{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:49:34Z","timestamp":1790880574129,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2016,5,20]],"date-time":"2016-05-20T00:00:00Z","timestamp":1463702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2016,9]]},"abstract":"<jats:sec><jats:title>BACKGROUND<\/jats:title><jats:p>More active high\u2010dose chemotherapy (HDC) regimens are needed for refractory lymphomas. The authors previously combined infusional gemcitabine with busulfan and melphalan (Gem\/Bu\/Mel) pursuing DNA damage repair inhibition. Subsequently, they combined Gem\/Bu\/Mel with vorinostat, which facilitates chemotherapy access to DNA. The resulting regimen was safe and synergistic. However, vorinostat induced DNA methyltransferase up\u2010regulation, which could be preclinically abrogated by azacitidine, increasing tumor\u2010cell kill. Those observations led to a clinical combination of azacitidine with vorinostat\/Gem\/Bu\/Mel.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS<\/jats:title><jats:p>Patients ages 12 to 65 years with refractory or poor\u2010risk relapsed lymphomas were eligible. They received intravenous azacitidine on days \u221211 through \u22123 at doses from 15 to 35 mg\/m<jats:sup>2<\/jats:sup> daily (dose levels 1\u20103), followed by oral vorinostat (1000 mg once daily on days \u221211 through \u22123), gemcitabine (2775 mg\/m<jats:sup>2<\/jats:sup> over 4.5 \u00d7 2), busulfan (at an area under the receiver operating characteristic curve of 4000 daily \u00d7 4), and melphalan (60 mg\/m<jats:sup>2<\/jats:sup> \u00d7 2). Patients who had tumors that were positive for CD20 (cluster of differentiation 20; B\u2010lymphocyte antigen) received rituximab on day \u22129.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS<\/jats:title><jats:p>In total, 60 patients were enrolled, including 26 with diffuse large B\u2010cell lymphoma (DLBCL) (10 double hit\/double expressors), 21 with Hodgkin lymphoma, 8 with T\u2010cell lymphoma, and 5 with other B\u2010cell lymphomas. The median patient age was 41 years (range, 16\u201065 years), patients had received a median of 3 prior lines of chemotherapy (range, 2\u20107 lines of chemotherapy); and 32% of tumors were positive on positron emission tomography studies at the time of HDC. Two patients died from treatment complications (respiratory syncytial virus pneumonia and sepsis, respectively). The maximum tolerated dose of azacitidine was encountered at dose level 1 (15 mg\/m<jats:sup>2<\/jats:sup> daily). The toxicity profile (mainly mucositis and dermatitis) was manageable and was identical to that of vorinostat\/Gem\/Bu\/Mel. Neutrophils and platelets engrafted promptly. At a median follow\u2010up of 15 months (range, 8\u201027 months), the event\u2010free and overall survival rates were 65% and 77%, respectively, among patients with DLBCL; 76% and 95%, respectively, among patients with Hodgkin lymphoma; and 88% for both among patients with T\u2010cell lymphoma.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS<\/jats:title><jats:p>Double epigenetic modulation of Gem\/Bu\/Mel with azacitidine\/vorinostat is feasible and highly active in patients with refractory\/poor\u2010risk relapsed lymphomas, warranting further evaluation. <jats:bold><jats:italic>Cancer<\/jats:italic> 2016<\/jats:bold>. \u00a9 <jats:italic>2016 American Cancer Society<\/jats:italic>. <jats:italic><jats:bold>Cancer 2016;122:2680\u20132688.<\/jats:bold> \u00a9 2016 American Cancer Society.<\/jats:italic><\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.30100","type":"journal-article","created":{"date-parts":[[2016,5,21]],"date-time":"2016-05-21T18:25:39Z","timestamp":1463855139000},"page":"2680-2688","source":"Crossref","is-referenced-by-count":48,"title":["Double epigenetic modulation of high\u2010dose chemotherapy with azacitidine and vorinostat for patients with refractory or poor\u2010risk relapsed lymphoma"],"prefix":"10.1002","volume":"122","author":[{"given":"Yago","family":"Nieto","sequence":"first","affiliation":[{"name":"Department of Stem Cell Transplantation and Cellular Therapy The University of Texas MD Anderson Cancer Center Houston Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benigno C.","family":"Valdez","sequence":"additional","affiliation":[{"name":"Department of Stem Cell Transplantation and Cellular Therapy The University of Texas MD Anderson Cancer Center Houston 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