Vorinostat in Combination with Other Agents for Therapy of Cutaneous T-Cell Lymphomas: A Case Series.

Abstract Background: Mycosis fungoides (MF) and Sezary Syndrome (SS) are types of cutaneous T-cell lymphoma (CTCL), a non-Hodgkin's lymphoma that mainly affects the skin but can progress to involve lymph nodes, blood, and visceral organs. Cure is rarely achieved in patients with advanced (≥Stage IIB) CTCL and patients progress after becoming intolerant of, or refractory to multiple treatment modalities. Treatment decisions for advanced CTCL are based on small prospective studies, retrospective observations, small case-series, and physician preference. Vorinostat (suberoylanilide hydroxamic acid, SAHA), the first histone deacetylase (HDAC) inhibitor, was approved by the FDA in October 2006 for CTCL patients with progressive, persistent, or recurrent disease on or following two systemic therapies based on the results of a Phase IIB trial which demonstrated an objective response in 30% of patients with ≥Stage IIB disease. It has been recently incorporated into the NCCN Clinical Practice Guidelines in Oncology™ for NHL. However, there are no reports available on use of vorinostat in combination regimens in CTCL. Here we present a case series of patients with advanced CTCL treated with vorinostat in combination with other therapies. Case series: Patient A, a 77-year-old female with Stage IVA SS, failed prior bexarotene and ECP and was initiated on vorinostat (400mg/day). Clinical improvement of erythroderma and pruritus symptoms was noted within 5 weeks and clinical response was maintained for 26 months. Grade 3 thrombocytopenia precipitated a dose reduction to 300mg/day and resulted in relapse. IFN-γ (100μg sc 3 x weekly) was added; improvement in symptoms was noted within 4 weeks with ongoing response (>5 months). Patient B was a 64-year-old male with progressive Stage III disease on bexarotene (150mg/day), ECP (monthly), and SDTs. He had failed three other systemic treatment modalities including IFN-α and was unable to tolerate higher doses of bexarotene due to severe lipid abnormalities. Vorinostat (200mg/day) was added and a clinical response (resolution of pruritus and improvement of erythroderma) was apparent within 4 weeks and is ongoing (>4 months). Patient C, a 47-year-old male with Stage IIA disease (folliculotropic MF), had failed prior SDTs but had shown significant clinical response to combined narrow-band (NB) UVB therapy and bexarotene (675mg/day). Bexarotene was discontinued due to elevated CPKs, with disease relapse. Vorinostat (400mg/day) was added to ongoing NB-UVB therapy (3 x weekly) and a clinical response (resolution of pruritis and all skin lesions) was achieved within 12 weeks and is ongoing (>4 months). Vorinostat was generally well tolerated; most adverse events were transient and Grade 1 or 2 in intensity. Consistent with previous reports all three patients experienced mild-to-moderate anemia and thrombocytopenia; patient A experienced Grade 3 thrombocytopenia that was effectively managed via a dose reduction; patient B experienced Grade 1 fatigue. Conclusions: This case series documents the clinical application of vorinostat in combination with multiple other agents. No unexpected side effects or toxicity were observed. Clinical responses were noted in patients with progressive disease on their current therapies. This report supports the efficacy of vorinostat in inducing relatively quick, meaningful and prolonged responses and is suggestive of synergistic effects of this drug when used with other agents. These combinations should be further evaluated systemically in order to establish the most effective place of vorinostat in treatment algorithms for CTCL.