EFFICACY OF DEFERIPRONE IN THALASSEMIA: POSSIBLE ROLE OF UGT1A6 GENETIC POLYMORPHISM AND NON-GENETIC FACTORS
(Abstract release date: 05/21/15)
EHA Library. Ang A. 06/12/15; 102667; PB2006
Disclosure(s): Singapore General HospitalHaematology
Ai Leen Ang
Contributions
Contributions
Abstract
Abstract: PB2006
Type: Publication Only
Background
Deferiprone(DFP) is an oral iron chelator widely used in thalassemia(thal) patients(pts). It is mostly glucuronidated by liver UGT1A6 to an inactive metabolite before renally excreted. UGT1A6 polymorphism has been studied as a potential cause for variability in DFP’s efficacy. No significant(sig) effect of UGT1A6 polymorphism was shown on the single-dose pharmacokinetics of DFP in healthy volunteers, while another study on β thal major pts treated with DFP showed an association of UGT1A6 single nucleotide polymorphism(SNP) 541A>G with lower ferritin. There are no studies on UGT1A6 polymorphism’s association with MRI-T2*, which allows more specific measurement of DFP response by non-invasive liver and heart iron quantification.
Aims
Determine associations of UGT1A6 genetic polymorphism and other non-genetic factors with MRI-T2* responses to DFP in thal.
Methods
Thal pts(aged ≥18 years) who had ≥1 year of DFP and at least two MRI-T2* of ≥1 year apart for assessment of DFP response were enrolled after consenting for UGT1A6 DNA analysis. 3 common non-synonymous SNPs(19T>G, 541A>G, 552A>C) and 1 synonymous SNP(105C>T) of UGT1A6 were detected by sequencing PCR-amplified target DNA segments. Data on MRI-T2* response to DFP was retrospectively collected and analysed for associations with UGT1A6 SNPs/haplotypes and other non-genetic factors(gender, race, splenectomy, baseline cardiac/liver T2*, type of thal, transfusional iron load, DFP and concomitant deferoxamine(DFO) doses). Liver T2* was converted to liver iron concentration(LIC). Improvement in cardiac T2*(if baseline cardiac T2* <20ms) or LIC without discrepant changes in corresponding LIC or cardiac T2* were considered to have responded to DFP.
Results
32 pts(Chinese 56%, Malay 35%, Indian 3%, others 6%) were treated with median 6(1-11) years of DFP at median average dose of 68.2(24.4-93.3) mg/kg/day. 53% received concomitant DFO at median average dose of 23.1(11.4-40.6) mg/kg/day; 84% was regularly transfused, with median transfusional iron load of 0.4(0.1-0.6) mg/kg/day. Genotypic frequency was UGT1A6*1/*1: 75%, UGT*1/*2: 18.8%, UGT*1/*4: 6.2% (UGT1A6*1=wild type haplotype; UGT1A6*2=variant haplotype with SNPs 19T>G, 541A>G, 552A>C; UGT1A6*4=variant haplotype with SNPs 19T>G and 552A>C). In addition, 15.6% were heterozygous for 105C>T SNP. On multivariate analysis, splenectomy(OR 0.002, 95% CI[0.000, 0.697], P=0.04) and UGT1A6 variant haplotypes(*2 or *4) without concurrent 105C>T(OR 0.016, 95% CI[0.000, 0.766], P=0.03) independently associated with absent DFP response. The median rate of LIC improvement was 2.7(-12.0 to 10.1) mg/g dw per year after excluding 2 patients with discordant liver and cardiac T2* changes. On multivariate analysis, thal major(-2.8, 95% CI[-5.5, -0.04] mg/g dw per year, P<0.05) and UGT1A6 variant haplotypes without concurrent 105C>T (-4.8, 95% CI[-7.8, -1.7] mg/g dw per year, P <0.01) independently associated with poorer LIC improvement rate (see Figure). Other analysed factors did not have sig independent associations with DFP response and LIC improvement rate(P>0.15).
Summary
Splenectomy decreases iron storage capacity, might lead to iron redistribution to other organs and poorer MRI-T2* responses to DFP. Thal majors had poorer DFP response than other types of thal likely due to higher body iron load. The poorer DFP response observed in our pts with UGT1A6 variant haplotypes (and no concurrent 105C>T) was contrary to expectations since recombinant UGT1A6 variants have slower in vitro DFP glucuronidation rates than wild type. One possibility is UGT1A6 variants have different in vivo activities on DFP since conflicting activities of recombinant and liver UGT1A6 allozymes are reported for other substrates. Concomitant 105C>T appeared to negate the adverse impact of UGT1A6 variants on DFP response in our pts. In vitro, this SNP increased mRNA stability despite no amino acid changes. This might influence mRNA or enzyme protein stability in vivo for heterozygotes of UGT1A6 variants, leading to changes in DFP metabolism and efficacy. More studies on UGT1A6 SNPs’ clinical impact and interactions with other factors on DFP’s efficacy are needed for better insights into individualisation of DFP therapy for thal.
Keyword(s): Deferiprone, Polymorphism
Session topic: Publication Only
Type: Publication Only
Background
Deferiprone(DFP) is an oral iron chelator widely used in thalassemia(thal) patients(pts). It is mostly glucuronidated by liver UGT1A6 to an inactive metabolite before renally excreted. UGT1A6 polymorphism has been studied as a potential cause for variability in DFP’s efficacy. No significant(sig) effect of UGT1A6 polymorphism was shown on the single-dose pharmacokinetics of DFP in healthy volunteers, while another study on β thal major pts treated with DFP showed an association of UGT1A6 single nucleotide polymorphism(SNP) 541A>G with lower ferritin. There are no studies on UGT1A6 polymorphism’s association with MRI-T2*, which allows more specific measurement of DFP response by non-invasive liver and heart iron quantification.
Aims
Determine associations of UGT1A6 genetic polymorphism and other non-genetic factors with MRI-T2* responses to DFP in thal.
Methods
Thal pts(aged ≥18 years) who had ≥1 year of DFP and at least two MRI-T2* of ≥1 year apart for assessment of DFP response were enrolled after consenting for UGT1A6 DNA analysis. 3 common non-synonymous SNPs(19T>G, 541A>G, 552A>C) and 1 synonymous SNP(105C>T) of UGT1A6 were detected by sequencing PCR-amplified target DNA segments. Data on MRI-T2* response to DFP was retrospectively collected and analysed for associations with UGT1A6 SNPs/haplotypes and other non-genetic factors(gender, race, splenectomy, baseline cardiac/liver T2*, type of thal, transfusional iron load, DFP and concomitant deferoxamine(DFO) doses). Liver T2* was converted to liver iron concentration(LIC). Improvement in cardiac T2*(if baseline cardiac T2* <20ms) or LIC without discrepant changes in corresponding LIC or cardiac T2* were considered to have responded to DFP.
Results
32 pts(Chinese 56%, Malay 35%, Indian 3%, others 6%) were treated with median 6(1-11) years of DFP at median average dose of 68.2(24.4-93.3) mg/kg/day. 53% received concomitant DFO at median average dose of 23.1(11.4-40.6) mg/kg/day; 84% was regularly transfused, with median transfusional iron load of 0.4(0.1-0.6) mg/kg/day. Genotypic frequency was UGT1A6*1/*1: 75%, UGT*1/*2: 18.8%, UGT*1/*4: 6.2% (UGT1A6*1=wild type haplotype; UGT1A6*2=variant haplotype with SNPs 19T>G, 541A>G, 552A>C; UGT1A6*4=variant haplotype with SNPs 19T>G and 552A>C). In addition, 15.6% were heterozygous for 105C>T SNP. On multivariate analysis, splenectomy(OR 0.002, 95% CI[0.000, 0.697], P=0.04) and UGT1A6 variant haplotypes(*2 or *4) without concurrent 105C>T(OR 0.016, 95% CI[0.000, 0.766], P=0.03) independently associated with absent DFP response. The median rate of LIC improvement was 2.7(-12.0 to 10.1) mg/g dw per year after excluding 2 patients with discordant liver and cardiac T2* changes. On multivariate analysis, thal major(-2.8, 95% CI[-5.5, -0.04] mg/g dw per year, P<0.05) and UGT1A6 variant haplotypes without concurrent 105C>T (-4.8, 95% CI[-7.8, -1.7] mg/g dw per year, P <0.01) independently associated with poorer LIC improvement rate (see Figure). Other analysed factors did not have sig independent associations with DFP response and LIC improvement rate(P>0.15).
Summary
Splenectomy decreases iron storage capacity, might lead to iron redistribution to other organs and poorer MRI-T2* responses to DFP. Thal majors had poorer DFP response than other types of thal likely due to higher body iron load. The poorer DFP response observed in our pts with UGT1A6 variant haplotypes (and no concurrent 105C>T) was contrary to expectations since recombinant UGT1A6 variants have slower in vitro DFP glucuronidation rates than wild type. One possibility is UGT1A6 variants have different in vivo activities on DFP since conflicting activities of recombinant and liver UGT1A6 allozymes are reported for other substrates. Concomitant 105C>T appeared to negate the adverse impact of UGT1A6 variants on DFP response in our pts. In vitro, this SNP increased mRNA stability despite no amino acid changes. This might influence mRNA or enzyme protein stability in vivo for heterozygotes of UGT1A6 variants, leading to changes in DFP metabolism and efficacy. More studies on UGT1A6 SNPs’ clinical impact and interactions with other factors on DFP’s efficacy are needed for better insights into individualisation of DFP therapy for thal.
Keyword(s): Deferiprone, Polymorphism
Session topic: Publication Only
Abstract: PB2006
Type: Publication Only
Background
Deferiprone(DFP) is an oral iron chelator widely used in thalassemia(thal) patients(pts). It is mostly glucuronidated by liver UGT1A6 to an inactive metabolite before renally excreted. UGT1A6 polymorphism has been studied as a potential cause for variability in DFP’s efficacy. No significant(sig) effect of UGT1A6 polymorphism was shown on the single-dose pharmacokinetics of DFP in healthy volunteers, while another study on β thal major pts treated with DFP showed an association of UGT1A6 single nucleotide polymorphism(SNP) 541A>G with lower ferritin. There are no studies on UGT1A6 polymorphism’s association with MRI-T2*, which allows more specific measurement of DFP response by non-invasive liver and heart iron quantification.
Aims
Determine associations of UGT1A6 genetic polymorphism and other non-genetic factors with MRI-T2* responses to DFP in thal.
Methods
Thal pts(aged ≥18 years) who had ≥1 year of DFP and at least two MRI-T2* of ≥1 year apart for assessment of DFP response were enrolled after consenting for UGT1A6 DNA analysis. 3 common non-synonymous SNPs(19T>G, 541A>G, 552A>C) and 1 synonymous SNP(105C>T) of UGT1A6 were detected by sequencing PCR-amplified target DNA segments. Data on MRI-T2* response to DFP was retrospectively collected and analysed for associations with UGT1A6 SNPs/haplotypes and other non-genetic factors(gender, race, splenectomy, baseline cardiac/liver T2*, type of thal, transfusional iron load, DFP and concomitant deferoxamine(DFO) doses). Liver T2* was converted to liver iron concentration(LIC). Improvement in cardiac T2*(if baseline cardiac T2* <20ms) or LIC without discrepant changes in corresponding LIC or cardiac T2* were considered to have responded to DFP.
Results
32 pts(Chinese 56%, Malay 35%, Indian 3%, others 6%) were treated with median 6(1-11) years of DFP at median average dose of 68.2(24.4-93.3) mg/kg/day. 53% received concomitant DFO at median average dose of 23.1(11.4-40.6) mg/kg/day; 84% was regularly transfused, with median transfusional iron load of 0.4(0.1-0.6) mg/kg/day. Genotypic frequency was UGT1A6*1/*1: 75%, UGT*1/*2: 18.8%, UGT*1/*4: 6.2% (UGT1A6*1=wild type haplotype; UGT1A6*2=variant haplotype with SNPs 19T>G, 541A>G, 552A>C; UGT1A6*4=variant haplotype with SNPs 19T>G and 552A>C). In addition, 15.6% were heterozygous for 105C>T SNP. On multivariate analysis, splenectomy(OR 0.002, 95% CI[0.000, 0.697], P=0.04) and UGT1A6 variant haplotypes(*2 or *4) without concurrent 105C>T(OR 0.016, 95% CI[0.000, 0.766], P=0.03) independently associated with absent DFP response. The median rate of LIC improvement was 2.7(-12.0 to 10.1) mg/g dw per year after excluding 2 patients with discordant liver and cardiac T2* changes. On multivariate analysis, thal major(-2.8, 95% CI[-5.5, -0.04] mg/g dw per year, P<0.05) and UGT1A6 variant haplotypes without concurrent 105C>T (-4.8, 95% CI[-7.8, -1.7] mg/g dw per year, P <0.01) independently associated with poorer LIC improvement rate (see Figure). Other analysed factors did not have sig independent associations with DFP response and LIC improvement rate(P>0.15).
Summary
Splenectomy decreases iron storage capacity, might lead to iron redistribution to other organs and poorer MRI-T2* responses to DFP. Thal majors had poorer DFP response than other types of thal likely due to higher body iron load. The poorer DFP response observed in our pts with UGT1A6 variant haplotypes (and no concurrent 105C>T) was contrary to expectations since recombinant UGT1A6 variants have slower in vitro DFP glucuronidation rates than wild type. One possibility is UGT1A6 variants have different in vivo activities on DFP since conflicting activities of recombinant and liver UGT1A6 allozymes are reported for other substrates. Concomitant 105C>T appeared to negate the adverse impact of UGT1A6 variants on DFP response in our pts. In vitro, this SNP increased mRNA stability despite no amino acid changes. This might influence mRNA or enzyme protein stability in vivo for heterozygotes of UGT1A6 variants, leading to changes in DFP metabolism and efficacy. More studies on UGT1A6 SNPs’ clinical impact and interactions with other factors on DFP’s efficacy are needed for better insights into individualisation of DFP therapy for thal.
Keyword(s): Deferiprone, Polymorphism
Session topic: Publication Only
Type: Publication Only
Background
Deferiprone(DFP) is an oral iron chelator widely used in thalassemia(thal) patients(pts). It is mostly glucuronidated by liver UGT1A6 to an inactive metabolite before renally excreted. UGT1A6 polymorphism has been studied as a potential cause for variability in DFP’s efficacy. No significant(sig) effect of UGT1A6 polymorphism was shown on the single-dose pharmacokinetics of DFP in healthy volunteers, while another study on β thal major pts treated with DFP showed an association of UGT1A6 single nucleotide polymorphism(SNP) 541A>G with lower ferritin. There are no studies on UGT1A6 polymorphism’s association with MRI-T2*, which allows more specific measurement of DFP response by non-invasive liver and heart iron quantification.
Aims
Determine associations of UGT1A6 genetic polymorphism and other non-genetic factors with MRI-T2* responses to DFP in thal.
Methods
Thal pts(aged ≥18 years) who had ≥1 year of DFP and at least two MRI-T2* of ≥1 year apart for assessment of DFP response were enrolled after consenting for UGT1A6 DNA analysis. 3 common non-synonymous SNPs(19T>G, 541A>G, 552A>C) and 1 synonymous SNP(105C>T) of UGT1A6 were detected by sequencing PCR-amplified target DNA segments. Data on MRI-T2* response to DFP was retrospectively collected and analysed for associations with UGT1A6 SNPs/haplotypes and other non-genetic factors(gender, race, splenectomy, baseline cardiac/liver T2*, type of thal, transfusional iron load, DFP and concomitant deferoxamine(DFO) doses). Liver T2* was converted to liver iron concentration(LIC). Improvement in cardiac T2*(if baseline cardiac T2* <20ms) or LIC without discrepant changes in corresponding LIC or cardiac T2* were considered to have responded to DFP.
Results
32 pts(Chinese 56%, Malay 35%, Indian 3%, others 6%) were treated with median 6(1-11) years of DFP at median average dose of 68.2(24.4-93.3) mg/kg/day. 53% received concomitant DFO at median average dose of 23.1(11.4-40.6) mg/kg/day; 84% was regularly transfused, with median transfusional iron load of 0.4(0.1-0.6) mg/kg/day. Genotypic frequency was UGT1A6*1/*1: 75%, UGT*1/*2: 18.8%, UGT*1/*4: 6.2% (UGT1A6*1=wild type haplotype; UGT1A6*2=variant haplotype with SNPs 19T>G, 541A>G, 552A>C; UGT1A6*4=variant haplotype with SNPs 19T>G and 552A>C). In addition, 15.6% were heterozygous for 105C>T SNP. On multivariate analysis, splenectomy(OR 0.002, 95% CI[0.000, 0.697], P=0.04) and UGT1A6 variant haplotypes(*2 or *4) without concurrent 105C>T(OR 0.016, 95% CI[0.000, 0.766], P=0.03) independently associated with absent DFP response. The median rate of LIC improvement was 2.7(-12.0 to 10.1) mg/g dw per year after excluding 2 patients with discordant liver and cardiac T2* changes. On multivariate analysis, thal major(-2.8, 95% CI[-5.5, -0.04] mg/g dw per year, P<0.05) and UGT1A6 variant haplotypes without concurrent 105C>T (-4.8, 95% CI[-7.8, -1.7] mg/g dw per year, P <0.01) independently associated with poorer LIC improvement rate (see Figure). Other analysed factors did not have sig independent associations with DFP response and LIC improvement rate(P>0.15).
Summary
Splenectomy decreases iron storage capacity, might lead to iron redistribution to other organs and poorer MRI-T2* responses to DFP. Thal majors had poorer DFP response than other types of thal likely due to higher body iron load. The poorer DFP response observed in our pts with UGT1A6 variant haplotypes (and no concurrent 105C>T) was contrary to expectations since recombinant UGT1A6 variants have slower in vitro DFP glucuronidation rates than wild type. One possibility is UGT1A6 variants have different in vivo activities on DFP since conflicting activities of recombinant and liver UGT1A6 allozymes are reported for other substrates. Concomitant 105C>T appeared to negate the adverse impact of UGT1A6 variants on DFP response in our pts. In vitro, this SNP increased mRNA stability despite no amino acid changes. This might influence mRNA or enzyme protein stability in vivo for heterozygotes of UGT1A6 variants, leading to changes in DFP metabolism and efficacy. More studies on UGT1A6 SNPs’ clinical impact and interactions with other factors on DFP’s efficacy are needed for better insights into individualisation of DFP therapy for thal.
Keyword(s): Deferiprone, Polymorphism
Session topic: Publication Only
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