Romidepsin

Romidepsin (Istodax) is an FDA-approved bicyclic depsipeptide histone deacetylase (HDAC) inhibitor used for the treatment of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Originally isolated from Chromobacterium violaceum, it was approved by the FDA in 2009 for CTCL and in 2011 for PTCL in patients who have received at least one prior therapy.

Romidepsin is a natural product bicyclic depsipeptide that functions as a prodrug. Upon cellular uptake, its disulfide bridge is reduced by intracellular glutathione, releasing the reduced thiol form, which then chelates the zinc ion in the active sites of class I HDAC enzymes (primarily HDAC1 and HDAC2). Inhibition of HDACs prevents the removal of acetyl groups from lysine residues on histone tails, resulting in hyperacetylation of histones, chromatin relaxation, and altered transcription of genes involved in cell cycle control and apoptosis. This leads to upregulation of p21 (cell cycle arrest), activation of intrinsic and extrinsic apoptotic pathways, and downregulation of anti-apoptotic proteins in T-cell lymphoma cells. Because malignant T cells show heightened dependence on HDAC1/2 activity, romidepsin exhibits selective cytotoxicity in this context.

FDA approval for CTCL in 2009 was based on two single-arm trials showing overall response rates of 34% and 35% in patients with refractory CTCL. The PTCL approval in 2011 was supported by a single-arm study demonstrating a 25% overall response rate in relapsed/refractory PTCL. Responses are often durable in responders. Cardiac monitoring (QT prolongation) is required prior to and during treatment. Ongoing studies are investigating romidepsin in combination with other lymphoma agents. Its unique bicyclic structure differentiates it from vorinostat and other HDAC inhibitors.