Acute lymphoblastic leukemia

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

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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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Acknowledgements

We thank all the patients and their families who participated in the study. We also thank all the researchers who scrutinized patient files and completed the phenotype questionnaire. The study was supported by The Danish Childhood Cancer Foundation.

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Correspondence to K Schmiegelow.

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The authors declare no conflict of interest.

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Author contributions

BOW, TLF and KS designed the study, analyzed and interpreted data and wrote the manuscript. BOW, MT and RY performed the GWAS quality control and analyzed associations; this was supervised by RG and KS. LRH and KKR were responsible for clinical data management and prepared DNA for the GWAS. BKA registered data on ASP therapy. JA, BKA, MH, OGJ, LTK, BL, RAR, MT, MRT, GEV, RY and RG provided critical input to the project and manuscript. All authors approved the final version of the manuscript.

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