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

• Published in: Leukemia Vol. 31; no. 2; pp. 325 - 332
• Main Authors: Wolthers, B O, Frandsen, T L, Abrahamsson, J, Albertsen, B K, Helt, L R, Heyman, M, Jónsson, Ó G, Kõrgvee, L T, Lund, B, Raja, R A, Rasmussen, K K, Taskinen, M, Tulstrup, M, Vaitkevičienė, G E, Yadav, R, Gupta, R, Schmiegelow, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2017; Nature Publishing Group
• Subjects: 38/43; 631/208/726/649; 692/308/2056; 692/499; 692/699/1503/1712/1714; 692/699/67/1990/283/2125; 692/699/67/69; 692/700/565/2194; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Adolescent; Alleles; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Asparaginase; Asparaginase - adverse effects; Asparaginase - therapeutic use; Autophagy; Biomarkers; Cancer Research; Care and treatment; Case-Control Studies; Causes of; Child; Child, Preschool; Complications; Critical Care Medicine; Cysts; Deoxyribonucleic acid; Diagnosis; DNA; Female; Gene Frequency; Genetic aspects; Genetic Association Studies; Genomes; Genotype; Genotype & phenotype; Genotypes; Health aspects; Hematology; Hospitals; Humans; Infant; Insulin; Intensive; Internal Medicine; Leukemia; Lymphatic leukemia; Male; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Odds Ratio; Oncology; original-article; Pain; Pancreatitis; Pancreatitis - diagnosis; Pancreatitis - epidemiology; Pancreatitis - etiology; Pediatrics; Phenotype; Phenotypes; Polymorphism, Single Nucleotide; Precursor Cell Lymphoblastic Leukemia-Lymphoma - complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Protein-Serine-Threonine Kinases - genetics; Risk factors; Severity of Illness Index; Toxicity; Europe; Sweden; Norway; Finland; Denmark; Lithuania; Iceland; Aarhus Denmark; Estonia
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/leu.2016.203

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.