L-Asparaginase Toxicity in the Treatment of Children and Adolescents with Acute Lymphoblastic Leukemia

Abstract

Asparaginase is a basic component of chemotherapy in pediatric acute lymphoblastic leukemia (ALL) and has played a crucial role in improving the long-term survival of this disease. The objectives of this retrospective study were to elucidate the toxicity profile associated with asparaginase in children and adolescents with ALL, to analyze the impact of each type of toxicity on long-term outcomes, and to identify risk factors. We analyzed the medical charts of 165 patients diagnosed with ALL at Sf. Maria Iasi Children’s Hospital from 2010 to 2019 and treated according to a chemotherapeutic protocol containing asparaginase. The median duration of follow-up was 5 years (0.1–11.5 years). Groups of patients with specific types of toxicity were compared to groups of patients without toxicity. We found the following incidence of asparaginase-associated toxicity: 24.1% clinical hypersensitivity, 19.4% hepatotoxicity, 6.7% hypertriglyceridemia, 4.2% hyperglycemia, 3.7% osteonecrosis, 3% pancreatitis, 2.4% thrombosis, and 1.2% cerebral thrombosis. Overall, 82 patients (49.7%) had at least one type of toxicity related to asparaginase. No type of toxicity had a significant impact on overall survival or event-free survival. Being older than 14 years was associated with a higher risk of osteonecrosis (p = 0.015) and hypertriglyceridemia (p = 0.043) and a lower risk of clinical hypersensitivity (p = 0.04). Asparaginase-related toxicity is common and has a varied profile, and its early detection is important for realizing efficient and appropriate management.

Risk Factors for Hepatotoxicity From L-Asparaginase Chemotherapy In Children With Acute Lymphoblastic Leukemia

“…25,26 The proportion of the high-risk group (53%) was higher than the proportion of the standard-risk group, even though the ALL-risk group was not a risk factor for hepatotoxicity because the high-risk group had no cases of non-hepatotoxicity. This study was also supported by the research of Schmidt et al 15 (2021), which stated that high-risk ALL chemotherapy was not significantly associated (p=0.239) with the incidence of hepatotoxicity due to L-asparaginase therapy in pediatric patients with ALL. 15 The incidence of hepatotoxicity caused by L-asparaginase chemotherapy in children with ALL was not related to the drug accumulation dose factor in this study either; however, a different study suggested that hepatotoxicity caused by L-asparaginase chemotherapy was related to higher doses and more intense dosing schedules.…”

“…Whereas in this study, more than half of the sample (56.7%) had platelet counts between <100,000 mm 3 with an average platelet level of 99,220 (37,230) mm 3 . A study by Schmidt et al 15 (2021) showed that hemoglobin concentration was not significantly related (p=0.867) to the incidence of hepatotoxicity due to L-asparaginase therapy in ALL patients. Approximately 70% had a leukocyte count of 4,000 -<10,000 mm 3 and only five children had a leukocyte count ≥ 10,000 mm 3 .…”

“…2.97 ± 0.28 3.00 (2.5 -3.5) Hepatotoxicity is the second most common case as an effect of L-asparaginase therapy in ALL patients with a prevalence of 19.4% with a severity level of 62.5% having hepatotoxicity greater than equal to 3, as many as 37.5% having hepatotoxicity below grade 3, even 12.5% experiencing hepatotoxicity grade 5 with fulminant liver failure and death. 15 In this study, the prevalence of hepatotoxicity due to L-asparaginase chemotherapy in pediatric patients with ALL was 73.3% with the hepatotoxicity category used being a cut-off > 45 U/L equivalent to grade 1 hepatotoxicity based on the Common Terminology Criteria for Adverse Events (CTCAE) 2017. 3 Management of hepatotoxicity associated with L-asparaginase chemotherapy depends on the severity of the hepatotoxicity.…”

<i>In vivo</i> stabilization of a less toxic asparaginase variant leads to a durable antitumor response in acute leukemia

“…Maaike Van Trimpont 1,2,3 , Amanda M. Schalk 4 , Yanti De Visser 1,2,5 , Hien Anh Nguyen 4 , Lindy Reunes 1,2 , Katrien Vandemeulebroecke 1,6,7 , Evelien Peeters 1,3 , Ying Su 4 , Hyun Lee 8,9 , Philip L. Lorenzi 10 , Wai-Kin Chan 10 , Veerle Mondelaers 1,6 , Barbara De Moerloose 1,6,7 , Tim Lammens 1,6,7 , Steven Goossens 1,3 , Pieter Van Vlierberghe 1,2** and Arnon Lavie…”

“…Since the introduction of L-ASNases, mortality rates in pediatric ALL patients have drastically decreased, currently reaching overall 5-year survival rates of almost 90% 3 . While the depletion of blood asparagine (Asn) represents a critical component of the multiple-drug ALL treatment regimen [3][4][5] , the use of L-ASNase is also associated with a variety of toxic side effects [6][7][8][9] . A large part of these unwanted effects can be attributed to the secondary L-glutaminase co-activity displayed by all clinically approved bacterial L-ASNases 10 .…”