Background: Genetic heterogeneity in drug-metabolizing enzyme and transporter genes affects specific drug-related phenotypes in cancer. In order to investigate a relationship between genetic variation and response in AML, we comprehensively assessed the allele frequencies of 1936 genetic variations of 225 absorption, distribution, metabolism and excretion genes in 94 CD33-positive AML patients younger than 65 years, using the new Affymetrix drug-metabolizing enzyme and transport (DMET Plus) genotyping platform. Patients and methods: All patients were enrolled in a phase III multicenter clinical trial combining low dose of Gemtuzumab-ozogamicin (GO) with FLAI regimen (Fludarabine, Cytarabine, Idarubicin) as Induction chemotherapy (ClinicalTrials.gov NCT00909168). Cytogenetics, multidrug-resistance phenotype, FLT3 and NPM mutation status, as well as WT1 quantitative expression analyses were performed at diagnosis. Furthermore, high-resolution single nucleotide polymorphism (SNP) array and DMET genotyping analyses (Affymetrix) were also performed. Results: Of the 94 patients, genotype results were evaluable for 91 cases. The median call rate was 99.48 (range, 96.32-100). Firstly, we tested the association among SNPs and response to the induction cycle (FLAI + GO) comparing the genotyping profile of 80 patients in complete (85%) and partial (3%) remission with that of patients (12%) with no response. A highly significant difference (p < 0.001) in the allele frequency of 2 variants, in complete linkage disequilibrium, in the alcohol dehydrogenase enzyme (ADH1A) was found. ADH1A metabolizes the conversion of ethanol to acetaldehyde which is thereafter converted to acetate by ALDH1, which is well known as stem cell marker. These variants were not associated with high risk AML, FLT3 and NPM1 mutations, but strongly influenced response to the induction phase also in a multivariate analysis. Secondly, SNPs were stratified according to liver toxicity and a significant difference in the allele frequency in CYP2E1, involved in the alcohol metabolism was found to be associated with a grade I/II liver toxicity. Conclusions: Genetic variations in ADH1A and CYP2E1 genes were for the first time identified and associated with response and toxicity in AML patients treated with a combination of GO and FLAI regimen. Supported by European LeukemiaNet, AIL, AIRC, FIRB 2006, Ateneo RFO grants, Project of integrated program, Programma di Ricerca Regione – Università 2007–2009.

GENETIC VARIATIONS IN ADH1A AND CYP2E1 STRONGLY AFFECTS RESPONSE AND TOXICITY TO A COMBINATION OF GEMTUZUMAB OZOGAMICIN PLUS FLUDARABINE, CYTARABINE, IDARUBICIN IN CD33-POSITIVE ACUTE MYELOID LEUKEMIA (AML) PATIENTS

IACOBUCCI, ILARIA;LONETTI, ANNALISA;Candoni A;SAZZINI, MARCO;FORMICA, SERENA;OTTAVIANI, EMANUELA;PAPAYANNIDIS, CRISTINA;ASTOLFI, ANNALISA;PAOLINI, STEFANIA;ABBENANTE, MARIACHIARA;Parisi S;CATTINA, FEDERICA;MARTINELLI, GIOVANNI
2011

Abstract

Background: Genetic heterogeneity in drug-metabolizing enzyme and transporter genes affects specific drug-related phenotypes in cancer. In order to investigate a relationship between genetic variation and response in AML, we comprehensively assessed the allele frequencies of 1936 genetic variations of 225 absorption, distribution, metabolism and excretion genes in 94 CD33-positive AML patients younger than 65 years, using the new Affymetrix drug-metabolizing enzyme and transport (DMET Plus) genotyping platform. Patients and methods: All patients were enrolled in a phase III multicenter clinical trial combining low dose of Gemtuzumab-ozogamicin (GO) with FLAI regimen (Fludarabine, Cytarabine, Idarubicin) as Induction chemotherapy (ClinicalTrials.gov NCT00909168). Cytogenetics, multidrug-resistance phenotype, FLT3 and NPM mutation status, as well as WT1 quantitative expression analyses were performed at diagnosis. Furthermore, high-resolution single nucleotide polymorphism (SNP) array and DMET genotyping analyses (Affymetrix) were also performed. Results: Of the 94 patients, genotype results were evaluable for 91 cases. The median call rate was 99.48 (range, 96.32-100). Firstly, we tested the association among SNPs and response to the induction cycle (FLAI + GO) comparing the genotyping profile of 80 patients in complete (85%) and partial (3%) remission with that of patients (12%) with no response. A highly significant difference (p < 0.001) in the allele frequency of 2 variants, in complete linkage disequilibrium, in the alcohol dehydrogenase enzyme (ADH1A) was found. ADH1A metabolizes the conversion of ethanol to acetaldehyde which is thereafter converted to acetate by ALDH1, which is well known as stem cell marker. These variants were not associated with high risk AML, FLT3 and NPM1 mutations, but strongly influenced response to the induction phase also in a multivariate analysis. Secondly, SNPs were stratified according to liver toxicity and a significant difference in the allele frequency in CYP2E1, involved in the alcohol metabolism was found to be associated with a grade I/II liver toxicity. Conclusions: Genetic variations in ADH1A and CYP2E1 genes were for the first time identified and associated with response and toxicity in AML patients treated with a combination of GO and FLAI regimen. Supported by European LeukemiaNet, AIL, AIRC, FIRB 2006, Ateneo RFO grants, Project of integrated program, Programma di Ricerca Regione – Università 2007–2009.
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Iacobucci I; Lonetti A; Candoni A; Sazzini M; Formica S; Ottaviani E; Ferrari A; Papayannidis C; Michelutti A; Toffoletti E; Astolfi A; Paolini S; Abbenante M; Parisi S; Cattina F; Russo D; Damiani D; Gherlinzoni F; Gottardi M; Baccarani M; Fanin R; Martinelli G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/154782
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