Summary

Romidepsin (Istodax, formerly FK228) is a natural-product-derived cyclic depsipeptide that functions as a potent class I histone deacetylase (HDAC) inhibitor. Originally isolated from Chromobacterium violaceum, it was approved by the FDA in 2009 for cutaneous T-cell lymphoma (CTCL) and in 2011 for peripheral T-cell lymphoma (PTCL). It acts as a prodrug: intracellular reduction of its disulphide bond releases a zinc-binding dithiol that inhibits HDAC1, 2, 3, and 8, leading to histone acetylation, altered gene expression, and apoptosis in malignant T-cells. Research use only — not for self-administration.

Mechanism

Romidepsin is a prodrug cyclic depsipeptide. Intracellularly, its disulphide bond is reduced (primarily by glutaredoxin), releasing a dithiol that chelates the zinc ion in the catalytic site of class I HDAC enzymes (HDAC1, 2, 3, 8). This inhibits deacetylation of histone and non-histone proteins, leading to increased acetylation, altered gene transcription, cell cycle arrest, differentiation, and apoptosis — particularly in malignant T-cells.

Evidence base

Phase 2 (CTCL): 96 patients, ORR 34% (95% CI 24–44%), median DOR 15 months. FDA approval basis (Whittaker et al., JCO, 2010).

Phase 2 (PTCL): 130 patients, ORR 25% (95% CI 18–33%), median DOR 17 months. FDA approval basis (Coiffier et al., JCO, 2012).

Safety: Cardiac toxicity (QT prolongation, ECG changes), myelosuppression, GI toxicity. FDA labelling updates 2021 re: combination therapy mortality.

Evidence grade: Strong — Phase 2 registration trials, FDA approval (2009 CTCL, 2011 PTCL). No Phase 3 RCTs conducted.

Protocols

Approved clinical protocol:

  • Dose: 14 mg/m² IV over 4 hours
  • Schedule: Days 1, 8, 15 of 28-day cycle
  • Duration: Repeat cycles until progression/unacceptable toxicity
  • Pre-medication: Antiemetics (high emetogenicity)
  • Monitoring: ECG, CBC, electrolytes, LFTs before each cycle

⚠️ Research use only. Not for self-administration.

UK Status: POM (prescription-only; withdrawn from EU market)

Romidepsin (Istodax) held EMA authorisation (2012) but was withdrawn in 2021 for commercial reasons. Not currently marketed in UK/EU. Not a controlled substance. Research-grade material legal for laboratory research. NHS access requires unlicensed import arrangements.

Vendor notes

Romidepsin is a former licensed medicine withdrawn from the EU market (2021). Not available from UK research peptide vendors. Researchers should consult accredited chemical suppliers for laboratory-grade material with verified COAs.

References

  1. Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol. 2010;28(33):4485-4491. doi:10.1200/JCO.2010.28.9066
  2. Coiffier B, Pro B, Prince HM, et al. Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy. J Clin Oncol. 2012;30(6):631-636. doi:10.1200/JCO.2011.37.4223
  3. FDA. Istodax (romidepsin) prescribing information. Celgene Corporation, 2009. Updated 2021.
  4. EMA. Istodax European Public Assessment Report (EPAR). EMA/CHMP, 2012. Withdrawn 2021.
  5. VanderMolen KM, McCulloch W, Pearce CJ, Oberlies NH. Romidepsin (Istodax, NSC 630176, FK228, FR901228, depsipeptide): a natural product recently approved for cutaneous T-cell lymphoma. J Antibiot (Tokyo). 2011;64(8):525-531. doi:10.1038/ja.2011.35
  6. Furumai R, Matsuyama A, Kobashi N, et al. FK228 (depsipeptide) as a natural prodrug that inhibits class I histone deacetylases. Cancer Res. 2002;62(17):4916-4921.