Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell lymphoma (CTCL)

Abstract

The activity and safety of the histone deacetylase inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) were evaluated in patients with refractory cutaneous T-cell lymphoma (CTCL). Group 1 received vorinostat 400 mg daily, group 2 received vorinostat 300 mg twice daily for 3 days with 4 days rest, and group 3 received vorinostat 300 mg twice daily for 14 days with 7 days rest followed by 200 mg twice daily. Treatment continued until disease progression or intolerable toxicity. The primary objective was to determine the complete and partial response (PR) rate. Time to response (TTR), time to progressive disease (TTP), response duration (DOR), pruritus relief, and safety were determined. Thirty-three patients who had received a median of 5 prior therapies were enrolled. Eight patients achieved a PR, including 7 with advanced disease and 4 with Sézary syndrome. The median TTR, DOR, and TTP for responders were 11.9, 15.1, and 30.2 weeks, respectively. Fourteen of 31 evaluable patients had pruritus relief. The most common drug-related AEs were fatigue, thrombocytopenia, diarrhea, and nausea. The most common grade 3 or 4 drug-related AEs were thrombocytopenia and dehydration. Vorinostat demonstrated activity in heavily pretreated patients with CTCL. The 400 mg daily regimen had the most favorable safety profile and is being further evaluated.

Figure 1

Percentage of change in body surface area (BSA) involvement of CTCL in evaluable patients with mycosis fungoides during vorinostat treatment. ■ indicates patients with greater than 100% increase in BSA involvement of CTCL.

Figure 2

Time to progression during treatment with vorinostat for the overall study population is shown. The median time to progression for all 33 patients based on the Kaplan-Meier estimate was 12.1 weeks.

Figure 3

Partial response observed in a patient with tumor stage IVB CTCL. This patient received 6 prior therapies, including total skin electron beam radiation therapy; cyclophosphamide, vincristine, and prednisolone; denileukin diftitox; and bexarotene. This patient was treated with vorinostat 400 mg every day at the time the response was observed. The CTCL lesions were assessed at baseline and visits at week 8 and week 24.

Figure 4

Decreased intensity of dermal lymphocytic infiltrates in paired mycosis fungoides lesions following oral vorinostat treatment: comparison of intensity of lymphocytic infiltrates before and after vorinostat therapy. A decrease in the intensity of the dermal infiltrates was observed after treatment in 9 (39.1%) of 23 sets of lesions after 4 weeks on oral vorinostat therapy. No obvious change in the staining intensity of dermal infiltrates was observed after only 2 hours of treatment.

Figure 5

Changes in histone acetylation, microvessel density by CD31⁺ dermal vessels, thrombospondin-1 (TSP-1) expression, and phospho–STAT-3 (p-STAT-3) localization following 4 weeks of vorinostat treatment. (A) Histone acetylation (Ac H4K8) of keratinocytes and lymphocytes was intense at baseline. (B) After vorinostat treatment, AC H4K8 was less intense because most of the lymphocytes were not present. (C-D) CD31⁺ dermal vessels were reduced following 4 weeks of therapy in all patients, including responders. (E-F) The antiangiogenic protein TSP-1 was up-regulated following vorinostat treatment, with increased staining in the epidermis and dermal infiltrates. (G-H) p-STAT-3 staining shifted from the nuclei to cytoplasm of keratinocytes and lymphocytes following vorinostat treatment.