| Autor: |
O’Connor, Owen A., Falchi, Lorenzo, Lue, Jennifer K., Marchi, Enrica, Kinahan, Cristina, Sawas, Ahmed, Deng, Changchun, Montanari, Francesca, Amengual, Jennifer E., Kim, Hye A., Rada, Aishling M., Khan, Karen, Jacob, Alice T., Malanga, Michelle, Francescone, Mark M., Nandakumar, Renu, Soderquist, Craig R., Park, David C., Bhagat, Govind, Cheng, Bin, Risueño, Alberto, Menezes, Daniel, Shustov, Andrei R., Sokol, Lubomir, Scotto, Luigi |
| Zdroj: |
Blood; October 2019, Vol. 134 Issue: 17 p1395-1405, 11p |
| Abstrakt: |
The peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase inhibitors and hypomethylating agents that we established in preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. According to a 3 + 3 design, patients were assigned to 1 of 7 cohorts with AZA doses ranging from 100 mg daily on days 1 to 14 to 300 mg daily on days 1 to 21, ROMI doses ranging from 10 mg/m2 on days 8 and 15 to 14 mg/m2 on days 8, 15, and 22, with cycles of 21 to 35 days. Coprimary end points included maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). We treated a total of 31 patients. The MTD was AZA 300 mg on days 1 to 14 and ROMI 14 mg/m2 on days 8, 15, and 22 on a 35-day cycle. DLTs included grade 4 thrombocytopenia, prolonged grade 3 thrombocytopenia, grade 4 neutropenia, and pleural effusion. There were no treatment-related deaths. The combination was substantially more active in patients with PTCL than in those with non–T-cell lymphoma. The overall response rate in all, non–T-cell, and T-cell lymphoma patients was 32%, 10%, and 73%, respectively, and the complete response rates were 23%, 5%, and 55%, respectively. We did not find an association between response and level of demethylation or tumor mutational profile. This study establishes that combined epigenetic modifiers are potently active in PTCL patients. This trial was registered at www.clinicaltrials.gov as NCT01998035. |
| Databáze: |
Supplemental Index |
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