Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy
Background and Objective Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6...
Gespeichert in:
| Veröffentlicht in: | Clinical pharmacokinetics 2024-08, Vol.63 (8), p.1089-1109 |
|---|---|
| Hauptverfasser: | , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 1109 |
|---|---|
| container_issue | 8 |
| container_start_page | 1089 |
| container_title | Clinical pharmacokinetics |
| container_volume | 63 |
| creator | Bayoumy, Ahmed B. Ansari, A. R. Mulder, C. J. J. Schmiegelow, K. Florin, Timothy De Boer, N. K. H. |
| description | Background and Objective
Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography–tandem mass spectrometry (LC–MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants.
Methods
A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword “DNA-TG” with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher’s
z
-transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle–Ot |
| doi_str_mv | 10.1007/s40262-024-01393-0 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11343975</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3100602578</sourcerecordid><originalsourceid>FETCH-LOGICAL-c356t-162018fa539e2afeca7098a128db4ba7a6aab724e5a3e87b6e89872a838723a73</originalsourceid><addsrcrecordid>eNp9ks1u1DAUhSMEokPhBVggS2zKIuCfJI7ZVEMLZaS2SFDW1k3mTuqSsYMdTzVv1UfE6ZTyJ7GxLZ3vHl_7nix7zuhrRql8EwrKK55TXuSUCSVy-iCbMSZVzhSvHmYzKhjPS1WJvexJCFeU0ppT-jjbE2qSeDHLbhbWug2Mxnbk4tK4IXpjMR3Rw4BxNC059rEjZ86a0SWte0vm5Ms2jLiGSf2MG4PXBOySnOEI-dxCvw0mEGfJ8fk8n0y7CHZyPY9tj240Swzk4FY8eUUgpGKysG0fg9kgeWfcGvw39MTYf1vaPs0eraAP-Oxu38--fnh_cfQxP_10sjian-atKKsxZxWnrF5BKRRyWGELkqoaGK-XTdGAhAqgkbzAEgTWsqmwVrXkUIu0CpBiPzvc-Q6xWeOyRTt66PXgTepuqx0Y_adizaXu3EYzJgqhZJkcDu4cvPseMYx6bUKLfQ8WXQxapGmoUpWSJvTlX-iViz79ZKLSqCvKS1kniu-o1rsQPK7uu2FUT4nQu0TolAh9mwg9Wb_4_R33JT8jkACxA8IwjRf9r7v_Y_sD3LXDpg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3100602578</pqid></control><display><type>article</type><title>Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy</title><source>MEDLINE</source><source>SpringerLink Journals - AutoHoldings</source><creator>Bayoumy, Ahmed B. ; Ansari, A. R. ; Mulder, C. J. J. ; Schmiegelow, K. ; Florin, Timothy ; De Boer, N. K. H.</creator><creatorcontrib>Bayoumy, Ahmed B. ; Ansari, A. R. ; Mulder, C. J. J. ; Schmiegelow, K. ; Florin, Timothy ; De Boer, N. K. H.</creatorcontrib><description>Background and Objective
Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography–tandem mass spectrometry (LC–MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants.
Methods
A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword “DNA-TG” with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher’s
z
-transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle–Ottowa quality assessment scale.
Results
In this systematic review, 21 studies were included that measured DNA-TG levels in white blood cells for either patients with ALL (
n
= 16) or IBD (
n
= 5). In our meta-analysis, the overall mean difference between patients with leukopenia (ALL + IBD) versus no leukopenia was 134.15 fmol TG/µg DNA [95% confidence interval (CI) (83.78–184.35),
P
< 0.00001; heterogeneity chi squared of 5.62,
I
2
of 47%]. There was a significant difference in DNA-TG levels for patients with IBD with and without leukopenia [161.76 fmol TG/µg DNA; 95% CI (126.23–197.29),
P
< 0.00001; heterogeneity chi squared of 0.20,
I
2
of 0%]. No significant difference was found in DNA-TG level between patients with ALL with or without leukopenia (57.71 fmol TG/µg DNA [95% CI (− 22.93 to 138.35),
P
< 0.80]). DNA-TG monitoring was found to be a promising method for predicting relapse rates in patients with ALL, and DNA-TG levels are likely a better predictor for leukopenia in patients with IBD than RBC 6-TGNs levels. DNA-TG levels have been shown to correlate with various gene variants (TPMT, NUDT15, ITPA, and MRP4) in various studies, points to its potential as a more informative marker for guiding thiopurine therapy across diverse genetic backgrounds.
Conclusions
This systematic review strongly supports the further investigation of DNA-TG as a marker for monitoring thiopurine therapy. Its correlation with treatment outcomes, such as relapse-free survival in ALL and the risk of leukopenia in IBD, underscores its role in enhancing personalized treatment approaches. DNA-TG effectively identifies NUDT15 variants and predicts late leukopenia in patients with IBD, regardless of their NUDT15 variant status. The recommended threshold for late leukopenia prediction in patients with IBD with DNA-TG is suggested to be between 320 and 340 fmol/µg DNA. More clinical research on DNA-TG implementation is mandatory to improve patient care and to improve inclusivity in thiopurine treatment.
Graphical Abstract</description><identifier>ISSN: 0312-5963</identifier><identifier>ISSN: 1179-1926</identifier><identifier>EISSN: 1179-1926</identifier><identifier>DOI: 10.1007/s40262-024-01393-0</identifier><identifier>PMID: 39031224</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Azathioprine - pharmacokinetics ; Azathioprine - therapeutic use ; Biomarkers - blood ; Blood ; Chromatography ; DNA - genetics ; Drug Monitoring - methods ; Guanine Nucleotides - blood ; Hispanic people ; Humans ; Inflammatory bowel disease ; Internal Medicine ; Investigations ; Leukemia ; Leukocytes ; Leukopenia ; Mass spectrometry ; Medicine ; Medicine & Public Health ; Mercaptopurine - blood ; Mercaptopurine - pharmacokinetics ; Mercaptopurine - therapeutic use ; Meta-analysis ; Metabolism ; Metabolites ; Minority & ethnic groups ; Nudix Hydrolases ; Pharmacology/Toxicology ; Pharmacotherapy ; Pyrophosphatases - genetics ; Pyrophosphatases - metabolism ; Scientific imaging ; Systematic Review ; Therapeutic drug monitoring ; Thioguanine - pharmacokinetics ; Thionucleotides - blood</subject><ispartof>Clinical pharmacokinetics, 2024-08, Vol.63 (8), p.1089-1109</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>Copyright Springer Nature B.V. Aug 2024</rights><rights>The Author(s) 2024 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c356t-162018fa539e2afeca7098a128db4ba7a6aab724e5a3e87b6e89872a838723a73</cites><orcidid>0000-0002-5302-9312</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s40262-024-01393-0$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s40262-024-01393-0$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39031224$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Bayoumy, Ahmed B.</creatorcontrib><creatorcontrib>Ansari, A. R.</creatorcontrib><creatorcontrib>Mulder, C. J. J.</creatorcontrib><creatorcontrib>Schmiegelow, K.</creatorcontrib><creatorcontrib>Florin, Timothy</creatorcontrib><creatorcontrib>De Boer, N. K. H.</creatorcontrib><title>Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy</title><title>Clinical pharmacokinetics</title><addtitle>Clin Pharmacokinet</addtitle><addtitle>Clin Pharmacokinet</addtitle><description>Background and Objective
Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography–tandem mass spectrometry (LC–MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants.
Methods
A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword “DNA-TG” with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher’s
z
-transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle–Ottowa quality assessment scale.
Results
In this systematic review, 21 studies were included that measured DNA-TG levels in white blood cells for either patients with ALL (
n
= 16) or IBD (
n
= 5). In our meta-analysis, the overall mean difference between patients with leukopenia (ALL + IBD) versus no leukopenia was 134.15 fmol TG/µg DNA [95% confidence interval (CI) (83.78–184.35),
P
< 0.00001; heterogeneity chi squared of 5.62,
I
2
of 47%]. There was a significant difference in DNA-TG levels for patients with IBD with and without leukopenia [161.76 fmol TG/µg DNA; 95% CI (126.23–197.29),
P
< 0.00001; heterogeneity chi squared of 0.20,
I
2
of 0%]. No significant difference was found in DNA-TG level between patients with ALL with or without leukopenia (57.71 fmol TG/µg DNA [95% CI (− 22.93 to 138.35),
P
< 0.80]). DNA-TG monitoring was found to be a promising method for predicting relapse rates in patients with ALL, and DNA-TG levels are likely a better predictor for leukopenia in patients with IBD than RBC 6-TGNs levels. DNA-TG levels have been shown to correlate with various gene variants (TPMT, NUDT15, ITPA, and MRP4) in various studies, points to its potential as a more informative marker for guiding thiopurine therapy across diverse genetic backgrounds.
Conclusions
This systematic review strongly supports the further investigation of DNA-TG as a marker for monitoring thiopurine therapy. Its correlation with treatment outcomes, such as relapse-free survival in ALL and the risk of leukopenia in IBD, underscores its role in enhancing personalized treatment approaches. DNA-TG effectively identifies NUDT15 variants and predicts late leukopenia in patients with IBD, regardless of their NUDT15 variant status. The recommended threshold for late leukopenia prediction in patients with IBD with DNA-TG is suggested to be between 320 and 340 fmol/µg DNA. More clinical research on DNA-TG implementation is mandatory to improve patient care and to improve inclusivity in thiopurine treatment.
Graphical Abstract</description><subject>Azathioprine - pharmacokinetics</subject><subject>Azathioprine - therapeutic use</subject><subject>Biomarkers - blood</subject><subject>Blood</subject><subject>Chromatography</subject><subject>DNA - genetics</subject><subject>Drug Monitoring - methods</subject><subject>Guanine Nucleotides - blood</subject><subject>Hispanic people</subject><subject>Humans</subject><subject>Inflammatory bowel disease</subject><subject>Internal Medicine</subject><subject>Investigations</subject><subject>Leukemia</subject><subject>Leukocytes</subject><subject>Leukopenia</subject><subject>Mass spectrometry</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mercaptopurine - blood</subject><subject>Mercaptopurine - pharmacokinetics</subject><subject>Mercaptopurine - therapeutic use</subject><subject>Meta-analysis</subject><subject>Metabolism</subject><subject>Metabolites</subject><subject>Minority & ethnic groups</subject><subject>Nudix Hydrolases</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacotherapy</subject><subject>Pyrophosphatases - genetics</subject><subject>Pyrophosphatases - metabolism</subject><subject>Scientific imaging</subject><subject>Systematic Review</subject><subject>Therapeutic drug monitoring</subject><subject>Thioguanine - pharmacokinetics</subject><subject>Thionucleotides - blood</subject><issn>0312-5963</issn><issn>1179-1926</issn><issn>1179-1926</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNp9ks1u1DAUhSMEokPhBVggS2zKIuCfJI7ZVEMLZaS2SFDW1k3mTuqSsYMdTzVv1UfE6ZTyJ7GxLZ3vHl_7nix7zuhrRql8EwrKK55TXuSUCSVy-iCbMSZVzhSvHmYzKhjPS1WJvexJCFeU0ppT-jjbE2qSeDHLbhbWug2Mxnbk4tK4IXpjMR3Rw4BxNC059rEjZ86a0SWte0vm5Ms2jLiGSf2MG4PXBOySnOEI-dxCvw0mEGfJ8fk8n0y7CHZyPY9tj240Swzk4FY8eUUgpGKysG0fg9kgeWfcGvw39MTYf1vaPs0eraAP-Oxu38--fnh_cfQxP_10sjian-atKKsxZxWnrF5BKRRyWGELkqoaGK-XTdGAhAqgkbzAEgTWsqmwVrXkUIu0CpBiPzvc-Q6xWeOyRTt66PXgTepuqx0Y_adizaXu3EYzJgqhZJkcDu4cvPseMYx6bUKLfQ8WXQxapGmoUpWSJvTlX-iViz79ZKLSqCvKS1kniu-o1rsQPK7uu2FUT4nQu0TolAh9mwg9Wb_4_R33JT8jkACxA8IwjRf9r7v_Y_sD3LXDpg</recordid><startdate>20240801</startdate><enddate>20240801</enddate><creator>Bayoumy, Ahmed B.</creator><creator>Ansari, A. R.</creator><creator>Mulder, C. J. J.</creator><creator>Schmiegelow, K.</creator><creator>Florin, Timothy</creator><creator>De Boer, N. K. H.</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>4T-</scope><scope>K9.</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-5302-9312</orcidid></search><sort><creationdate>20240801</creationdate><title>Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy</title><author>Bayoumy, Ahmed B. ; Ansari, A. R. ; Mulder, C. J. J. ; Schmiegelow, K. ; Florin, Timothy ; De Boer, N. K. H.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-162018fa539e2afeca7098a128db4ba7a6aab724e5a3e87b6e89872a838723a73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Azathioprine - pharmacokinetics</topic><topic>Azathioprine - therapeutic use</topic><topic>Biomarkers - blood</topic><topic>Blood</topic><topic>Chromatography</topic><topic>DNA - genetics</topic><topic>Drug Monitoring - methods</topic><topic>Guanine Nucleotides - blood</topic><topic>Hispanic people</topic><topic>Humans</topic><topic>Inflammatory bowel disease</topic><topic>Internal Medicine</topic><topic>Investigations</topic><topic>Leukemia</topic><topic>Leukocytes</topic><topic>Leukopenia</topic><topic>Mass spectrometry</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mercaptopurine - blood</topic><topic>Mercaptopurine - pharmacokinetics</topic><topic>Mercaptopurine - therapeutic use</topic><topic>Meta-analysis</topic><topic>Metabolism</topic><topic>Metabolites</topic><topic>Minority & ethnic groups</topic><topic>Nudix Hydrolases</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacotherapy</topic><topic>Pyrophosphatases - genetics</topic><topic>Pyrophosphatases - metabolism</topic><topic>Scientific imaging</topic><topic>Systematic Review</topic><topic>Therapeutic drug monitoring</topic><topic>Thioguanine - pharmacokinetics</topic><topic>Thionucleotides - blood</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Bayoumy, Ahmed B.</creatorcontrib><creatorcontrib>Ansari, A. R.</creatorcontrib><creatorcontrib>Mulder, C. J. J.</creatorcontrib><creatorcontrib>Schmiegelow, K.</creatorcontrib><creatorcontrib>Florin, Timothy</creatorcontrib><creatorcontrib>De Boer, N. K. H.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Docstoc</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Clinical pharmacokinetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bayoumy, Ahmed B.</au><au>Ansari, A. R.</au><au>Mulder, C. J. J.</au><au>Schmiegelow, K.</au><au>Florin, Timothy</au><au>De Boer, N. K. H.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy</atitle><jtitle>Clinical pharmacokinetics</jtitle><stitle>Clin Pharmacokinet</stitle><addtitle>Clin Pharmacokinet</addtitle><date>2024-08-01</date><risdate>2024</risdate><volume>63</volume><issue>8</issue><spage>1089</spage><epage>1109</epage><pages>1089-1109</pages><issn>0312-5963</issn><issn>1179-1926</issn><eissn>1179-1926</eissn><abstract>Background and Objective
Thioguanine (TG), azathioprine (AZA), and mercaptopurine (MP) are thiopurine prodrugs commonly used to treat diseases, such as leukemia and inflammatory bowel disease (IBD). 6-thioguanine nucleotides (6-TGNs) have been commonly used for monitoring treatment. High levels of 6-TGNs in red blood cells (RBCs) have been associated with leukopenia, the cutoff levels that predict this side effect remain uncertain. Thiopurines are metabolized and incorporated into leukocyte DNA. Measuring levels of DNA-incorporated thioguanine (DNA-TG) may be a more suitable method for predicting clinical response and toxicities such as leukopenia. Unfortunately, most methodologies to assay 6-TGNs are unable to identify the impact of NUDT15 variants, effecting mostly ethnic populations (e.g., Chinese, Indian, Malay, Japanese, and Hispanics). DNA-TG tackles this problem by directly measuring thioguanine in the DNA, which can be influenced by both TPMT and NUDT15 variants. While RBC 6-TGN concentrations have traditionally been used to optimize thiopurine therapy due to their ease and affordability of measurement, recent developments in liquid chromatography–tandem mass spectrometry (LC–MS/MS) techniques have made measuring DNA-TG concentrations in lymphocytes accurate, reproducible, and affordable. The objective of this systematic review was to assess the current evidence of DNA-TG levels as marker for thiopurine therapy, especially with regards to NUDT15 variants.
Methods
A systematic review and meta-analysis were performed on the current evidence for DNA-TG as a marker for monitoring thiopurine therapy, including methods for measurement and the illustrative relationship between DNA-TG and various gene variants (such as TPMT, NUDT15, ITPA, NT5C2, and MRP4). PubMed and Embase were systematically searched up to April 2024 for published studies, using the keyword “DNA-TG” with MeSH terms and synonyms. The electronic search strategy was augmented by a manual examination of references cited in articles, recent reviews, editorials, and meta-analyses. A meta-analysis was performed using R studio 4.1.3. to investigate the difference between the coefficients (Fisher’s
z
-transformed correlation coefficient) of DNA-TG and 6-TGNs levels. A meta-analysis was performed using RevMan version 5.4 to investigate the difference in DNA-TG levels between patients with or without leukopenia using randomized effect size model. The risk of bias was assessed using the Newcastle–Ottowa quality assessment scale.
Results
In this systematic review, 21 studies were included that measured DNA-TG levels in white blood cells for either patients with ALL (
n
= 16) or IBD (
n
= 5). In our meta-analysis, the overall mean difference between patients with leukopenia (ALL + IBD) versus no leukopenia was 134.15 fmol TG/µg DNA [95% confidence interval (CI) (83.78–184.35),
P
< 0.00001; heterogeneity chi squared of 5.62,
I
2
of 47%]. There was a significant difference in DNA-TG levels for patients with IBD with and without leukopenia [161.76 fmol TG/µg DNA; 95% CI (126.23–197.29),
P
< 0.00001; heterogeneity chi squared of 0.20,
I
2
of 0%]. No significant difference was found in DNA-TG level between patients with ALL with or without leukopenia (57.71 fmol TG/µg DNA [95% CI (− 22.93 to 138.35),
P
< 0.80]). DNA-TG monitoring was found to be a promising method for predicting relapse rates in patients with ALL, and DNA-TG levels are likely a better predictor for leukopenia in patients with IBD than RBC 6-TGNs levels. DNA-TG levels have been shown to correlate with various gene variants (TPMT, NUDT15, ITPA, and MRP4) in various studies, points to its potential as a more informative marker for guiding thiopurine therapy across diverse genetic backgrounds.
Conclusions
This systematic review strongly supports the further investigation of DNA-TG as a marker for monitoring thiopurine therapy. Its correlation with treatment outcomes, such as relapse-free survival in ALL and the risk of leukopenia in IBD, underscores its role in enhancing personalized treatment approaches. DNA-TG effectively identifies NUDT15 variants and predicts late leukopenia in patients with IBD, regardless of their NUDT15 variant status. The recommended threshold for late leukopenia prediction in patients with IBD with DNA-TG is suggested to be between 320 and 340 fmol/µg DNA. More clinical research on DNA-TG implementation is mandatory to improve patient care and to improve inclusivity in thiopurine treatment.
Graphical Abstract</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>39031224</pmid><doi>10.1007/s40262-024-01393-0</doi><tpages>21</tpages><orcidid>https://orcid.org/0000-0002-5302-9312</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0312-5963 |
| ispartof | Clinical pharmacokinetics, 2024-08, Vol.63 (8), p.1089-1109 |
| issn | 0312-5963 1179-1926 1179-1926 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11343975 |
| source | MEDLINE; SpringerLink Journals - AutoHoldings |
| subjects | Azathioprine - pharmacokinetics Azathioprine - therapeutic use Biomarkers - blood Blood Chromatography DNA - genetics Drug Monitoring - methods Guanine Nucleotides - blood Hispanic people Humans Inflammatory bowel disease Internal Medicine Investigations Leukemia Leukocytes Leukopenia Mass spectrometry Medicine Medicine & Public Health Mercaptopurine - blood Mercaptopurine - pharmacokinetics Mercaptopurine - therapeutic use Meta-analysis Metabolism Metabolites Minority & ethnic groups Nudix Hydrolases Pharmacology/Toxicology Pharmacotherapy Pyrophosphatases - genetics Pyrophosphatases - metabolism Scientific imaging Systematic Review Therapeutic drug monitoring Thioguanine - pharmacokinetics Thionucleotides - blood |
| title | Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-08T00%3A46%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Innovating%20Thiopurine%20Therapeutic%20Drug%20Monitoring:%20A%20Systematic%20Review%20and%20Meta-Analysis%20on%20DNA-Thioguanine%20Nucleotides%20(DNA-TG)%20as%20an%20Inclusive%20Biomarker%20in%20Thiopurine%20Therapy&rft.jtitle=Clinical%20pharmacokinetics&rft.au=Bayoumy,%20Ahmed%20B.&rft.date=2024-08-01&rft.volume=63&rft.issue=8&rft.spage=1089&rft.epage=1109&rft.pages=1089-1109&rft.issn=0312-5963&rft.eissn=1179-1926&rft_id=info:doi/10.1007/s40262-024-01393-0&rft_dat=%3Cproquest_pubme%3E3100602578%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3100602578&rft_id=info:pmid/39031224&rfr_iscdi=true |