(left) and Chengcheng Liu
Photo courtesy of St. Jude
Children’s Research Hospital
and Peter Barta
Researchers have identified several factors that may increase the risk of asparaginase-induced pancreatitis in patients with acute lymphoblastic leukemia (ALL).
The team found that 16 variants in the CPA2 gene—and 1 rare variant in particular—were associated with a higher risk of asparaginase-induced pancreatitis.
Patients also had a higher risk if they had genetically defined Native American ancestry, were older, and received higher doses of asparaginase.
The researchers reported these findings in the Journal of Clinical Oncology.
“In this study, we identified several independent risk factors for asparaginase-induced pancreatitis and also gained insight into the mechanism responsible for this serious treatment complication,” said study author Mary Relling, PharmD, of St. Jude Children’s Research Hospital in Memphis, Tennessee.
“Understanding the risk factors for acute pancreatitis is important because, in patients who can tolerate the drug, asparaginase reduces the likelihood that ALL patients will relapse.”
The research included 5398 ALL patients (ages 0 to 30) who were treated in clinical trials organized by St. Jude or the Children’s Oncology Group. In all, 188 patients developed pancreatitis at least once during ALL therapy.
To search for risk factors associated with asparaginase-induced pancreatitis, the researchers checked patient DNA for more than 920,000 gene variants.
The team also sequenced 283 genes, including genes associated with ALL risk and treatment outcome and genes linked to an elevated risk of pancreatitis in patients with different health problems.
The results revealed a rare nonsense variant in CPA2 (rs199695765) that yields a truncated version of the pancreatic enzyme proCPA2. The researchers said this variant was “highly associated” with pancreatitis, with a hazard ratio (HR) of 587 (P=9.0×10−9).
Two study participants each carried 1 copy of the variant, and both patients developed severe pancreatitis within weeks of receiving their first dose of asparaginase.
“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” Dr Relling said. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable.”
The researchers estimated that about 9 in 100,000 individuals carry the suspected high-risk CPA2 variant.
The team also found an excess of additional CPA2 variants in patients who developed pancreatitis compared to those who did not (P=0.001).
In all, the researchers identified 380 variants in CPA2. Sixteen of them were significantly associated (P<0.05) with pancreatitis, and 54% (13/24) of patients who carried at least 1 of these variants developed pancreatitis.
The researchers also found links between clinical factors and asparaginase-induced pancreatitis. A multivariate analysis suggested the following were associated with pancreatitis:
- Older age (HR=1.1 per year; P<0.001)
- Genetically defined Native American ancestry (HR=1.2 for every 10% increase in Native American ancestry; P<0.001)
- High-dose (≥240,000 U/m2) asparaginase regimens (HR=3.2; P<0.001).
