Novel Genetic Risk Factor Identified for L-Asparaginase-Induced Pancreatitis in Pediatric Patients With Cancer.
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Raack Edward J, Chang Wan-Chun, Cordova-Delgado Miguel, Anderson Spencer J, Trueman Jessica N, Scott Erika N, Loucks Catrina M, Rassekh Shahrad R, Groeneweg Gabriella S S, Higginson Michelle, Li Kathy, Miao Fudan, Yau Derek, Johnston Donna, Ibrahim Mounira, Krajinovic Maja, Tran Thai Hoa, Tewfik Jessica, Bussières Jean-François, Jean-Baptiste Thaïna-Rafi, Lebel Denis, Pecheux Lucie, Gyawali Bina, Guilcher Gregory, Riabowol Gesche, Jong Geert 't, Staub Michelle, Cuvelier Geoff, Felton Kathleen, Khalaj Sara, Rieder Michael, Abuzgaia Awatif, Lewis Tamorah, Ghimire Himal, Nathan Paul, Goralski Kerry, Kulkarni Ketan, Forbrigger Zara, Ross Colin J D, Carleton Bruce C
Аннотация
PROCEDURE: Genome-wide analyses were conducted to identify significant associations between single-nucleotide polymorphisms and risk for L-asparaginase-induced pancreatitis in 1086 pediatric patients treated on acute lymphoblastic leukemia treatment protocols. Patients were randomly split 75/25 into independent Discovery (n = 824) and Replication (n = 262) cohorts. Cases experienced Common Terminology Criteria for Adverse Events v5.0 Grades 3-4 acute pancreatitis reactions due to L-asparaginase treatment. Controls received L-asparaginase but did not develop acute pancreatitis.
RESULTS: A significant association was observed between the rs149210846 variant and L-asparaginase-induced pancreatitis (odds ratio [OR] = 8.9; 95% confidence interval [CI]: 3.6-22.3; p = 1.8 × 10-8) and was confirmed in the replication analysis (OR = 6.2; 95% CI: 1.1-35.0; p = 0.02). Carriers had 5.9-fold (95% CI: 1.9-16.3; p = 0.002) and 7.7-fold (95% CI: 1.3-29.3; p = 0.01) increased risk of severe Grade 3 and Grade 4 acute pancreatitis reactions, respectively, relative to non-carriers. Moreover, patients of Admixed-American (OR = 8.8; 95% CI: 2.4-34.6; p = 1.45 × 10-3) and Asian (OR = 10.0; 95% CI: 1.9-53.6; p = 8.06 × 10-3) genetic ancestries were at significantly higher risk.
CONCLUSIONS: These findings will allow clinicians to proactively conduct stricter monitoring of patients at higher risk for L-asparaginase-induced pancreatitis and inform future development of protective agents that can be used concomitantly to mitigate their risk.