Data from Polymorphisms of Asparaginase Pathway and Asparaginase-Related Complications in Children with Acute Lymphoblastic Leukemia

Abstract

<div>Abstract<p><b>Purpose:</b> Asparaginase (ASNase) is a standard and critical component in the therapy of childhood acute lymphoblastic leukemia (ALL), but it is also associated with several toxicities.</p><p><b>Experimental design:</b> We recently reported the results of an association study between ASNase pathway genes and event-free survival (EFS) in childhood patients with ALL. The same polymorphisms were interrogated here in relation to allergies, pancreatitis, and thrombotic events following treatment with <i>E. coli</i> ASNase.</p><p><b>Results:</b> Among patients of the discovery group, allergies, and pancreatitis were more frequent in individuals who are homozygous for the triple-repeat allele (<i>3R</i>) of the asparagine synthetase (<i>ASNS</i>) gene, resulting in remarkably higher risk of these toxicities associated with <i>3R3R</i> genotype [OR for allergies, 14.6; 95% confidence interval (CI), 3.6–58.7; <i>P</i> < 0.0005 and OR for pancreatitis, 8.6; 95% CI, 2.0–37.3; <i>P</i> = 0.01]. In contrast, the <i>ASNS</i> haplotype <i>*1</i> harboring double-repeat (<i>2R</i>) allele had protective effect against these adverse reactions (<i>P</i> ≤ 0.01). The same haplotype was previously reported to confer reduction in EFS. The risk effect of <i>3R3R</i> genotype was not replicated in the validation cohort, whereas the protective effect of haplotype <i>*1</i> against allergies was maintained (<i>P</i> ≤ 0.002). Analysis with additional polymorphisms in <i>ASNS</i> locus in lymphoblastoid cell lines showed that haplotype <i>*1</i> is diversified in several subtypes of which one was associated with reduced <i>in vitro</i> sensitivity to ASNase (<i>rs10486009</i>, <i>P</i> = 0.01) possibly explaining an association seen in clinical setting.</p><p><b>Conclusions:</b> This finding might have implication for treatment individualization in ALL and other cancers using asparagine depletion strategies. <i>Clin Cancer Res; 21(2); 329–34. ©2014 AACR</i>.</p><p><i>See related commentary by Avramis, p. 230</i></p></div>