Genetic, clinical risk factors identified for pancreatitis in ALL

Older age, higher asparaginase exposure and Native American ancestry served as independent risk factors for pancreatitis in children and young adults with acute lymphoblastic leukemia, according to the results of a cohort study.

Children and young adults who inherited a nonsense rare variant in the CPA2 gene exhibited an extremely high risk for asparaginase-induced pancreatitis, results showed.

Acute pancreatitis is a common cause of asparaginase intolerance. However, the mechanism remains unknown, and studies have not identified a genetic predisposition to asparaginase-induced pancreatitis.

Mary V. Relling, PharmD, chair of the pharmaceutical sciences department at St. Jude Children’s Research Hospital, and colleagues sought to determine risk factors for asparaginase-induced pancreatitis. They performed a genome-wide association study in a cohort of 5,185 children and young adults with ALL (age range, 0 years to 30 years), treated at St. Jude Children’s Research Hospital and in the Children’s Oncology Group with seven frontline protocols.

Of those, 117 patients had a diagnosed episode of acute pancreatitis during therapy, with the first episode occurring a median of 106 days from ALL diagnosis.

Pancreatitis developed during remission induction (defined as the first 4 to 6 weeks of treatment) in 24 patients (20.5%) and during the first year of therapy (including remission induction) in 104 patients (88.9%).

The researchers also performed a genome-wide association study in an independent case–control group of 213 patients to determine potential genetic risk factors.

Seventy-one patients in the case–control group developed pancreatitis, with the first episode occurring a median of 78 days from diagnosis. Twenty-four cases (33.8%) developed during remission induction and 65 cases (91.5%) developed during the first year.

A multivariate analysis connected an increased risk for pancreatitis to older age (HR per year = 1.1; P < .001) and genetically-defined Native American ancestry (HR for every 10% increase in ancestry = 1.2; P < .001).

Patients treated with high-dose asparaginase regimens ( 240,000 U/m²) had a greater risk for pancreatitis (HR = 3.2; P < .001).

No common variants reached genome-wide significance. However, the rare nonsense variant rs199695765 in CPA2 — which encodes carboxypeptidase A2 — appeared highly associated with pancreatitis (HR = 587; 95% CI, 66.8-5,166; P = 9 x 10^-9).

A gene-level analysis found that an excess of additional CPA2 single-nucleotide polymorphisms existed in patients who developed pancreatitis compared with those who did not (P = .001).

A total of 16 CPA2 SNPs were associated with pancreatitis (P < .05); 24 patients carried at least one of these variants, of whom 13 developed pancreatitis.

Some biologic functions, including purine metabolism and cytoskeleton regulation, were overrepresented by common variants modestly associated with pancreatitis.

“Our findings are consistent with a mixed genetic architecture underlying serious adverse drug effects, wherein a combination of rare but highly penetrant and common but weakly penetrant genetic risk factors contribute to genetic predisposition,” Relling and colleagues wrote. “For the small number of patients carrying the highly penetrant CPA2 variants, a precision medicine approach using ALL regimens containing less asparaginase should be considered.” – by Cameron Kelsall

Disclosure: Relling reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.