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

BO Wolthers, TL Frandsen, J Abrahamsson… - Leukemia, 2017 - nature.com
BO Wolthers, TL Frandsen, J Abrahamsson, BK Albertsen, LR Helt, M Heyman, ÓG Jónsson…
Leukemia, 2017nature.com
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%) …
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− 7; 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− 9; 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.
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