Analysis of Time to Complete Response after Defibrotide Initiation in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation
•We analyzed the time to complete response (CR) or discontinuation due to CR in 3 studies of post-hematopoietic stem cell transplantation hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS).•Complete response to defibrotide occurred beyond 21 days in >50% of patients.•Respons...
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| Veröffentlicht in: | Transplantation and cellular therapy 2021-01, Vol.27 (1), p.88.e1-88.e6 |
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| creator | Richardson, Paul G. Smith, Angela R. Kernan, Nancy A. Lehmann, Leslie Ryan, Robert J. Grupp, Stephan A. |
| description | •We analyzed the time to complete response (CR) or discontinuation due to CR in 3 studies of post-hematopoietic stem cell transplantation hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS).•Complete response to defibrotide occurred beyond 21 days in >50% of patients.•Response occurred after more than 28 days of defibrotide treatment in some patients.•The importance of continuing defibrotide until VOD/SOS resolution is highlighted.
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with defibrotide. The time to defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin |
| doi_str_mv | 10.1016/j.bbmt.2020.09.008 |
| format | Article |
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Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with defibrotide. The time to defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin <2 mg/dL with resolution of VOD/SOS-related MOD (renal and/or pulmonary dysfunction); the phase 2 study also required resolution of central nervous system dysfunction. In the T-IND, 390 patients discontinued treatment due to a CR and had sufficient data for analysis. The median time to discontinuation was 22 days (range, 2 to 64 days). Discontinuation due to CR occurred beyond 21 days in 235 patients (60%) and beyond 28 days in 57 patients (15%). The pooled phase 2 and 3 studies included 60 patients who achieved a CR, with a median time to CR of 24.5 days (range, 7 to 123 days). A CR was achieved beyond 21 days in 32 patients (53%) and beyond 28 days in 24 patients (40%). The Kaplan-Meier estimate of day +100 survival rate was substantially higher in patients who discontinued due to a CR compared with those who did not (92.5% versus 37.3%). Treatment-emergent adverse events occurred in 185 of 390 patients (47%) who discontinued due to a CR in the T-IND and in 55 of 60 patients (92%) who achieved a CR in the pooled phase 2 and 3 studies, and rates did not differ according to duration of treatment (≤21 days versus >21 days). Taken together, these results highlight the importance of continued defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.</description><identifier>ISSN: 2666-6367</identifier><identifier>ISSN: 2666-6375</identifier><identifier>EISSN: 2666-6367</identifier><identifier>DOI: 10.1016/j.bbmt.2020.09.008</identifier><identifier>PMID: 32950693</identifier><language>eng</language><publisher>Elsevier Inc</publisher><subject>Complete response ; Defibrotide ; Hematopoietic cell transplantation ; Veno-occlusive disease/sinusoidal obstruction syndrome</subject><ispartof>Transplantation and cellular therapy, 2021-01, Vol.27 (1), p.88.e1-88.e6</ispartof><rights>2020 American Society for Transplantation and Cellular Therapy</rights><rights>Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c455t-2098fcac5994b982628a18fbfa8c1baffb0f298ff49c808adbaa064e8cb07df03</citedby><cites>FETCH-LOGICAL-c455t-2098fcac5994b982628a18fbfa8c1baffb0f298ff49c808adbaa064e8cb07df03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32950693$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Richardson, Paul G.</creatorcontrib><creatorcontrib>Smith, Angela R.</creatorcontrib><creatorcontrib>Kernan, Nancy A.</creatorcontrib><creatorcontrib>Lehmann, Leslie</creatorcontrib><creatorcontrib>Ryan, Robert J.</creatorcontrib><creatorcontrib>Grupp, Stephan A.</creatorcontrib><title>Analysis of Time to Complete Response after Defibrotide Initiation in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation</title><title>Transplantation and cellular therapy</title><addtitle>Transplant Cell Ther</addtitle><description>•We analyzed the time to complete response (CR) or discontinuation due to CR in 3 studies of post-hematopoietic stem cell transplantation hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS).•Complete response to defibrotide occurred beyond 21 days in >50% of patients.•Response occurred after more than 28 days of defibrotide treatment in some patients.•The importance of continuing defibrotide until VOD/SOS resolution is highlighted.
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with defibrotide. The time to defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin <2 mg/dL with resolution of VOD/SOS-related MOD (renal and/or pulmonary dysfunction); the phase 2 study also required resolution of central nervous system dysfunction. In the T-IND, 390 patients discontinued treatment due to a CR and had sufficient data for analysis. The median time to discontinuation was 22 days (range, 2 to 64 days). Discontinuation due to CR occurred beyond 21 days in 235 patients (60%) and beyond 28 days in 57 patients (15%). The pooled phase 2 and 3 studies included 60 patients who achieved a CR, with a median time to CR of 24.5 days (range, 7 to 123 days). A CR was achieved beyond 21 days in 32 patients (53%) and beyond 28 days in 24 patients (40%). The Kaplan-Meier estimate of day +100 survival rate was substantially higher in patients who discontinued due to a CR compared with those who did not (92.5% versus 37.3%). Treatment-emergent adverse events occurred in 185 of 390 patients (47%) who discontinued due to a CR in the T-IND and in 55 of 60 patients (92%) who achieved a CR in the pooled phase 2 and 3 studies, and rates did not differ according to duration of treatment (≤21 days versus >21 days). Taken together, these results highlight the importance of continued defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.</description><subject>Complete response</subject><subject>Defibrotide</subject><subject>Hematopoietic cell transplantation</subject><subject>Veno-occlusive disease/sinusoidal obstruction syndrome</subject><issn>2666-6367</issn><issn>2666-6375</issn><issn>2666-6367</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kcFu1DAQhiMEolXpC3BAPnLZ7cRJXEdCSNUWupUqLaILV8t2xtSrxA62s2ifjZert9tW5cLJY_mf75_xXxTvS5iXULKzzVypIc0pUJhDOwfgr4pjyhibsYqdv35RHxWnMW4AgNYVlBW8LY4q2jbA2uq4-HvhZL-LNhJvyNoOSJInCz-MPSYk3zGO3kUk0iQM5BKNVcEn2yG5djZZmax3xDryLVfoUiR_bLojSxzzXZOf6PxspXU_RbtFcmkjyohnt9ZN0dtO9mSlYgqTfsDc7lwX_PBktsRBJj96i3vUAvuerIN0ceylSw_G74o3RvYRTx_Pk-LH1y_rxXJ2s7q6XlzczHTdNGlGoeVGS920ba1aThnlsuRGGcl1qaQxCgzNElO3mgOXnZISWI1cKzjvDFQnxecDd5zUgJ3OiwbZizHYQYad8NKKf1-cvRO__Fbwpm4b2mbAx0dA8L8njEkMNuq8kXTopyhoXdcMGFCepfQg1cHHGNA825Qg9sGLjdgHL_bBC2hFDj43fXg54HPLU8xZ8OkgwPxNW4tBRJ3z0tjZgDqJztv_8e8ByO3GfA</recordid><startdate>20210101</startdate><enddate>20210101</enddate><creator>Richardson, Paul G.</creator><creator>Smith, Angela R.</creator><creator>Kernan, Nancy A.</creator><creator>Lehmann, Leslie</creator><creator>Ryan, Robert J.</creator><creator>Grupp, Stephan A.</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20210101</creationdate><title>Analysis of Time to Complete Response after Defibrotide Initiation in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation</title><author>Richardson, Paul G. ; Smith, Angela R. ; Kernan, Nancy A. ; Lehmann, Leslie ; Ryan, Robert J. ; Grupp, Stephan A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c455t-2098fcac5994b982628a18fbfa8c1baffb0f298ff49c808adbaa064e8cb07df03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Complete response</topic><topic>Defibrotide</topic><topic>Hematopoietic cell transplantation</topic><topic>Veno-occlusive disease/sinusoidal obstruction syndrome</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Richardson, Paul G.</creatorcontrib><creatorcontrib>Smith, Angela R.</creatorcontrib><creatorcontrib>Kernan, Nancy A.</creatorcontrib><creatorcontrib>Lehmann, Leslie</creatorcontrib><creatorcontrib>Ryan, Robert J.</creatorcontrib><creatorcontrib>Grupp, Stephan A.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Transplantation and cellular therapy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Richardson, Paul G.</au><au>Smith, Angela R.</au><au>Kernan, Nancy A.</au><au>Lehmann, Leslie</au><au>Ryan, Robert J.</au><au>Grupp, Stephan A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Analysis of Time to Complete Response after Defibrotide Initiation in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation</atitle><jtitle>Transplantation and cellular therapy</jtitle><addtitle>Transplant Cell Ther</addtitle><date>2021-01-01</date><risdate>2021</risdate><volume>27</volume><issue>1</issue><spage>88.e1</spage><epage>88.e6</epage><pages>88.e1-88.e6</pages><issn>2666-6367</issn><issn>2666-6375</issn><eissn>2666-6367</eissn><abstract>•We analyzed the time to complete response (CR) or discontinuation due to CR in 3 studies of post-hematopoietic stem cell transplantation hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS).•Complete response to defibrotide occurred beyond 21 days in >50% of patients.•Response occurred after more than 28 days of defibrotide treatment in some patients.•The importance of continuing defibrotide until VOD/SOS resolution is highlighted.
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication that occurs after hematopoietic cell transplantation (HCT). The mortality associated with untreated VOD/SOS with multiorgan dysfunction (MOD) has been reported to be >80%. The recommended dose of defibrotide is 6.25 mg/kg every 6 hours, administered as a 2-hour i.v. infusion, for a minimum of 21 days or until resolution of VOD/SOS signs and symptoms. The objective of this analysis was to evaluate the time to complete response (CR) in patients with post-HCT VOD/SOS treated with defibrotide. The time to defibrotide discontinuation due to a CR served as a surrogate for time to CR in an expanded access study (T-IND; ClinicalTrials.gov NCT00628498; n = 1000), and was analyzed separately from the time to CR data pooled from a phase 2 randomized dose-finding study (NCT00003966; n = 74 patients who received 25 mg/kg/day) and a phase 3 historically controlled study (NCT00358501; n = 102). For all studies, a CR was defined as total serum bilirubin <2 mg/dL with resolution of VOD/SOS-related MOD (renal and/or pulmonary dysfunction); the phase 2 study also required resolution of central nervous system dysfunction. In the T-IND, 390 patients discontinued treatment due to a CR and had sufficient data for analysis. The median time to discontinuation was 22 days (range, 2 to 64 days). Discontinuation due to CR occurred beyond 21 days in 235 patients (60%) and beyond 28 days in 57 patients (15%). The pooled phase 2 and 3 studies included 60 patients who achieved a CR, with a median time to CR of 24.5 days (range, 7 to 123 days). A CR was achieved beyond 21 days in 32 patients (53%) and beyond 28 days in 24 patients (40%). The Kaplan-Meier estimate of day +100 survival rate was substantially higher in patients who discontinued due to a CR compared with those who did not (92.5% versus 37.3%). Treatment-emergent adverse events occurred in 185 of 390 patients (47%) who discontinued due to a CR in the T-IND and in 55 of 60 patients (92%) who achieved a CR in the pooled phase 2 and 3 studies, and rates did not differ according to duration of treatment (≤21 days versus >21 days). Taken together, these results highlight the importance of continued defibrotide therapy until resolution of VOD/SOS signs and symptoms, as currently indicated in the approved product labels, which may occur beyond the recommended minimum of 21 days.</abstract><pub>Elsevier Inc</pub><pmid>32950693</pmid><doi>10.1016/j.bbmt.2020.09.008</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Complete response Defibrotide Hematopoietic cell transplantation Veno-occlusive disease/sinusoidal obstruction syndrome |
| title | Analysis of Time to Complete Response after Defibrotide Initiation in Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation |
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