Abstract

Background: The current therapeutic strategy of applying pediatric-based regimens for acute lymphoblastic leukemia (ALL) to adults with ALL exposes these patients to multiple doses of asparaginase (ASP). Exposure to long-acting or pegylated ASP is particularly prominent due to dosing convenience, since pegylated ASP can be administered intravenously and requires fewer doses than shorter-acting forms. Previously, adult patients were much less likely to be treated with ASP-containing regimens due to reports from the 1970s of increased toxicity from ASP in adults compared with children. We report on the toxicities encountered in 3 protocols that include multiple doses of pegylated ASP as part of therapy for ALL in adult patients.

Methods: Thus far, the 3 protocols have enrolled 92 patients between the ages of 14 and 71 years. The pegylated ASP dose ranges from 2000–2500 IU/m2. Approximately 330 doses of pegylated ASP have been given.

Results: Grade 3–4 hepatic toxicity is the most prominent; grade 3–4 transaminase elevation occurred in 47 (51%) patients, and grade 3–4 hyperbilirubinemia was seen in 22 (24%) patients (Table). Hyperglycemia was grade 3–4 toxicity in 30 (33%) patients. Grade 3–4 allergic reactions to pegylated ASP occurred in 5 (5%) patients. Twelve (13%) patients developed thromboses. Of note, 3 (3%) patients have had leukoencephalopathy on magnetic resonance imaging scans with reversible stroke-like symptoms. The majority of hepatic toxicities resolve spontaneously, allowing patients to continue chemotherapy. All of the patients with stroke-like symptoms have fully recovered.

Conclusions: Considerable hepatotoxicity and hyperglycemia occur in adult ALL patients treated with polychemotherapy that includes long-acting ASP. Other toxicities occur with a frequency similar to that seen in pediatric patients treated with a long-acting ASP. This toxicity profile warrants close monitoring and continued data collection from clinical trials that use pegylated ASP in adults with ALL.

 USC Cleveland Clinic M.D. Anderson Total 
*No. of patients with grade 3–4 toxicities. 
Median age (years) 33 46 20 33 
Age range (years) 18–57 20–71 14–34 14–71 
No. doses/patients 127/39 56/25 147/28 330/92 
Toxicity* 
Elevated liver enzymes 23 17 47 
Hyperbilirubinemia 22 
Hyperglycemia 12 13 30 
Clinical pancreatitis N/A 
Fatigue 11 
Thrombosis 3 (SVC only) 12 
Hypofibrinogenemia N/A N/A 
Elevated PT / INR N/A N/A 
Bleeding N/A 
Nausea / vomiting 
Allergy / hypersensitivity 
Neuropathy N/A 
CNS stroke-like syndrome 
 USC Cleveland Clinic M.D. Anderson Total 
*No. of patients with grade 3–4 toxicities. 
Median age (years) 33 46 20 33 
Age range (years) 18–57 20–71 14–34 14–71 
No. doses/patients 127/39 56/25 147/28 330/92 
Toxicity* 
Elevated liver enzymes 23 17 47 
Hyperbilirubinemia 22 
Hyperglycemia 12 13 30 
Clinical pancreatitis N/A 
Fatigue 11 
Thrombosis 3 (SVC only) 12 
Hypofibrinogenemia N/A N/A 
Elevated PT / INR N/A N/A 
Bleeding N/A 
Nausea / vomiting 
Allergy / hypersensitivity 
Neuropathy N/A 
CNS stroke-like syndrome 

Disclosures: Rytting:Enzon: Speakers Bureau. Earl:Enzon: Consultancy. Douer:Enzon: Honoraria, Research Funding, Speakers Bureau; Cephalon: Honoraria, Research Funding, Speakers Bureau; Ortho-biothech: Research Funding; Genzyme: Research Funding. Advani:Enzon: Consultancy. Bleyer:Enzon: Honoraria.

Author notes

Corresponding author