title: Pharmacogenetics and induction/consolidation therapy toxicities in acute lymphoblastic leukemia patients treated with AIEOP-BFM ALL 2000 protocol.
abstract: Drug-related toxicities represent an important clinical concern in chemotherapy, genetic variants could help tailoring treatment to patient. A pharmacogenetic multicentric study was performed on 508 pediatric acute lymphoblastic leukemia patients treated with AIEOP-BFM 2000 protocol: 28 variants were genotyped by VeraCode and Taqman technologies, deletions of GST-M1 and GST-T1 by multiplex PCR. Toxicities were derived from a central database: 251 patients (49.4%) experienced at least one gastrointestinal (GI) or hepatic (HEP) or neurological (NEU) grade III/IV episode during the remission induction phase: GI occurred in 63 patients (12.4%); HEP in 204 (40.2%) and NEU in 44 (8.7%). Logistic regression model adjusted for sex, risk and treatment phase revealed that ITPA rs1127354 homozygous mutated patients showed an increased risk of severe GI and NEU. ABCC1 rs246240 and ADORA2A rs2236624 homozygous mutated genotypes were associated to NEU and HEP, respectively. These three variants could be putative predictive markers for chemotherapy-related toxicities in AIEOP-BFM protocols.
authors.affiliation: Institute for Maternal and Child Health (IRCCS) Burlo Garofolo, UO Pediatric Hemato-Oncology, Trieste, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Franca
authors.affiliation: Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Monza (Milan), Italy.
authors.forename: P
authors.initials: P
authors.lastname: Rebora
authors.affiliation: Paediatric Onco-Hematology and Stem Cell Transplant Unit, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Turin, Italy.
authors.forename: N
authors.initials: N
authors.lastname: Bertorello
authors.affiliation: Paediatric Onco-Hematology and Stem Cell Transplant Unit, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Turin, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Fagioli
authors.affiliation: Department of Pediatrics, S. Gerardo Hospital, MBBM Foundation, Monza (Milan), Italy.
authors.forename: V
authors.initials: V
authors.lastname: Conter
authors.affiliation: Department of Pediatrics, S. Gerardo Hospital, MBBM Foundation, Monza (Milan), Italy.
authors.forename: A
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Department of Pediatrics, S. Gerardo Hospital, MBBM Foundation, Monza (Milan), Italy.
authors.forename: A
authors.initials: A
authors.lastname: Colombini
authors.affiliation: Department of Pediatric Hematology and Oncology, G. Gaslini Institute, Genoa, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Micalizzi
authors.affiliation: Pediatric Hematology-Oncology, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Zecca
authors.affiliation: Department of Oncology, Azienda Ospedaliera Santobono Pausilipon, Naples, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Parasole
authors.affiliation: Department of Oncology, Azienda Ospedaliera Santobono Pausilipon, Naples, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Petruzziello
authors.affiliation: Department of Pediatric, Pediatric Hemato-Oncology Clinic, University of Padua, Padua, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Basso
authors.affiliation: Department of Pediatric, Pediatric Hemato-Oncology Clinic, University of Padua, Padua, Italy.
authors.forename: M C
authors.initials: MC
authors.lastname: Putti
authors.affiliation: Department of Pediatric Hematology/Oncology, IRCCS Ospedale Pediatrico Bambino Gesù, University of Pavia, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Institute for Maternal and Child Health (IRCCS) Burlo Garofolo, UO Pediatric Hemato-Oncology, Trieste, Italy.
authors.forename: P
authors.initials: P
authors.lastname: d'Adamo
authors.affiliation: Center of Biostatistics for Clinical Epidemiology, Department of Health Sciences, University of Milano-Bicocca, Monza (Milan), Italy.
authors.forename: M G
authors.initials: MG
authors.lastname: Valsecchi
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Decorti
authors.affiliation: Institute for Maternal and Child Health (IRCCS) Burlo Garofolo, UO Pediatric Hemato-Oncology, Trieste, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Rabusin
mesh_terms: D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000493:pharmacokinetics; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002986:Clinical Trials as Topic; D060830:Consolidation Chemotherapy / Q000009:adverse effects; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000235:genetics*; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D060828:Induction Chemotherapy / Q000009:adverse effects; D007223:Infant; D016015:Logistic Models; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D009422:Nervous System Diseases / Q000139:chemically induced / Q000235:genetics*; D010597:Pharmacogenetics / Q000379:methods*; D000071185:Pharmacogenomic Testing / Q000379:methods; D000071184:Pharmacogenomic Variants; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011237:Predictive Value of Tests; D011755:Pyrophosphatases / Q000235:genetics; D043705:Receptor, Adenosine A2A / Q000235:genetics; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D000097630:Inosine Triphosphatase
chemical_list: D005982:Glutathione Transferase; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011755:Pyrophosphatases; D043705:Receptor, Adenosine A2A; C413545:glutathione S-transferase T1; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase; C421109:multidrug resistance-associated protein 1