METHOTREXATE ELIMINATION AND TOXICITY: THE ROLE OF MTHFR 677C>T POLYMORPHISM IN PRIMARY CNS LYMPHOMA PATIENTS TREATED WITH HIGH DOSE METHOTREXATE MONOTHERAPY
(Abstract release date: 05/19/16)
EHA Library. Hyun Yoon D. 06/09/16; 132943; E1394
Dok Hyun Yoon
Contributions
Contributions
Abstract
Abstract: E1394
Type: Eposter Presentation
Background
Methylenetetrahydrofolate reductase (MTHFR) plays a key role in metabolism and homeostasis of intracellular folate, and substitution of C > T is reported to be associated with decreased MTHFR enzyme activity, contributing to low folate level. The genetic association of MTHFR 677C>T in methotrexate (MTX) toxicity was evaluated in a number of studies, however the results were conflicting. The substantial heterogeneity within the study population could compromise the effect of MTHFR 677C>T polymorphism on MTX toxicity, and conflicting published results may have attributed to this.
Aims
The aim of this study was to evaluate the role of MTHFR 677C>T polymorphism in MTX toxicity within a homogenous study population by limiting cancer type to primary central nervous system lymphoma (PCNSL) and chemotherapy protocol to the first four cycles of high dose methotrexate monotherapy and fixed leucovorin rescue regimen (HD-MTX & HD-ARA regimen).
Methods
Data of patients diagnosed with PCNSL treated with HD-MTX & HD-ARA regimen were retrieved. The effect of MTHFR 677C>T polymorphism on the incidence of MTX toxicity was evaluated using a generalized estimating equation analysis.
Results
A total of 111 patients (402 cycles) was included in the analysis. The hematologic toxicity and nephrotoxicity were most frequently presented in patient with heterozygous variant genotype, with an incidence of 57 (29.1%) and 7 (3.6%). The incidence rate of hepatotoxicity and oral mucositis requiring treatment was highest in patient with wild genotype (hepatotoxicity: 7.3%, oral mucositis: 4.1%). None of the patients with homozygous variant genotype experienced the oral mucositis. Twenty eight point six percent of nephrotoxicity occurred in cycles with delayed elimination, and delayed elimination was most frequently seen in patients with homozygous variant genotype (3.6%). The risk for developing clinically meaningful hematologic toxicity was higher in patients with heterozygous variant genotype than wild genotype (odds ratio; OR: 2.60, 95% confidence interval; CI: 1.32 – 5.09, P-value = 0.0055). No valid difference was observed between patients with homozygous variant and wild genotype in terms of hematologic toxicity. Other explanatory variables shown to increase the risk of hematologic toxicity were the presence of delayed elimination (OR: 10.06, 95% CI:2.87 – 35.31, P-value = 0.0003), high serum lactate dehydrogenase level exceeding the upper range of normal at the time of diagnosis (OR: 2.04, 95% CI:1.09 – 3.81, P-value = 0.0257) and concomitant administration of penicillin antibiotics with MTX (OR: 2.88, 95% CI:1.17 – 7.07, P-value = 0.0213). No correlation between age, sex, Eastern Cooperative Oncology Group performance status, concomitant administration of proton pump inhibitor and hematologic toxicity was demonstrated. For hepatotoxicity, MTHFR 677C>T polymorphism was the only explanatory variable included in the model. The MTHFR 677C>T polymorphism was not shown to be correlated with risk of hepatotoxicity (heterozygous variant genotype; OR: 0.75, 95% CI: 0.29 – 1.96, P-value = 0.5575, homozygous variant genotype; OR: 0.80, 95% CI: 0.24-2.69, P-value = 0.7176).
Conclusion
The MTHFR 677C>T polymorphism is shown to be a valid marker in predicting MTX associated hematologic toxicity. Clinically significant nephrotoxicity might occur in patients without delayed elimination, suggesting that factors other than serum MTX level could play a role. MTX induced hepatotoxicity and oral mucositis occur independently of the serum MTX level.
Session topic: E-poster
Keyword(s): Methotrexate, MTHFR
Type: Eposter Presentation
Background
Methylenetetrahydrofolate reductase (MTHFR) plays a key role in metabolism and homeostasis of intracellular folate, and substitution of C > T is reported to be associated with decreased MTHFR enzyme activity, contributing to low folate level. The genetic association of MTHFR 677C>T in methotrexate (MTX) toxicity was evaluated in a number of studies, however the results were conflicting. The substantial heterogeneity within the study population could compromise the effect of MTHFR 677C>T polymorphism on MTX toxicity, and conflicting published results may have attributed to this.
Aims
The aim of this study was to evaluate the role of MTHFR 677C>T polymorphism in MTX toxicity within a homogenous study population by limiting cancer type to primary central nervous system lymphoma (PCNSL) and chemotherapy protocol to the first four cycles of high dose methotrexate monotherapy and fixed leucovorin rescue regimen (HD-MTX & HD-ARA regimen).
Methods
Data of patients diagnosed with PCNSL treated with HD-MTX & HD-ARA regimen were retrieved. The effect of MTHFR 677C>T polymorphism on the incidence of MTX toxicity was evaluated using a generalized estimating equation analysis.
Results
A total of 111 patients (402 cycles) was included in the analysis. The hematologic toxicity and nephrotoxicity were most frequently presented in patient with heterozygous variant genotype, with an incidence of 57 (29.1%) and 7 (3.6%). The incidence rate of hepatotoxicity and oral mucositis requiring treatment was highest in patient with wild genotype (hepatotoxicity: 7.3%, oral mucositis: 4.1%). None of the patients with homozygous variant genotype experienced the oral mucositis. Twenty eight point six percent of nephrotoxicity occurred in cycles with delayed elimination, and delayed elimination was most frequently seen in patients with homozygous variant genotype (3.6%). The risk for developing clinically meaningful hematologic toxicity was higher in patients with heterozygous variant genotype than wild genotype (odds ratio; OR: 2.60, 95% confidence interval; CI: 1.32 – 5.09, P-value = 0.0055). No valid difference was observed between patients with homozygous variant and wild genotype in terms of hematologic toxicity. Other explanatory variables shown to increase the risk of hematologic toxicity were the presence of delayed elimination (OR: 10.06, 95% CI:2.87 – 35.31, P-value = 0.0003), high serum lactate dehydrogenase level exceeding the upper range of normal at the time of diagnosis (OR: 2.04, 95% CI:1.09 – 3.81, P-value = 0.0257) and concomitant administration of penicillin antibiotics with MTX (OR: 2.88, 95% CI:1.17 – 7.07, P-value = 0.0213). No correlation between age, sex, Eastern Cooperative Oncology Group performance status, concomitant administration of proton pump inhibitor and hematologic toxicity was demonstrated. For hepatotoxicity, MTHFR 677C>T polymorphism was the only explanatory variable included in the model. The MTHFR 677C>T polymorphism was not shown to be correlated with risk of hepatotoxicity (heterozygous variant genotype; OR: 0.75, 95% CI: 0.29 – 1.96, P-value = 0.5575, homozygous variant genotype; OR: 0.80, 95% CI: 0.24-2.69, P-value = 0.7176).
Conclusion
The MTHFR 677C>T polymorphism is shown to be a valid marker in predicting MTX associated hematologic toxicity. Clinically significant nephrotoxicity might occur in patients without delayed elimination, suggesting that factors other than serum MTX level could play a role. MTX induced hepatotoxicity and oral mucositis occur independently of the serum MTX level.
Session topic: E-poster
Keyword(s): Methotrexate, MTHFR
Abstract: E1394
Type: Eposter Presentation
Background
Methylenetetrahydrofolate reductase (MTHFR) plays a key role in metabolism and homeostasis of intracellular folate, and substitution of C > T is reported to be associated with decreased MTHFR enzyme activity, contributing to low folate level. The genetic association of MTHFR 677C>T in methotrexate (MTX) toxicity was evaluated in a number of studies, however the results were conflicting. The substantial heterogeneity within the study population could compromise the effect of MTHFR 677C>T polymorphism on MTX toxicity, and conflicting published results may have attributed to this.
Aims
The aim of this study was to evaluate the role of MTHFR 677C>T polymorphism in MTX toxicity within a homogenous study population by limiting cancer type to primary central nervous system lymphoma (PCNSL) and chemotherapy protocol to the first four cycles of high dose methotrexate monotherapy and fixed leucovorin rescue regimen (HD-MTX & HD-ARA regimen).
Methods
Data of patients diagnosed with PCNSL treated with HD-MTX & HD-ARA regimen were retrieved. The effect of MTHFR 677C>T polymorphism on the incidence of MTX toxicity was evaluated using a generalized estimating equation analysis.
Results
A total of 111 patients (402 cycles) was included in the analysis. The hematologic toxicity and nephrotoxicity were most frequently presented in patient with heterozygous variant genotype, with an incidence of 57 (29.1%) and 7 (3.6%). The incidence rate of hepatotoxicity and oral mucositis requiring treatment was highest in patient with wild genotype (hepatotoxicity: 7.3%, oral mucositis: 4.1%). None of the patients with homozygous variant genotype experienced the oral mucositis. Twenty eight point six percent of nephrotoxicity occurred in cycles with delayed elimination, and delayed elimination was most frequently seen in patients with homozygous variant genotype (3.6%). The risk for developing clinically meaningful hematologic toxicity was higher in patients with heterozygous variant genotype than wild genotype (odds ratio; OR: 2.60, 95% confidence interval; CI: 1.32 – 5.09, P-value = 0.0055). No valid difference was observed between patients with homozygous variant and wild genotype in terms of hematologic toxicity. Other explanatory variables shown to increase the risk of hematologic toxicity were the presence of delayed elimination (OR: 10.06, 95% CI:2.87 – 35.31, P-value = 0.0003), high serum lactate dehydrogenase level exceeding the upper range of normal at the time of diagnosis (OR: 2.04, 95% CI:1.09 – 3.81, P-value = 0.0257) and concomitant administration of penicillin antibiotics with MTX (OR: 2.88, 95% CI:1.17 – 7.07, P-value = 0.0213). No correlation between age, sex, Eastern Cooperative Oncology Group performance status, concomitant administration of proton pump inhibitor and hematologic toxicity was demonstrated. For hepatotoxicity, MTHFR 677C>T polymorphism was the only explanatory variable included in the model. The MTHFR 677C>T polymorphism was not shown to be correlated with risk of hepatotoxicity (heterozygous variant genotype; OR: 0.75, 95% CI: 0.29 – 1.96, P-value = 0.5575, homozygous variant genotype; OR: 0.80, 95% CI: 0.24-2.69, P-value = 0.7176).
Conclusion
The MTHFR 677C>T polymorphism is shown to be a valid marker in predicting MTX associated hematologic toxicity. Clinically significant nephrotoxicity might occur in patients without delayed elimination, suggesting that factors other than serum MTX level could play a role. MTX induced hepatotoxicity and oral mucositis occur independently of the serum MTX level.
Session topic: E-poster
Keyword(s): Methotrexate, MTHFR
Type: Eposter Presentation
Background
Methylenetetrahydrofolate reductase (MTHFR) plays a key role in metabolism and homeostasis of intracellular folate, and substitution of C > T is reported to be associated with decreased MTHFR enzyme activity, contributing to low folate level. The genetic association of MTHFR 677C>T in methotrexate (MTX) toxicity was evaluated in a number of studies, however the results were conflicting. The substantial heterogeneity within the study population could compromise the effect of MTHFR 677C>T polymorphism on MTX toxicity, and conflicting published results may have attributed to this.
Aims
The aim of this study was to evaluate the role of MTHFR 677C>T polymorphism in MTX toxicity within a homogenous study population by limiting cancer type to primary central nervous system lymphoma (PCNSL) and chemotherapy protocol to the first four cycles of high dose methotrexate monotherapy and fixed leucovorin rescue regimen (HD-MTX & HD-ARA regimen).
Methods
Data of patients diagnosed with PCNSL treated with HD-MTX & HD-ARA regimen were retrieved. The effect of MTHFR 677C>T polymorphism on the incidence of MTX toxicity was evaluated using a generalized estimating equation analysis.
Results
A total of 111 patients (402 cycles) was included in the analysis. The hematologic toxicity and nephrotoxicity were most frequently presented in patient with heterozygous variant genotype, with an incidence of 57 (29.1%) and 7 (3.6%). The incidence rate of hepatotoxicity and oral mucositis requiring treatment was highest in patient with wild genotype (hepatotoxicity: 7.3%, oral mucositis: 4.1%). None of the patients with homozygous variant genotype experienced the oral mucositis. Twenty eight point six percent of nephrotoxicity occurred in cycles with delayed elimination, and delayed elimination was most frequently seen in patients with homozygous variant genotype (3.6%). The risk for developing clinically meaningful hematologic toxicity was higher in patients with heterozygous variant genotype than wild genotype (odds ratio; OR: 2.60, 95% confidence interval; CI: 1.32 – 5.09, P-value = 0.0055). No valid difference was observed between patients with homozygous variant and wild genotype in terms of hematologic toxicity. Other explanatory variables shown to increase the risk of hematologic toxicity were the presence of delayed elimination (OR: 10.06, 95% CI:2.87 – 35.31, P-value = 0.0003), high serum lactate dehydrogenase level exceeding the upper range of normal at the time of diagnosis (OR: 2.04, 95% CI:1.09 – 3.81, P-value = 0.0257) and concomitant administration of penicillin antibiotics with MTX (OR: 2.88, 95% CI:1.17 – 7.07, P-value = 0.0213). No correlation between age, sex, Eastern Cooperative Oncology Group performance status, concomitant administration of proton pump inhibitor and hematologic toxicity was demonstrated. For hepatotoxicity, MTHFR 677C>T polymorphism was the only explanatory variable included in the model. The MTHFR 677C>T polymorphism was not shown to be correlated with risk of hepatotoxicity (heterozygous variant genotype; OR: 0.75, 95% CI: 0.29 – 1.96, P-value = 0.5575, homozygous variant genotype; OR: 0.80, 95% CI: 0.24-2.69, P-value = 0.7176).
Conclusion
The MTHFR 677C>T polymorphism is shown to be a valid marker in predicting MTX associated hematologic toxicity. Clinically significant nephrotoxicity might occur in patients without delayed elimination, suggesting that factors other than serum MTX level could play a role. MTX induced hepatotoxicity and oral mucositis occur independently of the serum MTX level.
Session topic: E-poster
Keyword(s): Methotrexate, MTHFR
{{ help_message }}
{{filter}}