Can Machine Learning Models Predict Asparaginase-associated Pancreatitis in Childhood Acute Lymphoblastic Leukemia

Publisher Copyright: © 2021 Lippincott Williams and Wilkins. All rights reserved.Asparaginase-associated pancreatitis (AAP) frequently affects children treated for acute lymphoblastic leukemia (ALL) causing severe acute and persisting complications. Known risk factors such as asparaginase dosing, older age and single nucleotide polymorphisms (SNPs) have insufficient odds ratios to allow personalized asparaginase therapy. In this study, we explored machine learning strategies for prediction of individual AAP risk. We integrated information on age, sex, and SNPs based on Illumina Omni2.5exome-8 arrays of patients with childhood ALL (N=1564, 244 with AAP aged 1.0 to 17.9 y) from 10 international ALL consortia into machine learning models including regression, random forest, AdaBoost and artificial neural networks. A model with only age and sex had area under the receiver operating characteristic curve (ROC-AUC) of 0.62. Inclusion of 6 pancreatitis candidate gene SNPs or 4 validated pancreatitis SNPs boosted ROC-AUC somewhat (0.67) while 30 SNPs, identified through our AAP genome-wide association study cohort, boosted performance (0.80). Most predictive features included rs10273639 (PRSS1-PRSS2), rs10436957 (CTRC), rs13228878 (PRSS1/PRSS2), rs1505495 (GALNTL6), rs4655107 (EPHB2) and age (1 to 7 y). Second AAP following asparaginase re-exposure was predicted with ROC-AUC: 0.65. The machine learning models assist individual-level risk assessment of AAP for future prevention trials, and may legitimize asparaginase re-exposure when AAP risk is predicted to be low.Peer reviewe

Genome-Wide Association Meta-Analysis of Single-Nucleotide Polymorphisms and Symptomatic Venous Thromboembolism during Therapy for Acute Lymphoblastic Leukemia and Lymphoma in Caucasian Children

Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied. Methods: We undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included. Results: No SNPs reached genome-wide significance (p <5 x 10(-8)) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p <1 x 10(-6)), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 x 10(-7)) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 x 10(-7)) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease. Conclusion: This represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.Peer reviewe

Genome-wide association meta-analysis of single-nucleotide polymorphisms and symptomatic venous thromboembolism during therapy for acute lymphoblastic leukemia and lymphoma in caucasian children

Symptomatic venous thromboembolism (VTE) occurs in five percent of children treated for acute lymphoblastic leukemia (ALL), but whether a genetic predisposition exists across different ALL treatment regimens has not been well studied.MethodsWe undertook a genome-wide association study (GWAS) meta-analysis for VTE in consecutively treated children in the Nordic/Baltic acute lymphoblastic leukemia 2008 (ALL2008) cohort and the Australian Evaluation of Risk of ALL Treatment-Related Side-Effects (ERASE) cohort. A total of 92 cases and 1481 controls of European ancestry were included.ResultsNo SNPs reached genome-wide significance (p -8) in either cohort. Among the top 34 single-nucleotide polymorphisms (SNPs) (p -6), two loci had concordant effects in both cohorts: ALOX15B (rs1804772) (MAF: 1%; p = 3.95 × 10-7) that influences arachidonic acid metabolism and thus platelet aggregation, and KALRN (rs570684) (MAF: 1%; p = 4.34 × 10-7) that has been previously associated with risk of ischemic stroke, atherosclerosis, and early-onset coronary artery disease.ConclusionThis represents the largest GWAS meta-analysis conducted to date associating SNPs to VTE in children and adolescents treated on childhood ALL protocols. Validation of these findings is needed and may then lead to patient stratification for VTE preventive interventions. As VTE hemostasis involves multiple pathways, a more powerful GWAS is needed to detect combination of variants associated with VTE.Marion K. Mateos, Morten Tulstrup, Michael CJ Quinn, Ruta Tuckuviene, Glenn M. Marshall, Ramneek Gupt

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

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.Danish Childhood Cancer Foundatio

Genetic predisposition to PEG-asparaginase hypersensitivity in children treated according to NOPHO ALL2008

To access publisher's full text version of this article click on the hyperlink belowAsparaginase is essential in childhood acute lymphoblastic leukaemia (ALL) treatment, however hypersensitivity reactions to pegylated asparaginase (PEG-asparaginase) hampers anti-neoplastic efficacy. Patients with PEG-asparaginase hypersensitivity have been shown to possess zero asparaginase enzyme activity. Using this measurement to define the phenotype, we investigated genetic predisposition to PEG-asparaginase hypersensitivity in a genome-wide association study (GWAS). From July 2008 to March 2016, 1494 children were treated on the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol. Cases were defined by clinical hypersensitivity and no enzyme activity, controls had enzyme activity ≥ 100 iu/l and no hypersensitivity symptoms. PEG-asparaginase hypersensitivity was reported in 13·8% (206/1494) of patients. Fifty-nine cases and 772 controls fulfilled GWAS inclusion criteria. The CNOT3 variant rs73062673 on 19q13.42, was associated with PEG-asparaginase allergy (P = 4·68 × 10Danish Childhood Cancer Foundatio