Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial
Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy. This open-la...
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| Veröffentlicht in: | The lancet oncology 2021-11, Vol.22 (11), p.1597-1608 |
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| creator | DiNardo, Courtney D Schuh, Andre C Stein, Eytan M Montesinos, Pau Wei, Andrew H de Botton, Stéphane Zeidan, Amer M Fathi, Amir T Kantarjian, Hagop M Bennett, John M Frattini, Mark G Martin-Regueira, Patricia Lersch, Frederik Gong, Jing Hasan, Maroof Vyas, Paresh Döhner, Hartmut |
| description | Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy.
This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea). Eligible patients were aged 18 years or older and had newly diagnosed, mutant-IDH2 acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. In the phase 1b dose-finding portion, patients received oral enasidenib 100 mg/day or 200 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m2 per day for 7 days of each cycle. In phase 2, patients were randomly assigned (2:1) via an interactive web response system to enasidenib plus azacitidine or azacitidine-only, stratified by acute myeloid leukaemia subtype (de novo or secondary). The primary endpoint in the phase 2 portion was the overall response rate in the intention-to-treat population at a prespecified interim analysis (Aug 20, 2019) when all patients had at least 1 year of follow-up. Safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT02677922, and is ongoing.
Between June 3, 2016, and Aug 2, 2018, 322 patients were screened and 107 patients with mutant-IDH2 acute myeloid leukaemia were enrolled. At data cutoff for the interim analysis, 24 patients (including two from the phase 1 portion) were still receiving their assigned treatment. Six patients were enrolled in the phase 1b dose-finding portion of the trial and received enasidenib 100 mg (n=3) or 200 mg (n=3) in combination with azacitidine. No dose-limiting toxicities occurred and the enasidenib 100 mg dose was selected for phase 2. In phase 2, 101 patients were randomly assigned to enasidenib plus azacitidine (n=68) or azacitidine only (n=33). Median age was 75 years (IQR 71–78). 50 (74%; 95% CI 61–84) patients in the enasidenib plus azacitidine combination group and 12 (36%; 20–55) patients in the azacitidine monotherapy group achieved an overall response (odds ratio 4·9 [95% CI 2·0–11·9]; p=0·0003). Common treatment-related grade 3 or 4 adverse events with enasidenib plus azacitidine were thrombocytopenia (25 [37%] of 68 vs six [ |
| doi_str_mv | 10.1016/S1470-2045(21)00494-0 |
| format | Article |
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This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea). Eligible patients were aged 18 years or older and had newly diagnosed, mutant-IDH2 acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. In the phase 1b dose-finding portion, patients received oral enasidenib 100 mg/day or 200 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m2 per day for 7 days of each cycle. In phase 2, patients were randomly assigned (2:1) via an interactive web response system to enasidenib plus azacitidine or azacitidine-only, stratified by acute myeloid leukaemia subtype (de novo or secondary). The primary endpoint in the phase 2 portion was the overall response rate in the intention-to-treat population at a prespecified interim analysis (Aug 20, 2019) when all patients had at least 1 year of follow-up. Safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT02677922, and is ongoing.
Between June 3, 2016, and Aug 2, 2018, 322 patients were screened and 107 patients with mutant-IDH2 acute myeloid leukaemia were enrolled. At data cutoff for the interim analysis, 24 patients (including two from the phase 1 portion) were still receiving their assigned treatment. Six patients were enrolled in the phase 1b dose-finding portion of the trial and received enasidenib 100 mg (n=3) or 200 mg (n=3) in combination with azacitidine. No dose-limiting toxicities occurred and the enasidenib 100 mg dose was selected for phase 2. In phase 2, 101 patients were randomly assigned to enasidenib plus azacitidine (n=68) or azacitidine only (n=33). Median age was 75 years (IQR 71–78). 50 (74%; 95% CI 61–84) patients in the enasidenib plus azacitidine combination group and 12 (36%; 20–55) patients in the azacitidine monotherapy group achieved an overall response (odds ratio 4·9 [95% CI 2·0–11·9]; p=0·0003). Common treatment-related grade 3 or 4 adverse events with enasidenib plus azacitidine were thrombocytopenia (25 [37%] of 68 vs six [19%] of 32 in the azacitidine-only group), neutropenia (25 [37%] vs eight [25%]), anaemia (13 [19%] vs seven [22%]), and febrile neutropenia (11 [16%] vs five [16%]). Serious treatment-related adverse events were reported in 29 (43%) patients in the combination group and 14 (44%) patients in the azacitidine-only group; serious treatment-related adverse events occurring in more than 5% of patients in either group were febrile neutropenia (nine [13%] in the combination group vs five [16%] in the azacitidine-only group), differentiation syndrome (seven [10%] vs none), and pneumonia (three [4%] vs two [6%]). No treatment-related deaths were reported.
Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia.
Bristol Myers Squibb.</description><identifier>ISSN: 1470-2045</identifier><identifier>EISSN: 1474-5488</identifier><identifier>DOI: 10.1016/S1470-2045(21)00494-0</identifier><identifier>PMID: 34672961</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Acute myeloid leukemia ; Adverse events ; Aged ; Aminopyridines - therapeutic use ; Antimetabolites, Antineoplastic - therapeutic use ; Antineoplastic Combined Chemotherapy Protocols - therapeutic use ; Apoptosis ; Azacitidine - therapeutic use ; Bone marrow ; Chemotherapy ; Dehydrogenases ; Drug Administration Schedule ; Drug-Related Side Effects and Adverse Reactions - diagnosis ; Drug-Related Side Effects and Adverse Reactions - epidemiology ; Enzymes ; Female ; Hematology ; Hemoglobin ; Humans ; Isocitrate dehydrogenase ; Isocitrate Dehydrogenase - antagonists & inhibitors ; Isocitrate Dehydrogenase - genetics ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - genetics ; Male ; Mutants ; Mutation ; Neutropenia ; Patients ; Progression-Free Survival ; Proteins ; Random Allocation ; Response rates ; Thrombocytopenia ; Treatment Outcome ; Triazines - therapeutic use</subject><ispartof>The lancet oncology, 2021-11, Vol.22 (11), p.1597-1608</ispartof><rights>2021 Elsevier Ltd</rights><rights>Copyright © 2021 Elsevier Ltd. All rights reserved.</rights><rights>2021. Elsevier Ltd</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c459t-f42079a2ac47b45559961e51ecdf8504f8c8f1c85e723e51e300b677873d51b43</citedby><cites>FETCH-LOGICAL-c459t-f42079a2ac47b45559961e51ecdf8504f8c8f1c85e723e51e300b677873d51b43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.proquest.com/docview/2591172134?pq-origsite=primo$$EHTML$$P50$$Gproquest$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976,64364,64368,72218</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34672961$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>DiNardo, Courtney D</creatorcontrib><creatorcontrib>Schuh, Andre C</creatorcontrib><creatorcontrib>Stein, Eytan M</creatorcontrib><creatorcontrib>Montesinos, Pau</creatorcontrib><creatorcontrib>Wei, Andrew H</creatorcontrib><creatorcontrib>de Botton, Stéphane</creatorcontrib><creatorcontrib>Zeidan, Amer M</creatorcontrib><creatorcontrib>Fathi, Amir T</creatorcontrib><creatorcontrib>Kantarjian, Hagop M</creatorcontrib><creatorcontrib>Bennett, John M</creatorcontrib><creatorcontrib>Frattini, Mark G</creatorcontrib><creatorcontrib>Martin-Regueira, Patricia</creatorcontrib><creatorcontrib>Lersch, Frederik</creatorcontrib><creatorcontrib>Gong, Jing</creatorcontrib><creatorcontrib>Hasan, Maroof</creatorcontrib><creatorcontrib>Vyas, Paresh</creatorcontrib><creatorcontrib>Döhner, Hartmut</creatorcontrib><title>Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial</title><title>The lancet oncology</title><addtitle>Lancet Oncol</addtitle><description>Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy.
This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea). Eligible patients were aged 18 years or older and had newly diagnosed, mutant-IDH2 acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. In the phase 1b dose-finding portion, patients received oral enasidenib 100 mg/day or 200 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m2 per day for 7 days of each cycle. In phase 2, patients were randomly assigned (2:1) via an interactive web response system to enasidenib plus azacitidine or azacitidine-only, stratified by acute myeloid leukaemia subtype (de novo or secondary). The primary endpoint in the phase 2 portion was the overall response rate in the intention-to-treat population at a prespecified interim analysis (Aug 20, 2019) when all patients had at least 1 year of follow-up. Safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT02677922, and is ongoing.
Between June 3, 2016, and Aug 2, 2018, 322 patients were screened and 107 patients with mutant-IDH2 acute myeloid leukaemia were enrolled. At data cutoff for the interim analysis, 24 patients (including two from the phase 1 portion) were still receiving their assigned treatment. Six patients were enrolled in the phase 1b dose-finding portion of the trial and received enasidenib 100 mg (n=3) or 200 mg (n=3) in combination with azacitidine. No dose-limiting toxicities occurred and the enasidenib 100 mg dose was selected for phase 2. In phase 2, 101 patients were randomly assigned to enasidenib plus azacitidine (n=68) or azacitidine only (n=33). Median age was 75 years (IQR 71–78). 50 (74%; 95% CI 61–84) patients in the enasidenib plus azacitidine combination group and 12 (36%; 20–55) patients in the azacitidine monotherapy group achieved an overall response (odds ratio 4·9 [95% CI 2·0–11·9]; p=0·0003). Common treatment-related grade 3 or 4 adverse events with enasidenib plus azacitidine were thrombocytopenia (25 [37%] of 68 vs six [19%] of 32 in the azacitidine-only group), neutropenia (25 [37%] vs eight [25%]), anaemia (13 [19%] vs seven [22%]), and febrile neutropenia (11 [16%] vs five [16%]). Serious treatment-related adverse events were reported in 29 (43%) patients in the combination group and 14 (44%) patients in the azacitidine-only group; serious treatment-related adverse events occurring in more than 5% of patients in either group were febrile neutropenia (nine [13%] in the combination group vs five [16%] in the azacitidine-only group), differentiation syndrome (seven [10%] vs none), and pneumonia (three [4%] vs two [6%]). No treatment-related deaths were reported.
Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia.
Bristol Myers Squibb.</description><subject>Acute myeloid leukemia</subject><subject>Adverse events</subject><subject>Aged</subject><subject>Aminopyridines - therapeutic use</subject><subject>Antimetabolites, Antineoplastic - therapeutic use</subject><subject>Antineoplastic Combined Chemotherapy Protocols - therapeutic use</subject><subject>Apoptosis</subject><subject>Azacitidine - therapeutic use</subject><subject>Bone marrow</subject><subject>Chemotherapy</subject><subject>Dehydrogenases</subject><subject>Drug Administration Schedule</subject><subject>Drug-Related Side Effects and Adverse Reactions - diagnosis</subject><subject>Drug-Related Side Effects and Adverse Reactions - epidemiology</subject><subject>Enzymes</subject><subject>Female</subject><subject>Hematology</subject><subject>Hemoglobin</subject><subject>Humans</subject><subject>Isocitrate dehydrogenase</subject><subject>Isocitrate Dehydrogenase - antagonists & inhibitors</subject><subject>Isocitrate Dehydrogenase - genetics</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Male</subject><subject>Mutants</subject><subject>Mutation</subject><subject>Neutropenia</subject><subject>Patients</subject><subject>Progression-Free Survival</subject><subject>Proteins</subject><subject>Random Allocation</subject><subject>Response rates</subject><subject>Thrombocytopenia</subject><subject>Treatment Outcome</subject><subject>Triazines - therapeutic use</subject><issn>1470-2045</issn><issn>1474-5488</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><recordid>eNqFkcFu1DAQhiMEoqXwCKCRuLRSDbZjrxMuaFVKW2kRB-BsOfakdUmcYDutlqfj0chuCgcuXMbW73_-0fgripeMvmGUrd5-YUJRwqmQx5ydUCpqQeij4nCWBZGiqh7v74vloHiW0i2lTDEqnxYHpVgpXq_YYfHrPJjkHQbfwNhNCcxPY332zgeEO4zpH8l0w1x9gNFkjyEnuPf5BgLed1tw3lyHIaE7hX7KJmRy9eGSg7FTRui32A3eQYfTd4O9N3C8vuCckfWnDaFUnrwDA8mH6w6Jif0pjDcmIbAGTHAQ5zL0fp-9PHDI0ZvuefGkNV3CFw_nUfHt4_nXs0uy-XxxdbbeECtknUkrOFW14cYK1QgpZT2vj5KhdW0lqWgrW7XMVhIVL3d6SWmzUqpSpZOsEeVR8XrJHePwY8KU9e0wxTCP1FzWjCnOyp1LLi4bh5QitnqMvjdxqxnVO256z03voGjO9J6bpnPfq4f0qenR_e36A2o2vF8MOO945zHqZOf_t-h8RJu1G_x_RvwGCPGmzA</recordid><startdate>202111</startdate><enddate>202111</enddate><creator>DiNardo, Courtney D</creator><creator>Schuh, Andre C</creator><creator>Stein, Eytan M</creator><creator>Montesinos, Pau</creator><creator>Wei, Andrew H</creator><creator>de Botton, Stéphane</creator><creator>Zeidan, Amer M</creator><creator>Fathi, Amir T</creator><creator>Kantarjian, Hagop M</creator><creator>Bennett, John M</creator><creator>Frattini, Mark G</creator><creator>Martin-Regueira, Patricia</creator><creator>Lersch, Frederik</creator><creator>Gong, Jing</creator><creator>Hasan, Maroof</creator><creator>Vyas, Paresh</creator><creator>Döhner, Hartmut</creator><general>Elsevier Ltd</general><general>Elsevier Limited</general><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>0TZ</scope><scope>3V.</scope><scope>7RV</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8C2</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope></search><sort><creationdate>202111</creationdate><title>Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial</title><author>DiNardo, Courtney D ; Schuh, Andre C ; Stein, Eytan M ; Montesinos, Pau ; Wei, Andrew H ; de Botton, Stéphane ; Zeidan, Amer M ; Fathi, Amir T ; Kantarjian, Hagop M ; Bennett, John M ; Frattini, Mark G ; Martin-Regueira, Patricia ; Lersch, Frederik ; Gong, Jing ; Hasan, Maroof ; Vyas, Paresh ; Döhner, Hartmut</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c459t-f42079a2ac47b45559961e51ecdf8504f8c8f1c85e723e51e300b677873d51b43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Acute myeloid leukemia</topic><topic>Adverse events</topic><topic>Aged</topic><topic>Aminopyridines - 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therapeutic use</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DiNardo, Courtney D</creatorcontrib><creatorcontrib>Schuh, Andre C</creatorcontrib><creatorcontrib>Stein, Eytan M</creatorcontrib><creatorcontrib>Montesinos, Pau</creatorcontrib><creatorcontrib>Wei, Andrew H</creatorcontrib><creatorcontrib>de Botton, Stéphane</creatorcontrib><creatorcontrib>Zeidan, Amer M</creatorcontrib><creatorcontrib>Fathi, Amir T</creatorcontrib><creatorcontrib>Kantarjian, Hagop M</creatorcontrib><creatorcontrib>Bennett, John M</creatorcontrib><creatorcontrib>Frattini, Mark G</creatorcontrib><creatorcontrib>Martin-Regueira, Patricia</creatorcontrib><creatorcontrib>Lersch, Frederik</creatorcontrib><creatorcontrib>Gong, Jing</creatorcontrib><creatorcontrib>Hasan, Maroof</creatorcontrib><creatorcontrib>Vyas, Paresh</creatorcontrib><creatorcontrib>Döhner, Hartmut</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>ProQuest Nursing and Allied Health Source</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>ProQuest Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>AUTh Library subscriptions: ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><jtitle>The lancet oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>DiNardo, Courtney D</au><au>Schuh, Andre C</au><au>Stein, Eytan M</au><au>Montesinos, Pau</au><au>Wei, Andrew H</au><au>de Botton, Stéphane</au><au>Zeidan, Amer M</au><au>Fathi, Amir T</au><au>Kantarjian, Hagop M</au><au>Bennett, John M</au><au>Frattini, Mark G</au><au>Martin-Regueira, Patricia</au><au>Lersch, Frederik</au><au>Gong, Jing</au><au>Hasan, Maroof</au><au>Vyas, Paresh</au><au>Döhner, Hartmut</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial</atitle><jtitle>The lancet oncology</jtitle><addtitle>Lancet Oncol</addtitle><date>2021-11</date><risdate>2021</risdate><volume>22</volume><issue>11</issue><spage>1597</spage><epage>1608</epage><pages>1597-1608</pages><issn>1470-2045</issn><eissn>1474-5488</eissn><abstract>Enasidenib is an oral inhibitor of mutant isocitrate dehydrogenase-2 (IDH2) proteins. We evaluated the safety and activity of enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia ineligible for intensive chemotherapy.
This open-label, phase 1b/2 trial was done at 43 clinical sites in 12 countries (the USA, Germany, Canada, the UK, France, Spain, Australia, Italy, the Netherlands, Portugal, Switzerland, and South Korea). Eligible patients were aged 18 years or older and had newly diagnosed, mutant-IDH2 acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0–2. In the phase 1b dose-finding portion, patients received oral enasidenib 100 mg/day or 200 mg/day in continuous 28-day cycles, plus subcutaneous azacitidine 75 mg/m2 per day for 7 days of each cycle. In phase 2, patients were randomly assigned (2:1) via an interactive web response system to enasidenib plus azacitidine or azacitidine-only, stratified by acute myeloid leukaemia subtype (de novo or secondary). The primary endpoint in the phase 2 portion was the overall response rate in the intention-to-treat population at a prespecified interim analysis (Aug 20, 2019) when all patients had at least 1 year of follow-up. Safety was assessed in all patients who received at least one dose of study drug. The trial is registered with ClinicalTrials.gov, NCT02677922, and is ongoing.
Between June 3, 2016, and Aug 2, 2018, 322 patients were screened and 107 patients with mutant-IDH2 acute myeloid leukaemia were enrolled. At data cutoff for the interim analysis, 24 patients (including two from the phase 1 portion) were still receiving their assigned treatment. Six patients were enrolled in the phase 1b dose-finding portion of the trial and received enasidenib 100 mg (n=3) or 200 mg (n=3) in combination with azacitidine. No dose-limiting toxicities occurred and the enasidenib 100 mg dose was selected for phase 2. In phase 2, 101 patients were randomly assigned to enasidenib plus azacitidine (n=68) or azacitidine only (n=33). Median age was 75 years (IQR 71–78). 50 (74%; 95% CI 61–84) patients in the enasidenib plus azacitidine combination group and 12 (36%; 20–55) patients in the azacitidine monotherapy group achieved an overall response (odds ratio 4·9 [95% CI 2·0–11·9]; p=0·0003). Common treatment-related grade 3 or 4 adverse events with enasidenib plus azacitidine were thrombocytopenia (25 [37%] of 68 vs six [19%] of 32 in the azacitidine-only group), neutropenia (25 [37%] vs eight [25%]), anaemia (13 [19%] vs seven [22%]), and febrile neutropenia (11 [16%] vs five [16%]). Serious treatment-related adverse events were reported in 29 (43%) patients in the combination group and 14 (44%) patients in the azacitidine-only group; serious treatment-related adverse events occurring in more than 5% of patients in either group were febrile neutropenia (nine [13%] in the combination group vs five [16%] in the azacitidine-only group), differentiation syndrome (seven [10%] vs none), and pneumonia (three [4%] vs two [6%]). No treatment-related deaths were reported.
Combination enasidenib plus azacitidine was well tolerated and significantly improved overall response rates compared with azacitidine monotherapy, suggesting that this regimen can improve outcomes for patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia.
Bristol Myers Squibb.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>34672961</pmid><doi>10.1016/S1470-2045(21)00494-0</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1470-2045 |
| ispartof | The lancet oncology, 2021-11, Vol.22 (11), p.1597-1608 |
| issn | 1470-2045 1474-5488 |
| language | eng |
| recordid | cdi_proquest_journals_2591172134 |
| source | MEDLINE; Elsevier ScienceDirect Journals; ProQuest Central |
| subjects | Acute myeloid leukemia Adverse events Aged Aminopyridines - therapeutic use Antimetabolites, Antineoplastic - therapeutic use Antineoplastic Combined Chemotherapy Protocols - therapeutic use Apoptosis Azacitidine - therapeutic use Bone marrow Chemotherapy Dehydrogenases Drug Administration Schedule Drug-Related Side Effects and Adverse Reactions - diagnosis Drug-Related Side Effects and Adverse Reactions - epidemiology Enzymes Female Hematology Hemoglobin Humans Isocitrate dehydrogenase Isocitrate Dehydrogenase - antagonists & inhibitors Isocitrate Dehydrogenase - genetics Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Male Mutants Mutation Neutropenia Patients Progression-Free Survival Proteins Random Allocation Response rates Thrombocytopenia Treatment Outcome Triazines - therapeutic use |
| title | Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial |
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