Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial
Identifieur interne : 000804 ( Pmc/Checkpoint ); précédent : 000803; suivant : 000805Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial
Auteurs : A. Hochhaus [Allemagne] ; G. Saglio [Italie] ; T P Hughes [Australie] ; R A Larson [États-Unis] ; D-W Kim [Corée du Sud] ; S. Issaragrisil [Thaïlande] ; P D Le Coutre [Allemagne] ; G. Etienne [France] ; P E Dorlhiac-Llacer [Brésil] ; R E Clark [Royaume-Uni] ; I W Flinn [États-Unis] ; H. Nakamae [Japon] ; B. Donohue [États-Unis] ; W. Deng [États-Unis] ; D. Dalal [États-Unis] ; H D Menssen [Suisse] ; H M Kantarjian [États-Unis]Source :
- Leukemia [ 0887-6924 ] ; 2016.
Abstract
In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54% 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR4.5;
Url:
DOI: 10.1038/leu.2016.5
PubMed: 26837842
PubMed Central: 4858585
Affiliations:
- Allemagne, Australie, Brésil, Corée du Sud, France, Italie, Japon, Royaume-Uni, Suisse, Thaïlande, États-Unis
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Saglio</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Division of Internal Medicine & Hematology, University of Turin</institution>, Orbassano,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hughes, T P" sort="Hughes, T P" uniqKey="Hughes T" first="T P" last="Hughes">T P Hughes</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide, SA Pathology</institution>, Adelaide, South Australia,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Larson, R A" sort="Larson, R A" uniqKey="Larson R" first="R A" last="Larson">R A Larson</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Medicine, The University of Chicago</institution>, Chicago, IL,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, D W" sort="Kim, D W" uniqKey="Kim D" first="D-W" last="Kim">D-W Kim</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Leukemia Research Institute, Seoul St Mary's Hospital, The Catholic University of Korea</institution>, Seoul,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Issaragrisil, S" sort="Issaragrisil, S" uniqKey="Issaragrisil S" first="S" last="Issaragrisil">S. 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Nakamae</name><affiliation wicri:level="1"><nlm:aff id="aff12"><institution>Department of Hematology, Osaka City University</institution>, Osaka,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Donohue, B" sort="Donohue, B" uniqKey="Donohue B" first="B" last="Donohue">B. Donohue</name><affiliation wicri:level="1"><nlm:aff id="aff13"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Deng, W" sort="Deng, W" uniqKey="Deng W" first="W" last="Deng">W. Deng</name><affiliation wicri:level="1"><nlm:aff id="aff13"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Dalal, D" sort="Dalal, D" uniqKey="Dalal D" first="D" last="Dalal">D. 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Hochhaus</name><affiliation wicri:level="1"><nlm:aff id="aff1"><institution>Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena</institution>, Jena,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Saglio, G" sort="Saglio, G" uniqKey="Saglio G" first="G" last="Saglio">G. Saglio</name><affiliation wicri:level="1"><nlm:aff id="aff2"><institution>Division of Internal Medicine & Hematology, University of Turin</institution>, Orbassano,<country>Italy</country></nlm:aff><country xml:lang="fr">Italie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Hughes, T P" sort="Hughes, T P" uniqKey="Hughes T" first="T P" last="Hughes">T P Hughes</name><affiliation wicri:level="1"><nlm:aff id="aff3"><institution>South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide, SA Pathology</institution>, Adelaide, South Australia,<country>Australia</country></nlm:aff><country xml:lang="fr">Australie</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Larson, R A" sort="Larson, R A" uniqKey="Larson R" first="R A" last="Larson">R A Larson</name><affiliation wicri:level="1"><nlm:aff id="aff4"><institution>Department of Medicine, The University of Chicago</institution>, Chicago, IL,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kim, D W" sort="Kim, D W" uniqKey="Kim D" first="D-W" last="Kim">D-W Kim</name><affiliation wicri:level="1"><nlm:aff id="aff5"><institution>Leukemia Research Institute, Seoul St Mary's Hospital, The Catholic University of Korea</institution>, Seoul,<country>Korea</country></nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Issaragrisil, S" sort="Issaragrisil, S" uniqKey="Issaragrisil S" first="S" last="Issaragrisil">S. Issaragrisil</name><affiliation wicri:level="1"><nlm:aff id="aff6"><institution>Faculty of Medicine Siriraj Hospital, Mahidol University</institution>, Bangkok,<country>Thailand</country></nlm:aff><country xml:lang="fr">Thaïlande</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Le Coutre, P D" sort="Le Coutre, P D" uniqKey="Le Coutre P" first="P D" last="Le Coutre">P D Le Coutre</name><affiliation wicri:level="1"><nlm:aff id="aff7"><institution>Charité—Universitätsmedizin Berlin</institution>, Berlin,<country>Germany</country></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Etienne, G" sort="Etienne, G" uniqKey="Etienne G" first="G" last="Etienne">G. Etienne</name><affiliation wicri:level="1"><nlm:aff id="aff8"><institution>Centre Régional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest, Institut Bergonié, Département d'Oncologie Médicale</institution>, Bordeaux,<country>France</country></nlm:aff><country xml:lang="fr">France</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Dorlhiac Llacer, P E" sort="Dorlhiac Llacer, P E" uniqKey="Dorlhiac Llacer P" first="P E" last="Dorlhiac-Llacer">P E Dorlhiac-Llacer</name><affiliation wicri:level="1"><nlm:aff id="aff9"><institution>Hospital das Clinicas FMUSP</institution>, São Paulo,<country>Brazil</country></nlm:aff><country xml:lang="fr">Brésil</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Clark, R E" sort="Clark, R E" uniqKey="Clark R" first="R E" last="Clark">R E Clark</name><affiliation wicri:level="1"><nlm:aff id="aff10"><institution>Royal Liverpool University Hospital</institution>, Liverpool,<country>UK</country></nlm:aff><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Flinn, I W" sort="Flinn, I W" uniqKey="Flinn I" first="I W" last="Flinn">I W Flinn</name><affiliation wicri:level="1"><nlm:aff id="aff11"><institution>Sarah Cannon Research Institute</institution>, Nashville, TN,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Nakamae, H" sort="Nakamae, H" uniqKey="Nakamae H" first="H" last="Nakamae">H. Nakamae</name><affiliation wicri:level="1"><nlm:aff id="aff12"><institution>Department of Hematology, Osaka City University</institution>, Osaka,<country>Japan</country></nlm:aff><country xml:lang="fr">Japon</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Donohue, B" sort="Donohue, B" uniqKey="Donohue B" first="B" last="Donohue">B. Donohue</name><affiliation wicri:level="1"><nlm:aff id="aff13"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Deng, W" sort="Deng, W" uniqKey="Deng W" first="W" last="Deng">W. Deng</name><affiliation wicri:level="1"><nlm:aff id="aff13"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Dalal, D" sort="Dalal, D" uniqKey="Dalal D" first="D" last="Dalal">D. Dalal</name><affiliation wicri:level="1"><nlm:aff id="aff13"><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Menssen, H D" sort="Menssen, H D" uniqKey="Menssen H" first="H D" last="Menssen">H D Menssen</name><affiliation wicri:level="1"><nlm:aff id="aff14"><institution>Novartis Pharma AG</institution>, Basel,<country>Switzerland</country></nlm:aff><country xml:lang="fr">Suisse</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Kantarjian, H M" sort="Kantarjian, H M" uniqKey="Kantarjian H" first="H M" last="Kantarjian">H M Kantarjian</name><affiliation wicri:level="1"><nlm:aff id="aff15"><institution>The University of Texas MD Anderson Cancer Center</institution>, Houston, TX,<country>USA</country></nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author></analytic><series><title level="j">Leukemia</title><idno type="ISSN">0887-6924</idno><idno type="eISSN">1476-5551</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54% 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR<sup>4.5</sup>; <italic>BCR-ABL</italic>⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Leukemia</journal-id><journal-id journal-id-type="iso-abbrev">Leukemia</journal-id><journal-title-group><journal-title>Leukemia</journal-title></journal-title-group><issn pub-type="ppub">0887-6924</issn><issn pub-type="epub">1476-5551</issn><publisher><publisher-name>Nature Publishing Group</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26837842</article-id><article-id pub-id-type="pmc">4858585</article-id><article-id pub-id-type="pii">leu20165</article-id><article-id pub-id-type="doi">10.1038/leu.2016.5</article-id><article-categories><subj-group subj-group-type="heading"><subject>Original Article</subject></subj-group></article-categories><title-group><article-title>Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial</article-title><alt-title alt-title-type="running">Frontline nilotinib vs imatinib for CML</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Hochhaus</surname><given-names>A</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="corresp" rid="caf1">*</xref><xref ref-type="author-notes" rid="note1"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Saglio</surname><given-names>G</given-names></name><xref ref-type="aff" rid="aff2">2</xref><xref ref-type="author-notes" rid="note1"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hughes</surname><given-names>T P</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Larson</surname><given-names>R A</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>D-W</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Issaragrisil</surname><given-names>S</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>le Coutre</surname><given-names>P D</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Etienne</surname><given-names>G</given-names></name><xref ref-type="aff" rid="aff8">8</xref></contrib><contrib contrib-type="author"><name><surname>Dorlhiac-Llacer</surname><given-names>P E</given-names></name><xref ref-type="aff" rid="aff9">9</xref></contrib><contrib contrib-type="author"><name><surname>Clark</surname><given-names>R E</given-names></name><xref ref-type="aff" rid="aff10">10</xref></contrib><contrib contrib-type="author"><name><surname>Flinn</surname><given-names>I W</given-names></name><xref ref-type="aff" rid="aff11">11</xref></contrib><contrib contrib-type="author"><name><surname>Nakamae</surname><given-names>H</given-names></name><xref ref-type="aff" rid="aff12">12</xref></contrib><contrib contrib-type="author"><name><surname>Donohue</surname><given-names>B</given-names></name><xref ref-type="aff" rid="aff13">13</xref></contrib><contrib contrib-type="author"><name><surname>Deng</surname><given-names>W</given-names></name><xref ref-type="aff" rid="aff13">13</xref></contrib><contrib contrib-type="author"><name><surname>Dalal</surname><given-names>D</given-names></name><xref ref-type="aff" rid="aff13">13</xref></contrib><contrib contrib-type="author"><name><surname>Menssen</surname><given-names>H D</given-names></name><xref ref-type="aff" rid="aff14">14</xref></contrib><contrib contrib-type="author"><name><surname>Kantarjian</surname><given-names>H M</given-names></name><xref ref-type="aff" rid="aff15">15</xref></contrib><aff id="aff1"><label>1</label><institution>Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena</institution>, Jena,<country>Germany</country></aff><aff id="aff2"><label>2</label><institution>Division of Internal Medicine & Hematology, University of Turin</institution>, Orbassano,<country>Italy</country></aff><aff id="aff3"><label>3</label><institution>South Australian Health and Medical Research Institute (SAHMRI), University of Adelaide, SA Pathology</institution>, Adelaide, South Australia,<country>Australia</country></aff><aff id="aff4"><label>4</label><institution>Department of Medicine, The University of Chicago</institution>, Chicago, IL,<country>USA</country></aff><aff id="aff5"><label>5</label><institution>Leukemia Research Institute, Seoul St Mary's Hospital, The Catholic University of Korea</institution>, Seoul,<country>Korea</country></aff><aff id="aff6"><label>6</label><institution>Faculty of Medicine Siriraj Hospital, Mahidol University</institution>, Bangkok,<country>Thailand</country></aff><aff id="aff7"><label>7</label><institution>Charité—Universitätsmedizin Berlin</institution>, Berlin,<country>Germany</country></aff><aff id="aff8"><label>8</label><institution>Centre Régional de Lutte Contre le Cancer de Bordeaux et du Sud-Ouest, Institut Bergonié, Département d'Oncologie Médicale</institution>, Bordeaux,<country>France</country></aff><aff id="aff9"><label>9</label><institution>Hospital das Clinicas FMUSP</institution>, São Paulo,<country>Brazil</country></aff><aff id="aff10"><label>10</label><institution>Royal Liverpool University Hospital</institution>, Liverpool,<country>UK</country></aff><aff id="aff11"><label>11</label><institution>Sarah Cannon Research Institute</institution>, Nashville, TN,<country>USA</country></aff><aff id="aff12"><label>12</label><institution>Department of Hematology, Osaka City University</institution>, Osaka,<country>Japan</country></aff><aff id="aff13"><label>13</label><institution>Novartis Pharmaceuticals Corporation</institution>, East Hanover, NJ,<country>USA</country></aff><aff id="aff14"><label>14</label><institution>Novartis Pharma AG</institution>, Basel,<country>Switzerland</country></aff><aff id="aff15"><label>15</label><institution>The University of Texas MD Anderson Cancer Center</institution>, Houston, TX,<country>USA</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label><institution>Abteilung Hämatologie/Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena</institution>, Erlanger Allee 101, 07740 Jena, <country>Germany</country>. E-mail: <email>andreas.hochhaus@med.uni-jena.de</email></corresp><fn fn-type="present-address" id="note1"><label>16</label><p>These authors contributed equally to this work as first authors.</p></fn></author-notes><pub-date pub-type="ppub"><month>05</month><year>2016</year></pub-date><pub-date pub-type="epreprint"><day>03</day><month>02</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>04</day><month>03</month><year>2016</year></pub-date><volume>30</volume><issue>5</issue><fpage>1044</fpage><lpage>1054</lpage><history><date date-type="received"><day>02</day><month>11</month><year>2015</year></date><date date-type="rev-recd"><day>06</day><month>01</month><year>2016</year></date><date date-type="accepted"><day>18</day><month>01</month><year>2016</year></date></history><permissions><copyright-statement>Copyright © 2016 Macmillan Publishers Limited</copyright-statement><copyright-year>2016</copyright-year><copyright-holder>Macmillan Publishers Limited</copyright-holder><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/"><pmc-comment>author-paid</pmc-comment>
<license-p>This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by-nc-nd/4.0/">http://creativecommons.org/licenses/by-nc-nd/4.0/</ext-link></license-p></license></permissions><abstract><p>In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54% 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR<sup>4.5</sup>; <italic>BCR-ABL</italic>⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.</p></abstract></article-meta></front><floats-group><fig id="fig1"><label>Figure 1</label><caption><p>CONSORT diagram for ENESTnd 5-year analysis (data cutoff 30 September 2013). Efficacy analyses, including molecular and cytogenetic response rates, were based on all randomized patients (intent-to-treat population). Safety analyses were based on patients who received ⩾1 dose of study treatment. <sup>a</sup>Reasons for discontinuation: AEs/abnormal laboratory values (<italic>n</italic>=34), suboptimal response/treatment failure (<italic>n</italic>=34), withdrawal of consent (<italic>n</italic>=17), death (<italic>n</italic>=6), disease progression (<italic>n</italic>=2), other (<italic>n</italic>=17). On discontinuation, 24 patients entered the extension study. <sup>b</sup>Reasons for discontinuation: AEs/abnormal laboratory values (<italic>n</italic>=56), withdrawal of consent (<italic>n</italic>=16), suboptimal response/treatment failure (<italic>n</italic>=13), disease progression (<italic>n</italic>=4), death (<italic>n</italic>=1), other (<italic>n</italic>=15). On discontinuation, three patients entered the extension study. <sup>c</sup>Reasons for discontinuation: suboptimal response/treatment failure (<italic>n</italic>=59), AEs/abnormal laboratory values (<italic>n</italic>=38), withdrawal of consent (<italic>n</italic>=17), disease progression (<italic>n</italic>=12), death (<italic>n</italic>=1), other (<italic>n</italic>=12). On discontinuation, 43 patients entered the extension study. <sup>d</sup>Discontinued before receiving intervention owing to protocol deviation (<italic>n</italic>=1), withdrawal of consent (<italic>n</italic>=2). <sup>e</sup>Discontinued before receiving intervention owing to protocol deviation (<italic>n</italic>=1), withdrawal of consent (<italic>n</italic>=2), QTc>450 ms at baseline (<italic>n</italic>=1). <sup>f</sup>One patient allocated to nilotinib 400 mg twice daily received imatinib 400 mg once daily for 6 days before discontinuing intervention and was excluded from safety analysis for nilotinib 400 mg twice daily. <sup>g</sup>Discontinued before receiving intervention owing to protocol deviation (<italic>n</italic>=2), withdrawal of consent (<italic>n</italic>=1), QTc>450 ms at baseline (<italic>n</italic>=1). <sup>h</sup>One patient allocated to nilotinib 400 mg twice daily received imatinib 400 mg once daily for 6 days before discontinuing intervention and was included in safety analysis for imatinib 400 mg once daily. <sup>i</sup>Owing to atypical transcripts at baseline (<italic>n</italic>=5), discontinuation prior to the month 3 assessment (<italic>n</italic>=15), or missing month 3 assessment (<italic>n</italic>=4). <sup>j</sup>Owing to atypical transcripts at baseline (<italic>n</italic>=1), discontinuation prior to the month 3 assessment (<italic>n</italic>=17), or missing month 3 assessment (<italic>n</italic>=3). <sup>k</sup>Owing to atypical transcripts at baseline (<italic>n</italic>=2), discontinuation prior to the month 3 assessment (<italic>n</italic>=12), or missing month 3 assessment (<italic>n</italic>=5).</p></caption><graphic xlink:href="leu20165f1"></graphic></fig><fig id="fig2"><label>Figure 2</label><caption><p>Cumulative molecular response rates. Cumulative proportion of patients with (<bold>a</bold>) major molecular response (MMR; <italic>BCR-ABL</italic><sup>IS</sup>⩽0.1%), (<bold>b</bold>) molecular response 4 (MR<sup>4</sup>; <italic>BCR-ABL</italic><sup>IS</sup>⩽0.01%) and (<bold>c</bold>) molecular response 4.5 (MR<sup>4.5</sup>; <italic>BCR-ABL</italic><sup>IS</sup>⩽0.0032%). <italic>P</italic> values vs imatinib are nominal. IS, International Scale.</p></caption><graphic xlink:href="leu20165f2"></graphic></fig><fig id="fig3"><label>Figure 3</label><caption><p>Summary of deaths on study by treatment arm. <sup>a</sup>The presence/absence of cardiovascular events (CVEs) was collected during treatment (core or extension) only. <sup>b</sup>Death due to advanced chronic myeloid leukemia (CML) was defined as any death for which the principal cause was reported by the investigator as ‘study indication' or, if subsequent to documented progression to accelerated phase/blast crisis (AP/BC), any death for which the cause was reported as ‘unknown' or was not reported. <sup>c</sup>One patient randomized to imatinib who died prior to receiving treatment is not shown. CABG, coronary artery bypass grafting.</p></caption><graphic xlink:href="leu20165f3"></graphic></fig><fig id="fig4"><label>Figure 4</label><caption><p>Kaplan–Meier estimated (<bold>a</bold>) progression-free survival on study and (<bold>b</bold>) overall survival on study.</p></caption><graphic xlink:href="leu20165f4"></graphic></fig><fig id="fig5"><label>Figure 5</label><caption><p>Kaplan–Meier estimated time to first cardiovascular event (CVE) on study. The shaded portion of the graph shows censored data and events that occurred after 60 months of treatment and up to the data cutoff date. Because patients had variable follow-up durations beyond the 60-month time point at the data cutoff for this exploratory analysis, the shaded portion of the graph does not fully reflect outcomes after 60 months of treatment exposure.</p></caption><graphic xlink:href="leu20165f5"></graphic></fig><table-wrap id="tbl1"><label>Table 1</label><caption><title>Long-term patient outcomes</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="center"></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th><th align="center" valign="top" charoff="50"><italic>Nilotinib 300 mg twice daily (</italic>n=<italic>282)</italic></th><th align="center" valign="top" charoff="50"><italic>Nilotinib 400 mg twice daily (</italic>n=<italic>281)</italic></th><th align="center" valign="top" charoff="50"><italic>Imatinib 400 mg once daily (</italic>n=<italic>283)</italic></th></tr></thead><tbody valign="top"><tr><td colspan="4" align="left" valign="top" charoff="50"><italic>Progression to AP/BC</italic></td></tr><tr><td align="left" valign="top" charoff="50"> Progression to AP/BC on core treatment, <italic>n</italic></td><td align="center" valign="top" charoff="50">2</td><td align="center" valign="top" charoff="50">3</td><td align="center" valign="top" charoff="50">12</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year freedom from progression to AP/BC on core treatment, % (95% CI)<xref ref-type="fn" rid="t1-fn2">a</xref></td><td align="center" valign="top" charoff="50">99.3 (98.2–100)</td><td align="center" valign="top" charoff="50">98.7 (97.2–100)</td><td align="center" valign="top" charoff="50">95.2 (92.6–97.9)</td></tr><tr><td align="left" valign="top" charoff="50"> HR vs imatinib (95% CI)<xref ref-type="fn" rid="t1-fn3">b</xref></td><td align="center" valign="top" charoff="50">0.1599 (0.0358–0.7143)</td><td align="center" valign="top" charoff="50">0.2457 (0.0693–0.8713)</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>P</italic> vs imatinib<xref ref-type="fn" rid="t1-fn4">c</xref></td><td align="center" valign="top" charoff="50">0.0059</td><td align="center" valign="top" charoff="50">0.0185</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Progression to AP/BC on study, <italic>n</italic></td><td align="center" valign="top" charoff="50">10</td><td align="center" valign="top" charoff="50">6</td><td align="center" valign="top" charoff="50">21</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year freedom from progression to AP/BC on study, % (95% CI)<xref ref-type="fn" rid="t1-fn2">a</xref></td><td align="center" valign="top" charoff="50">96.3 (94.1–98.6)</td><td align="center" valign="top" charoff="50">97.8 (96.0–99.5)</td><td align="center" valign="top" charoff="50">92.1 (88.8–95.3)</td></tr><tr><td align="left" valign="top" charoff="50"> HR vs imatinib (95% CI)<xref ref-type="fn" rid="t1-fn3">b</xref></td><td align="center" valign="top" charoff="50">0.4636 (0.2183–0.9845)</td><td align="center" valign="top" charoff="50">0.2753 (0.1111–0.6821)</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>P</italic> vs imatinib<xref ref-type="fn" rid="t1-fn4">c</xref></td><td align="center" valign="top" charoff="50">0.0403</td><td align="center" valign="top" charoff="50">0.0028</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td colspan="4" align="left" valign="top" charoff="50"><italic>EFS</italic></td></tr><tr><td align="left" valign="top" charoff="50"> EFS events on core treatment, <italic>n</italic></td><td align="center" valign="top" charoff="50">12</td><td align="center" valign="top" charoff="50">7</td><td align="center" valign="top" charoff="50">18</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year EFS on core treatment, % (95% CI)<xref ref-type="fn" rid="t1-fn2">a</xref></td><td align="center" valign="top" charoff="50">95.0 (92.1–97.8)</td><td align="center" valign="top" charoff="50">96.9 (94.6–99.2)</td><td align="center" valign="top" charoff="50">92.6 (89.3–95.9)</td></tr><tr><td align="left" valign="top" charoff="50"> HR vs imatinib (95% CI)<xref ref-type="fn" rid="t1-fn3">b</xref></td><td align="center" valign="top" charoff="50">0.6145 (0.2957–1.2767)</td><td align="center" valign="top" charoff="50">0.3656 (0.1525–0.8769)</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>P</italic> vs imatinib<xref ref-type="fn" rid="t1-fn4">c</xref></td><td align="center" valign="top" charoff="50">0.1874</td><td align="center" valign="top" charoff="50">0.0188</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td colspan="4" align="left" valign="top" charoff="50"><italic>PFS</italic></td></tr><tr><td align="left" valign="top" charoff="50"> PFS events on core treatment, <italic>n</italic></td><td align="center" valign="top" charoff="50">8</td><td align="center" valign="top" charoff="50">4</td><td align="center" valign="top" charoff="50">13</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year PFS on core treatment, % (95% CI)<xref ref-type="fn" rid="t1-fn2">a</xref></td><td align="center" valign="top" charoff="50">96.5 (94.2–98.9)</td><td align="center" valign="top" charoff="50">98.3 (96.6–100)</td><td align="center" valign="top" charoff="50">94.7 (91.9–97.5)</td></tr><tr><td align="left" valign="top" charoff="50"> HR vs imatinib (95% CI)<xref ref-type="fn" rid="t1-fn3">b</xref></td><td align="center" valign="top" charoff="50">0.5684 (0.2354–1.3729)</td><td align="center" valign="top" charoff="50">0.3011 (0.0981–0.9241)</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>P</italic> vs imatinib<xref ref-type="fn" rid="t1-fn4">c</xref></td><td align="center" valign="top" charoff="50">0.2032</td><td align="center" valign="top" charoff="50">0.0260</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> PFS events on study, <italic>n</italic></td><td align="center" valign="top" charoff="50">22</td><td align="center" valign="top" charoff="50">11</td><td align="center" valign="top" charoff="50">24</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year PFS on study, % (95% CI)<xref ref-type="fn" rid="t1-fn2">a</xref></td><td align="center" valign="top" charoff="50">92.2 (89.0–95.4)</td><td align="center" valign="top" charoff="50">95.8 (93.4–98.3)</td><td align="center" valign="top" charoff="50">91.0 (87.5–94.4)</td></tr><tr><td align="left" valign="top" charoff="50"> HR vs imatinib (95% CI)<xref ref-type="fn" rid="t1-fn3">b</xref></td><td align="center" valign="top" charoff="50">0.8883 (0.4980–1.5843)</td><td align="center" valign="top" charoff="50">0.4399 (0.2155–0.8981)</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>P</italic> vs imatinib<xref ref-type="fn" rid="t1-fn4">c</xref></td><td align="center" valign="top" charoff="50">0.6879</td><td align="center" valign="top" charoff="50">0.0204</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td colspan="4" align="left" valign="top" charoff="50"><italic>OS</italic></td></tr><tr><td align="left" valign="top" charoff="50"> Total deaths on study, <italic>n</italic></td><td align="center" valign="top" charoff="50">18</td><td align="center" valign="top" charoff="50">10</td><td align="center" valign="top" charoff="50">22</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year OS on study, % (95% CI)<xref ref-type="fn" rid="t1-fn2">a</xref></td><td align="center" valign="top" charoff="50">93.7 (90.8–96.6)</td><td align="center" valign="top" charoff="50">96.2 (93.9–98.5)</td><td align="center" valign="top" charoff="50">91.7 (88.3–95.0)</td></tr><tr><td align="left" valign="top" charoff="50"> HR vs imatinib (95% CI)<xref ref-type="fn" rid="t1-fn3">b</xref></td><td align="center" valign="top" charoff="50">0.8026 (0.4305–1.4964)</td><td align="center" valign="top" charoff="50">0.4395 (0.2081–0.9281)</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>P</italic> vs imatinib<xref ref-type="fn" rid="t1-fn4">c</xref></td><td align="center" valign="top" charoff="50">0.4881</td><td align="center" valign="top" charoff="50">0.0266</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td><td align="center" valign="top" charoff="50"> </td></tr><tr><td align="left" valign="top" charoff="50"> Deaths due to advanced CML, <italic>n</italic></td><td align="center" valign="top" charoff="50">6</td><td align="center" valign="top" charoff="50">4</td><td align="center" valign="top" charoff="50">16</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year freedom from death due to advanced CML, % (95% CI)<xref ref-type="fn" rid="t1-fn2">a</xref></td><td align="center" valign="top" charoff="50">97.7 (96.0–99.5)</td><td align="center" valign="top" charoff="50">98.5 (97.1–100)</td><td align="center" valign="top" charoff="50">93.8 (90.8–96.7)</td></tr><tr><td align="left" valign="top" charoff="50"> HR vs imatinib (95% CI)<xref ref-type="fn" rid="t1-fn3">b</xref></td><td align="center" valign="top" charoff="50">0.3673 (0.1437–0.9387)</td><td align="center" valign="top" charoff="50">0.2411 (0.0806–0.7214)</td><td align="center" valign="top" charoff="50">—</td></tr><tr><td align="left" valign="top" charoff="50"> <italic>P</italic> vs imatinib<xref ref-type="fn" rid="t1-fn4">c</xref></td><td align="center" valign="top" charoff="50">0.0292</td><td align="center" valign="top" charoff="50">0.0057</td><td align="center" valign="top" charoff="50">—</td></tr></tbody></table><table-wrap-foot><fn id="t1-fn1"><p>Abbreviations: AP/BC, accelerated phase/blast crisis; CI, confidence interval; CML, chronic myeloid leukemia; EFS, event-free survival; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.</p></fn><fn id="t1-fn2"><label>a</label><p>Estimated by Kaplan–Meier analysis; 95% two-sided CIs for Kaplan–Meier estimates were derived using the standard error calculated with Greenwood's formula.</p></fn><fn id="t1-fn3"><label>b</label><p>HR and two-sided 95% CIs were derived from a Cox model stratified by Sokal risk group.</p></fn><fn id="t1-fn4"><label>c</label><p>Log-rank test stratified by Sokal risk group; two-sided <italic>P</italic> value is nominal.</p></fn></table-wrap-foot></table-wrap><table-wrap id="tbl2"><label>Table 2</label><caption><title>Five-year outcomes according to Sokal risk score</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="center"></col><col align="center"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th><th align="center" valign="top" charoff="50"><italic>Nilotinib 300 mg twice daily</italic></th><th align="center" valign="top" charoff="50"><italic>Nilotinib 400 mg twice daily</italic></th><th align="center" valign="top" charoff="50"><italic>Imatinib 400 mg once daily</italic></th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">Low Sokal risk, <italic>n</italic></td><td align="center" valign="top" charoff="50">103</td><td align="center" valign="top" charoff="50">103</td><td align="center" valign="top" charoff="50">104</td></tr><tr><td align="left" valign="top" charoff="50"> MR<sup>4.5</sup> by 5 years, <italic>n</italic> (%)</td><td align="center" valign="top" charoff="50">55 (53.4)</td><td align="center" valign="top" charoff="50">64 (62.1)</td><td align="center" valign="top" charoff="50">38 (36.5)</td></tr><tr><td align="left" valign="top" charoff="50"> Progression to AP/BC on study, <italic>n</italic> (%)</td><td align="center" valign="top" charoff="50">1 (1.0)</td><td align="center" valign="top" charoff="50">1 (1.0)</td><td align="center" valign="top" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year PFS on study, %<xref ref-type="fn" rid="t2-fn2">a</xref></td><td align="center" valign="top" charoff="50">96.0</td><td align="center" valign="top" charoff="50">99.0</td><td align="center" valign="top" charoff="50">100</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year OS on study, %<xref ref-type="fn" rid="t2-fn2">a</xref></td><td align="center" valign="top" charoff="50">97.0</td><td align="center" valign="top" charoff="50">99.0</td><td align="center" valign="top" charoff="50">100</td></tr><tr><td align="left" valign="top" charoff="50"> Treatment-emergent mutations, <italic>n</italic> (%)<xref ref-type="fn" rid="t2-fn3">b</xref></td><td align="center" valign="top" charoff="50">1 (1.0)</td><td align="center" valign="top" charoff="50">2 (1.9)</td><td align="center" valign="top" charoff="50">1 (1.0)</td></tr><tr><td align="left" valign="top" charoff="50">Intermediate Sokal risk, <italic>n</italic></td><td align="center" valign="top" charoff="50">101</td><td align="center" valign="top" charoff="50">100</td><td align="center" valign="top" charoff="50">101</td></tr><tr><td align="left" valign="top" charoff="50"> MR<sup>4.5</sup> by 5 years, <italic>n</italic> (%)</td><td align="center" valign="top" charoff="50">61 (60.4)</td><td align="center" valign="top" charoff="50">50 (50.0)</td><td align="center" valign="top" charoff="50">33 (32.7)</td></tr><tr><td align="left" valign="top" charoff="50"> Progression to AP/BC on study, <italic>n</italic> (%)</td><td align="center" valign="top" charoff="50">2 (2.0)</td><td align="center" valign="top" charoff="50">1 (1.0)</td><td align="center" valign="top" charoff="50">10 (9.9)</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year PFS on study, %<xref ref-type="fn" rid="t2-fn2">a</xref></td><td align="center" valign="top" charoff="50">92.9</td><td align="center" valign="top" charoff="50">96.9</td><td align="center" valign="top" charoff="50">87.9</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year OS on study, %<xref ref-type="fn" rid="t2-fn2">a</xref></td><td align="center" valign="top" charoff="50">93.8</td><td align="center" valign="top" charoff="50">96.9</td><td align="center" valign="top" charoff="50">88.5</td></tr><tr><td align="left" valign="top" charoff="50"> Treatment-emergent mutations, <italic>n</italic> (%)<xref ref-type="fn" rid="t2-fn3">b</xref></td><td align="center" valign="top" charoff="50">5 (5.0)</td><td align="center" valign="top" charoff="50">3 (3.0)</td><td align="center" valign="top" charoff="50">8 (7.9)</td></tr><tr><td align="left" valign="top" charoff="50">High Sokal risk, <italic>n</italic></td><td align="center" valign="top" charoff="50">78</td><td align="center" valign="top" charoff="50">78</td><td align="center" valign="top" charoff="50">78</td></tr><tr><td align="left" valign="top" charoff="50"> MR<sup>4.5</sup> by 5 years, <italic>n</italic> (%)</td><td align="center" valign="top" charoff="50">35 (44.9)</td><td align="center" valign="top" charoff="50">33 (42.3)</td><td align="center" valign="top" charoff="50">18 (23.1)</td></tr><tr><td align="left" valign="top" charoff="50"> Progression to AP/BC on study, <italic>n</italic> (%)</td><td align="center" valign="top" charoff="50">7 (9.0)</td><td align="center" valign="top" charoff="50">4 (5.1)</td><td align="center" valign="top" charoff="50">11 (14.1)</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year PFS on study, %<xref ref-type="fn" rid="t2-fn2">a</xref></td><td align="center" valign="top" charoff="50">86.2</td><td align="center" valign="top" charoff="50">90.0</td><td align="center" valign="top" charoff="50">82.6</td></tr><tr><td align="left" valign="top" charoff="50"> Estimated 5-year OS on study, %<xref ref-type="fn" rid="t2-fn2">a</xref></td><td align="center" valign="top" charoff="50">88.8</td><td align="center" valign="top" charoff="50">91.5</td><td align="center" valign="top" charoff="50">84.2</td></tr><tr><td align="left" valign="top" charoff="50"> Treatment-emergent mutations, <italic>n</italic> (%)<xref ref-type="fn" rid="t2-fn3">b</xref></td><td align="center" valign="top" charoff="50">6 (7.7)</td><td align="center" valign="top" charoff="50">6 (7.7)</td><td align="center" valign="top" charoff="50">13 (16.7)</td></tr></tbody></table><table-wrap-foot><fn id="t2-fn1"><p>Abbreviations: AP/BC, accelerated phase/blast crisis; MMR, major molecular response; MR<sup>4.5</sup>, molecular response 4.5 (<italic>BCR-ABL</italic>⩽0.0032% on the International Scale); OS, overall survival; PFS, progression-free survival.</p></fn><fn id="t2-fn2"><label>a</label><p>Estimated by Kaplan–Meier analysis.</p></fn><fn id="t2-fn3"><label>b</label><p>Post-baseline mutational analysis in patients without baseline mutations was triggered by failure to achieve MMR at 1 year, confirmed loss of MMR, ⩾fivefold rise in <italic>BCR-ABL</italic> transcript levels and end of treatment. Evaluation of the frequency of treatment-emergent mutations according to Sokal risk score was exploratory. In the nilotinib 300-mg twice-daily, nilotinib 400-mg twice-daily and imatinib arms, respectively, 48, 43 and 74 patients with low Sokal risk scores; 34, 52 and 67 patients with intermediate Sokal risk scores; and 38, 41 and 58 patients with high Sokal risk scores had post-baseline mutational analyses by the data cutoff for this analysis.</p></fn></table-wrap-foot></table-wrap><table-wrap id="tbl3"><label>Table 3</label><caption><title>Adverse events (regardless of relationship to study drug) and newly occurring or worsening hematologic and biochemical laboratory abnormalities reported by the data cutoff</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="char" char="("></col><col align="char" char="("></col><col align="char" char="("></col><col align="char" char="("></col><col align="char" char="("></col><col align="char" char="("></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th><th colspan="2" align="center" valign="top" char="(" charoff="50"><italic>Nilotinib 300 mg twice daily (</italic>n=<italic>279)</italic><hr></hr></th><th colspan="2" align="center" valign="top" char="(" charoff="50"><italic>Nilotinib 400 mg twice daily (</italic>n=<italic>277)</italic><hr></hr></th><th colspan="2" align="center" valign="top" char="(" charoff="50"><italic>Imatinib 400 mg once daily (</italic>n=<italic>280)</italic><hr></hr></th></tr><tr><th align="left" valign="top" charoff="50"> </th><th align="center" valign="top" char="(" charoff="50"><italic>Any grade</italic></th><th align="center" valign="top" char="(" charoff="50"><italic>Grade 3/4</italic></th><th align="center" valign="top" char="(" charoff="50"><italic>Any grade</italic></th><th align="center" valign="top" char="(" charoff="50"><italic>Grade 3/4</italic></th><th align="center" valign="top" char="(" charoff="50"><italic>Any grade</italic></th><th align="center" valign="top" char="(" charoff="50"><italic>Grade 3/4</italic></th></tr></thead><tbody valign="top"><tr><td colspan="7" align="left" valign="top" charoff="50"><italic>Nonhematologic AEs reported in</italic> ⩾<italic>20% of patients in any arm,</italic> n <italic>(%)</italic></td></tr><tr><td align="left" valign="top" charoff="50"> Rash</td><td align="char" valign="top" char="(" charoff="50">107 (38.4)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">124 (44.8)</td><td align="char" valign="top" char="(" charoff="50">7 (2.5)</td><td align="char" valign="top" char="(" charoff="50">52 (18.6)</td><td align="char" valign="top" char="(" charoff="50">5 (1.8)</td></tr><tr><td align="left" valign="top" charoff="50"> Headache</td><td align="char" valign="top" char="(" charoff="50">89 (31.9)</td><td align="char" valign="top" char="(" charoff="50">9 (3.2)</td><td align="char" valign="top" char="(" charoff="50">100 (36.1)</td><td align="char" valign="top" char="(" charoff="50">7 (2.5)</td><td align="char" valign="top" char="(" charoff="50">64 (22.9)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td></tr><tr><td align="left" valign="top" charoff="50"> Nasopharyngitis</td><td align="char" valign="top" char="(" charoff="50">75 (26.9)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">63 (22.7)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">60 (21.4)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Fatigue</td><td align="char" valign="top" char="(" charoff="50">65 (23.3)</td><td align="char" valign="top" char="(" charoff="50">3 (1.1)</td><td align="char" valign="top" char="(" charoff="50">54 (19.5)</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td><td align="char" valign="top" char="(" charoff="50">56 (20.0)</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td></tr><tr><td align="left" valign="top" charoff="50"> Nausea</td><td align="char" valign="top" char="(" charoff="50">62 (22.2)</td><td align="char" valign="top" char="(" charoff="50">6 (2.2)</td><td align="char" valign="top" char="(" charoff="50">85 (30.7)</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td><td align="char" valign="top" char="(" charoff="50">115 (41.1)</td><td align="char" valign="top" char="(" charoff="50">5 (1.8)</td></tr><tr><td align="left" valign="top" charoff="50"> Arthralgia</td><td align="char" valign="top" char="(" charoff="50">61 (21.9)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">56 (20.2)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">47 (16.8)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td></tr><tr><td align="left" valign="top" charoff="50"> Pruritus</td><td align="char" valign="top" char="(" charoff="50">59 (21.1)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">52 (18.8)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">20 (7.1)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Constipation</td><td align="char" valign="top" char="(" charoff="50">56 (20.1)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">46 (16.6)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">23 (8.2)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Diarrhea</td><td align="char" valign="top" char="(" charoff="50">54 (19.4)</td><td align="char" valign="top" char="(" charoff="50">3 (1.1)</td><td align="char" valign="top" char="(" charoff="50">63 (22.7)</td><td align="char" valign="top" char="(" charoff="50">7 (2.5)</td><td align="char" valign="top" char="(" charoff="50">129 (46.1)</td><td align="char" valign="top" char="(" charoff="50">10 (3.6)</td></tr><tr><td align="left" valign="top" charoff="50"> Upper respiratory tract infection</td><td align="char" valign="top" char="(" charoff="50">47 (16.8)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">59 (21.3)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">40 (14.3)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Vomiting</td><td align="char" valign="top" char="(" charoff="50">42 (15.1)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">56 (20.2)</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td><td align="char" valign="top" char="(" charoff="50">75 (26.8)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td></tr><tr><td align="left" valign="top" charoff="50"> Muscle spasms</td><td align="char" valign="top" char="(" charoff="50">34 (12.2)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">32 (11.6)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">95 (33.9)</td><td align="char" valign="top" char="(" charoff="50">3 (1.1)</td></tr><tr><td align="left" valign="top" charoff="50"> Peripheral edema</td><td align="char" valign="top" char="(" charoff="50">26 (9.3)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">37 (13.4)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">56 (20.0)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td></tr><tr><td colspan="7" align="left" valign="top" charoff="50"><italic>Other AEs of interest,</italic> n <italic>(%)</italic><xref ref-type="fn" rid="t3-fn2">a</xref></td></tr><tr><td align="left" valign="top" charoff="50"> Medically severe fluid retention<xref ref-type="fn" rid="t3-fn3">b</xref></td><td align="char" valign="top" char="(" charoff="50">31 (11.1)</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td><td align="char" valign="top" char="(" charoff="50">40 (14.4)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">65 (23.2)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Peripheral edema</td><td align="char" valign="top" char="(" charoff="50">26 (9.3)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">37 (13.4)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">56 (20.0)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Pleural effusion</td><td align="char" valign="top" char="(" charoff="50">5 (1.8)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">3 (1.1)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Pericardial effusion</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">3 (1.1)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Pulmonary edema</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Fluid retention</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">7 (2.5)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Second malignancies</td><td align="char" valign="top" char="(" charoff="50">13 (4.7)</td><td align="char" valign="top" char="(" charoff="50">8 (2.9)</td><td align="char" valign="top" char="(" charoff="50">9 (3.2)</td><td align="char" valign="top" char="(" charoff="50">8 (2.9)</td><td align="char" valign="top" char="(" charoff="50">9 (3.2)</td><td align="char" valign="top" char="(" charoff="50">7 (2.5)</td></tr><tr><td align="left" valign="top" charoff="50"> Hepatotoxicity</td><td align="char" valign="top" char="(" charoff="50">5 (1.8)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">15 (5.4)</td><td align="char" valign="top" char="(" charoff="50">5 (1.8)</td><td align="char" valign="top" char="(" charoff="50">7 (2.5)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td></tr><tr><td align="left" valign="top" charoff="50"> Pancreatitis</td><td align="char" valign="top" char="(" charoff="50">5 (1.8)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">8 (2.9)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Significant bleeding</td><td align="char" valign="top" char="(" charoff="50">10 (3.6)</td><td align="char" valign="top" char="(" charoff="50">3 (1.1)</td><td align="char" valign="top" char="(" charoff="50">15 (5.4)</td><td align="char" valign="top" char="(" charoff="50">5 (1.8)</td><td align="char" valign="top" char="(" charoff="50">5 (1.8)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td></tr><tr><td align="left" valign="top" charoff="50"> CNS hemorrhage</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td></tr><tr><td align="left" valign="top" charoff="50"> Gastrointestinal hemorrhage</td><td align="char" valign="top" char="(" charoff="50">8 (2.9)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">14 (5.1)</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Hypertension</td><td align="char" valign="top" char="(" charoff="50">29 (10.4)</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td><td align="char" valign="top" char="(" charoff="50">23 (8.3)</td><td align="char" valign="top" char="(" charoff="50">3 (1.1)</td><td align="char" valign="top" char="(" charoff="50">12 (4.3)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td></tr><tr><td align="left" valign="top" charoff="50"> Pulmonary hypertension</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Symptomatic QT prolongation<xref ref-type="fn" rid="t3-fn4">c</xref></td><td align="char" valign="top" char="(" charoff="50">5 (1.8)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">7 (2.5)</td><td align="char" valign="top" char="(" charoff="50">2 (0.7)</td><td align="char" valign="top" char="(" charoff="50">8 (2.9)</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td></tr><tr><td align="left" valign="top" charoff="50"> Retinal vein occlusion</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Thrombophlebitis</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">3 (1.1)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Superficial thrombophlebitis</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Deep venous thrombosis</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> Cardiovascular events</td><td align="char" valign="top" char="(" charoff="50">21 (7.5)</td><td align="char" valign="top" char="(" charoff="50">13 (4.7)</td><td align="char" valign="top" char="(" charoff="50">37 (13.4)</td><td align="char" valign="top" char="(" charoff="50">24 (8.7)</td><td align="char" valign="top" char="(" charoff="50">6 (2.1)</td><td align="char" valign="top" char="(" charoff="50">5 (1.8)</td></tr><tr><td align="left" valign="top" charoff="50"> Ischemic heart disease</td><td align="char" valign="top" char="(" charoff="50">11 (3.9)</td><td align="char" valign="top" char="(" charoff="50">6 (2.2)</td><td align="char" valign="top" char="(" charoff="50">24 (8.7)</td><td align="char" valign="top" char="(" charoff="50">17 (6.1)</td><td align="char" valign="top" char="(" charoff="50">5 (1.8)</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td></tr><tr><td align="left" valign="top" charoff="50"> Ischemic cerebrovascular event</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td><td align="char" valign="top" char="(" charoff="50">3 (1.1)</td><td align="char" valign="top" char="(" charoff="50">9 (3.2)</td><td align="char" valign="top" char="(" charoff="50">6 (2.2)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td></tr><tr><td align="left" valign="top" charoff="50"> Peripheral artery disease</td><td align="char" valign="top" char="(" charoff="50">7 (2.5)</td><td align="char" valign="top" char="(" charoff="50">4 (1.4)</td><td align="char" valign="top" char="(" charoff="50">7 (2.5)</td><td align="char" valign="top" char="(" charoff="50">3 (1.1)</td><td align="center" valign="top" char="(" charoff="50">0</td><td align="center" valign="top" char="(" charoff="50">0</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td></tr><tr><td colspan="7" align="left" valign="top" charoff="50"><italic>Grade 3/4 hematologic abnormalities reported in</italic> ⩾<italic>5% of patients in any arm,</italic> n <italic>(%)</italic></td></tr><tr><td align="left" valign="top" charoff="50"> Lymphopenia</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">35 (12.5)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">23 (8.3)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">40 (14.3)</td></tr><tr><td align="left" valign="top" charoff="50"> Neutropenia</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">34 (12.2)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">31 (11.2)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">61 (21.8)</td></tr><tr><td align="left" valign="top" charoff="50"> Thrombocytopenia</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">29 (10.4)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">34 (12.3)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">25 (8.9)</td></tr><tr><td align="left" valign="top" charoff="50"> Anemia</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">11 (3.9)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">13 (4.7)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">18 (6.4)</td></tr><tr><td align="left" valign="top" charoff="50"> Leukopenia</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">9 (3.2)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">9 (3.2)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">29 (10.4)</td></tr><tr><td align="left" valign="top" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50"> </td></tr><tr><td colspan="7" align="left" valign="top" charoff="50"><italic>Grade 3/4 biochemical abnormalities reported in</italic> ⩾<italic>5% of patients in any arm,</italic> n <italic>(%)</italic></td></tr><tr><td align="left" valign="top" charoff="50"> Increased lipase (blood)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">25 (9.0)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">28 (10.1)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">12 (4.3)</td></tr><tr><td align="left" valign="top" charoff="50"> Decreased phosphate</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">22 (7.9)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">28 (10.1)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">29 (10.4)</td></tr><tr><td align="left" valign="top" charoff="50"> Increased glucose</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">20 (7.2)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">19 (6.9)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td></tr><tr><td align="left" valign="top" charoff="50"> Increased alanine aminotransferase</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">12 (4.3)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">26 (9.4)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">7 (2.5)</td></tr><tr><td align="left" valign="top" charoff="50"> Increased total bilirubin</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">12 (4.3)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">25 (9.0)</td><td align="char" valign="top" char="(" charoff="50"> </td><td align="char" valign="top" char="(" charoff="50">1 (0.4)</td></tr></tbody></table><table-wrap-foot><fn id="t3-fn1"><p>Abbreviations: AE, adverse event; CNS, central nervous system.</p></fn><fn id="t3-fn2"><label>a</label><p>Medically severe fluid retention, hepatotoxicity, pancreatitis, significant bleeding, CNS hemorrhage, gastrointestinal hemorrhage, symptomatic QT prolongation, cardiovascular events, ischemic heart disease, ischemic cerebrovascular events and peripheral artery disease refer to predefined groupings of Medical Dictionary for Regulatory Activities (MedDRA) preferred terms or standardized MedDRA queries. Patients with multiple events for a given AE term or category were counted only once for the AE term or category.</p></fn><fn id="t3-fn3"><label>b</label><p>No cases of cardiac tamponade were reported in any arm by the 5-year data cutoff.</p></fn><fn id="t3-fn4"><label>c</label><p>By the 5-year data cutoff, all reported symptomatic QT prolongation events were either syncope or convulsion. The other preferred terms included in the symptomatic QT prolongation group (torsade de pointes, sudden death, ventricular tachycardia, ventricular fibrillation and ventricular flutter) were not reported in any patient by the data cutoff.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list><country><li>Allemagne</li><li>Australie</li><li>Brésil</li><li>Corée du Sud</li><li>France</li><li>Italie</li><li>Japon</li><li>Royaume-Uni</li><li>Suisse</li><li>Thaïlande</li><li>États-Unis</li></country></list><tree><country name="Allemagne"><noRegion><name sortKey="Hochhaus, A" sort="Hochhaus, A" uniqKey="Hochhaus A" first="A" last="Hochhaus">A. Hochhaus</name></noRegion><name sortKey="Le Coutre, P D" sort="Le Coutre, P D" uniqKey="Le Coutre P" first="P D" last="Le Coutre">P D Le Coutre</name></country><country name="Italie"><noRegion><name sortKey="Saglio, G" sort="Saglio, G" uniqKey="Saglio G" first="G" last="Saglio">G. Saglio</name></noRegion></country><country name="Australie"><noRegion><name sortKey="Hughes, T P" sort="Hughes, T P" uniqKey="Hughes T" first="T P" last="Hughes">T P Hughes</name></noRegion></country><country name="États-Unis"><noRegion><name sortKey="Larson, R A" sort="Larson, R A" uniqKey="Larson R" first="R A" last="Larson">R A Larson</name></noRegion><name sortKey="Dalal, D" sort="Dalal, D" uniqKey="Dalal D" first="D" last="Dalal">D. Dalal</name><name sortKey="Deng, W" sort="Deng, W" uniqKey="Deng W" first="W" last="Deng">W. Deng</name><name sortKey="Donohue, B" sort="Donohue, B" uniqKey="Donohue B" first="B" last="Donohue">B. Donohue</name><name sortKey="Flinn, I W" sort="Flinn, I W" uniqKey="Flinn I" first="I W" last="Flinn">I W Flinn</name><name sortKey="Kantarjian, H M" sort="Kantarjian, H M" uniqKey="Kantarjian H" first="H M" last="Kantarjian">H M Kantarjian</name></country><country name="Corée du Sud"><noRegion><name sortKey="Kim, D W" sort="Kim, D W" uniqKey="Kim D" first="D-W" last="Kim">D-W Kim</name></noRegion></country><country name="Thaïlande"><noRegion><name sortKey="Issaragrisil, S" sort="Issaragrisil, S" uniqKey="Issaragrisil S" first="S" last="Issaragrisil">S. Issaragrisil</name></noRegion></country><country name="France"><noRegion><name sortKey="Etienne, G" sort="Etienne, G" uniqKey="Etienne G" first="G" last="Etienne">G. Etienne</name></noRegion></country><country name="Brésil"><noRegion><name sortKey="Dorlhiac Llacer, P E" sort="Dorlhiac Llacer, P E" uniqKey="Dorlhiac Llacer P" first="P E" last="Dorlhiac-Llacer">P E Dorlhiac-Llacer</name></noRegion></country><country name="Royaume-Uni"><noRegion><name sortKey="Clark, R E" sort="Clark, R E" uniqKey="Clark R" first="R E" last="Clark">R E Clark</name></noRegion></country><country name="Japon"><noRegion><name sortKey="Nakamae, H" sort="Nakamae, H" uniqKey="Nakamae H" first="H" last="Nakamae">H. Nakamae</name></noRegion></country><country name="Suisse"><noRegion><name sortKey="Menssen, H D" sort="Menssen, H D" uniqKey="Menssen H" first="H D" last="Menssen">H D Menssen</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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