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Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia.

ABSTRACT: 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.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 E. coli ASNase.Among patients of the discovery group, allergies, and pancreatitis were more frequent in individuals who are homozygous for the triple-repeat allele (3R) of the asparagine synthetase (ASNS) gene, resulting in remarkably higher risk of these toxicities associated with 3R3R genotype [OR for allergies, 14.6; 95% confidence interval (CI), 3.6-58.7; P < 0.0005 and OR for pancreatitis, 8.6; 95% CI, 2.0-37.3; P = 0.01]. In contrast, the ASNS haplotype *1 harboring double-repeat (2R) allele had protective effect against these adverse reactions (P ? 0.01). The same haplotype was previously reported to confer reduction in EFS. The risk effect of 3R3R genotype was not replicated in the validation cohort, whereas the protective effect of haplotype *1 against allergies was maintained (P ? 0.002). Analysis with additional polymorphisms in ASNS locus in lymphoblastoid cell lines showed that haplotype *1 is diversified in several subtypes of which one was associated with reduced in vitro sensitivity to ASNase (rs10486009, P = 0.01) possibly explaining an association seen in clinical setting.This finding might have implication for treatment individualization in ALL and other cancers using asparagine depletion strategies. Clin Cancer Res; 21(2); 329-34. ©2014 AACR. See related commentary by Avramis, p. 230.

SUBMITTER: Ben Tanfous M

PROVIDER: S-EPMC4258187 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia.

Ben Tanfous Mohsen M Sharif-Askari Bahram B Ceppi Francesco F Laaribi Haithem H Gagné Vincent V Rousseau Julie J Labuda Malgorzata M Silverman Lewis B LB Sallan Stephen E SE Neuberg Donna D Kutok Jeffery L JL Sinnett Daniel D Laverdière Caroline C Krajinovic Maja M

Clinical cancer research : an official journal of the American Association for Cancer Research 20140606 2

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 E. ...[more]

PMID: 24907114

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Project description:Comprehensive studies on neutropenia and infection-related complications in patients with acute lymphoblastic leukemia (ALL) are lacking.We evaluated infection-related complications that were grade??3 on National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0) and their risk factors in 409 children with newly diagnosed ALL throughout the treatment period.Of the 2420 infection episodes, febrile neutropenia and clinically or microbiologically documented infection were seen in 1107 and 1313 episodes, respectively. Among documented infection episodes, upper respiratory tract was the most common site (n?=?389), followed by ear (n?=?151), bloodstream (n?=?147), and gastrointestinal tract (n?=?145) infections. These episodes were more common during intensified therapy phases such as remission induction and reinduction, but respiratory and ear infections, presumably viral in origin, also occurred during continuation phases. The 3-year cumulative incidence of infection-related death was low (1.0±0.9%, n?=?4), including 2 from Bacillus cereus bacteremia. There was no fungal infection-related mortality. Age 1-9.9 years at diagnosis was associated with febrile neutropenia (P?=?0.002) during induction and febrile neutropenia and documented infection (both P?<?0.001) during later continuation. White race was associated with documented infection (P?=?0.034) during induction. Compared with low-risk patients, standard- and high-risk patients received more intensive therapy during early continuation and had higher incidences of febrile neutropenia (P?<?0.001) and documented infections (P?=?0.043). Furthermore, poor neutrophil surge after dexamethasone pulses during continuation, which can reflect the poor bone marrow reserve, was associated with infections (P?<?0.001).The incidence of infection-related death was low. However, young age, white race, intensive chemotherapy, and lack of neutrophil surge after dexamethasone treatment were associated with infection-related complications. Close monitoring for prompt administration of antibiotics and modification of chemotherapy should be considered in these patients.

Dataset Information

Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia.

Publications

Polymorphisms of asparaginase pathway and asparaginase-related complications in children with acute lymphoblastic leukemia.

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