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 : 003415 ( PascalFrancis/Corpus ); précédent : 003414; suivant : 003416Intermittent 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 ; 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.
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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.
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| NO : | PASCAL 08-0353275 INIST |
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| ET : | Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia |
| AU : | SHAH (Neil P.); KANTARJIAN (Hagop M.); KIM (Dong-Wook); REA (Delphine); DORLHIAC-LLACER (Pedro E.); MILONE (Jorge H.); VELA-OJEDA (Jorge); SILVER (Richard T.); KHOURY (H. Jean); CHARBONNIER (Aude); KHOROSHKO (Nina); PAQUETTE (Ronald L.); DEININGER (Michael); COLLINS (Robert H.); OTERO (Irma); HUGHES (Timothy); BLEICKARDT (Eric); STRAUSS (Lewis); FRANCIS (Stephen); HOCHHAUS (Andreas) |
| AF : | Division of Hematology/Oncology, University of California at San Francisco School of Medicine/San Francisco/Etats-Unis; University of California at Los Angeles/Los Angeles, CA/Etats-Unis; Department of Leukemia, M.D Anderson Cancer Center/Houston/Etats-Unis; University of Texas Southwestern Medical Center/Dallas, TX/Etats-Unis; Weill Medical College of Cornell University, New York Presbyterian Hospital/New York, NY/Etats-Unis; Emory University School of Medicine, Winship Cancer Institute/Atlanta, GA/Etats-Unis; Oregon Health Science University, Portland, OR; Bristol-Myers Squibb Co/Wallingford, CT/Etats-Unis; Department of Internal Medicine, St Mary's Hospital, The Catholic University of Korea/Seoul/Corée, République de; Hopital Saint-Louis/Paris/France; Département d'Onco-hématologie, Institut Paoli Calmettes/Marseille/France; Department of Hematology and Hemotherapy, Hospital das Clínicas, University of São Paulo/São Paulo/Brésil; Institute de Trasplante de Medula Osea/Inconnu; Division of Hematology and Medical Oncology, Hospital Ramos Mejia/Buenos Aires/Argentine; National Medical Center, La Raza, IMSS/Mexique; National Research Hematology Center/Moscow/Russie; Division of Hematology, Institute of Medical and Veterinary Science/Adelaide/Australie; III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg/Mannheim/Allemagne |
| DT : | Publication en série; Compte-rendu; Niveau analytique |
| SO : | Journal of clinical oncology; ISSN 0732-183X; Etats-Unis; Da. 2008; Vol. 26; No. 19; Pp. 3204-3212; Bibl. 24 ref. |
| LA : | Anglais |
| EA : | 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. |
| CC : | 002B04; 002B19B |
| FD : | Dasatinib; Ciblage; Inhibiteur enzyme; Imatinib; Anticancéreux; Dose journalière; Efficacité traitement; Protein-tyrosine kinase; Résistance; Leucémie myéloïde chronique; Cancérologie |
| FG : | Transferases; Enzyme; Inhibiteur de la tyrosine kinase; Inhibiteur multikinase; Hémopathie maligne; Cancer; Syndrome myéloprolifératif |
| ED : | Dasatinib; Targeting; Enzyme inhibitor; Imatinib; Antineoplastic agent; Daily dose; Treatment efficiency; Protein-tyrosine kinase; Resistance; Chronic myelogenous leukemia; Cancerology |
| EG : | Transferases; Enzyme; Tyrosine kinase inhibitor; Multikinase inhibitor; Malignant hemopathy; Cancer; Myeloproliferative syndrome |
| SD : | Dasatinib; Blancado; Inhibidor enzima; Imatinib; Anticanceroso; Dosis diaria; Eficacia tratamiento; Protein-tyrosine kinase; Resistencia; Leucemia mieloidea crónica; Cancerología |
| LO : | INIST-20094.354000197631440170 |
| ID : | 08-0353275 |
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Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</s1><s2>Mannheim</s2><s3>DEU</s3></inist:fA14></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></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">08-0353275</idno><date when="2008">2008</date><idno type="stanalyst">PASCAL 08-0353275 INIST</idno><idno type="RBID">Pascal:08-0353275</idno><idno type="wicri:Area/PascalFrancis/Corpus">003415</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia</title><author><name sortKey="Shah, Neil P" sort="Shah, Neil P" uniqKey="Shah N" first="Neil P." last="Shah">Neil P. Shah</name><affiliation><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></affiliation><affiliation><inist:fA14 i1="02"><s1>University of California at Los Angeles</s1><s2>Los Angeles, CA</s2><s3>USA</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="03"><s1>Department of Leukemia, M.D Anderson Cancer Center</s1><s2>Houston</s2><s3>USA</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="04"><s1>University of Texas Southwestern Medical Center</s1><s2>Dallas, TX</s2><s3>USA</s3></inist:fA14></affiliation><affiliation><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></affiliation><affiliation><inist:fA14 i1="06"><s1>Emory University School of Medicine, Winship Cancer Institute</s1><s2>Atlanta, GA</s2><s3>USA</s3></inist:fA14></affiliation><affiliation><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></affiliation><affiliation><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></affiliation><affiliation><inist:fA14 i1="09"><s1>Hopital Saint-Louis</s1><s2>Paris</s2><s3>FRA</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="10"><s1>Département d'Onco-hématologie, Institut Paoli Calmettes</s1><s2>Marseille</s2><s3>FRA</s3></inist:fA14></affiliation><affiliation><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></affiliation><affiliation><inist:fA14 i1="12"><s1>Institute de Trasplante de Medula Osea</s1><s3>INC</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="13"><s1>Division of Hematology and Medical Oncology, Hospital Ramos Mejia</s1><s2>Buenos Aires</s2><s3>ARG</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="14"><s1>National Medical Center, La Raza, IMSS</s1><s3>MEX</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="15"><s1>National Research Hematology Center</s1><s2>Moscow</s2><s3>RUS</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="16"><s1>Division of Hematology, Institute of Medical and Veterinary Science</s1><s2>Adelaide</s2><s3>AUS</s3></inist:fA14></affiliation><affiliation><inist:fA14 i1="17"><s1>III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</s1><s2>Mannheim</s2><s3>DEU</s3></inist:fA14></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><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0732-183X</s0></fA01><fA03 i2="1"><s0>J. clin. oncol.</s0></fA03><fA05><s2>26</s2></fA05><fA06><s2>19</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia</s1></fA08><fA11 i1="01" i2="1"><s1>SHAH (Neil P.)</s1></fA11><fA11 i1="02" i2="1"><s1>KANTARJIAN (Hagop M.)</s1></fA11><fA11 i1="03" i2="1"><s1>KIM (Dong-Wook)</s1></fA11><fA11 i1="04" i2="1"><s1>REA (Delphine)</s1></fA11><fA11 i1="05" i2="1"><s1>DORLHIAC-LLACER (Pedro E.)</s1></fA11><fA11 i1="06" i2="1"><s1>MILONE (Jorge H.)</s1></fA11><fA11 i1="07" i2="1"><s1>VELA-OJEDA (Jorge)</s1></fA11><fA11 i1="08" i2="1"><s1>SILVER (Richard T.)</s1></fA11><fA11 i1="09" i2="1"><s1>KHOURY (H. Jean)</s1></fA11><fA11 i1="10" i2="1"><s1>CHARBONNIER (Aude)</s1></fA11><fA11 i1="11" i2="1"><s1>KHOROSHKO (Nina)</s1></fA11><fA11 i1="12" i2="1"><s1>PAQUETTE (Ronald L.)</s1></fA11><fA11 i1="13" i2="1"><s1>DEININGER (Michael)</s1></fA11><fA11 i1="14" i2="1"><s1>COLLINS (Robert H.)</s1></fA11><fA11 i1="15" i2="1"><s1>OTERO (Irma)</s1></fA11><fA11 i1="16" i2="1"><s1>HUGHES (Timothy)</s1></fA11><fA11 i1="17" i2="1"><s1>BLEICKARDT (Eric)</s1></fA11><fA11 i1="18" i2="1"><s1>STRAUSS (Lewis)</s1></fA11><fA11 i1="19" i2="1"><s1>FRANCIS (Stephen)</s1></fA11><fA11 i1="20" i2="1"><s1>HOCHHAUS (Andreas)</s1></fA11><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></fA14><fA14 i1="02"><s1>University of California at Los Angeles</s1><s2>Los Angeles, CA</s2><s3>USA</s3></fA14><fA14 i1="03"><s1>Department of Leukemia, M.D Anderson Cancer Center</s1><s2>Houston</s2><s3>USA</s3></fA14><fA14 i1="04"><s1>University of Texas Southwestern Medical Center</s1><s2>Dallas, TX</s2><s3>USA</s3></fA14><fA14 i1="05"><s1>Weill Medical College of Cornell University, New York Presbyterian Hospital</s1><s2>New York, NY</s2><s3>USA</s3></fA14><fA14 i1="06"><s1>Emory University School of Medicine, Winship Cancer Institute</s1><s2>Atlanta, GA</s2><s3>USA</s3></fA14><fA14 i1="07"><s1>Oregon Health Science University, Portland, OR; Bristol-Myers Squibb Co</s1><s2>Wallingford, CT</s2><s3>USA</s3></fA14><fA14 i1="08"><s1>Department of Internal Medicine, St Mary's Hospital, The Catholic University of Korea</s1><s2>Seoul</s2><s3>KOR</s3></fA14><fA14 i1="09"><s1>Hopital Saint-Louis</s1><s2>Paris</s2><s3>FRA</s3></fA14><fA14 i1="10"><s1>Département d'Onco-hématologie, Institut Paoli Calmettes</s1><s2>Marseille</s2><s3>FRA</s3></fA14><fA14 i1="11"><s1>Department of Hematology and Hemotherapy, Hospital das Clínicas, University of São Paulo</s1><s2>São Paulo</s2><s3>BRA</s3></fA14><fA14 i1="12"><s1>Institute de Trasplante de Medula Osea</s1><s3>INC</s3></fA14><fA14 i1="13"><s1>Division of Hematology and Medical Oncology, Hospital Ramos Mejia</s1><s2>Buenos Aires</s2><s3>ARG</s3></fA14><fA14 i1="14"><s1>National Medical Center, La Raza, IMSS</s1><s3>MEX</s3></fA14><fA14 i1="15"><s1>National Research Hematology Center</s1><s2>Moscow</s2><s3>RUS</s3></fA14><fA14 i1="16"><s1>Division of Hematology, Institute of Medical and Veterinary Science</s1><s2>Adelaide</s2><s3>AUS</s3></fA14><fA14 i1="17"><s1>III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg</s1><s2>Mannheim</s2><s3>DEU</s3></fA14><fA20><s1>3204-3212</s1></fA20><fA21><s1>2008</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>20094</s2><s5>354000197631440170</s5></fA43><fA44><s0>0000</s0><s1>© 2008 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>24 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>08-0353275</s0></fA47><fA60><s1>P</s1><s3>C</s3></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Journal of clinical oncology</s0></fA64><fA66 i1="01"><s0>USA</s0></fA66><fC01 i1="01" l="ENG"><s0>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.</s0></fC01><fC02 i1="01" i2="X"><s0>002B04</s0></fC02><fC02 i1="02" i2="X"><s0>002B19B</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>Dasatinib</s0><s2>FR</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>Dasatinib</s0><s2>FR</s2><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>Dasatinib</s0><s2>FR</s2><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Ciblage</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Targeting</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Blancado</s0><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Inhibiteur enzyme</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Enzyme inhibitor</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Inhibidor enzima</s0><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Imatinib</s0><s2>FR</s2><s5>04</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Imatinib</s0><s2>FR</s2><s5>04</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Imatinib</s0><s2>FR</s2><s5>04</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Anticancéreux</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Antineoplastic agent</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Anticanceroso</s0><s5>05</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Dose journalière</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Daily dose</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Dosis diaria</s0><s5>06</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Efficacité traitement</s0><s5>08</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Treatment efficiency</s0><s5>08</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Eficacia tratamiento</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Protein-tyrosine kinase</s0><s2>FE</s2><s5>09</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Protein-tyrosine kinase</s0><s2>FE</s2><s5>09</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Protein-tyrosine kinase</s0><s2>FE</s2><s5>09</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Résistance</s0><s5>11</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Resistance</s0><s5>11</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Resistencia</s0><s5>11</s5></fC03><fC03 i1="10" i2="X" l="FRE"><s0>Leucémie myéloïde chronique</s0><s5>12</s5></fC03><fC03 i1="10" i2="X" l="ENG"><s0>Chronic myelogenous leukemia</s0><s5>12</s5></fC03><fC03 i1="10" i2="X" l="SPA"><s0>Leucemia mieloidea crónica</s0><s5>12</s5></fC03><fC03 i1="11" i2="X" l="FRE"><s0>Cancérologie</s0><s5>17</s5></fC03><fC03 i1="11" i2="X" l="ENG"><s0>Cancerology</s0><s5>17</s5></fC03><fC03 i1="11" i2="X" l="SPA"><s0>Cancerología</s0><s5>17</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Transferases</s0><s2>FE</s2></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Transferases</s0><s2>FE</s2></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Transferases</s0><s2>FE</s2></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Enzyme</s0><s2>FE</s2></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Enzima</s0><s2>FE</s2></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Inhibiteur de la tyrosine kinase</s0><s5>37</s5></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Tyrosine kinase inhibitor</s0><s5>37</s5></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Inhibidor tyrosine kinase</s0><s5>37</s5></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Inhibiteur multikinase</s0><s5>38</s5></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Multikinase inhibitor</s0><s5>38</s5></fC07><fC07 i1="04" i2="X" l="SPA"><s0>inhibidor multicinasa</s0><s5>38</s5></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Hémopathie maligne</s0><s2>NM</s2><s5>39</s5></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Malignant hemopathy</s0><s2>NM</s2><s5>39</s5></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Hemopatía maligna</s0><s2>NM</s2><s5>39</s5></fC07><fC07 i1="06" i2="X" l="FRE"><s0>Cancer</s0><s2>NM</s2></fC07><fC07 i1="06" i2="X" l="ENG"><s0>Cancer</s0><s2>NM</s2></fC07><fC07 i1="06" i2="X" l="SPA"><s0>Cáncer</s0><s2>NM</s2></fC07><fC07 i1="07" i2="X" l="FRE"><s0>Syndrome myéloprolifératif</s0><s5>40</s5></fC07><fC07 i1="07" i2="X" l="ENG"><s0>Myeloproliferative syndrome</s0><s5>40</s5></fC07><fC07 i1="07" i2="X" l="SPA"><s0>Mieloproliferativo síndrome</s0><s5>40</s5></fC07><fN21><s1>224</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard><server><NO>PASCAL 08-0353275 INIST</NO><ET>Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia</ET><AU>SHAH (Neil P.); KANTARJIAN (Hagop M.); KIM (Dong-Wook); REA (Delphine); DORLHIAC-LLACER (Pedro E.); MILONE (Jorge H.); VELA-OJEDA (Jorge); SILVER (Richard T.); KHOURY (H. Jean); CHARBONNIER (Aude); KHOROSHKO (Nina); PAQUETTE (Ronald L.); DEININGER (Michael); COLLINS (Robert H.); OTERO (Irma); HUGHES (Timothy); BLEICKARDT (Eric); STRAUSS (Lewis); FRANCIS (Stephen); HOCHHAUS (Andreas)</AU><AF>Division of Hematology/Oncology, University of California at San Francisco School of Medicine/San Francisco/Etats-Unis; University of California at Los Angeles/Los Angeles, CA/Etats-Unis; Department of Leukemia, M.D Anderson Cancer Center/Houston/Etats-Unis; University of Texas Southwestern Medical Center/Dallas, TX/Etats-Unis; Weill Medical College of Cornell University, New York Presbyterian Hospital/New York, NY/Etats-Unis; Emory University School of Medicine, Winship Cancer Institute/Atlanta, GA/Etats-Unis; Oregon Health Science University, Portland, OR; Bristol-Myers Squibb Co/Wallingford, CT/Etats-Unis; Department of Internal Medicine, St Mary's Hospital, The Catholic University of Korea/Seoul/Corée, République de; Hopital Saint-Louis/Paris/France; Département d'Onco-hématologie, Institut Paoli Calmettes/Marseille/France; Department of Hematology and Hemotherapy, Hospital das Clínicas, University of São Paulo/São Paulo/Brésil; Institute de Trasplante de Medula Osea/Inconnu; Division of Hematology and Medical Oncology, Hospital Ramos Mejia/Buenos Aires/Argentine; National Medical Center, La Raza, IMSS/Mexique; National Research Hematology Center/Moscow/Russie; Division of Hematology, Institute of Medical and Veterinary Science/Adelaide/Australie; III. Medizinische Klinik, Medizinische Fakultät Mannheim, Universität Heidelberg/Mannheim/Allemagne</AF><DT>Publication en série; Compte-rendu; Niveau analytique</DT><SO>Journal of clinical oncology; ISSN 0732-183X; Etats-Unis; Da. 2008; Vol. 26; No. 19; Pp. 3204-3212; Bibl. 24 ref.</SO><LA>Anglais</LA><EA>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.</EA><CC>002B04; 002B19B</CC><FD>Dasatinib; Ciblage; Inhibiteur enzyme; Imatinib; Anticancéreux; Dose journalière; Efficacité traitement; Protein-tyrosine kinase; Résistance; Leucémie myéloïde chronique; Cancérologie</FD><FG>Transferases; Enzyme; Inhibiteur de la tyrosine kinase; Inhibiteur multikinase; Hémopathie maligne; Cancer; Syndrome myéloprolifératif</FG><ED>Dasatinib; Targeting; Enzyme inhibitor; Imatinib; Antineoplastic agent; Daily dose; Treatment efficiency; Protein-tyrosine kinase; Resistance; Chronic myelogenous leukemia; Cancerology</ED><EG>Transferases; Enzyme; Tyrosine kinase inhibitor; Multikinase inhibitor; Malignant hemopathy; Cancer; Myeloproliferative syndrome</EG><SD>Dasatinib; Blancado; Inhibidor enzima; Imatinib; Anticanceroso; Dosis diaria; Eficacia tratamiento; Protein-tyrosine kinase; Resistencia; Leucemia mieloidea crónica; Cancerología</SD><LO>INIST-20094.354000197631440170</LO><ID>08-0353275</ID></server></inist></record>Pour manipuler ce document sous Unix (Dilib)
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