{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:01:27Z","timestamp":1791331287539,"version":"4.3.1"},"reference-count":32,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,9,23]],"date-time":"2022-09-23T00:00:00Z","timestamp":1663891200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["AMED 19ck0106418h0002"],"award-info":[{"award-number":["AMED 19ck0106418h0002"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["AMED 20ck0106418h0003"],"award-info":[{"award-number":["AMED 20ck0106418h0003"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>We recently showed that pharmacological inhibition of plasminogen activator inhibitor\u20101 (PAI\u20101) activity, based on TM5614, increases cell motility and induces the detachment of hematopoietic stem cells from their niches. In this TM5614 phase II clinical trial, we investigated whether the combination of a PAI\u20101 inhibitor and tyrosine kinase inhibitors (TKIs) would induce a deep molecular response (DMR) in patients affected by chronic myeloid leukemia (CML) by quantifying <jats:italic>BCR\u2010ABL1<\/jats:italic> transcripts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients with chronic phase CML treated with a stable daily dose of TKIs for at least 1\u00a0year and yielding a major molecular response (MMR) but not achieving MR<jats:sup>4.5<\/jats:sup> were eligible for this study. After inclusion, patients began to receive TM5614 as well as a TKI. The primary objective was an evaluation of the cumulative incidence of patient progression from an MMR\/MR<jats:sup>4<\/jats:sup> to MR<jats:sup>4.5<\/jats:sup> by 12\u2009months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Thirty\u2010three patients were enrolled in the study. The median age was 59.0\u2009years and 58% were male. No Sokal high\u2010risk patients were enrolled in this trial. The median TKI treatment duration was 4.8\u2009years. At the start of this study, seven patients and 26 patients received imatinib and second\u2010generation TKIs, respectively. The cumulative MR<jats:sup>4.5<\/jats:sup> incidence by 12\u2009months was 33.3% (95% confidence interval, 18.0%\u201351.8%). The cumulative MR<jats:sup>4.5<\/jats:sup> spontaneous conversion over 12\u2009months was estimated as 8% with TKIs alone based on historical controls. The halving time of <jats:italic>BCR\u2010ABL1<\/jats:italic> at 2\u00a0months was significantly shorter for patients who achieved an MR<jats:sup>4.5<\/jats:sup>, by 12\u2009months than for the other patients (cutoff value: 48\u2009days; sensitivity: 0.80; specificity: 0.91; ROC\u2010AUC: 0.83). During this study, bleeding events and abnormal coagulation related to the drug were not reported, and TM5614 was found to be highly safe.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>TM5614 combined with TKI was well tolerated and induced MR<jats:sup>4.5<\/jats:sup> in more patients than stand\u2010alone TKI treatment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.5292","type":"journal-article","created":{"date-parts":[[2022,9,24]],"date-time":"2022-09-24T04:53:49Z","timestamp":1663995229000},"page":"4250-4258","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Deep molecular response in patients with chronic phase chronic myeloid leukemia treated with the plasminogen activator inhibitor\u20101 inhibitor <scp>TM5614<\/scp> combined with a tyrosine kinase inhibitor"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6758-3787","authenticated-orcid":false,"given":"Naoto","family":"Takahashi","sequence":"first","affiliation":[{"name":"Akita University School of Medicine  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Kameoka","sequence":"additional","affiliation":[{"name":"Akita University School of Medicine  Akita Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Onizuka","sequence":"additional","affiliation":[{"name":"Tokai University School of Medicine  Isehara Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Onishi","sequence":"additional","affiliation":[{"name":"Tohoku University, Sendai  Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiaki","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Iwate Medical University  Morioka Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Dan","sequence":"additional","affiliation":[{"name":"Renascience Inc.  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