Romidepsin

Summary

Romidepsin is a cyclic depsipeptide histone deacetylase (HDAC) inhibitor approved for certain T‑cell lymphomas. Administered by intravenous infusion, it is used chiefly in relapsed or refractory peripheral T‑cell lymphoma (PTCL) and cutaneous T‑cell lymphoma, often in combination with other epigenetic or targeted agents to improve response rates.

Mechanism of Action

Romidepsin binds to the catalytic pocket of class I HDAC enzymes (HDAC1, 2, 3, and 8), chelating the zinc ion required for deacetylation. This blocks removal of acetyl groups from histone tails, leading to hyper‑acetylated chromatin, re‑expression of silenced tumor‑suppressor genes, cell‑cycle arrest, and apoptosis of malignant lymphocytes.

What the Research Shows

Clinical evidence for romidepsin centres on T‑cell lymphomas. In a phase 2 trial of oral azacitidine plus romidepsin in relapsed/refractory PTCL, the combination achieved a 61% overall response rate (48% complete responses), with especially high activity (80% ORR) in the TFH subtype. A phase 1b/2a study combining duvelisib with romidepsin in relapsed/refractory TCL reported a 55% overall response and 34% complete response, while reducing duvelisib‑related hepatotoxicity. In the ORACLE trial, romidepsin served as an investigator‑choice comparator for follicular helper T‑cell lymphoma, illustrating its role as a standard salvage option. Across studies, the drug consistently induces hematologic toxicities but shows meaningful efficacy in heavily pre‑treated patients.

Reported Benefits

Romidepsin provides a therapeutic option for patients with relapsed or refractory PTCL, delivering overall response rates around 60% when paired with azacitidine and 55% when combined with duvelisib. It shows particular efficacy in TFH‑type PTCL, achieving up to 80% response. Combination regimens may enhance activity and mitigate toxicities of partner drugs, offering a potential platform for future multi‑agent strategies.

Limitations of the Evidence

Evidence is largely confined to early‑phase (phase 1/2) trials with modest patient numbers; no large randomized controlled trials directly compare romidepsin to newer agents. Benefit appears variable across PTCL subtypes, and the drug is not approved for all T‑cell lymphomas. Reported toxicities, especially hematologic, limit its use in patients with poor marrow reserve, and long‑term safety data remain limited.

Safety Considerations

The most frequent grade 3–4 adverse events are thrombocytopenia (≈48%), neutropenia (≈40%), lymphopenia (≈32%) and anemia (≈16%). Infections and febrile neutropenia are common, and treatment‑related deaths have occurred from infections and cardiac events. Combination with duvelisib reduced hepatotoxicity compared with duvelisib alone, but neutropenia and fatigue remained prominent. Careful monitoring of blood counts and liver function is essential.

How It Is Administered

Romidepsin is supplied for intravenous infusion, typically dosed at 14 mg/m² on days 1, 8 and 15 of a 28‑day cycle. In combination studies, it is given alongside oral azacitidine (days 1‑14) or duvelisib (twice daily). Infusions are administered in a clinical setting with appropriate monitoring for infusion‑related reactions.

Routes of Administration

Goals & Uses

• Treatment of peripheral T-cell lymphoma (PTCL)OncologyHigh
• Other hematologic malignanciesOncologyModerate
• HIV latency reversalInfectious Disease / ResearchLow
• Peripheral T‑cell lymphomaOncologyHigh
• Treatment of cutaneous T-cell lymphoma (CTCL)OncologyHigh
• Epigenetic modulation in solid tumorsOncology / ResearchLow
• Cutaneous T‑cell lymphomaOncologyHigh

Contraindications

• Severe hepatic impairment (Child-Pugh C)HepaticModerate
• QTc prolongation / pre-existing significant cardiac arrhythmiaCardiovascularHigh
• Severe hepatic impairmentOrganModerateLiver function concerns
• Congenital long QT syndromeCardiovascular / GeneticHigh
• PregnancyPopulationHighPotential fetal risk or insufficient safety data
• Hypersensitivity to romidepsin or any excipientsAllergyHigh

Adverse Effects

• ThrombocytopeniaHematologicCommonLow platelet count
• Nausea/vomitingGastrointestinalCommon
• QTc prolongation / ECG changesCardiovascularUncommon
• NeutropeniaHematologicCommonLow neutrophil count
• NauseaGastrointestinalCommonFeeling of sickness or urge to vomit
• FatigueGeneralCommonLow energy or tiredness
• InfectionsImmunologicCommon
• QT prolongationCardiovascularUncommonExtended QT interval on ECG
• Neutropenia/anemiaHematologicCommon

Drug Interactions

• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine)High
• WarfarinModerate
• QT-prolonging agents (e.g., antiarrhythmics, certain antipsychotics)High
• Strong CYP3A4 inducers (e.g., rifampin)Moderate
• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin)High
• Strong CYP3A4 inhibitors (e.g., ketoconazole)Moderate

Population Constraints

• PregnancyReproductive SafetyRelative
• Pediatric patientsAgeRelative
• Breastfeeding womenReproductiveAbsolute
• Patients with electrolyte abnormalities (hypokalemia, hypomagnesemia)MetabolicRelative
• Pregnant womenReproductiveAbsolute
• BreastfeedingReproductiveAbsolute

Regulatory Status

• European UnionApprovedApproved: Cutaneous T‑cell lymphoma, Peripheral T‑cell lymphomaEMA approval 2009
• United StatesApprovedApproved: Cutaneous T‑cell lymphoma, Peripheral T‑cell lymphomaFDA approval 2009
• United KingdomApprovedApproved: Cutaneous T‑cell lymphoma, Peripheral T‑cell lymphomaMHRA approval

FDA approved in 2009 for CTCL; EMA approved in 2009 for CTCL and PTCL. Marketed under the brand Istodax.

Evidence & Sources

• Oral azacitidine compared with standard therapy in patients with relapsed or refractory follicular helper T-cell lymphoma (ORACLE): an open-label randomised, phase 3 study
  Journal ArticleModerateDupuis J, et al.2024-01-01T00:00:00.000000Z
• Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study
  Journal ArticleModerateFalchi L, et al.2021-01-01T00:00:00.000000Z
• Recent histone deacetylase inhibitors in cancer therapy
  Journal ArticleModerateParveen R, Harihar D, Chatterji BP2023-01-01T00:00:00.000000Z
• HDAC6 as privileged target in drug discovery: A perspective
  Journal ArticleModeratePulya S, et al.2021-01-01T00:00:00.000000Z
• Duvelisib plus romidepsin in relapsed/refractory T cell lymphomas: a phase 1b/2a trial
  Journal ArticleModerateHorwitz SM, et al.2024-01-01T00:00:00.000000Z

Frequently Asked Questions