IMPACT OF SINGLE NUCLEOTIDE POLYMORPHISMS OF ABCB1 GENE UPON THE EFFECTIVENESS AND TOXICITY OF INDUCTION CHEMOTHERAPY IN PATIENTS WITH ACUTE MYELOID LEUKEMIA
(Abstract release date: 05/19/16)
EHA Library. Megías-Vericat J. 06/09/16; 132464; E915
Dr. Juan Eduardo Megías-Vericat
Contributions
Contributions
Abstract
Abstract: E915
Type: Eposter Presentation
Background
The intake of anthracyclines in blast cells could be affected by efflux pumps of ABC family.
Aims
Previous studies suggested that single nucleotide polymorphisms (SNPs) of ABCB1 may influence anthracycline effectiveness in acute myeloid leukemia (AML) induction therapy, although their impact in induction death and anthracycline-related organ toxicity.
Methods
The SNPs of ABCB1 gene (rs1128503, rs1045642, rs2032582 and haplotype) were evaluated in 225 adult patients at initial diagnosis from AML using a Sequenom (iPLEX) mass spectrometry–based multiplex genotyping assay (Sequenom, San Diego, CA). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA-LMA 99, 2007 and 2010 trials). Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission (PR) or resistance, excluding these patients dying during induction. Induction death was defined as patients dying during induction against CR, excluding these patients with PR or resistance. Based on WHO grading scale, toxicities were grouped as binary variables (grade 0-1 vs. grade 2-4). The grade of toxicity assigned to an organ group was the maximum grade of all the specific toxicities within that group. Genotypes were studied with a co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, cytogenetic risk, ECOG, leukocyte and platelet count, hemoglobin, creatinine, bilirubin, albumin and LDH level at diagnosis (R® version 3.1.2).
Results
The median age of patients was 51.1 years (16-78 years). There were no statistically significant differences in CR. Nevertheless, induction death was associated to ABCB1 triple variant haplotype (40.0% vs. 17.2%; OR: 0.2; 95%CI: 0.05-0.8; P=0.017). Besides, the ABCB1 triple variant haplotype was related to more nephrotoxicity than the other genotypes (OR: 3.6; 95%CI: 1.3-10.4; p=0.016). The variant alleles of ABCB1 rs1128503, rs2032582 and recessive haplotype were also related to hepatotoxicity (OR: 6.9; 95%CI: 2.2-21.2; p= 0.001; OR: 2.9; 95%CI: 1.01-8.1; p=0.049; OR: 6.0; 95%CI: 2.1-16.3; p<0.001; respectively). Regarding hematologic toxicity, time to neutropenia recovery was delayed with variant allele of ABCB1 rs2032582 (OR: 3.0; 95%CI: 1.1-10.1; P=0.047).
Conclusion
The variant alleles of ABCB1 polymorphisms have been related to lower anthraclycline clearance and higher tissue exposure. This could be the reason of the higher toxicity and induction death observed. This study shows a prognostic impact of ABCB1 polymorphisms in adult AML patients regarding induction chemotherapy toxicity. Further studies with larger population are needed to validate these associations, which could be useful biomarkers in clinical practice. Study supported by grants from the “Instituto Carlos III” (PIE13/00046), “Instituto Investigación Sanitaria La Fe” (2013/0331) and the Cooperative Research Thematic Network (RTICC), Grant RD12/0036/014 (ISCIII & ERDF). Samples have been managed by the La Fe Biobank, licensed as required by Spanish Royal Decree 1716/2011 of 18 November (Ref.: PT13 / 0010/0026).
Session topic: E-poster
Keyword(s): ABC transporter, Anthracycline, Polymorphism, Toxicity
Type: Eposter Presentation
Background
The intake of anthracyclines in blast cells could be affected by efflux pumps of ABC family.
Aims
Previous studies suggested that single nucleotide polymorphisms (SNPs) of ABCB1 may influence anthracycline effectiveness in acute myeloid leukemia (AML) induction therapy, although their impact in induction death and anthracycline-related organ toxicity.
Methods
The SNPs of ABCB1 gene (rs1128503, rs1045642, rs2032582 and haplotype) were evaluated in 225 adult patients at initial diagnosis from AML using a Sequenom (iPLEX) mass spectrometry–based multiplex genotyping assay (Sequenom, San Diego, CA). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA-LMA 99, 2007 and 2010 trials). Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission (PR) or resistance, excluding these patients dying during induction. Induction death was defined as patients dying during induction against CR, excluding these patients with PR or resistance. Based on WHO grading scale, toxicities were grouped as binary variables (grade 0-1 vs. grade 2-4). The grade of toxicity assigned to an organ group was the maximum grade of all the specific toxicities within that group. Genotypes were studied with a co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, cytogenetic risk, ECOG, leukocyte and platelet count, hemoglobin, creatinine, bilirubin, albumin and LDH level at diagnosis (R® version 3.1.2).
Results
The median age of patients was 51.1 years (16-78 years). There were no statistically significant differences in CR. Nevertheless, induction death was associated to ABCB1 triple variant haplotype (40.0% vs. 17.2%; OR: 0.2; 95%CI: 0.05-0.8; P=0.017). Besides, the ABCB1 triple variant haplotype was related to more nephrotoxicity than the other genotypes (OR: 3.6; 95%CI: 1.3-10.4; p=0.016). The variant alleles of ABCB1 rs1128503, rs2032582 and recessive haplotype were also related to hepatotoxicity (OR: 6.9; 95%CI: 2.2-21.2; p= 0.001; OR: 2.9; 95%CI: 1.01-8.1; p=0.049; OR: 6.0; 95%CI: 2.1-16.3; p<0.001; respectively). Regarding hematologic toxicity, time to neutropenia recovery was delayed with variant allele of ABCB1 rs2032582 (OR: 3.0; 95%CI: 1.1-10.1; P=0.047).
Conclusion
The variant alleles of ABCB1 polymorphisms have been related to lower anthraclycline clearance and higher tissue exposure. This could be the reason of the higher toxicity and induction death observed. This study shows a prognostic impact of ABCB1 polymorphisms in adult AML patients regarding induction chemotherapy toxicity. Further studies with larger population are needed to validate these associations, which could be useful biomarkers in clinical practice. Study supported by grants from the “Instituto Carlos III” (PIE13/00046), “Instituto Investigación Sanitaria La Fe” (2013/0331) and the Cooperative Research Thematic Network (RTICC), Grant RD12/0036/014 (ISCIII & ERDF). Samples have been managed by the La Fe Biobank, licensed as required by Spanish Royal Decree 1716/2011 of 18 November (Ref.: PT13 / 0010/0026).
Session topic: E-poster
Keyword(s): ABC transporter, Anthracycline, Polymorphism, Toxicity
Abstract: E915
Type: Eposter Presentation
Background
The intake of anthracyclines in blast cells could be affected by efflux pumps of ABC family.
Aims
Previous studies suggested that single nucleotide polymorphisms (SNPs) of ABCB1 may influence anthracycline effectiveness in acute myeloid leukemia (AML) induction therapy, although their impact in induction death and anthracycline-related organ toxicity.
Methods
The SNPs of ABCB1 gene (rs1128503, rs1045642, rs2032582 and haplotype) were evaluated in 225 adult patients at initial diagnosis from AML using a Sequenom (iPLEX) mass spectrometry–based multiplex genotyping assay (Sequenom, San Diego, CA). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA-LMA 99, 2007 and 2010 trials). Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission (PR) or resistance, excluding these patients dying during induction. Induction death was defined as patients dying during induction against CR, excluding these patients with PR or resistance. Based on WHO grading scale, toxicities were grouped as binary variables (grade 0-1 vs. grade 2-4). The grade of toxicity assigned to an organ group was the maximum grade of all the specific toxicities within that group. Genotypes were studied with a co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, cytogenetic risk, ECOG, leukocyte and platelet count, hemoglobin, creatinine, bilirubin, albumin and LDH level at diagnosis (R® version 3.1.2).
Results
The median age of patients was 51.1 years (16-78 years). There were no statistically significant differences in CR. Nevertheless, induction death was associated to ABCB1 triple variant haplotype (40.0% vs. 17.2%; OR: 0.2; 95%CI: 0.05-0.8; P=0.017). Besides, the ABCB1 triple variant haplotype was related to more nephrotoxicity than the other genotypes (OR: 3.6; 95%CI: 1.3-10.4; p=0.016). The variant alleles of ABCB1 rs1128503, rs2032582 and recessive haplotype were also related to hepatotoxicity (OR: 6.9; 95%CI: 2.2-21.2; p= 0.001; OR: 2.9; 95%CI: 1.01-8.1; p=0.049; OR: 6.0; 95%CI: 2.1-16.3; p<0.001; respectively). Regarding hematologic toxicity, time to neutropenia recovery was delayed with variant allele of ABCB1 rs2032582 (OR: 3.0; 95%CI: 1.1-10.1; P=0.047).
Conclusion
The variant alleles of ABCB1 polymorphisms have been related to lower anthraclycline clearance and higher tissue exposure. This could be the reason of the higher toxicity and induction death observed. This study shows a prognostic impact of ABCB1 polymorphisms in adult AML patients regarding induction chemotherapy toxicity. Further studies with larger population are needed to validate these associations, which could be useful biomarkers in clinical practice. Study supported by grants from the “Instituto Carlos III” (PIE13/00046), “Instituto Investigación Sanitaria La Fe” (2013/0331) and the Cooperative Research Thematic Network (RTICC), Grant RD12/0036/014 (ISCIII & ERDF). Samples have been managed by the La Fe Biobank, licensed as required by Spanish Royal Decree 1716/2011 of 18 November (Ref.: PT13 / 0010/0026).
Session topic: E-poster
Keyword(s): ABC transporter, Anthracycline, Polymorphism, Toxicity
Type: Eposter Presentation
Background
The intake of anthracyclines in blast cells could be affected by efflux pumps of ABC family.
Aims
Previous studies suggested that single nucleotide polymorphisms (SNPs) of ABCB1 may influence anthracycline effectiveness in acute myeloid leukemia (AML) induction therapy, although their impact in induction death and anthracycline-related organ toxicity.
Methods
The SNPs of ABCB1 gene (rs1128503, rs1045642, rs2032582 and haplotype) were evaluated in 225 adult patients at initial diagnosis from AML using a Sequenom (iPLEX) mass spectrometry–based multiplex genotyping assay (Sequenom, San Diego, CA). All patients received induction chemotherapy consisting of idarubicin plus cytarabine (PETHEMA-LMA 99, 2007 and 2010 trials). Efficacy of first induction cycle was evaluated comparing complete remission (CR) vs. partial remission (PR) or resistance, excluding these patients dying during induction. Induction death was defined as patients dying during induction against CR, excluding these patients with PR or resistance. Based on WHO grading scale, toxicities were grouped as binary variables (grade 0-1 vs. grade 2-4). The grade of toxicity assigned to an organ group was the maximum grade of all the specific toxicities within that group. Genotypes were studied with a co-dominant model. Association between variables was assessed using linear and logistic regression adjusting for age, gender, cytogenetic risk, ECOG, leukocyte and platelet count, hemoglobin, creatinine, bilirubin, albumin and LDH level at diagnosis (R® version 3.1.2).
Results
The median age of patients was 51.1 years (16-78 years). There were no statistically significant differences in CR. Nevertheless, induction death was associated to ABCB1 triple variant haplotype (40.0% vs. 17.2%; OR: 0.2; 95%CI: 0.05-0.8; P=0.017). Besides, the ABCB1 triple variant haplotype was related to more nephrotoxicity than the other genotypes (OR: 3.6; 95%CI: 1.3-10.4; p=0.016). The variant alleles of ABCB1 rs1128503, rs2032582 and recessive haplotype were also related to hepatotoxicity (OR: 6.9; 95%CI: 2.2-21.2; p= 0.001; OR: 2.9; 95%CI: 1.01-8.1; p=0.049; OR: 6.0; 95%CI: 2.1-16.3; p<0.001; respectively). Regarding hematologic toxicity, time to neutropenia recovery was delayed with variant allele of ABCB1 rs2032582 (OR: 3.0; 95%CI: 1.1-10.1; P=0.047).
Conclusion
The variant alleles of ABCB1 polymorphisms have been related to lower anthraclycline clearance and higher tissue exposure. This could be the reason of the higher toxicity and induction death observed. This study shows a prognostic impact of ABCB1 polymorphisms in adult AML patients regarding induction chemotherapy toxicity. Further studies with larger population are needed to validate these associations, which could be useful biomarkers in clinical practice. Study supported by grants from the “Instituto Carlos III” (PIE13/00046), “Instituto Investigación Sanitaria La Fe” (2013/0331) and the Cooperative Research Thematic Network (RTICC), Grant RD12/0036/014 (ISCIII & ERDF). Samples have been managed by the La Fe Biobank, licensed as required by Spanish Royal Decree 1716/2011 of 18 November (Ref.: PT13 / 0010/0026).
Session topic: E-poster
Keyword(s): ABC transporter, Anthracycline, Polymorphism, Toxicity
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