Risk Factors that Can Disrupt Acute Lymphoblastic Leukemia Treatment

The association between a rare variation in the CPA2 gene and the chemotherapy drug asparaginase showed a dramatic increase of severe acute pancreatitis in patients with acute lymphoblastic leukemia (ALL).

Although asparaginase is an important agent used to treat ALL, it is also a major cause of acute pancreatitis, a life threatening condition that occurs in 2% to 18% of ALL patients.

In an article published in the Journal of Clinical Oncology, researchers looked to identify risk factors for the development of this disease in ALL patients.

The study included 5398 patients with ALL who ranged from infants to young adults and were treated in clinical trials by St. Jude or the Children’s Oncology Group.

There were 188 patients out of 5398 participants who developed pancreatitis at least once during ALL treatment.

To find risk factors, researchers checked patient DNA for more than 920,000 genetic variants. Additionally, 283 genes were sequenced and included genes that were associated with ALL risk and treatment outcome and genes linked to an increased risk of pancreatitis in patients with various health problems.

The results of the study showed that 2 participants were carriers of 1 copy of a CPA2 variant, each, that yielded a truncated version of the pancreatic enzyme proCPA2. Both of these patients ended up developing severe pancreatitis within weeks of their first dose of asparaginase.

“That suggests patients with this rare variant cannot tolerate the drug long enough to benefit from treatment,” said corresponding author Mary Relling, PharmD. “For these patients, ALL treatment regimens that do not depend on asparaginase may be preferable,”

It is estimated that approximately 9 in 100,000 people carry the potential high-risk CPA2 variant. An association was also found between patients with a Native American ancestry and an increased risk of pancreatitis after asparaginase therapy.

Researchers genetically defined ancestry with a higher Native American ancestry in Hispanic ALL patients. The results of the study found that for every 10% increase in Native American ancestry, the risk for developing pancreatitis increase by 20%.

Additionally, the study’s findings confirmed prior reports that older age, higher doses, and longer duration of the therapy was associated with a greater risk of pancreatitis. The risk in ALL patients was found to be higher in teenagers than in young children.

“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,” Relling said. “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.”