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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Inaba H, Greaves M, Mullighan CG . Acute lymphoblastic leukemia. Lancet 2013; 381: 1–27.
Gregers J, Dalhoff K, Lausen B, Schroeder H, Rosthoej S, Carlsen N et al. The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number. Blood 2010; 115: 4671–4677.
Stanulla M, Schrappe M . Treatment of childhood acute lymphoblastic leukemia. Semin Hematol 2009; 46: 52–63.
Slats AM, Egeler RM, van der Does-van den Berg A, Korbijn C, Hählen K, Kamps WA et al. Causes of death—other than progressive leukemia—in childhood acute lymphoblastic (ALL) and myeloid leukemia (AML): the Dutch Childhood Oncology Group experience. Leukemia 2005; 19: 537–544.
Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Löning L et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood 2013; 111: 4477–4489.
Vilmer E, Suciu S, Ferster A, Bertrand Y, Cavé H, Thyss A et al. Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report. Children Leukemia Cooperative Group. Leukemia 2000; 14: 2257–2266.
Conter V, Aricò M, Basso G, Biondi A, Barisone E, Messina C et al. Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) Studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia. Leukemia 2010; 24: 255–264.
Prucker C, Attarbaschi A, Peters C, Dworzak MN, Pötschger U, Urban C et al. Induction death and treatment-related mortality in first remission of children with acute lymphoblastic leukemia: a population-based analysis of the Austrian Berlin-Frankfurt-Münster study group. Leukemia 2009; 23: 1264–1269.
Rubnitz JE, Lensing S, Zhou Y, Sandlund JT, Razzouk BI, Ribeiro RC et al. Death during induction therapy and first remission of acute leukemia in childhood: The St. Jude experience. Cancer 2004; 101: 1677–1684.
Hargrave DR, Hann IM, Richards SM, Hill FG, Lilleyman JS, Kinsey S et al. Progressive reduction in treatment-related deaths in Medical Research Council childhood lymphoblastic leukaemia trials from 1980 to 1997 (UKALL VIII, X and XI). Br J Haematol 2001; 112: 293–299.
Schmiegelow K, Forestier E, Hellebostad M, Heyman M, Kristinsson J, Söderhäll S . Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia. Leukemia 2010; 2: 345–354.
Lund B, Åsberg A, Heyman M, Kanerva J, Harila-Saari A, Hasle H et al. Risk factors for treatment related mortality in childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2011; 56: 551–559.
Schmiegelow K, Levinsen MF, Attarbaschi A, Baruchel A, Devidas M, Escherich G et al. Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 2013; 31: 2469–2476.
Silverman LB, Gelber RD, Dalton VK, Asselin BL, Barr RD, Clavell L A et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood 2001; 97: 1211–1218.
Amylon MD, Shuster J, Pullen J, Berard C, Link MP, Wharam M et al. Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study. Leukemia 1999; 13: 335–342.
Duval M, Suciu S, Ferster A, Rialland X, Nelken B, Lutz P et al. Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children’s Leukemia Group phase 3 trial. Blood 2002; 99: 2734–2739.
Pession A, Valsecchi M G, Masera G, Kamps WA, Magyarosy E, Rizzari C et al. Long-term results of a randomized trial on extended use of high dose l-asparaginase for standard risk childhood acute lymphoblastic leukemia. J. Clin. Oncol. 2005; 23: 7161–7167.
van den Berg H . Asparaginase revisited. Leuk Lymphoma 2011; 52: 168–178.
Pieters R, Hunger SP, Boos J, Rizzari C, Silverman L, Baruchel A et al. L-asparaginase treatment in acute lymphoblastic leukemia: a focus on Erwinia asparaginase. Cancer 2011; 117: 238–249.
Raja RA, Schmiegelow K, Frandsen TL . Asparaginase-associated pancreatitis in children. Br J Haematol 2012; 159: 18–27.
Raja RA, Schmiegelow K, Albertsen BK, Prunsild K, Zeller B, Vaitkeviciene G et al. Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol. Br J Haematol 2014; 165: 126–133.
Kearney SL, Dahlberg SE, Levy DE, Voss SD, Sallan SE, Silverman LB . Clinical course and outcome in children with acute lymphoblastic leukemia and asparaginase-associated pancreatitis. Pediatr Blood Cancer 2009; 53: 162–167.
Samarasinghe S, Dhir S, Slack J, Iyer P, Wade R, Clack R et al. Incidence and outcome of pancreatitis in children and young adults with acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003. Br J Haematol 2013; 162: 710–713.
Alvarez OA, Zimmerman G . Pegaspargase-induced pancreatitis. Med Pediatr Oncol 2000; 34: 200–205.
Tenner S, Baillie J, DeWitt J, Vege SS . American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol 2013; 108: 1400–1415, 1416.
Stock W, Douer D, DeAngelo DJ, Arellano M, Advani A, Damon L et al. Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. Leuk Lymphoma 2011; 52: 2237–2253.
Frandsen TL, Heyman M, Abrahamsson J, Vettenranta K, Åsberg A, Vaitkeviciene G et al. Complying with the European Clinical Trials directive while surviving the administrative pressure - an alternative approach to toxicity registration in a cancer trial. Eur J Cancer 2014; 50: 251–259.
Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007; 81: 559–575.
Zerbino DR, Wilder SP, Johnson N, Juettemann T, Flicek PR . The ensembl regulatory build. Genome Biol 2015; 16: 56.
Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 2015; 43: D447–D452.
Toft N, Birgens H, Abrahamsson J, Bernell P, Griškevičius L, Hallböök H et al. Risk group assignment differs for children and adults 1-45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol. Eur J Haematol 2013; 90: 404–412.
Bradley EL, Frey CF . A clinically based classification system for acute pancreatitis: summary of the International Symposium on Acute Pancreatitis, Atlanta, GA, September 11 through 13, 1992. Invited commentary. Arch Surg 1993; 128: 586–590.
Banks PA, Bollen TL, Dervenis C, Gooszen HG, Johnson CD, Sarr MG et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut 2012; 62: 102–111.
Schmiegelow K, Attarbaschi A, Barzilai S, Escherich G, Frandsen TL, Halsey C et al. Consensus definitions of fourteen severe acute toxicities during childhood lymphoblastic leukaemia therapy. Lancet Oncol 2016; 17: e231–e239.
Bone R, Balk R, Cerra F, Dellinger R, Fein A, Knaus W et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101: 1644–1655.
Team RC. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria, 2015. Available at http://www.r-project.org/.
Kirkwood and Sterne. Medical Statistics. 2nd ed. Blackwell Science Ltd, 2003.
Bush WS, Moore JH . Chapter 11: Genome-wide association studies. PLoS Comput Biol 2012; 8: e1002822.
The 1000 Genomes Project Consortium. An integrated map of genetic variation from 1,092 human genomes. Nature 2012; 491: 56–65.
Liu C, Yang W, Devidas M, Cheng C, Pei D, Smith C et al. Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia. J Clin Oncol 2016; 34: 2133–2140.
Vrooman LM, Supko JG, Neuberg DS, Asselin BL, Athale UH, Clavell L et al. Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2010; 54: 99–205.
Holmqvist AS, Olsen JH, Andersen KK, de Fine Licht S, Hjorth L, Garwicz S et al. Adult life after childhood cancer in Scandinavia: diabetes mellitus following treatment for cancer in childhood. Eur J Cancer 2014; 50: 1169–1175.
Knoderer HM, Robarge J, Flockhart DA . Predicting asparaginase-associated pancreatitis. Pediatr Blood Cancer 2007; 49: 634–639.
Stewart A, Fisher RA . Introduction: G protein-coupled receptors and RGS proteins. Prog Mol Biol Transl Sci 2015; 133: 1–11.
Samuel I, Chaudhary A, Chatterjee TK, Ficher RA . Bile-pancreatic juice exclusion induces expression of RGS6 in rat exocrine pancreas. FASEB J 2006; 20: A256.
Mizushima N . The role of the Atg1/ULK1 complex in autophagy regulation. Curr Opin Cell Biol 2010; 22: 132–139.
Ohmuraya M, Yamamura KI . Autophagy and acute pancreatitis: a novel autophagy theory for trypsinogen activation. Autophagy 2008; 4: 1060–1062.
Levine B, Mizushima N, Virgin HW . Autophagy in immunity and inflammation. Nature 2011; 469: 323–335.
Mareninova OA, Hermann K, French SW, Konski MSO, Pandol SJ, Webster P et al. Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis. J Clin Invest 2009; 119: 3340–3355.
Hall JC, Crawford HC . The conspiracy of autophagy, stress and inflammation in acute pancreatitis. Curr Opin Gastroenterol 2014; 30: 1–5.
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.
The authors declare no conflict of interest.
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.
Supplementary Information accompanies this paper on the Leukemia website
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Intermittent Versus Continuous PEG-Asparaginase to Reduce Asparaginase-Associated Toxicities: A NOPHO ALL2008 Randomized Study
Journal of Clinical Oncology (2019)
Journal of Clinical Investigation (2018)
The Lancet Haematology (2018)
Pediatric Blood & Cancer (2018)