Risk Factors For Acute Pancreatitis In Patients With Acute Lymphoblastic Leukemia
Authors: Liu Chengcheng , Pei Deqing , Devidas Meenakshi , Cheng Cheng , Yang Wenjian , Howard Scott C. , Loh Mignon L. , Martin Paul L. , Winick Naomi J. , Bowman William Paul , Larsen Eric C. , Carroll William L. , Raetz Elizabeth A. , Bhojwani Deepa , Jeha Sima , Pui Ching-Hon , Evans William E. , Hunger Stephen P. , Relling Mary V. 
Published: October 2019

Abstract
Acute pancreatitis is a life-threatening complication of acute lymphoblastic leukemia (ALL) treatment. Previous studies have reported that intensive chemotherapy (especially asparaginase) and older age may predispose patients to pancreatitis (Samarasinghe et al. Br J Haematol 2013, Kearney et al. Pediatr Blood Cancer 2009;53:162 and Knoderer et al. Pediatr Blood Cancer 2007;49:634); however only a few large trials and case series have been reported. We studied 5185 ALL patients (age 0 to 30 years) enrolled between 1994 and 2012 on six front-line protocols for childhood ALL (St. Jude Total XIIIB and Total XV; COG P9904/P9905/P9906 and AALL0232) at St. Jude Children’s Research Hospital and in the Children’s Oncology Group. Pancreatitis was diagnosed in 117 (2.3%) patients by clinical symptoms, elevation in the serum amylase or lipase levels and abnormal radiographic or surgical findings according to NCI CTCAE version 2.0 (grade 3-4) or 3.0 (grade 2-4). The first episode of pancreatitis developed during remission induction in 24 of 117 (20.5%) patients and during the first year of therapy (including remission induction) in 104 of 117 (88.9%) patients.
We investigated whether age, gender, race, immunophenotype, cumulative asparaginase dose and formulation (native E. coli-asparaginase [Elspar] vs PEG-asparaginase [Oncaspar]) were associated with the development of pancreatitis. Race was categorized as white, black, Hispanic, Asian and other based on inferred genetic ancestry (European, African, Native American and Asian) using STRUCTURE (Yang et al. Nat Genet 2011;43:237-241). Patients with pancreatitis were significantly older than those without the complication (median age, 11.7 years vs 7.3 years; P = 2.2 × 10-9). Hispanics (46 of 1177, 3.9%) and blacks (11 of 350, 3.1%) had a higher risk of pancreatitis than did whites (46 of 3069, 1.5%) and Asians (1 of 99, 1.0%; P = 1.6 × 10-5). Patients treated on protocols featuring higher cumulative dose of asparaginase (Total XV, COG P9906 and AALL0232) developed more pancreatitis than those on the protocols with lower dose of asparaginase (Total XIIIB and COG P9904/P9905) (103 of 3358, 3.1% vs 14 of 1827, 0.8%; P = 1.2 × 10-8; Figure 1). Gender, immunophenotype and asparaginase formulation were not associated with the development of pancreatitis. In a multivariate model, Native American ancestry (hazard ratio = 1.20 for every 10% increase; P = 8.4 × 10-8), older age (hazard ratio = 1.08 for every 1 year increase; P = 1.2 × 10-5) and higher cumulative dose of asparaginase (hazard ratio = 3.27 for those receiving native E.coli-asparaginase [or PEG-asparaginase equivalent] ≥ 240,000 U/m2 vs< 240,000 U/m2; P = 1.1 × 10-4) remained independent risk factors for pancreatitis, while African ancestry was only marginally significant (hazard ratio = 1.08 for every 10% increase; P = 0.053). In summary, older age, Native American ancestry and higher asparaginase exposure independently predict the development of pancreatitis in children treated for ALL.Figure 1Comparison of asparaginase dose and 3-year cumulative incidence of pancreatitis in different protocols. Native E. coli-asparaginase (E.coli-ASP) and PEG-asparaginase (PEG-ASP) were given intramuscularly at doses shown in the table. *Total dose of native E.coli-ASP (excluding the Extended Induction phase), according to protocol. PEG-ASP administration at 2,500 U/m2 is considered equivalent to native E. coli-ASP at 50,000 U/m2. #Dichotomized by total dose of native E.coli-ASP (or equivalent dose of PEG-ASP) above or below 240,000 U/m2. Abbreviations: ASP, asparaginase.Figure 1. Comparison of asparaginase dose and 3-year cumulative incidence of pancreatitis in different protocols. Native E. coli-asparaginase (E.coli-ASP) and PEG-asparaginase (PEG-ASP) were given intramuscularly at doses shown in the table. *Total dose of native E.coli-ASP (excluding the Extended Induction phase), according to protocol. PEG-ASP administration at 2,500 U/m2 is considered equivalent to native E. coli-ASP at 50,000 U/m2. #Dichotomized by total dose of native E.coli-ASP (or equivalent dose of PEG-ASP) above or below 240,000 U/m2. Abbreviations: ASP, asparaginase.

Disclosures:
Evans: St. Jude: In accordance with institutional policy, St. Jude allocates a portion of the income it receives from licensing inventions and tangible research materials to those researchers responsible for creating this intellectual property., In accordance with institutional policy, St. Jude allocates a portion of the income it receives from licensing inventions and tangible research materials to those researchers responsible for creating this intellectual property. Patents & Royalties, Under this policy, I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Other. Hunger:Jazz Pharmaceuticals: I receive funding for investigator-initiated research of asparaginase from Jazz Pharmaceuticals., I receive funding for investigator-initiated research of asparaginase from Jazz Pharmaceuticals. Other; Sigma-Tau Pharmaceuticals: I receive funding for investigator-initiated research of asparaginase from Sigma-Tau Pharmaceuticals. Other. Relling:Sigma-Tau Pharmaceuticals: I receive funding for investigator-initiated research on the pharmacology of asparaginase from Sigma-Tau Pharmaceuticals., I receive funding for investigator-initiated research on the pharmacology of asparaginase from Sigma-Tau Pharmaceuticals. Other; St. Jude Children’s Research Hospital : I have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics., I have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties.