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Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study
Owen A O'Connor1, Lorenzo Falchi1, Jennifer K Lue1
1Center for Lymphoid Malignancies, Department of Medicine.
Abstract:
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.
Insights
This phase 1 trial combined epigenetic modifiers 5-azacytidine (AZA) and romidepsin (ROMI) for advanced lymphoid malignancies. The combination showed significant activity in peripheral T-cell lymphoma (PTCL) patients.
Area of Science:
- Oncology
- Pharmacology
- Epigenetics
Background:
- Peripheral T-cell lymphomas (PTCLs) exhibit unique sensitivity to epigenetic modifiers.
- Preclinical models demonstrated synergy between histone deacetylase inhibitors and hypomethylating agents in PTCL.
- This provided a rationale for combining these drug classes in clinical settings.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of oral 5-azacytidine (AZA) and romidepsin (ROMI).
- To evaluate the preliminary efficacy of the AZA and ROMI combination in patients with advanced lymphoid malignancies, particularly PTCL.
- To explore potential associations between treatment response and epigenetic/mutational profiles.
Main Methods:
- A phase 1, 3+3 dose-escalation study design was employed.
- Patients received oral AZA and romidepsin (ROMI) on various schedules within 21- to 35-day cycles.
- Coprimary endpoints were MTD and DLTs, with response rates assessed in PTCL and non-T-cell lymphoma subgroups.
Main Results:
- The MTD was determined as AZA 300 mg daily (days 1-14) and ROMI 14 mg/m2 (days 8, 15, 22) on a 35-day cycle.
- DLTs included thrombocytopenia and neutropenia; no treatment-related deaths occurred.
- The combination demonstrated high activity in PTCL patients (73% overall response rate, 55% complete response rate) compared to non-T-cell lymphomas (10% ORR, 5% CR).
Conclusions:
- Combined epigenetic modifiers (AZA and ROMI) are potently active in patients with PTCL.
- The established MTD and DLT profile provide a basis for further clinical investigation.
- The study highlights the therapeutic potential of epigenetic-modifying agents in PTCL.
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