Owen A O'Connor, Lorenzo Falchi, Jennifer K Lue, Enrica Marchi, Cristina Kinahan, Ahmed Sawas, Changchun Deng, Francesca Montanari, Jennifer Effie Amengual, HYE A KIM, Aishling M Rada, Karen Khan, Alice T. Jacob, Michelle Malanga, Mark Francescone, Renu Nandakumar, Craig Soderquist, David C Park, Govind Bhagat, Bin Cheng, Alberto Risueno, Daniel Menezes, Andrei R. Shustov, Lubomir Sokol and Luigi Scotto

Key Points

  • Combined 5-azacytidine and romidepsin are reasonably well tolerated in patients with relapsed/refractory lymphoid malignancies

  • This combination produced an overall and complete response rate of 73% and 55%, respectively, in patients with T-cell lymphoma


The peripheral T-cell lymphoma (PTCL) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase (HDAC) inhibitors and hypomethylating agents 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. Following a 3 + 3 design patients were assigned to one of seven cohorts with AZA doses ranging from 100 mg daily on days 1-14 to 300 mg daily on days 1-21, ROMI doses ranging from 10 mg/m2 on days 8 and 15, to 14 mg/m2 on days 8, 15, and 22, and cycles of 21 to 35 days. Co-primary endpoints 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 1-14 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 non-T-cell lymphoma. The overall response rate in all, non-T-cell and T-cell lymphoma patients was 32%, 10% and 73%, respectively, while 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 is registered at as NCT01998035

  • Submitted April 24, 2019.
  • Revision received August 29, 2019.
  • Accepted July 30, 2019.