Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia
Identifieur interne : 008C48 ( Main/Exploration ); précédent : 008C47; suivant : 008C49Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia
Auteurs : Neil P. Shah [États-Unis, Corée du Sud, France, Brésil, Argentine, Mexique, Russie, Australie, Allemagne] ; Hagop M. Kantarjian ; Dong-Wook Kim ; Delphine Rea ; Pedro E. Dorlhiac-Llacer ; Jorge H. Milone ; Jorge Vela-Ojeda ; Richard T. Silver ; H. Jean Khoury ; Aude Charbonnier ; Nina Khoroshko ; Ronald L. Paquette ; Michael Deininger ; Robert H. Collins ; Irma Otero ; Timothy Hughes ; Eric Bleickardt ; Lewis Strauss ; Stephen Francis ; Andreas HochhausSource :
- Journal of clinical oncology [ 0732-183X ] ; 2008.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
Purpose Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported. Patients and Methods In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. Results With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41 % to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11 % of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P =.024) and grade 3 to 4 thrombocytopenia (22% v37%; P =.004), and fewer patients required dose interruption (51% v68%), reduction (30% v 55%), or discontinuation (16% v 23%). Conclusion Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.
Affiliations:
- Allemagne, Argentine, Australie, Brésil, Corée du Sud, France, Mexique, Russie, États-Unis
- Bade-Wurtemberg, Californie, District de Karlsruhe, District fédéral central, Provence-Alpes-Côte d'Azur, Région capitale de Séoul, Texas, État de São Paulo, Île-de-France
- Houston, Mannheim, Marseille, Moscou, Paris, San Francisco, São Paulo, Séoul
- Université de São Paulo
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Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</s1><s2>Mannheim</s2><s3>DEU</s3></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Mannheim</settlement></placeName></affiliation></author><author><name sortKey="Kantarjian, Hagop M" sort="Kantarjian, Hagop M" uniqKey="Kantarjian H" first="Hagop M." last="Kantarjian">Hagop M. Kantarjian</name></author><author><name sortKey="Kim, Dong Wook" sort="Kim, Dong Wook" uniqKey="Kim D" first="Dong-Wook" last="Kim">Dong-Wook Kim</name></author><author><name sortKey="Rea, Delphine" sort="Rea, Delphine" uniqKey="Rea D" first="Delphine" last="Rea">Delphine Rea</name></author><author><name sortKey="Dorlhiac Llacer, Pedro E" sort="Dorlhiac Llacer, Pedro E" uniqKey="Dorlhiac Llacer P" first="Pedro E." last="Dorlhiac-Llacer">Pedro E. 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Shah</name><affiliation wicri:level="3"><inist:fA14 i1="01"><s1>Division of Hematology/Oncology, University of California at San Francisco School of Medicine</s1><s2>San Francisco</s2><s3>USA</s3></inist:fA14><country>États-Unis</country><placeName><settlement type="city">San Francisco</settlement><region type="state">Californie</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="02"><s1>University of California at Los Angeles</s1><s2>Los Angeles, CA</s2><s3>USA</s3></inist:fA14><country>États-Unis</country><wicri:noRegion>University of California at Los Angeles</wicri:noRegion></affiliation><affiliation wicri:level="3"><inist:fA14 i1="03"><s1>Department of Leukemia, M.D Anderson Cancer Center</s1><s2>Houston</s2><s3>USA</s3></inist:fA14><country>États-Unis</country><placeName><settlement type="city">Houston</settlement><region type="state">Texas</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>University of Texas Southwestern Medical Center</s1><s2>Dallas, TX</s2><s3>USA</s3></inist:fA14><country>États-Unis</country><wicri:noRegion>University of Texas Southwestern Medical Center</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="05"><s1>Weill Medical College of Cornell University, New York Presbyterian Hospital</s1><s2>New York, NY</s2><s3>USA</s3></inist:fA14><country>États-Unis</country><wicri:noRegion>New York, NY</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="06"><s1>Emory University School of Medicine, Winship Cancer Institute</s1><s2>Atlanta, GA</s2><s3>USA</s3></inist:fA14><country>États-Unis</country><wicri:noRegion>Atlanta, GA</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="07"><s1>Oregon Health Science University, Portland, OR; Bristol-Myers Squibb Co</s1><s2>Wallingford, CT</s2><s3>USA</s3></inist:fA14><country>États-Unis</country><wicri:noRegion>Wallingford, CT</wicri:noRegion></affiliation><affiliation wicri:level="3"><inist:fA14 i1="08"><s1>Department of Internal Medicine, St Mary's Hospital, The Catholic University of Korea</s1><s2>Seoul</s2><s3>KOR</s3></inist:fA14><country>Corée du Sud</country><placeName><settlement type="city">Séoul</settlement><region type="capital">Région capitale de Séoul</region></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="09"><s1>Hopital Saint-Louis</s1><s2>Paris</s2><s3>FRA</s3></inist:fA14><country>France</country><placeName><region type="region">Île-de-France</region><region type="old region">Île-de-France</region><settlement type="city">Paris</settlement></placeName></affiliation><affiliation wicri:level="3"><inist:fA14 i1="10"><s1>Département d'Onco-hématologie, Institut Paoli Calmettes</s1><s2>Marseille</s2><s3>FRA</s3></inist:fA14><country>France</country><placeName><region type="region">Provence-Alpes-Côte d'Azur</region><region type="old region">Provence-Alpes-Côte d'Azur</region><settlement type="city">Marseille</settlement></placeName></affiliation><affiliation wicri:level="4"><inist:fA14 i1="11"><s1>Department of Hematology and Hemotherapy, Hospital das Clínicas, University of São Paulo</s1><s2>São Paulo</s2><s3>BRA</s3></inist:fA14><country>Brésil</country><placeName><settlement type="city">São Paulo</settlement><region type="state">État de São Paulo</region><settlement type="city">São Paulo</settlement></placeName><orgName type="university">Université de São Paulo</orgName></affiliation><affiliation><inist:fA14 i1="12"><s1>Institute de Trasplante de Medula Osea</s1><s3>INC</s3></inist:fA14><wicri:noCountry>INC</wicri:noCountry></affiliation><affiliation wicri:level="1"><inist:fA14 i1="13"><s1>Division of Hematology and Medical Oncology, Hospital Ramos Mejia</s1><s2>Buenos Aires</s2><s3>ARG</s3></inist:fA14><country>Argentine</country><wicri:noRegion>Buenos Aires</wicri:noRegion></affiliation><affiliation wicri:level="1"><inist:fA14 i1="14"><s1>National Medical Center, La Raza, IMSS</s1><s3>MEX</s3></inist:fA14><country>Mexique</country><wicri:noRegion>National Medical Center, La Raza, IMSS</wicri:noRegion></affiliation><affiliation wicri:level="3"><inist:fA14 i1="15"><s1>National Research Hematology Center</s1><s2>Moscow</s2><s3>RUS</s3></inist:fA14><country>Russie</country><placeName><settlement type="city">Moscou</settlement><region>District fédéral central</region></placeName></affiliation><affiliation wicri:level="1"><inist:fA14 i1="16"><s1>Division of Hematology, Institute of Medical and Veterinary Science</s1><s2>Adelaide</s2><s3>AUS</s3></inist:fA14><country>Australie</country><wicri:noRegion>Adelaide</wicri:noRegion></affiliation><affiliation wicri:level="3"><inist:fA14 i1="17"><s1>III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</s1><s2>Mannheim</s2><s3>DEU</s3></inist:fA14><country>Allemagne</country><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Karlsruhe</region><settlement type="city">Mannheim</settlement></placeName></affiliation></author><author><name sortKey="Kantarjian, Hagop M" sort="Kantarjian, Hagop M" uniqKey="Kantarjian H" first="Hagop M." last="Kantarjian">Hagop M. Kantarjian</name></author><author><name sortKey="Kim, Dong Wook" sort="Kim, Dong Wook" uniqKey="Kim D" first="Dong-Wook" last="Kim">Dong-Wook Kim</name></author><author><name sortKey="Rea, Delphine" sort="Rea, Delphine" uniqKey="Rea D" first="Delphine" last="Rea">Delphine Rea</name></author><author><name sortKey="Dorlhiac Llacer, Pedro E" sort="Dorlhiac Llacer, Pedro E" uniqKey="Dorlhiac Llacer P" first="Pedro E." last="Dorlhiac-Llacer">Pedro E. Dorlhiac-Llacer</name></author><author><name sortKey="Milone, Jorge H" sort="Milone, Jorge H" uniqKey="Milone J" first="Jorge H." last="Milone">Jorge H. Milone</name></author><author><name sortKey="Vela Ojeda, Jorge" sort="Vela Ojeda, Jorge" uniqKey="Vela Ojeda J" first="Jorge" last="Vela-Ojeda">Jorge Vela-Ojeda</name></author><author><name sortKey="Silver, Richard T" sort="Silver, Richard T" uniqKey="Silver R" first="Richard T." last="Silver">Richard T. Silver</name></author><author><name sortKey="Khoury, H Jean" sort="Khoury, H Jean" uniqKey="Khoury H" first="H. Jean" last="Khoury">H. Jean Khoury</name></author><author><name sortKey="Charbonnier, Aude" sort="Charbonnier, Aude" uniqKey="Charbonnier A" first="Aude" last="Charbonnier">Aude Charbonnier</name></author><author><name sortKey="Khoroshko, Nina" sort="Khoroshko, Nina" uniqKey="Khoroshko N" first="Nina" last="Khoroshko">Nina Khoroshko</name></author><author><name sortKey="Paquette, Ronald L" sort="Paquette, Ronald L" uniqKey="Paquette R" first="Ronald L." last="Paquette">Ronald L. Paquette</name></author><author><name sortKey="Deininger, Michael" sort="Deininger, Michael" uniqKey="Deininger M" first="Michael" last="Deininger">Michael Deininger</name></author><author><name sortKey="Collins, Robert H" sort="Collins, Robert H" uniqKey="Collins R" first="Robert H." last="Collins">Robert H. Collins</name></author><author><name sortKey="Otero, Irma" sort="Otero, Irma" uniqKey="Otero I" first="Irma" last="Otero">Irma Otero</name></author><author><name sortKey="Hughes, Timothy" sort="Hughes, Timothy" uniqKey="Hughes T" first="Timothy" last="Hughes">Timothy Hughes</name></author><author><name sortKey="Bleickardt, Eric" sort="Bleickardt, Eric" uniqKey="Bleickardt E" first="Eric" last="Bleickardt">Eric Bleickardt</name></author><author><name sortKey="Strauss, Lewis" sort="Strauss, Lewis" uniqKey="Strauss L" first="Lewis" last="Strauss">Lewis Strauss</name></author><author><name sortKey="Francis, Stephen" sort="Francis, Stephen" uniqKey="Francis S" first="Stephen" last="Francis">Stephen Francis</name></author><author><name sortKey="Hochhaus, Andreas" sort="Hochhaus, Andreas" uniqKey="Hochhaus A" first="Andreas" last="Hochhaus">Andreas Hochhaus</name></author></analytic><series><title level="j" type="main">Journal of clinical oncology</title><title level="j" type="abbreviated">J. clin. oncol.</title><idno type="ISSN">0732-183X</idno><imprint><date when="2008">2008</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of clinical oncology</title><title level="j" type="abbreviated">J. clin. oncol.</title><idno type="ISSN">0732-183X</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Antineoplastic agent</term><term>Cancerology</term><term>Chronic myelogenous leukemia</term><term>Daily dose</term><term>Dasatinib</term><term>Enzyme inhibitor</term><term>Imatinib</term><term>Protein-tyrosine kinase</term><term>Resistance</term><term>Targeting</term><term>Treatment efficiency</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Dasatinib</term><term>Ciblage</term><term>Inhibiteur enzyme</term><term>Imatinib</term><term>Anticancéreux</term><term>Dose journalière</term><term>Efficacité traitement</term><term>Protein-tyrosine kinase</term><term>Résistance</term><term>Leucémie myéloïde chronique</term><term>Cancérologie</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Purpose Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported. Patients and Methods In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. Results With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41 % to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11 % of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P =.024) and grade 3 to 4 thrombocytopenia (22% v37%; P =.004), and fewer patients required dose interruption (51% v68%), reduction (30% v 55%), or discontinuation (16% v 23%). Conclusion Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Argentine</li><li>Australie</li><li>Brésil</li><li>Corée du Sud</li><li>France</li><li>Mexique</li><li>Russie</li><li>États-Unis</li></country><region><li>Bade-Wurtemberg</li><li>Californie</li><li>District de Karlsruhe</li><li>District fédéral central</li><li>Provence-Alpes-Côte d'Azur</li><li>Région capitale de Séoul</li><li>Texas</li><li>État de São Paulo</li><li>Île-de-France</li></region><settlement><li>Houston</li><li>Mannheim</li><li>Marseille</li><li>Moscou</li><li>Paris</li><li>San Francisco</li><li>São Paulo</li><li>Séoul</li></settlement><orgName><li>Université de São Paulo</li></orgName></list><tree><noCountry><name sortKey="Bleickardt, Eric" sort="Bleickardt, Eric" uniqKey="Bleickardt E" first="Eric" last="Bleickardt">Eric Bleickardt</name><name sortKey="Charbonnier, Aude" sort="Charbonnier, Aude" uniqKey="Charbonnier A" first="Aude" last="Charbonnier">Aude Charbonnier</name><name sortKey="Collins, Robert H" sort="Collins, Robert H" uniqKey="Collins R" first="Robert H." last="Collins">Robert H. Collins</name><name sortKey="Deininger, Michael" sort="Deininger, Michael" uniqKey="Deininger M" first="Michael" last="Deininger">Michael Deininger</name><name sortKey="Dorlhiac Llacer, Pedro E" sort="Dorlhiac Llacer, Pedro E" uniqKey="Dorlhiac Llacer P" first="Pedro E." last="Dorlhiac-Llacer">Pedro E. Dorlhiac-Llacer</name><name sortKey="Francis, Stephen" sort="Francis, Stephen" uniqKey="Francis S" first="Stephen" last="Francis">Stephen Francis</name><name sortKey="Hochhaus, Andreas" sort="Hochhaus, Andreas" uniqKey="Hochhaus A" first="Andreas" last="Hochhaus">Andreas Hochhaus</name><name sortKey="Hughes, Timothy" sort="Hughes, Timothy" uniqKey="Hughes T" first="Timothy" last="Hughes">Timothy Hughes</name><name sortKey="Kantarjian, Hagop M" sort="Kantarjian, Hagop M" uniqKey="Kantarjian H" first="Hagop M." last="Kantarjian">Hagop M. Kantarjian</name><name sortKey="Khoroshko, Nina" sort="Khoroshko, Nina" uniqKey="Khoroshko N" first="Nina" last="Khoroshko">Nina Khoroshko</name><name sortKey="Khoury, H Jean" sort="Khoury, H Jean" uniqKey="Khoury H" first="H. Jean" last="Khoury">H. Jean Khoury</name><name sortKey="Kim, Dong Wook" sort="Kim, Dong Wook" uniqKey="Kim D" first="Dong-Wook" last="Kim">Dong-Wook Kim</name><name sortKey="Milone, Jorge H" sort="Milone, Jorge H" uniqKey="Milone J" first="Jorge H." last="Milone">Jorge H. Milone</name><name sortKey="Otero, Irma" sort="Otero, Irma" uniqKey="Otero I" first="Irma" last="Otero">Irma Otero</name><name sortKey="Paquette, Ronald L" sort="Paquette, Ronald L" uniqKey="Paquette R" first="Ronald L." last="Paquette">Ronald L. Paquette</name><name sortKey="Rea, Delphine" sort="Rea, Delphine" uniqKey="Rea D" first="Delphine" last="Rea">Delphine Rea</name><name sortKey="Silver, Richard T" sort="Silver, Richard T" uniqKey="Silver R" first="Richard T." last="Silver">Richard T. Silver</name><name sortKey="Strauss, Lewis" sort="Strauss, Lewis" uniqKey="Strauss L" first="Lewis" last="Strauss">Lewis Strauss</name><name sortKey="Vela Ojeda, Jorge" sort="Vela Ojeda, Jorge" uniqKey="Vela Ojeda J" first="Jorge" last="Vela-Ojeda">Jorge Vela-Ojeda</name></noCountry><country name="États-Unis"><region name="Californie"><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name></region><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name></country><country name="Corée du Sud"><region name="Région capitale de Séoul"><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name></region></country><country name="France"><region name="Île-de-France"><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name></region><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name></country><country name="Brésil"><region name="État de São Paulo"><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name></region></country><country name="Argentine"><noRegion><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name></noRegion></country><country name="Mexique"><noRegion><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name></noRegion></country><country name="Russie"><region name="District fédéral central"><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name></region></country><country name="Australie"><noRegion><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name></noRegion></country><country name="Allemagne"><region name="Bade-Wurtemberg"><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name></region></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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