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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Low incidence of peripheral arterial disease in patients receiving dasatinib in clinical trials</title><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><nlm:aff id="aff1"><institution>Charité, Campus Virchow Klinikum, Medizinische Klinik m.S. Hämatologie und Onkologie, Universitätsmedizin Berlin</institution>, Berlin,<country>Germany</country></nlm:aff></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><nlm:aff id="aff2"><institution>Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Department of Haematology, SA Pathology, University of Adelaide</institution>, Adelaide, South Australia,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Mahon, F X" sort="Mahon, F X" uniqKey="Mahon F" first="F-X" last="Mahon">F-X Mahon</name><affiliation><nlm:aff id="aff3"><institution>Centre Hospitalier Universitaire de Bordeaux, Laboratoire d'Hématologie et Service des Maladies du Sang, Bordeaux et Institut Bergonié</institution>, Bordeaux,<country>France</country></nlm:aff></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><nlm:aff id="aff4"><institution>Division of Hematology, Seoul St Mary's Hospital, The Catholic University of Korea</institution>, Seoul,<country>South Korea</country></nlm:aff></affiliation></author><author><name sortKey="Steegmann, J L" sort="Steegmann, J L" uniqKey="Steegmann J" first="J L" last="Steegmann">J L Steegmann</name><affiliation><nlm:aff id="aff5"><institution>Department of Hematology and IIS-IP, Hospital Universitario de la Princesa</institution>, Madrid,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Shah, N P" sort="Shah, N P" uniqKey="Shah N" first="N P" last="Shah">N P Shah</name><affiliation><nlm:aff id="aff6"><institution>Department of Medicine, Division of Hematology/Oncology, University of California at San Francisco School of Medicine</institution>, San Francisco, CA,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Gooden, K" sort="Gooden, K" uniqKey="Gooden K" first="K" last="Gooden">K. Gooden</name><affiliation><nlm:aff id="aff7"><institution>Bristol-Myers Squibb</institution>, Princeton, NJ,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Wallis, N" sort="Wallis, N" uniqKey="Wallis N" first="N" last="Wallis">N. Wallis</name><affiliation><nlm:aff id="aff7"><institution>Bristol-Myers Squibb</institution>, Princeton, NJ,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Cortes, J E" sort="Cortes, J E" uniqKey="Cortes J" first="J E" last="Cortes">J E Cortes</name><affiliation><nlm:aff id="aff8"><institution>Division of Cancer Medicine, Department of Leukemia, The University of Texas, MD Anderson Cancer Center</institution>, Houston, TX,<country>USA</country></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26686247</idno><idno type="pmc">4935977</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4935977</idno><idno type="RBID">PMC:4935977</idno><idno type="doi">10.1038/leu.2015.352</idno><date when="2016">2016</date><idno type="wicri:Area/Pmc/Corpus">000677</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000677</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Low incidence of peripheral arterial disease in patients receiving dasatinib in clinical trials</title><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><nlm:aff id="aff1"><institution>Charité, Campus Virchow Klinikum, Medizinische Klinik m.S. Hämatologie und Onkologie, Universitätsmedizin Berlin</institution>, Berlin,<country>Germany</country></nlm:aff></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><nlm:aff id="aff2"><institution>Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Department of Haematology, SA Pathology, University of Adelaide</institution>, Adelaide, South Australia,<country>Australia</country></nlm:aff></affiliation></author><author><name sortKey="Mahon, F X" sort="Mahon, F X" uniqKey="Mahon F" first="F-X" last="Mahon">F-X Mahon</name><affiliation><nlm:aff id="aff3"><institution>Centre Hospitalier Universitaire de Bordeaux, Laboratoire d'Hématologie et Service des Maladies du Sang, Bordeaux et Institut Bergonié</institution>, Bordeaux,<country>France</country></nlm:aff></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><nlm:aff id="aff4"><institution>Division of Hematology, Seoul St Mary's Hospital, The Catholic University of Korea</institution>, Seoul,<country>South Korea</country></nlm:aff></affiliation></author><author><name sortKey="Steegmann, J L" sort="Steegmann, J L" uniqKey="Steegmann J" first="J L" last="Steegmann">J L Steegmann</name><affiliation><nlm:aff id="aff5"><institution>Department of Hematology and IIS-IP, Hospital Universitario de la Princesa</institution>, Madrid,<country>Spain</country></nlm:aff></affiliation></author><author><name sortKey="Shah, N P" sort="Shah, N P" uniqKey="Shah N" first="N P" last="Shah">N P Shah</name><affiliation><nlm:aff id="aff6"><institution>Department of Medicine, Division of Hematology/Oncology, University of California at San Francisco School of Medicine</institution>, San Francisco, CA,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Gooden, K" sort="Gooden, K" uniqKey="Gooden K" first="K" last="Gooden">K. Gooden</name><affiliation><nlm:aff id="aff7"><institution>Bristol-Myers Squibb</institution>, Princeton, NJ,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Wallis, N" sort="Wallis, N" uniqKey="Wallis N" first="N" last="Wallis">N. Wallis</name><affiliation><nlm:aff id="aff7"><institution>Bristol-Myers Squibb</institution>, Princeton, NJ,<country>USA</country></nlm:aff></affiliation></author><author><name sortKey="Cortes, J E" sort="Cortes, J E" uniqKey="Cortes J" first="J E" last="Cortes">J E Cortes</name><affiliation><nlm:aff id="aff8"><institution>Division of Cancer Medicine, Department of Leukemia, The University of Texas, MD Anderson Cancer Center</institution>, Houston, TX,<country>USA</country></nlm:aff></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><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></listBibl></div1></back></TEI><pmc article-type="letter"><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">26686247</article-id><article-id pub-id-type="pmc">4935977</article-id><article-id pub-id-type="pii">leu2015352</article-id><article-id pub-id-type="doi">10.1038/leu.2015.352</article-id><article-categories><subj-group subj-group-type="heading"><subject>Letter to the Editor</subject></subj-group></article-categories><title-group><article-title>Low incidence of peripheral arterial disease in patients receiving dasatinib in clinical trials</article-title><alt-title alt-title-type="running">Letter to the Editor</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>le Coutre</surname><given-names>P D</given-names></name><xref ref-type="aff" rid="aff1">1</xref><xref ref-type="corresp" rid="caf1">*</xref></contrib><contrib contrib-type="author"><name><surname>Hughes</surname><given-names>T P</given-names></name><xref ref-type="aff" rid="aff2">2</xref></contrib><contrib contrib-type="author"><name><surname>Mahon</surname><given-names>F-X</given-names></name><xref ref-type="aff" rid="aff3">3</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>D-W</given-names></name><xref ref-type="aff" rid="aff4">4</xref></contrib><contrib contrib-type="author"><name><surname>Steegmann</surname><given-names>J L</given-names></name><xref ref-type="aff" rid="aff5">5</xref></contrib><contrib contrib-type="author"><name><surname>Shah</surname><given-names>N P</given-names></name><xref ref-type="aff" rid="aff6">6</xref></contrib><contrib contrib-type="author"><name><surname>Gooden</surname><given-names>K</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Wallis</surname><given-names>N</given-names></name><xref ref-type="aff" rid="aff7">7</xref></contrib><contrib contrib-type="author"><name><surname>Cortes</surname><given-names>J E</given-names></name><xref ref-type="aff" rid="aff8">8</xref></contrib><aff id="aff1"><label>1</label><institution>Charité, Campus Virchow Klinikum, Medizinische Klinik m.S. Hämatologie und Onkologie, Universitätsmedizin Berlin</institution>, Berlin,<country>Germany</country></aff><aff id="aff2"><label>2</label><institution>Cancer Theme, South Australian Health and Medical Research Institute (SAHMRI), Department of Haematology, SA Pathology, University of Adelaide</institution>, Adelaide, South Australia,<country>Australia</country></aff><aff id="aff3"><label>3</label><institution>Centre Hospitalier Universitaire de Bordeaux, Laboratoire d'Hématologie et Service des Maladies du Sang, Bordeaux et Institut Bergonié</institution>, Bordeaux,<country>France</country></aff><aff id="aff4"><label>4</label><institution>Division of Hematology, Seoul St Mary's Hospital, The Catholic University of Korea</institution>, Seoul,<country>South Korea</country></aff><aff id="aff5"><label>5</label><institution>Department of Hematology and IIS-IP, Hospital Universitario de la Princesa</institution>, Madrid,<country>Spain</country></aff><aff id="aff6"><label>6</label><institution>Department of Medicine, Division of Hematology/Oncology, University of California at San Francisco School of Medicine</institution>, San Francisco, CA,<country>USA</country></aff><aff id="aff7"><label>7</label><institution>Bristol-Myers Squibb</institution>, Princeton, NJ,<country>USA</country></aff><aff id="aff8"><label>8</label><institution>Division of Cancer Medicine, Department of Leukemia, The University of Texas, MD Anderson Cancer Center</institution>, Houston, TX,<country>USA</country></aff></contrib-group><author-notes><corresp id="caf1"><label>*</label>E-mail: <email>Philipp.lecoutre@charite.de</email></corresp></author-notes><pub-date pub-type="ppub"><month>07</month><year>2016</year></pub-date><pub-date pub-type="epreprint"><day>21</day><month>12</month><year>2015</year></pub-date><pub-date pub-type="epub"><day>12</day><month>01</month><year>2016</year></pub-date><volume>30</volume><issue>7</issue><fpage>1593</fpage><lpage>1596</lpage><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></article-meta></front><body><p>The oral tyrosine kinase inhibitors (TKI) dasatinib, imatinib, ponatinib, nilotinib and bosutinib each target BCR-ABL, yet are structurally distinct from one another.<sup><xref ref-type="bibr" rid="bib1">1</xref>, <xref ref-type="bibr" rid="bib2">2</xref>, <xref ref-type="bibr" rid="bib3">3</xref>, <xref ref-type="bibr" rid="bib4">4</xref>, <xref ref-type="bibr" rid="bib5">5</xref>, <xref ref-type="bibr" rid="bib6">6</xref></sup> The selection of BCR-ABL TKI treatment for an individual patient is influenced by factors including any previous treatment, likelihood of benefit, risk of toxicities and the potential for end-organ damage resulting from use, particularly as a long-term therapy is expected in chronic myeloid leukemia in chronic phase (CML-CP). Despite considerable overlap of safety profiles, there are distinct drug-specific adverse events associated with each TKI.<sup><xref ref-type="bibr" rid="bib2">2</xref></sup></p><p>Peripheral arterial disease (PAD) is often associated with claudication, and may result in critical limb ischemia, and increased risks of loss of limb or death.<sup><xref ref-type="bibr" rid="bib7">7</xref></sup> We evaluated safety databases of dasatinib clinical trials in patients with Philadelphia chromosome-positive (Ph+) leukemias to identify PAD or PAD-related events. We also conducted a standardized incidence ratio (SIR) analysis to evaluate the rate of PAD or PAD-related events in the trials relative to the rate in external reference populations derived from administrative data sets, representing a general adult population in the United States and a CML population that did not receive dasatinib. This retrospective analysis used pooled safety data from 2712 adults with CML or Ph+ acute lymphoblastic leukemia (ALL) treated with dasatinib in 11 clinical trials, including two first-line trials (<italic>n</italic>=324) and nine trials in imatinib-resistant or -intolerant patients (<italic>n</italic>=2388; <xref ref-type="supplementary-material" rid="sup1">Supplementary Table S1</xref>). The median duration of dasatinib treatment was 19 months (range: 0.03–93 months). The trial enrollment criteria permitted inclusion of patients with myocardial infarction >6 months prior, congestive heart failure >3 months prior and previously uncontrolled angina controlled ⩾3 months.</p><p>Bristol-Myers Squibb safety databases for the included trials were examined to identify PAD or PAD-related events, using the following Medical Dictionary for Regulatory Activities preferred terms: arterial stenosis, arterial thrombosis, arteriosclerosis, arterial stenosis limb, intermittent claudication, femoral artery occlusion, necrosis ischemic and PAD.</p><p>For the SIR analysis (SIR=observed number of events/expected number of events; detailed description in <xref ref-type="supplementary-material" rid="sup1">Supplementary Materials</xref>), two external populations were extracted from Truven Health Analytics Marketscan Commercial Claims and Medicare <xref ref-type="supplementary-material" rid="sup1">Supplementary database</xref> (Ann Arbor, MI, USA) between 2008 and 2013. MarketScan consists of data from commercial health plans, Medicaid, Medicare, and self-insurance for Americans. Each reference population included individuals enrolled in the databases for ⩾60 days before the index date. Adult patients were included in the general reference population (<italic>n</italic>=90 000 000), and the CML reference population had ⩾2 diagnostic codes for CML and were not using dasatinib (<italic>n</italic>=15 000). To obtain the expected number of cases, the age and gender-specific person-time of dasatinib-treated patients in the trials were multiplied by the age and gender-specific rates of events in the external populations.</p><p>PAD or PAD-related events were detected in 11 patients during dasatinib treatment among 2712 individuals with a cumulative dasatinib exposure of 6421 patient-years, which corresponds to a cumulative incidence of 0.4% and an incidence rate (per 100 patient-years) of 0.2%. Of the 11 patients, all were previously treated with a TKI; 8 were resistant and 3 were intolerant to prior imatinib therapy (<xref rid="tbl1" ref-type="table">Table 1</xref>). No cases of PAD or PAD-related events were identified among the 258 patients treated with first-line dasatinib in DASatinib versus Imatinib Study In treatment-Naive CML patients (DASISION) (median duration of 60 months (range: 0.03–73 months)). Characteristics, comorbidities and risk factors of the 11 patients with PAD or a PAD-related event are shown in <xref rid="tbl1" ref-type="table">Table 1</xref>. For these patients, median age at baseline was 68 years (range: 44–80 years) and median duration of dasatinib before diagnosis of PAD or PAD-related event was 777 days (range: 3–2227 days). Median duration of prior imatinib therapy amongst these patients was 29 months (<italic>n</italic>=9; range: 2–74 months). Of the 11 patients, 8 had CML-CP, 2 had CML in accelerated phase (CML-AP) and one had CML in blast phase (CML-BP) of lymphoid phenotype. Ten of the 11 patients were on BID (twice daily) dosing regimens. Of the eight patients with CML-CP, only one started at a dose of 100 mg QD (once daily), the current recommended dose of dasatinib for CML-CP.<sup><xref ref-type="bibr" rid="bib2">2</xref></sup> Dosing regimens for the other seven patients with CML-CP ranged from 25 to 70 mg BID. The current recommended dose for CML-AP or CML-BP is 140 mg QD;<sup><xref ref-type="bibr" rid="bib2">2</xref></sup> however, the patients with CML-AP (<italic>n</italic>=2) and CML-BP (<italic>n</italic>=1) received a 70 mg BID starting dose of dasatinib.</p><p>All 11 patients had pre-existing comorbidities/conditions that potentially increased the risk of developing PAD (<xref rid="tbl1" ref-type="table">Table 1</xref>), including one patient who had prior arterial bypass surgery, one with a history of angioplasty and stent, and one who had pre-existing PAD. Furthermore, six patients had hypertension, four had pre-existing ischemic heart disease, four were former or current smokers, two had pre-existing noncardiac atherosclerosis, two had hypercholesterolemia, two had diabetes mellitus and one had deep vein thrombosis (DVT). Of nine patients with PAD or a PAD-related event with available data, all were receiving other medications at baseline. The PAD or PAD-related events in the 11 cases included intermittent claudication (four patients), femoral artery occlusion (two patients), PAD (two patients), peripheral ischemia (two patients), peripheral artery thrombosis (one patients) and peripheral vascular disorder (one patient), with one patient experiencing two of these events (<xref rid="tbl1" ref-type="table">Table 1</xref>). All events identified were Common Terminology Criteria grade ⩽3. Of seven patients with available molecular response data, best responses at any time included 27% (<italic>n</italic>=3) with a major molecular response, 18% (<italic>n</italic>=2) achieving complete molecular response (CMR<sub>4.5</sub>) and 36% (<italic>n</italic>=4) achieving a complete cytogenetic response. Dasatinib treatment was interrupted in five patients due to PAD or a PAD-related event, and no patients discontinued dasatinib because of PAD or PAD-related events (<xref rid="tbl1" ref-type="table">Table 1</xref>).</p><p>SIR analysis showed that the observed number of PAD or PAD-related events (<italic>n</italic>=11) in the pooled population did not exceed the expected number of events (<italic>n</italic>=20) in the general population (SIR (95% confidence interval; CI), 0.56 (0.31–1.01)). Similarly, the observed number of PAD or PAD-related events (<italic>n</italic>=11) in the pooled population did not exceed the expected number (<italic>n</italic>=43) based on rates in the reference CML population (SIR (95% CI), 0.26 (0.14–0.46); <xref ref-type="supplementary-material" rid="sup1">Supplementary Table S2</xref>).</p><p>The current analysis investigated the incidence of PAD or PAD-related events in patients treated with dasatinib to test the hypothesis that PAD might be a class effect among second- and third-generation BCR-ABL TKIs. Previous reports have described an association of PAD with either ponatinib or nilotinib treatment.<sup><xref ref-type="bibr" rid="bib4">4</xref>, <xref ref-type="bibr" rid="bib5">5</xref></sup> The cumulative incidence and incidence rate (per 100 patient-years) reported here are higher than those previously published in a retrospective analysis by Giles and colleagues for imatinib (0.2% and 0.1%, respectively); however, they are lower than cited for nilotinib (1.3% and 0.5%, respectively) and interferon-α plus cytarabine (0.6% and 0.6%, respectively; <xref rid="tbl2" ref-type="table">Table 2</xref>).<sup><xref ref-type="bibr" rid="bib8">8</xref></sup> No PAD or PAD-related events were identified in newly diagnosed CML patients treated with dasatinib in the DASISION trial, which has the longest median exposure time to dasatinib of any study.</p><p>Generally, risk factors for cardiovascular disease are also risk factors for PAD or PAD-related events.<sup><xref ref-type="bibr" rid="bib7">7</xref>, <xref ref-type="bibr" rid="bib9">9</xref></sup> The prevalence of PAD increases with age and concomitant cardiovascular disease risk factors.<sup><xref ref-type="bibr" rid="bib8">8</xref>, <xref ref-type="bibr" rid="bib10">10</xref></sup> Some clinical trials report a lower incidence of PAD in CML and Ph+ ALL compared with published rates for the general population; however, this may be affected by the study entry criteria that exclude patients with significant cardiovascular disease.<sup><xref ref-type="bibr" rid="bib7">7</xref>, <xref ref-type="bibr" rid="bib8">8</xref>, <xref ref-type="bibr" rid="bib9">9</xref>, <xref ref-type="bibr" rid="bib11">11</xref></sup> The included dasatinib clinical trials (with the exception of CA180-002) allowed the participation of patients with diabetes and patients with a history of cardiac comorbidities. Ten of the 11 patients with PAD or PAD-related events had at least one potential risk factor for PAD (the remaining patient had DVT).</p><p>The extended survival of CML patients in the TKI era makes it important to understand the implications of long-term treatment and understand better the potentially irreversible and severe toxicities of some TKIs. The results presented here do not show an association between dasatinib treatment and development of symptomatic PAD in patients with CML or Ph+ ALL, and are consistent with the hypothesis that PAD observed in CML patients is not a class effect of second- and third-generation BCR-ABL TKIs. Similar analyses evaluating cardiac and cerebrovascular adverse events in CML patients treated with BCR-ABL TKIs are warranted, based on the findings by Chai-Adisaksopha <italic>et al.</italic><sup><xref ref-type="bibr" rid="bib12">12</xref></sup> Second-generation TKIs, including dasatinib, have established higher rates of molecular remission in CML than reported with imatinib, with the hope for cure or at least treatment-free remissions. When selecting treatment for Ph+ leukemia, physicians should carefully assess overall cardiovascular health, as well as pre-existing comorbidities and risk factors present at baseline.</p></body><back><ack><p>We acknowledge Jeanette A Preston, formerly of BMS, for review of the manuscript. This analysis was supported by BMS. Professional medical writing support was provided by Ami P Modi, PhD and Beverly E Barton, PhD of StemScientific, an Ashfield Company, part of UDG Healthcare plc. We did not receive financial compensation for the manuscript.</p><p><bold>Author contributions</bold></p><p>All authors provided feedback and guidance on the analysis and interpretation of the results, critically reviewed the manuscript and approved the final draft for submission. The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and medical expertise.</p></ack><fn-group><fn><p><xref ref-type="supplementary-material" rid="sup1">Supplementary Information</xref> accompanies this paper on the Leukemia website (http://www.nature.com/leu)</p></fn><fn fn-type="conflict"><p>PDL has received honoraria from BMS, Novartis and Pfizer, and has received research funding from Novartis. TPH has received honoraria and research funding from BMS and Novartis, and has acted in an advisory role for both companies. F-XM has served as a consultant for and has received research funding from BMS and Novartis; he has served on advisory boards for BMS, Novartis, Pfizer and Ariad. D-WK has served as a consultant for and has received honoraria and research funding from Novartis, BMS, Pfizer and Ilyang. JLS has served as a consultant for and received honoraria from BMS, Novartis and Pfizer. NPS has received research funding from BMS, Ariad and Pfizer, and serves as a DSMB member for Teva. KG and NW are employees of BMS. 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Peripheral arterial occlusive disease</article-title>. <source>Scand J Prim Health Care</source><year>1998</year>; <volume>16</volume>: <fpage>177</fpage>–182.<pub-id pub-id-type="pmid">9800232</pub-id></mixed-citation></ref><ref id="bib12"><mixed-citation publication-type="other">Chai-Adisaksopha C, Lam W, Hillis C. <article-title>Major arterial events in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: a meta-analysis</article-title>. <source>Leuk Lymphoma</source><year>2015</year>; e-pub ahead of print 20 October 2015; doi:10.3109/10428194.2015.1091929.</mixed-citation></ref></ref-list><sec sec-type="supplementary-material" id="sup1"><title>Supplementary Material</title><supplementary-material content-type="local-data" id="xob1"><label>Supplementary Informations</label><media xlink:href="leu2015352x1.docx"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></back><floats-group><table-wrap id="tbl1"><label>Table 1</label><caption><title>Characteristics, outcomes, risk factors and management of PAD and PAD-related adverse events</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="center"></col><col align="center"></col><col align="char" char="."></col><col align="center"></col><col align="char" char="."></col><col align="center"></col><col align="center"></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"><italic>Age/CML phase</italic></th><th align="left" valign="top" charoff="50"><italic>Pre-existing comorbidities and risk factors present at baseline</italic></th><th colspan="5" align="center" valign="top" charoff="50"><italic>Adverse event characteristics</italic><hr></hr></th><th colspan="3" align="center" valign="top" charoff="50"><italic>Outcomes (best response at any time)</italic><hr></hr></th><th align="left" valign="top" charoff="50"><italic>Adverse event management</italic></th></tr><tr><th align="left" valign="top" charoff="50"> </th><th align="left" valign="top" charoff="50"> </th><th align="left" valign="top" charoff="50"><italic>Preferred term</italic></th><th align="center" valign="top" char="." charoff="50"><italic>CTC grade</italic><xref ref-type="fn" rid="t1-fn2">a</xref></th><th align="center" valign="top" charoff="50"><italic>Dasatinib starting dose</italic></th><th align="center" valign="top" char="." charoff="50"><italic>Time on dasatinib before onset, days</italic></th><th align="left" valign="top" charoff="50"><italic>First occurrence?</italic></th><th align="left" valign="top" charoff="50"><italic>MMR</italic></th><th align="left" valign="top" charoff="50"><italic>CMR</italic><sub>4.5</sub></th><th align="left" valign="top" charoff="50"><italic>CCyR</italic></th><th align="left" valign="top" charoff="50"><italic>Dasatinib dose modification</italic></th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">73/CP</td><td align="left" valign="top" charoff="50">Pre-existing heart disease, previous smoker</td><td align="left" valign="top" charoff="50">Femoral artery occlusion</td><td align="center" valign="top" char="." charoff="50">1</td><td align="center" valign="top" charoff="50">25 mg BID, 5 d per wk</td><td align="center" valign="top" char="." charoff="50">2227</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">NR</td><td align="left" valign="top" charoff="50">NR</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">Interrupted</td></tr><tr><td align="left" valign="top" charoff="50">68/AP</td><td align="left" valign="top" charoff="50">Previous smoker</td><td align="left" valign="top" charoff="50">Intermittent claudication</td><td align="center" valign="top" char="." charoff="50">2, 2</td><td align="center" valign="top" charoff="50">70 mg BID</td><td align="center" valign="top" char="." charoff="50">NR, 42</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">None</td></tr><tr><td align="left" valign="top" charoff="50">80/AP<xref ref-type="fn" rid="t1-fn3">b</xref></td><td align="left" valign="top" charoff="50">Pre-existing noncardiac atherosclerosis, hypertension, hypercholesterolemia</td><td align="left" valign="top" charoff="50">Femoral artery occlusion</td><td align="center" valign="top" char="." charoff="50">2</td><td align="center" valign="top" charoff="50">70 mg BID</td><td align="center" valign="top" char="." charoff="50">3</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">Interrupted</td></tr><tr><td align="left" valign="top" charoff="50">63/CP</td><td align="left" valign="top" charoff="50">Diabetes mellitus</td><td align="left" valign="top" charoff="50">PAD</td><td align="center" valign="top" char="." charoff="50">1, 3</td><td align="center" valign="top" charoff="50">70 mg BID</td><td align="center" valign="top" char="." charoff="50">343, 657</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">None</td></tr><tr><td align="left" valign="top" charoff="50">74/CP</td><td align="left" valign="top" charoff="50">Pre-existing ischemic heart disease, hypertension, diabetes mellitus</td><td align="left" valign="top" charoff="50">Intermittent claudication</td><td align="center" valign="top" char="." charoff="50">2</td><td align="center" valign="top" charoff="50">70 mg BID</td><td align="center" valign="top" char="." charoff="50">868</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">None</td></tr><tr><td align="left" valign="top" charoff="50">71/CP</td><td align="left" valign="top" charoff="50">Hypertension</td><td align="left" valign="top" charoff="50">Peripheral artery thrombosis</td><td align="center" valign="top" char="." charoff="50">3, 3</td><td align="center" valign="top" charoff="50">50 mg BID</td><td align="center" valign="top" char="." charoff="50">777, 870</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">Interrupted</td></tr><tr><td align="left" valign="top" charoff="50">54/LBP</td><td align="left" valign="top" charoff="50">Deep vein thrombosis</td><td align="left" valign="top" charoff="50">Intermittent claudication</td><td align="center" valign="top" char="." charoff="50">2</td><td align="center" valign="top" charoff="50">70 mg BID</td><td align="center" valign="top" char="." charoff="50">151</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">NR</td><td align="left" valign="top" charoff="50">NR</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">None</td></tr><tr><td align="left" valign="top" charoff="50">67/CP<xref ref-type="fn" rid="t1-fn4">c</xref></td><td align="left" valign="top" charoff="50">Pre-existing ischemic heart disease, pre-existing noncardiac atherosclerosis, hypertension</td><td align="left" valign="top" charoff="50">PAD</td><td align="center" valign="top" char="." charoff="50">3</td><td align="center" valign="top" charoff="50">70 mg BID</td><td align="center" valign="top" char="." charoff="50">367</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">NR</td><td align="left" valign="top" charoff="50">NR</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">None</td></tr><tr><td align="left" valign="top" charoff="50">75/CP</td><td align="left" valign="top" charoff="50">Arterial bypass surgery, pre-existing ischemic heart disease</td><td align="left" valign="top" charoff="50">Intermittent claudication
Peripheral vascular disorder</td><td align="center" valign="top" char="." charoff="50">1
3</td><td align="center" valign="top" charoff="50">50 mg BID</td><td align="center" valign="top" char="." charoff="50">1177
1323</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">NR</td><td align="left" valign="top" charoff="50">NR</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">None
Interrupted</td></tr><tr><td align="left" valign="top" charoff="50">65/CP</td><td align="left" valign="top" charoff="50">PAD on a pre-existing lesion, hypertension, previous smoker</td><td align="left" valign="top" charoff="50">Peripheral ischemia</td><td align="center" valign="top" char="." charoff="50">3, 3, 3</td><td align="center" valign="top" charoff="50">100 mg QD</td><td align="center" valign="top" char="." charoff="50">1229, 1361, 1447</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">No</td><td align="left" valign="top" charoff="50">None</td></tr><tr><td align="left" valign="top" charoff="50">44/CP</td><td align="left" valign="top" charoff="50">History of angioplasty and stent, hypertension, hypercholesterolemia, smoker</td><td align="left" valign="top" charoff="50">Peripheral ischemia</td><td align="center" valign="top" char="." charoff="50">3</td><td align="center" valign="top" charoff="50">50 mg BID</td><td align="center" valign="top" char="." charoff="50">1692</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">Yes</td><td align="left" valign="top" charoff="50">Interrupted</td></tr></tbody></table><table-wrap-foot><fn id="t1-fn1"><p>Abbreviations: AP, accelerated phase; BID, twice daily; CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; CMR, complete molecular response; CP, chronic phase; CTC, Common Terminology Criteria; d, day; LBP, lymphoid blast phase; MMR, major molecular response; NR, not reported; PAD, peripheral arterial disease; QD, once daily; wk, week.</p></fn><fn id="t1-fn2"><label>a</label><p>National Cancer Institute CTCAE v.3.0.</p></fn><fn id="t1-fn3"><label>b</label><p>This patient was the sole patient for whom the PAD-related adverse event was not a first occurrence.</p></fn><fn id="t1-fn4"><label>c</label><p>The chronic phase disease of this patient had clonal evolution.</p></fn></table-wrap-foot></table-wrap><table-wrap id="tbl2"><label>Table 2</label><caption><title>Incidence of PAD and PAD-related events in patients receiving treatment for Ph+ leukemia in clinical trials</title></caption><table frame="hsides" rules="groups" border="1"><colgroup><col align="left"></col><col align="left"></col><col align="center"></col><col align="left"></col><col align="center"></col></colgroup><thead valign="bottom"><tr><th align="left" valign="top" charoff="50"> </th><th align="left" valign="top" charoff="50"><italic>Dasatinib</italic></th><th align="left" valign="top" charoff="50"><italic>Imatinib</italic></th><th align="left" valign="top" charoff="50"><italic>Nilotinib</italic></th><th align="left" valign="top" charoff="50"><italic>No BCR-ABL inhibitor</italic></th></tr></thead><tbody valign="top"><tr><td align="left" valign="top" charoff="50">Dose</td><td align="left" valign="top" charoff="50">15–240 mg per day</td><td align="left" valign="top" charoff="50">400 mg QD or BID</td><td align="left" valign="top" charoff="50">300 or 400 mg BID</td><td align="left" valign="top" charoff="50">IFN 5 × 10<sup>6</sup> U/m<sup>2</sup> per day; Ara-C 20 mg/m<sup>2</sup> per day for 10 days per month</td></tr><tr><td align="left" valign="top" charoff="50">Trial</td><td align="left" valign="top" charoff="50">11 dasatinib trials</td><td align="left" valign="top" charoff="50">TOPS, IRIS, ENESTnd</td><td align="left" valign="top" charoff="50">ENESTnd</td><td align="left" valign="top" charoff="50">IRIS</td></tr><tr><td align="left" valign="top" charoff="50">Study population</td><td align="left" valign="top" charoff="50">Ph+ leukemia<xref ref-type="fn" rid="t2-fn2">a</xref></td><td align="left" valign="top" charoff="50">Newly diagnosed CML-CP</td><td align="left" valign="top" charoff="50">Newly diagnosed CML-CP</td><td align="left" valign="top" charoff="50">Newly diagnosed CML-CP</td></tr><tr><td align="left" valign="top" charoff="50">Patients treated (<italic>n</italic>)</td><td align="left" valign="top" charoff="50">2712</td><td align="left" valign="top" charoff="50">1301</td><td align="left" valign="top" charoff="50">556</td><td align="left" valign="top" charoff="50">533</td></tr><tr><td align="left" valign="top" charoff="50">PAD cases<xref ref-type="fn" rid="t2-fn3">b</xref> (<italic>n</italic>)</td><td align="left" valign="top" charoff="50">11</td><td align="left" valign="top" charoff="50">2</td><td align="left" valign="top" charoff="50">7</td><td align="left" valign="top" charoff="50">3</td></tr><tr><td align="left" valign="top" charoff="50">Cumulative incidence (%)</td><td align="left" valign="top" charoff="50">0.4</td><td align="left" valign="top" charoff="50">0.2</td><td align="left" valign="top" charoff="50">1.3</td><td align="left" valign="top" charoff="50">0.6</td></tr><tr><td align="left" valign="top" charoff="50">Exposure, patient-years</td><td align="left" valign="top" charoff="50">6421</td><td align="left" valign="top" charoff="50">4523</td><td align="left" valign="top" charoff="50">1464</td><td align="left" valign="top" charoff="50">534<xref ref-type="fn" rid="t2-fn4">c</xref></td></tr><tr><td align="left" valign="top" charoff="50">Incidence rate (per 100 patient-years), %</td><td align="left" valign="top" charoff="50">0.2</td><td align="left" valign="top" charoff="50">0.1</td><td align="left" valign="top" charoff="50">0.5</td><td align="left" valign="top" charoff="50">0.6</td></tr><tr><td align="left" valign="top" charoff="50">Data source</td><td align="left" valign="top" charoff="50">Current analysis</td><td align="center" valign="top" charoff="50"> </td><td colspan="2" align="left" valign="top" charoff="50">Adapted from Giles <italic>et al</italic><italic>.</italic><sup><xref ref-type="bibr" rid="bib7">7</xref>, <xref ref-type="bibr" rid="bib8">8</xref></sup></td></tr></tbody></table><table-wrap-foot><fn id="t2-fn1"><p>Abbreviations: Ara-C, cytarabine; BID, twice daily; CML, chronic myeloid leukemia; CP, chronic phase; ENESTnd, Evaluating Nilotinib Efficacy and Safety in clinical Trials-newly diagnosed patients; IFN, interferon; IRIS, International Randomized Study of Interferon and ST1571; PAD, peripheral arterial disease; Ph+, Philadelphia chromosome-positive; QD, once daily; TOPS, Tyrosine Kinase Inhibitor Optimization and Selectivity Study.</p></fn><fn id="t2-fn2"><label>a</label><p>Includes newly diagnosed CML-CP (<italic>n</italic>=324) and imatinib-resistant or -intolerant CML (any phase) and Ph+ ALL (<italic>n</italic>=2388).</p></fn><fn id="t2-fn3"><label>b</label><p>In Giles <italic>et al</italic>,<sup><xref ref-type="bibr" rid="bib7">7</xref></sup> PAD included atherosclerotic and thrombotic events, excluding functional (vasoreactive), embolic or aneurysmal disorders, in the arteries of lower and upper extremities. Terms indicative of PAD included: arterial disorder, peripheral ischemia, arterial insufficiency, arteriosclerosis obliterans, peripheral vascular disorder, arterial occlusive disease, femoral arterial stenosis, arterial stenosis, femoral artery occlusion, peripheral artery angioplasty, arterial stenosis limb, intermittent claudication, peripheral revascularization, arterial thrombosis limb and PAD.<sup><xref ref-type="bibr" rid="bib8">8</xref></sup></p></fn><fn id="t2-fn4"><label>c</label><p>Patients treated with IFN+Ara-C had shorter median duration of therapy (8 months) compared with nilotinib (36 months) and imatinib (45 months) cohorts, because of early crossover to imatinib.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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