GWAS Identifies Pharmacogenetic Markers Associated with Premedication-Related Pegaspargase Hypersensitivity and Toxicities in Pediatric and Adolescent Young Adults (AYAs) with Acute Lymphoblastic Leukemia or Lymphoma

• Published in: Blood 2024-11, Vol.144, p.2846-2846
• Main Authors: Shastri, Vivek M., Ahmed, Jennifer, Spin, Eva, Morales, Sonia, Agrawal, Anurag K., Phillips, Christine L., August, Keith J, Guest, Erin M., Lin, Carol Hwang, Apsel Winger, Beth, Aftandilian, Catherine, Huynh, Van Thu, Lamba, Jatinder K.
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-208260

Background: Pediatric acute lymphoblastic leukemia (ALL) patients have significantly improved outcomes over the last few decades with overall survival (OS) rates exceeding 90%. Several factors, including incorporation of asparaginase therapy in chemotherapy regimens of pediatric and adolescent and young adult (AYA) patients with ALL have played a critical role in improving outcomes. Asparaginase is a bacterial enzyme which depletes non-essential amino acid asparagine leading to apoptosis in lymphoblastic leukemia cells. Limitations of frontline pegaspargase (PEG) chemotherapy include hypersensitivity reactions and other asparaginase associated toxicity. A prospective multi-institutional study initiated by Children's Hospital of Orange County (CHOC) and conducted at 6 pediatric cancer centers: 1) evaluated the efficacy of premedicating pediatric and AYA patients with B or T-ALL or lymphoblastic lymphoma (Lly) receiving PEG with antihistamines (H1 and H2 blockers), and 2) performed therapeutic drug monitoring to better identify patients with true hypersensitivity reactions versus those with non-antibody mediated infusion reactions. Here, we report findings from a genome-wide association study (GWAS) in these patients to identify pharmacogenomic markers associated with premedication-related PEG hypersensitivity or grade >3 toxicities and determine whether certain populations are more at risk for hypersensitivity and PEG-associated toxicities. Patients and Methods: GWAS was performed on 87 patients with ALL/Lly. Median age was 8.3 years, 64.4% were male, and 55.2% identified as Hispanic. Overall, 17 (19.5%) patients had hypersensitive reaction to PEG and 44 (50.6%) had an incidence of CTCAE V5 Grade > 3 toxicity (hyperbilirubinemia, hyper/hypoglycemia, hypertriglyceridemia, pancreatitis, or thrombosis) with onset ≤30 days from PEG infusion. Infinium GSA-24 v3.0 was used to genotype 650k single nucleotide polymorphisms (SNPs) and post standard QC, 233,798 SNPs were tested for association with hypersensitivity and grade >3 toxicities by logistic regression analysis using PLINK. Principal component analysis (PCA) was performed for ethnicity and 2 components explaining 67% variance within ethnicity (Hispanic or non-Hispanic) were used to perform ethnicity-adjusted association analyses with 74,198 SNPs post- Hardy-Weinberg equilibrium (HWE) and linkage disequilibrium (LD) pruning. Results: 72 SNPs in 59 genes were associated with incidence of premedication-related