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Histone Deacetylase (HDAC) Inhibitors

What are the chemotherapy agents in the HDAC inhibitor class?

   •   Vorinostat (Zolinza^®), romidepsin (Istodax^®), belinostat (Beleodaq^®), panobinostat (Farydaq^®)

What malignancies are each HDAC inhibitor approved for?

FDA-Approved Uses of HDAC Inhibitors

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Agent	FDA Approval
Vorinostat	Cutaneous T-cell lymphoma (CTCL)
Romidepsin	CTCL, peripheral T-cell lymphoma (PTCL)
Belinostat	PTCL
Panobinostat	Multiple myeloma

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Abbreviations: FDA, U.S. Food and Drug Administration; HDAC, histone deacetylase.

How do the HDAC inhibitors work?

   •   HDAC is an enzyme that catalyzes the removal of acetyl groups from histones. By removing acetyl groups, DNA wraps more tightly around histones, preventing gene expression of tumor suppressor genes

   •   HDAC inhibitors bind to this enzyme and inhibit its function, leading to increased acetylation of DNA and expression of previously silenced genes

   •   Ultimately, reactivated gene effects lead to cell cycle arrest and apoptosis

   •   In patients with multiple myeloma, panobinostat and other HDAC inhibitors act synergistically with proteasome inhibitors. Proteasome inhibitors lead to the accumulation of ubiquitinated protein aggregates, which contribute to cell death. Ubiquitinated proteins can be alternatively degraded by the aggresome pathway, which is dependent on HDAC6. Inhibition of HDAC6 by HDAC inhibitors leads to synergistic cytotoxicity of myeloma cells in combination with proteasome inhibitors.

What are the common mechanisms of resistance to HDAC inhibitor therapy?

   •   Romidepsin, belinostat, and panobinostat are substrates for P-glycoprotein (P-gp). Increased P-gp expression can increase active drug efflux from malignant cells

   •   Overexpression of antiapoptotic proteins, such as BCL-2 or BCL-X_L

   •   Overexpression and increased activation of the Jak/STAT pathway

What are the common dosing ranges for each HDAC inhibitor?

   •   Vorinostat: 400 mg orally (PO) once daily with food

   •   Romidepsin: 14 mg/m² intravenous (IV) on days 1, 8, and 15 of a 28-day cycle

   •   Belinostat: 1,000 mg/m² IV daily × 5 days of a 21-day cycle

     –  Patients homozygous for the UGT1A1*28 allele have significantly reduced UGT1A1 activity (responsible for the metabolism of belinostat) and require a lower starting dose of belinostat (750 mg/m²)

   •   Panobinostat: 20 mg PO every other day for three doses each week for 2 weeks of a 21-day cycle (days 1, 3, 5, 8, 10, and 12)

Are the HDAC inhibitors metabolized/eliminated renally or hepatically?

   •   The HDAC inhibitors are all metabolized hepatically and require dose adjustment for hepatic dysfunction

Are there drug interactions with any of the HDAC inhibitors?

   •   All HDAC inhibitors: additional QTc prolonging agents

   •   Vorinostat: warfarin (increases in international normalized ratio [INR] have been documented)

   •   Romidepsin: modulators of the CYP3A4 pathway (responsible for romidepsin metabolism), warfarin (increases in INR have been documented)

   •   Belinostat: inhibitors or inducers of UGT1A1

   •   Panobinostat: modulators of the CYP3A4 pathway (responsible for the metabolism of panobinostat); drugs metabolized through CYP2D6 (panobinostat inhibits CYP2D6)

What are the most common adverse effects of the HDAC inhibitors?

   •   EKG changes (including QTc prolongation)

   •   Nausea, vomiting, dysgeusia, diarrhea

   •   Mild myelosuppression (typically more thrombocytopenia and anemia)

What is the emetogenicity level of the HDAC inhibitors?

   •   All six agents are categorized as low (10%–30% frequency)

Are the HDAC inhibitors vesicants or irritants?

   •   The HDAC inhibitors are neither vesicants nor irritants