Risk factors for asparaginase-associated pancreatitis identified in patients with acute lymphoblastic leukemia

1. In a retrospective review of over 5000 children with acute lymphoblastic leukemia (ALL) who received asparaginase induction therapy, independent clinical risk factors for pancreatitis include Native American ancestry, older age, and higher cumulative doses of asparaginase.

2. Patients with specific mutations to CPA2 gene were at a significantly higher risk of developing asparaginase-associated pancreatitis

Evidence Rating Level: 3 (Average)       

Study Rundown: Asparaginase is an E. coli derived enzyme frequently used as an acute therapy agent in ALL. However, asparaginase use has been associated with a number of significant side effects including pancreatitis, which significantly increases morbidity and disrupts leukemia treatment. To date, there has been a paucity of evidence investigating the pathophysiology of asparaginase-associated pancreatitis. The purpose of this study was to determine potential clinical risk factors of this condition in children with ALL.

The study retrospective reviewed patient outcomes of over 5000 children with ALL who underwent asparaginase therapy. At the conclusion of the trial, independent risk factors for the development of asparaginase-associated pancreatitis included patients of Native American heritage, older age, and high cumulative doses of asparaginase. Furthermore, in an additional genome-wide association analysis, patients with specific mutations in the CPA2 gene were significantly associated with asparaginase-associated pancreatitis. This was one of the largest studies to identify genetic and clinical risk factors for asparaginase-associated pancreatitis and supports increased vigilance for patients in these risk factor groups. Additional trials into the mechanism of the CPA2 gene association with pancreatitis are warranted to better understand the pathophysiological mechanism of this iatrogenic side effect and for the development of potential personalized approaches to future treatment therapies for ALL.

Click to read the study in JCO

Relevant Reading: Predicting asparaginase-associated pancreatitis

In-Depth [retrospective cohort]: This was a retrospective cohort study of 5185 children and young adults (aged 0 to 30) with a diagnosis of ALL and used asparaginase-based induction therapy in a large tertiary children’s hospital in the United States. The selection of pancreatitis cases were based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 3.0.  An additional genome-wide association study was performed within this cohort among patients with available germline DNA for study. Overall, there were 117 (2.3%) cases of pancreatitis recorded in this cohort. At the conclusion of the study, Native American heritage (p < 0.001), older age (p < 0.001), and high-dose use of asparaginase (p < 0.001) were significantly associated with increased risk of pancreatitis. Additionally, there was a significantly higher incidence of patients with CPA2 mutations in patients who develop pancreatitis (95% CI: 66.8 to 5166; p = 9.0×109).

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