In a study reported in the Journal of Clinical Oncology, Liu et al found that Native American ancestry, older age, higher cumulative dose of asparaginase, and a rare variant of the CPA2 gene increased risk for pancreatitis in children/young adults with acute lymphoblastic leukemia (ALL).
The study involved data from a cohort of 5,185 children and young adults with ALL, including 117 (2.3%) diagnosed with at least one episode of acute pancreatitis during therapy. A genome-wide association study was performed in the cohort and in an independent case-control group of 213 patients to identify potential genetic risk factors.
On multivariate analysis, older age (hazard ratio [HR] = 1.1 per year, P < .001), genetically defined Native American ancestry (HR = 1.2 for every 10% increase in ancestry, P < .001), and high-dose asparaginase regimens (≥ 240,000 U/m2; HR = 3.2, P < .001) were associated with increased risk of pancreatitis.
No common gene variants showed significance in the genome-wide association study. However, a rare nonsense variant, rs199695765 in CPA2 (encoding carboxypeptidase A2), was highly associated with pancreatitis (HR = 587, P = 9.0 × 10-9). Patients who developed pancreatitis had an excess of additional CPA2 variants vs those who did not develop pancreatitis (P = .001). Overall, 16 CPA2 single-nucleotide polymorphisms were associated (P < .05) with pancreatitis, with pancreatitis developing in 13 of 24 patients who harbored at least one of the variants. Biologic functions overrepresented by common variants associated with pancreatitis included purine metabolism and cytoskeleton regulation.
The investigators concluded, “Older age, higher exposure to asparaginase, and higher Native American ancestry were independent risk factors for pancreatitis in patients with acute lymphoblastic leukemia. Those who inherit a nonsense rare variant in the CPA2 gene had a markedly increased risk of asparaginase-induced pancreatitis.”
The study was supported by the National Cancer Institute and American Lebanese Syrian Associated Charities.
Mary V. Relling, PharmD, of St. Jude Children’s Research Hospital, is the corresponding author for the Journal of Clinical Oncology article.
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