Background
Phase IIb, multicenter, open-label, single-arm trial. 74 patients with persistent, progressive, or treatment-refractory mycosis fungoides or Sézary syndrome (MF/SS), stage IB–IVA. Vorinostat (suberoylanilide hydroxamic acid, SAHA) is an oral pan-HDAC inhibitor. Patients required ≥2 prior systemic therapies, at least one of which included bexarotene unless intolerable. Median age 63 years; 61/74 patients had stage IIB or higher disease.
Interventions and follow up
Regimen: Vorinostat 400 mg orally once daily continuously until progression or intolerance (treatment-refractory CTCL)
Primary endpoint: Objective response rate (ORR) by modified SWAT tool
Median follow up: NR (open-label ongoing trial at time of analysis)
Primary endpoint: Objective response rate (ORR) by modified SWAT tool
Median follow up: NR (open-label ongoing trial at time of analysis)
Results
ORR (overall): 29.7% (22/74 patients)
ORR (stage IIB or higher): 29.5% (18/61 patients)
Median time to response: 56 days (stage IIB or higher)
Median duration of response: Not reached (estimated ≥185 days)
Median time to progression (overall): 4.9 months
Median time to progression (stage IIB+ responders): 9.8 months
Pruritus relief: 32% of patients
ORR (stage IIB or higher): 29.5% (18/61 patients)
Median time to response: 56 days (stage IIB or higher)
Median duration of response: Not reached (estimated ≥185 days)
Median time to progression (overall): 4.9 months
Median time to progression (stage IIB+ responders): 9.8 months
Pruritus relief: 32% of patients
Adverse events
Gastrointestinal/constitutional: Diarrhea 49%, fatigue 46%, nausea 43%, anorexia 26%; most grade 1–2
Grade ≥3 / cardiac: Fatigue 5%, pulmonary embolism 5%, thrombocytopenia 5%, nausea 4%. Eleven patients required dose modification; 9 discontinued for AEs. Dose-dependent QTc prolongation occurs at higher doses; QTc monitoring is recommended
Grade ≥3 / cardiac: Fatigue 5%, pulmonary embolism 5%, thrombocytopenia 5%, nausea 4%. Eleven patients required dose modification; 9 discontinued for AEs. Dose-dependent QTc prolongation occurs at higher doses; QTc monitoring is recommended
Conclusions
Vorinostat achieved a 29.7% ORR with durable responses (estimated DOR ≥185 days) and meaningful pruritus relief in treatment-refractory MF/SS. The oral formulation and acceptable tolerability profile led to FDA approval as the first HDAC inhibitor approved in oncology. Vorinostat established proof-of-concept for HDAC inhibition as a mechanism of action in CTCL.
Key Limitations
Single-arm, non-randomized phase IIb design without a comparator precludes assessment of relative efficacy. The modified SWAT response tool limits cross-trial comparability, and the median follow-up/DOR were not mature at analysis. ORR of ~30% is modest with few complete responses. QTc prolongation and thromboembolic events (pulmonary embolism 5%) are clinically relevant safety signals requiring monitoring. No randomized PFS or OS data are available, and durability of benefit remains uncertain.
Clinical Context
Vorinostat (Zolinza) received FDA approval in October 2006 for cutaneous manifestations of CTCL in patients with progressive, persistent, or recurrent disease on or following two systemic therapies — the first HDAC inhibitor approved in oncology. It served as the active comparator in MAVORIC, where it was outperformed by mogamulizumab. Vorinostat remains a later-line oral option for refractory MF/SS; brentuximab vedotin (CD30+) and mogamulizumab (Sézary syndrome) are now generally preferred. ESMO includes HDAC inhibitors among systemic options for advanced/refractory CTCL.