A new research study, led by scientists at St. Jude Children's Research Hospital, has identified a rare genetic variation associated with a dramatically increased risk of severe acute pancreatitis in acute lymphoblastic leukemia (ALL) patients treated with the chemotherapy agent asparaginase.
Asparaginase is an essential agent used to treat ALL and some mast cell tumor types, but it has been linked as a principal cause of acute pancreatitis in ALL patients. This often painful and sometimes life-threatening condition occurs in approximately 2–18% of patients, complicating their treatment and threatening their overall chances of being cured.
Researchers have often suspected an association of asparaginase-induced pancreatitis with a rare variation in the CPA2 gene. Thus, confirmation of this association could help identify patients who are candidates for chemotherapeutic regimes that do not include the drug.
"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," explained senior study author Mary Relling, Pharm.D., chair of the St. Jude Department of Pharmaceutical Sciences. "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 findings from this study were published recently in the Journal of Clinical Oncology in an article entitled "Clinical and Genetic Risk Factors for Acute Pancreatitis in Patients With Acute Lymphoblastic Leukemia.”
Interestingly, the St. Jude team was able to identify an association between Native American ancestry and an increased risk of pancreatitis following asparaginase therapy. Ancestry was genetically defined in this study, with higher Native American ancestry in Hispanic ALL patients. For every 10% increase in Native American ancestry, the risk of pancreatitis increased 20%.
This new study also confirmed previous reports that older age as well as higher doses and longer duration of asparaginase therapy were associated with a greater risk of pancreatitis. The investigators found that the risk in ALL patients was higher in teenagers than in young children.
Incorporating a genome-wide association study (GWAS), the scientists included 5398 ALL patients, ranging from infants to young adults, who were treated in clinical trials organized by St. Jude or the Children's Oncology Group, a federally funded pediatric cancer clinical trials network. The study included 188 patients who developed pancreatitis at least once during ALL therapy.
To identify the pancreatitis risk factors, the research team checked patient DNA for more than 920,000 gene variants. Furthermore, they also sequenced 283 genes, including genes associated with ALL risk and treatment outcome plus genes linked to an elevated risk of pancreatitis in patients with different health problems.
The St. Jude team also identified two study participants, each of which carried one copy of a CPA2 variant that yielded a truncated version of the pancreatic enzyme proCPA2. 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 noted. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable."
While the study scientists estimated that roughly 9 in 100,000 individuals carry the suspected high-risk CPA2 variant, they were also able to uncover more commonly occurring gene variants, providing insight into the mechanisms underlying asparaginase-associated pancreatitis. However, these variants were more modestly associated with pancreatitis and included genes involved in purine metabolism and the cytoskeleton, which typically helps cells maintain their shape.