DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy : call for a drug label update

The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. This toxicity is strongly affected by interindividual variability in activity of dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for inactivation of fluoropyrimidines, with an estimated 3%-8% of the population being partially DPD deficient. A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency. When these partially DPD deficient patients are treated with a full dose of fluoropyrimidines, they are generally exposed to toxic levels of 5-FU and its metabolites, and the risk of developing severe treatment-related toxicity is therefore significantly increased.Currently, functional and clinical validity is well established for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A), as those variants have retrospectively and in a large population study prospectively been shown to be associated with increased risk of fluoropyrimidine-associated toxicity. Patient safety of fluoropyrimidine treatment can be significantly improved by pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers, thereby normalizing 5-FU exposure. Based on the critical appraisal of currently available data, adjusting the labels of capecitabine and 5-FU by including recommendations on pre-emptive screening for DPYD variants and DPYD genotype-guided dose adjustments should be the new standard of care

DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy : call for a drug label update

The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. This toxicity is strongly affected by interindividual variability in activity of dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for inactivation of fluoropyrimidines, with an estimated 3%-8% of the population being partially DPD deficient. A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency. When these partially DPD deficient patients are treated with a full dose of fluoropyrimidines, they are generally exposed to toxic levels of 5-FU and its metabolites, and the risk of developing severe treatment-related toxicity is therefore significantly increased.Currently, functional and clinical validity is well established for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A), as those variants have retrospectively and in a large population study prospectively been shown to be associated with increased risk of fluoropyrimidine-associated toxicity. Patient safety of fluoropyrimidine treatment can be significantly improved by pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers, thereby normalizing 5-FU exposure. Based on the critical appraisal of currently available data, adjusting the labels of capecitabine and 5-FU by including recommendations on pre-emptive screening for DPYD variants and DPYD genotype-guided dose adjustments should be the new standard of care

Letter regarding Zhao et al. entitled "DPYD gene polymorphisms are associated with risk and chemotherapy prognosis in pediatric patients with acute lymphoblastic leukemia"

Zhao et al. investigated the association between germline genetic polymorphisms in DPYD, the gene encoding dihydropyrimidine dehydrogenase, and (1) the risk of developing pediatric acute lymphoblastic leukemia and (2) outcome of acute lymphoblastic leukemia following the treatment with 5-fluorouracil plus oxaliplatin (FOLFOX). The authors found that the common DPYD variant c.85T>C (rs1801265, DPYD*9A) was significantly associated with (1) risk of developing pediatric acute lymphoblastic leukemia, (2) complete response rate, (3) event-free survival, and (4) treatment-related toxicity. The authors conclude that patients carrying the c.85T>C C allele have an increased risk of developing acute lymphoblastic leukemia and have inferior outcome, and that DPYD c.85T>C can be used as a guide for individualized treatment and the decision to utilize 5-fluorouracil in acute lymphoblastic leukemia patients. In our view, the published article gives rise to multiple critical issues regarding the study's rationale and the methodology used, which strongly question the validity of the authors' conclusions

Letter regarding Zhao et al. entitled "DPYD gene polymorphisms are associated with risk and chemotherapy prognosis in pediatric patients with acute lymphoblastic leukemia"

Zhao et al. investigated the association between germline genetic polymorphisms in DPYD, the gene encoding dihydropyrimidine dehydrogenase, and (1) the risk of developing pediatric acute lymphoblastic leukemia and (2) outcome of acute lymphoblastic leukemia following the treatment with 5-fluorouracil plus oxaliplatin (FOLFOX). The authors found that the common DPYD variant c.85T>C (rs1801265, DPYD*9A) was significantly associated with (1) risk of developing pediatric acute lymphoblastic leukemia, (2) complete response rate, (3) event-free survival, and (4) treatment-related toxicity. The authors conclude that patients carrying the c.85T>C C allele have an increased risk of developing acute lymphoblastic leukemia and have inferior outcome, and that DPYD c.85T>C can be used as a guide for individualized treatment and the decision to utilize 5-fluorouracil in acute lymphoblastic leukemia patients. In our view, the published article gives rise to multiple critical issues regarding the study's rationale and the methodology used, which strongly question the validity of the authors' conclusions

Development and validation of a rapid and sensitive UPLC-MS/MS method for determination of uracil and dihydrouracil in human plasma

Quantification of the endogenous dihydropyrimidine dehydrogenase (DPD) substrate uracil (U) and the reaction product dihydrouracil (UH2) in plasma might be suitable for identification of patients at risk of fluoropyrimidine-induced toxicity as a result of DPD deficiency. In this paper, we describe the development and validation of a rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay for quantification of U and UH2 in human plasma. Analytes were extracted by protein precipitation, chromatographically separated on an Acquity UPLC(®) HSS T3 column with gradient elution and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. U was quantified in the negative ion mode and UH2 in the positive ion mode. Stable isotopes for U and UH2 were used as internal standards. Total chromatographic run time was 5min. Validated concentration ranges for U and UH2 were from 1 to 100ng/mL and 10 to 1000ng/mL, respectively. Inter-assay bias and inter-assay precision for U were within ±2.8% and ≤12.4%. For UH2, inter-assay bias and inter-assay precision were within ±2.9% and ≤7.2%. Adequate stability of U and UH2 in dry extract, final extract, stock solution and plasma was demonstrated. Stability of U and UH2 in whole blood was only satisfactory when stored up to 4hours at 2-8°C, but not at ambient temperatures. An accurate, precise and sensitive UPLC-MS/MS assay for quantification of U and UH2 in plasma was developed. This assay is now applied to support clinical studies with fluoropyrimidine drugs

Acute haemolytic transfusion reaction after transfusion of fresh frozen plasma in a neonate—Preventable by using solvent/detergent-treated pooled plasma?

Background: Plasma is a commonly used blood product and is available in the form of fresh frozen plasma (FFP) or pooled solvent/detergent-treated plasma. In the Netherlands, solvent/detergent-treated plasma has become the standard product in the adult population since several years, but for neonatal use, FFP remains the product of preference. Description: A preterm neonate developed lung bleeding at day 8 postpartum, for which intubation and mechanical ventilation was required and transfusions with packed red blood cells and plasma, in the form of FFP, were given. Five hours after transfusion, a red discoloration of the urine occurred. An acute haemolytic transfusion was suspected, confirmed by laboratory investigations (fast decrease in haemoglobin, increased free haemoglobin, decreased haptoglobin, increased lactate dehydrogenase and a positive direct antiglobulin test [IgG 2+]). Additional research showed that the FFP product contained nonspecific auto-antibodies that reacted with the transfused erythrocytes, most test erythrocytes and the donor's own erythrocytes. Conclusion: A neonate experienced an acute haemolytic reaction, most probably caused by administrating a FFP product containing auto-antibodies. If transfused with solvent/detergent-treated plasma, such antibodies would have been diluted or captured. This case adds a new argument to the discussion on expanding the use of solvent/detergent-treated plasma to the paediatric population

Prospective DPYD genotyping to reduce the risk of fluoropyrimidine-induced severe toxicity : Ready for prime time

5-Fluorouracil (5-FU) and capecitabine (CAP) are among the most frequently prescribed anticancer drugs. They are inactivated in the liver by the enzyme dihydropyrimidine dehydrogenase (DPD). Up to 5% of the population is DPD deficient and these patients have a significantly increased risk of severe and potentially lethal toxicity when treated with regular doses of 5-FU or CAP. DPD is encoded by the gene DPYD and variants in DPYD can lead to a decreased DPD activity. Although prospective DPYD genotyping is a valuable tool to identify patients with DPD deficiency, and thus those at risk for severe and potential life-threatening toxicity, prospective genotyping has not yet been implemented in daily clinical care. Our goal was to present the available evidence in favour of prospective genotyping, including discussion of unjustified worries on cost-effectiveness, and potential underdosing. We conclude that there is convincing evidence to implement prospective DPYD genotyping with an upfront dose adjustment in DPD deficient patients. Immediate benefit in patient care can be expected through decreasing toxicity, while maintaining efficacy

Effectiveness and safety of reduced-dose fluoropyrimidine therapy in patients carrying the DPYD*2A variant : a matched pair analysis

Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine-associated toxicity. Upfront DPYD*2A genotype-based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, this study investigated effectiveness and safety of DPYD*2A genotype-guided dosing. A cohort of 40 prospectively identified heterozygous DPYD*2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair-analysis was performed where for each DPYD*2A carrier a matched DPYD*2A wild-type patient was identified. Overall survival and progression-free survival were compared between the matched groups. The frequency of severe (grade≥3) treatment-related toxicity was compared to 1] a cohort of 1606 wild-type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86 DPYD*2A variant carriers who received a full fluoropyrimidine dose. For 37 out of 40 DPYD*2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months versus 24 months, P=0.47) nor progression-free survival (median 14 months versus 10 months, P=0.54). Risk of severe fluoropyrimidine-related toxicity in DPYD*2A carriers treated with reduced dose was 18%, comparable to wild-type patients (23%, P=0.57) and significantly lower than the risk of 77% in DPYD*2A carriers treated with full dose (P<0.001). This study is the first to show that DPYD*2A genotype-guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine-based chemotherapy, while resulting in significantly improved patient safety. This article is protected by copyright. All rights reserved

Effectiveness and safety of reduced-dose fluoropyrimidine therapy in patients carrying the DPYD*2A variant : a matched pair analysis

Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine-associated toxicity. Upfront DPYD*2A genotype-based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, this study investigated effectiveness and safety of DPYD*2A genotype-guided dosing. A cohort of 40 prospectively identified heterozygous DPYD*2A carriers, treated with a ~50% reduced fluoropyrimidine dose, was identified. For effectiveness analysis, a matched pair-analysis was performed where for each DPYD*2A carrier a matched DPYD*2A wild-type patient was identified. Overall survival and progression-free survival were compared between the matched groups. The frequency of severe (grade≥3) treatment-related toxicity was compared to 1] a cohort of 1606 wild-type patients treated with full dose and 2] a cohort of historical controls derived from literature, i.e. 86 DPYD*2A variant carriers who received a full fluoropyrimidine dose. For 37 out of 40 DPYD*2A carriers, a matched control could be identified. Compared to matched controls, reduced doses did not negatively affect overall survival (median 27 months versus 24 months, P=0.47) nor progression-free survival (median 14 months versus 10 months, P=0.54). Risk of severe fluoropyrimidine-related toxicity in DPYD*2A carriers treated with reduced dose was 18%, comparable to wild-type patients (23%, P=0.57) and significantly lower than the risk of 77% in DPYD*2A carriers treated with full dose (P<0.001). This study is the first to show that DPYD*2A genotype-guided dosing appears to have no negative effect on effectiveness of fluoropyrimidine-based chemotherapy, while resulting in significantly improved patient safety. This article is protected by copyright. All rights reserved