Asparaginase-associated pancreatitis: a study on phenotype and genotype in the NOPHO ALL2008 protocol

Abstract

Asparaginase (ASP)-associated pancreatitis (AAP) occurs during acute lymphoblastic leukemia treatment. Among 1285 children (1.0-17.9 years) diagnosed during July 2008-December 2014 and treated according to the Nordic/Baltic ALL2008 protocol, 86 (cumulative incidence=6.8%) developed AAP. Seventy-three cases were severe (diagnostic AAP criteria persisting >72 h) and 13 mild. Cases were older than controls (median: 6.5 vs 4.5 years; P=0.001). Pseudocysts developed in 28%. Of the 20 re-exposed to ASP, 9 (45%) developed a second AAP. After a median follow-up of 2.3 years, 8% needed permanent insulin therapy, and 7% had recurrent abdominal pain. Germline DNA on 62 cases and 638 controls was genotyped on Omni2.5exome-8-v1.2 BeadChip arrays. Overall, the ULK2 variant rs281366 showed the strongest association with AAP (P=5.8 × 10; odds ratio (OR)=6.7). Cases with the rs281366 variant were younger (4.3 vs 8 years; P=0.015) and had lower risk of AAP-related complications (15% vs 43%; P=0.13) compared with cases without this variant. Among 45 cases and 517 controls <10 years, the strongest associations with AAP were found for RGS6 variant rs17179470 (P=9.8 × 10; OR=7.3). Rs281366 is located in the ULK2 gene involved in autophagy, and RGS6 regulates G-protein signaling regulating cell dynamics. More than 50% of AAP cases <10 years carried one or both risk alleles.

Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

“…Retreatment with asparaginase after an episode of pancreatitis is associated with a high risk of recurrent pancreatitis, so this complication often leads to early cessation of asparaginase therapy, which can negatively affect survival [92]. Genes in the asparaginase pathway, such as ASNS, as well as genes involved in autophagy and cell signaling such as ULK2 and RGS6 have been shown to mediate risk of pancreatitis, though this association was found in a single study and has yet to be independently verified [94].…”

Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy

“…The risk of a second AAP after re-exposing patients with AAP to asparaginase is almost 50% and does not seem to be significantly lower if the first AAP episode was classified as mild 170, 174, 175 .…”

“…Asparaginase-associated pancreatitis (AAP) has a reported incidence of 2 to 18% depending on the cumulative asparaginase dose (that is, treatment duration) and toxicity capture strategies but seemingly not on the route of administration 7, 158, 169– 174 . AAP is most often diagnosed within two weeks of asparaginase exposure (median of 11 days with PEG-asparaginase), but the interval may be longer 175 .…”

Galactose protects against cell damage in mouse models of acute pancreatitis

“…Another cause of AP is the l -asparaginase treatment of acute lymphoblastic leukemia (ALL) (6, 7). According to Cancer Research UK, there were 832 new cases of ALL diagnosed in the United Kingdom in 2015.…”

“…Antileukemic drugs based on l -asparaginase are currently used in the clinic as an effective treatment for childhood ALL (8–12). However, in up to 10% of cases, the asparaginase treatment has to be truncated due to development of AP, a serious and incurable illness (6, 7, 13–17). Although asparaginase-based drugs have been used in the clinic for many years (8), the mechanism of this side effect has not been well explored and understood.…”