The combination 5-azacitidine and romidepsin was found to be safe and efficacious in patients with peripheral T-cell lymphoma (PTCL), according to results of a phase 2 study published in Blood.1

PTCL is known to be characterized by extensive epigenetic dysregulation. Furthermore, results of previously conducted preclinical studies and a phase 1 trial provided support for use of combination epigenetic therapy with 5-azacitidine and romidepsin for the treatment of patients with PTCL.

“Our group was the first to report that combinations of epigenetic drugs including [histone deacetylase] inhibitors and DNA methyl transferase (DNMT) inhibitors exhibited marked synergy in preclinical models of PTCL across a variety of cell lines and xenograft models,” the study investigators noted.

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Specifically, 5-azacitidine is a hypomethylating agent that is targeted to DNMTs and also involved in RNA synthesis disruption, whereas romidepsin is an inhibitor of histone deacetylases, and acts by loosening interactions between DNA and histones, thereby increasing accessibility of DNA to RNA polymerase.2 Romidepsin has received approval from the US Food and Drug Administration (FDA) as a single agent in the treatment of patients with PTCL.3

In this multicenter, open-label, single-arm, phase 2 trial ( Identifier: NCT01998035), adult patients with either treatment-naive or relapsed/refractory PTCL were treated with the combination of oral 5-azacitidine and romidepsin, administered orally and intravenously, respectively. The primary study endpoint was investigator-assessed objective response rate (ORR), and secondary study endpoints included progression-free survival, duration of response, overall survival, and safety. Pretreatment tumor specimens were characterized by comprehensive genomic profiling using next-generation sequencing (NGS), and response was assessed according to the presence/absence of particular biomarkers.

Of the 25 patients enrolled in the study, 11 and 14 were classified as treatment-naïve and relapsed/refractory, respectively. Nearly 90% of patients had stage III/IV disease.

Key findings from this study included an ORR of 61% with a complete response (CR) of 43% for the 23 patients evaluable for response. Response rates were observed to be slightly higher for those with treatment-naïve compared with relapsed/refractory disease. In addition, there was evidence for time-dependent improvement in the depth of response for some patients.

Regarding safety, grade 3 or higher thrombocytopenia, neutropenia, and lymphopenia were reported in 38%, 40%, and 32% of patients, respectively. Treatment was permanently discontinued for 1 patient, and dose reductions were implemented for 7 patients.

Of the 22 patients with tumor specimens on which NGS was performed, approximately three-fourths were characterized by TET2 mutations.  When the number of mutations in somatic genes in general, epigenetic regulator genes, and genes specifically involved in DNA methylation and histone methylation/acetylation were separately assessed in responders and nonresponders, no significant differences were found.

“No clear molecular biomarker has emerged as being predictive of response, though clearly more research is needed to validate gene panels of interest,” the study authors commented.

Some of the limitations of this study mentioned by the study authors included its small size, relatively short follow-up, heterogeneity in PTCL histology, and the use of different NGS platforms to characterized tumor specimens.

In their concluding remarks, the study investigators noted that “our data support the notion that targeting the PTCL epigenome with two distinct classes of epigenetic drugs can produce frequent and durable responses, supporting the notion that chemotherapy may not be a requisite to achieve clinically meaningful benefit.”


  1. Falchi L, Ma H, Klein S, et al. Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: A multicenter phase 2 study. Blood. Published online November 10, 2020.  doi:10.1182/blood.2020009004
  2. Park S-Y, Kim J-S. A short guide to histone deacetylases including recent progress on class II enzymes. Experimental & Molecular Medicine. 2020;52:204-212. doi:10.1038/s12276-020-0382-4
  3. Romdepsin (Istodax) [package insert]. Summit, NJ: Celgene Corporation.; 2020.