title: Association of the hOCT1/ABCB1 genotype with efficacy and tolerability of imatinib in patients affected by chronic myeloid leukemia.
abstract: The present study was aimed at investigating whether imatinib pharmacogenetics is related to its pharmacodynamics in patients affected by chronic myeloid leukemia.
  
  
  
  Through a procedure based on a sequence of classical statistics methods, we investigated the possible relationships between treatment efficacy/tolerability and combinations of time-independent variables as gender and genetic covariates in the form of single nucleotide polymorphisms (SNPs) or combinations thereof. Moreover, since the drug tolerability has a strong incidence on the discontinuation of the therapy, we investigated whether the time of manifestation of the most frequent toxic effects can be related to time-independent patients' characteristics or not.
  
  
  
  We found that a combination of two polymorphisms, namely hOCT1 c.480C>G (rs683369) and ABCB1 c.3435C>T (rs1045642), seems to play the role of predictor for imatinib in both efficacy and toxicity. Furthermore, the time of manifestation of edema toxicity is found to be associated to a combination of gender and ABCB1 c.3435C>T, whereas the time of manifestation of cramp toxicity appears related to gender.
  
  
  
  The novelty of this study is dual: the achievement of results that potentially have a significant clinical interest and the demonstration that the adoption of composed covariates may represent a unique tool to study different aspects of the treatment with imatinib.
authors.affiliation: Phymtech Srl, Via Giuntini 63, Navacchio, 56023, Pisa, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Galeotti
authors.affiliation: Phymtech Srl, Via Giuntini 63, Navacchio, 56023, Pisa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ceccherini
authors.affiliation: Phymtech Srl, Via Giuntini 63, Navacchio, 56023, Pisa, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Domingo
authors.affiliation: Phymtech Srl, Via Giuntini 63, Navacchio, 56023, Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Laurino
authors.affiliation: Section of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Polillo
authors.affiliation: Section of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy. antonello.dipaolo@med.unipi.it.
authors.forename: Antonello
authors.identifier: 0000-0002-2661-6183
authors.initials: A
authors.lastname: Di Paolo
authors.affiliation: Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Baratè
authors.affiliation: Department of Biological and Clinical Sciences, University of Torino, San Luigi Gonzaga Hospital, Regione Gonzole 10, 143 Orbassano, Turin, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Fava
authors.affiliation: Laboratory of Clinical Pharmacology and Pharmacogenetics, Department of Medical Sciences, Unit of Infectious Diseases, University of Torino, Amedeo di Savoia Hospital, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.affiliation: Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Cervetti
authors.affiliation: Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Guerrini
authors.affiliation: Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fontanelli
authors.affiliation: Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Ciabatti
authors.affiliation: Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Grassi
authors.affiliation: Section of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Arrigoni
authors.affiliation: Section of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.affiliation: Section of Hematology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Petrini
authors.affiliation: Phymtech Srl, Via Giuntini 63, Navacchio, 56023, Pisa, Italy.|Department of Physics, University of Pisa, Largo Pontecorvo 3, 56127, Pisa, Italy.
authors.forename: Fulvio
authors.initials: F
authors.lastname: Cornolti
authors.affiliation: Department of Biological and Clinical Sciences, University of Torino, San Luigi Gonzaga Hospital, Regione Gonzole 10, 143 Orbassano, Turin, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.affiliation: Section of Pharmacology, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, 56126, Pisa, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Galimberti
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D004487:Edema / Q000139:chemically induced / Q000235:genetics; D005163:Factor Analysis, Statistical; D005260:Female; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate / Q000009:adverse effects* / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009120:Muscle Cramp / Q000139:chemically induced / Q000235:genetics; D050811:Octamer Transcription Factor-1 / Q000235:genetics*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011379:Prognosis; D012727:Sex Characteristics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D000068877:Imatinib Mesylate
keywords: ABCB1; Complete cytogenetic response; Factor analysis of mixed data; Imatinib; Tolerability; hOCT1