title: Genetic predisposition and induced pro-inflammatory/pro-oxidative status may play a role in increased atherothrombotic events in nilotinib treated chronic myeloid leukemia patients.
abstract: Several reports described an increased risk of cardiovascular (CV) events, mainly atherothrombotic, in Chronic Myeloid Leukemia (CML) patients receiving nilotinib. However, the underlying mechanism remains elusive. The objective of the current cross-sectional retrospective study is to address a potential correlation between Tyrosine Kinase Inhibitors (TKIs) treatment and CV events. One hundred and 10 chronic phase CML patients in complete cytogenetic response during nilotinib or imatinib, were screened for CV events and evaluated for: traditional CV risk factors, pro/anti-inflammatory biochemical parameters and detrimental ORL1 gene polymorphisms (encoding for altered oxidized LDL receptor-1). Multivariate analysis of the whole cohort showed that the cluster of co-existing nilotinib treatment, dyslipidaemia and G allele of LOX-1 polymorphism was the only significant finding associated with CV events. Furthermore, multivariate analysis according to TKI treatment confirmed IVS4-14 G/G LOX-1 polymorphism as the strongest predictive factor for a higher incidence of CV events in nilotinib patients. Biochemical assessment showed an unbalanced pro-inflammatory cytokines network in nilotinib vs imatinib patients. Surprisingly, pre-existing traditional CV risk factors were not always predictive of CV events. We believe that in nilotinib patients an induced "inflammatory/oxidative status", together with a genetic pro-atherothrombotic predisposition, may favour the increased incidence of CV events. Prospective studies focused on this issue are ongoing.
authors.affiliation: Department of Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Bocchia
authors.affiliation: Department of Clinical and Experimental Medicine, U.O. Hematology, University of Pisa, Pisa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Galimberti
authors.affiliation: Department of Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Lara
authors.initials: L
authors.lastname: Aprile
authors.affiliation: Department of Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sicuranza
authors.affiliation: Functional Unit of Hematology, University of Florence, Florence, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Gozzini
authors.affiliation: Department of Medicine and Aging, University of Chieti, Chieti, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Santilli
authors.affiliation: Hematology Unit, S. Eugenio Hospital, Tor Vergata University, Rome, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Abruzzese
authors.affiliation: Department of Clinical and Experimental Medicine, U.O. Hematology, University of Pisa, Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Baratè
authors.affiliation: Functional Unit of Hematology, University of Florence, Florence, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Scappini
authors.affiliation: Department of Clinical and Experimental Medicine, U.O. Hematology, University of Pisa, Pisa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fontanelli
authors.affiliation: Hematology Unit, S. Eugenio Hospital, Tor Vergata University, Rome, Italy.
authors.forename: Monika Malgorzata
authors.initials: MM
authors.lastname: Trawinska
authors.affiliation: Department of Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Marzia
authors.initials: M
authors.lastname: Defina
authors.affiliation: Department of Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gozzetti
authors.affiliation: Functional Unit of Hematology, University of Florence, Florence, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosi
authors.affiliation: Department of Clinical and Experimental Medicine, U.O. Hematology, University of Pisa, Pisa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Petrini
authors.affiliation: Department of Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Puccetti
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D050197:Atherosclerosis / Q000097:blood / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism; D003430:Cross-Sectional Studies; D016207:Cytokines / Q000097:blood / Q000378:metabolism; D050171:Dyslipidemias / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D015994:Incidence; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction / Q000187:drug effects; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D012189:Retrospective Studies; D012307:Risk Factors; D051127:Scavenger Receptors, Class E / Q000235:genetics; D013927:Thrombosis / Q000097:blood / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D016207:Cytokines; C495137:OLR1 protein, human; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051127:Scavenger Receptors, Class E; D000068877:Imatinib Mesylate; C498826:nilotinib
keywords: CML; PAOD; TKI; atherothrombotic risk; inflammation