigated with the Fisher's exact tests. Finally, Spearman correlation coefficients were used to evaluate the relations between triglyceride, cholesterol, and asparaginase activity levels.
Results
In total, 89 patients were enrolled from two pediatric oncology centers. Triglyceride, cholesterol and ammonia levels increased rapidly in children with PEGasparaginase and remained temporary elevated, but normalized after the finishing the last asparaginase dose. Hypertriglyceridemia and hypercholesterolemia (grade 3/4) were found in 47% and in 25%, respectively, of the patients treated with PEGasparaginase. Studying the correlations between PEGasparaginase activity levels and triglyceride levels showed the strongest correlation at week 5 (Rs = 0.36, p=0.005). Children >= 10 years had higher triglyceride levels as compared to younger patients (< 10 years) adjusted for asparaginase preparations: median levels of 4.9 mmol/L versus 1.6 mmol/L (p<0.001).
In patients receiving Erwinia asparaginase, triglyceride levels increased in the first weeks as well, but no hypertriglyceridemia and hypercholesterolemia (grade 3/4) were found. Hyperammonemia (grade 3/4) was only found in Erwinia asparaginase treated patients (9%). No associations were found between pancreatitis and hypertriglyceridemia nor between ammonia and central neurotoxicity. Thrombosis occurred in 4.5%, pancreatitis in 7% and central neurotoxicity in 9% of the patients using each of both asparaginase agents; these toxicities were not related to asparaginase activity levels nor to triglyceride levels.
Conclusions
Severe dyslipidemia occurred frequently, but was temporary and was not associated with relevant clinical events and therefore should not be considered a reason for asparaginase treatment modifications. We show that high asparaginase activity levels are associated with high triglyceride and high cholesterol levels. However, pancreatitis, thrombosis and central neurotoxicity appear unrelated to asparaginase activity levels. Also, no associations were found between pancreatitis and hypertriglyceridemia and between ammonia level and central neurotoxicity.
Table 1 Toxicity table, p-values are given for comparisons of grade 3/4 toxicities between both asparaginase agents, ns; not significant. PEGasparaginase (n=67) Erwinia asparaginase (n=22) p-value Grade 1/2 Grade 3/4 Grade 1/2 Grade 3/4 n % n % n % n % Pancreatitis 0 0 4 6 1 5 2 9 ns Hypertriglyceridemia 15 22 31 47 7 32 0 0 p<0.001 Hypercholesterolemia 6 9 17 25 8 37 0 0 p=0.01 Hyperammonemia 34 51 0 0 9 41 2 9 ns Thrombosis 0 0 2 3 0 0 2 9 ns Central neurotoxicity 0 0 7 10 0 0 1 5 ns

Disclosures
Tong: EUSA Pharma: Research Funding.