Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia
Purpose An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy. Methods The association between the plasma concentration, aft...
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| Veröffentlicht in: | Cancer chemotherapy and pharmacology 2024-08, Vol.94 (2), p.285-296 |
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| creator | Kobayashi, Takahiro Sato, Honami Miura, Masatomo Fukushi, Yayoi Kuroki, Wataru Ito, Fumiko Teshima, Kazuaki Watanabe, Atsushi Fujishima, Naohito Kobayashi, Isuzu Kameoka, Yoshihiro Takahashi, Naoto |
| description | Purpose
An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy.
Methods
The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML.
Results
Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (
P
= 0.01). Median duration of grade 3 neutropenia was 28 days (range 8–46 days). Area under the concentration–time curve (AUC
0–24
) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration ( |
| doi_str_mv | 10.1007/s00280-024-04673-5 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_3153793135</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3060375629</sourcerecordid><originalsourceid>FETCH-LOGICAL-c359t-3158bbd67120ae1d4180b788f8687d72588ba0bc26c806487226df87e97f4c073</originalsourceid><addsrcrecordid>eNqFkctu1TAQhi0EoocDL8ACWWLDJjC-JHaWqOKqSt3AOnLiSeuS2MF2Sg-PxFPiQ8pFLGBlyfrm_2f0EfKYwXMGoF4kAK6hAi4rkI0SVX2H7JgUvAItxV2yAyFlVSuQJ-RBSlcAIJkQ98mJ0Epz1cKOfDu_xog3S0hrRJoDvUaPOQyTuaEuUZNSGJzJaOkXly_pEsMU_AXayq7RZBc8DSP1uOYYFvTO0PLv_MWfMcZbar6awWVnnS8llxjNcqDO0_dmMR4T0qVkoc9pazHDmpHOB5yCs3TC9RPOzjwk90YzJXx0--7Jx9evPpy-rc7O37w7fXlWDaJucyVYrfveNopxMMisZBp6pfWoG62s4rXWvYF-4M2goZFacd7YUSts1SgHUGJPnm255djPK6bczS4NOE1l1bCmrhQI1Qom6v-j0IBQdcPbgj79C70Ka_TlkBIIAoqrom5P-EYNMaQUceyW6GYTDx2D7ii926R3RXr3Q3p33OLJbfTaz2h_jfy0XACxAWk5ysH4u_sfsd8BYZ66gQ</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3103003414</pqid></control><display><type>article</type><title>Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia</title><source>Springer Nature - Complete Springer Journals</source><creator>Kobayashi, Takahiro ; Sato, Honami ; Miura, Masatomo ; Fukushi, Yayoi ; Kuroki, Wataru ; Ito, Fumiko ; Teshima, Kazuaki ; Watanabe, Atsushi ; Fujishima, Naohito ; Kobayashi, Isuzu ; Kameoka, Yoshihiro ; Takahashi, Naoto</creator><creatorcontrib>Kobayashi, Takahiro ; Sato, Honami ; Miura, Masatomo ; Fukushi, Yayoi ; Kuroki, Wataru ; Ito, Fumiko ; Teshima, Kazuaki ; Watanabe, Atsushi ; Fujishima, Naohito ; Kobayashi, Isuzu ; Kameoka, Yoshihiro ; Takahashi, Naoto</creatorcontrib><description>Purpose
An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy.
Methods
The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML.
Results
Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (
P
= 0.01). Median duration of grade 3 neutropenia was 28 days (range 8–46 days). Area under the concentration–time curve (AUC
0–24
) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (
P
= 0.03); multivariate analysis revealed that a higher AUC
0–24
was a significant predictor of a longer duration of neutropenia (odds ratio 54.3,
P
= 0.007).
Conclusion
Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.</description><identifier>ISSN: 0344-5704</identifier><identifier>ISSN: 1432-0843</identifier><identifier>EISSN: 1432-0843</identifier><identifier>DOI: 10.1007/s00280-024-04673-5</identifier><identifier>PMID: 38782790</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Acute myeloid leukemia ; Cancer Research ; drugs ; Hematology ; Leukemia ; Medicine ; Medicine & Public Health ; Multivariate analysis ; myeloid leukemia ; Neutropenia ; observational studies ; odds ratio ; Oncology ; Original Article ; Pharmacokinetics ; Pharmacology/Toxicology ; Pharmacovigilance ; Remission ; Remission (Medicine) ; therapeutics</subject><ispartof>Cancer chemotherapy and pharmacology, 2024-08, Vol.94 (2), p.285-296</ispartof><rights>The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c359t-3158bbd67120ae1d4180b788f8687d72588ba0bc26c806487226df87e97f4c073</cites><orcidid>0000-0002-8058-7301</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/s00280-024-04673-5$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00280-024-04673-5$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,778,782,27907,27908,41471,42540,51302</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38782790$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kobayashi, Takahiro</creatorcontrib><creatorcontrib>Sato, Honami</creatorcontrib><creatorcontrib>Miura, Masatomo</creatorcontrib><creatorcontrib>Fukushi, Yayoi</creatorcontrib><creatorcontrib>Kuroki, Wataru</creatorcontrib><creatorcontrib>Ito, Fumiko</creatorcontrib><creatorcontrib>Teshima, Kazuaki</creatorcontrib><creatorcontrib>Watanabe, Atsushi</creatorcontrib><creatorcontrib>Fujishima, Naohito</creatorcontrib><creatorcontrib>Kobayashi, Isuzu</creatorcontrib><creatorcontrib>Kameoka, Yoshihiro</creatorcontrib><creatorcontrib>Takahashi, Naoto</creatorcontrib><title>Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia</title><title>Cancer chemotherapy and pharmacology</title><addtitle>Cancer Chemother Pharmacol</addtitle><addtitle>Cancer Chemother Pharmacol</addtitle><description>Purpose
An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy.
Methods
The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML.
Results
Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (
P
= 0.01). Median duration of grade 3 neutropenia was 28 days (range 8–46 days). Area under the concentration–time curve (AUC
0–24
) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (
P
= 0.03); multivariate analysis revealed that a higher AUC
0–24
was a significant predictor of a longer duration of neutropenia (odds ratio 54.3,
P
= 0.007).
Conclusion
Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.</description><subject>Acute myeloid leukemia</subject><subject>Cancer Research</subject><subject>drugs</subject><subject>Hematology</subject><subject>Leukemia</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Multivariate analysis</subject><subject>myeloid leukemia</subject><subject>Neutropenia</subject><subject>observational studies</subject><subject>odds ratio</subject><subject>Oncology</subject><subject>Original Article</subject><subject>Pharmacokinetics</subject><subject>Pharmacology/Toxicology</subject><subject>Pharmacovigilance</subject><subject>Remission</subject><subject>Remission (Medicine)</subject><subject>therapeutics</subject><issn>0344-5704</issn><issn>1432-0843</issn><issn>1432-0843</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNqFkctu1TAQhi0EoocDL8ACWWLDJjC-JHaWqOKqSt3AOnLiSeuS2MF2Sg-PxFPiQ8pFLGBlyfrm_2f0EfKYwXMGoF4kAK6hAi4rkI0SVX2H7JgUvAItxV2yAyFlVSuQJ-RBSlcAIJkQ98mJ0Epz1cKOfDu_xog3S0hrRJoDvUaPOQyTuaEuUZNSGJzJaOkXly_pEsMU_AXayq7RZBc8DSP1uOYYFvTO0PLv_MWfMcZbar6awWVnnS8llxjNcqDO0_dmMR4T0qVkoc9pazHDmpHOB5yCs3TC9RPOzjwk90YzJXx0--7Jx9evPpy-rc7O37w7fXlWDaJucyVYrfveNopxMMisZBp6pfWoG62s4rXWvYF-4M2goZFacd7YUSts1SgHUGJPnm255djPK6bczS4NOE1l1bCmrhQI1Qom6v-j0IBQdcPbgj79C70Ka_TlkBIIAoqrom5P-EYNMaQUceyW6GYTDx2D7ii926R3RXr3Q3p33OLJbfTaz2h_jfy0XACxAWk5ysH4u_sfsd8BYZ66gQ</recordid><startdate>20240801</startdate><enddate>20240801</enddate><creator>Kobayashi, Takahiro</creator><creator>Sato, Honami</creator><creator>Miura, Masatomo</creator><creator>Fukushi, Yayoi</creator><creator>Kuroki, Wataru</creator><creator>Ito, Fumiko</creator><creator>Teshima, Kazuaki</creator><creator>Watanabe, Atsushi</creator><creator>Fujishima, Naohito</creator><creator>Kobayashi, Isuzu</creator><creator>Kameoka, Yoshihiro</creator><creator>Takahashi, Naoto</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><orcidid>https://orcid.org/0000-0002-8058-7301</orcidid></search><sort><creationdate>20240801</creationdate><title>Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia</title><author>Kobayashi, Takahiro ; Sato, Honami ; Miura, Masatomo ; Fukushi, Yayoi ; Kuroki, Wataru ; Ito, Fumiko ; Teshima, Kazuaki ; Watanabe, Atsushi ; Fujishima, Naohito ; Kobayashi, Isuzu ; Kameoka, Yoshihiro ; Takahashi, Naoto</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c359t-3158bbd67120ae1d4180b788f8687d72588ba0bc26c806487226df87e97f4c073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Acute myeloid leukemia</topic><topic>Cancer Research</topic><topic>drugs</topic><topic>Hematology</topic><topic>Leukemia</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Multivariate analysis</topic><topic>myeloid leukemia</topic><topic>Neutropenia</topic><topic>observational studies</topic><topic>odds ratio</topic><topic>Oncology</topic><topic>Original Article</topic><topic>Pharmacokinetics</topic><topic>Pharmacology/Toxicology</topic><topic>Pharmacovigilance</topic><topic>Remission</topic><topic>Remission (Medicine)</topic><topic>therapeutics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kobayashi, Takahiro</creatorcontrib><creatorcontrib>Sato, Honami</creatorcontrib><creatorcontrib>Miura, Masatomo</creatorcontrib><creatorcontrib>Fukushi, Yayoi</creatorcontrib><creatorcontrib>Kuroki, Wataru</creatorcontrib><creatorcontrib>Ito, Fumiko</creatorcontrib><creatorcontrib>Teshima, Kazuaki</creatorcontrib><creatorcontrib>Watanabe, Atsushi</creatorcontrib><creatorcontrib>Fujishima, Naohito</creatorcontrib><creatorcontrib>Kobayashi, Isuzu</creatorcontrib><creatorcontrib>Kameoka, Yoshihiro</creatorcontrib><creatorcontrib>Takahashi, Naoto</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><jtitle>Cancer chemotherapy and pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kobayashi, Takahiro</au><au>Sato, Honami</au><au>Miura, Masatomo</au><au>Fukushi, Yayoi</au><au>Kuroki, Wataru</au><au>Ito, Fumiko</au><au>Teshima, Kazuaki</au><au>Watanabe, Atsushi</au><au>Fujishima, Naohito</au><au>Kobayashi, Isuzu</au><au>Kameoka, Yoshihiro</au><au>Takahashi, Naoto</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia</atitle><jtitle>Cancer chemotherapy and pharmacology</jtitle><stitle>Cancer Chemother Pharmacol</stitle><addtitle>Cancer Chemother Pharmacol</addtitle><date>2024-08-01</date><risdate>2024</risdate><volume>94</volume><issue>2</issue><spage>285</spage><epage>296</epage><pages>285-296</pages><issn>0344-5704</issn><issn>1432-0843</issn><eissn>1432-0843</eissn><abstract>Purpose
An observational study was conducted to evaluate the pharmacokinetics of venetoclax and its impact on the efficacy and safety for Japanese patients with acute myeloid leukemia (AML) treated with venetoclax and azacitidine therapy.
Methods
The association between the plasma concentration, after the first cycle of azacitidine and venetoclax therapy, and the efficacy and safety was evaluated in 33 patients with untreated or relapsed/refractory AML.
Results
Full dose of venetoclax was administered to all patients. Venetoclax treatment was 28 day long in 82% of patients; the relative dose intensity of azacitidine was 82%. Trough concentration was significantly higher among patients with complete remission (CR) and CR with incomplete hematologic recovery (CRi) than those with the morphologic leukemia-free state and partial remission, and no response groups (
P
= 0.01). Median duration of grade 3 neutropenia was 28 days (range 8–46 days). Area under the concentration–time curve (AUC
0–24
) was significantly higher among patients with protracted grade 3 neutropenia (≥ 28 days) than those with a shorter duration (< 28 days) (
P
= 0.03); multivariate analysis revealed that a higher AUC
0–24
was a significant predictor of a longer duration of neutropenia (odds ratio 54.3,
P
= 0.007).
Conclusion
Plasma concentrations of venetoclax were variable in Japanese patients with AML. Higher plasma concentrations were associated with CR/CRi and protracted grade 3 neutropenia. Therefore, it is essential to adjust the duration of venetoclax administration based on individual pharmacokinetic data to limit total drug exposure, reduce severe neutropenia, and achieve higher efficacy.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>38782790</pmid><doi>10.1007/s00280-024-04673-5</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0002-8058-7301</orcidid></addata></record> |
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| source | Springer Nature - Complete Springer Journals |
| subjects | Acute myeloid leukemia Cancer Research drugs Hematology Leukemia Medicine Medicine & Public Health Multivariate analysis myeloid leukemia Neutropenia observational studies odds ratio Oncology Original Article Pharmacokinetics Pharmacology/Toxicology Pharmacovigilance Remission Remission (Medicine) therapeutics |
| title | Overexposure to venetoclax is associated with prolonged-duration of neutropenia during venetoclax and azacitidine therapy in Japanese patients with acute myeloid leukemia |
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