Completion of the First Cohort of Patients with Cutaneous T-Cell Lymphoma Enrolled on a Phase II Trial of Depsipeptide.

Histone deacetylase inhibitors, such as depsipeptide or FK228 (Gloucester Pharmaceuticals), form a new class of antineoplastic agents found to have activity in T-cell lymphoma. A multi-institutional phase II trial of depsipeptide is ongoing; accrual is complete for the first cohort, comprised of patients with cutaneous T-cell lymphoma who had disease that had progressed or was refractory to prior therapy and who had fewer than three prior regimens of systemic cytotoxic chemotherapy. Depsipeptide is administered as a 4 hr infusion on days 1, 8, and 15 of a 28 d cycle with a starting dose of 14 mg/m². The first 3 patients enrolled were treated on the earlier NCI schedule, on days 1 and 5 of a 21 day cycle. Twenty-seven patients with a median age of 57 (31–77) were enrolled in this cohort and received a median of 5 (1–56) cycles and 14 (2–111) doses. Patients had received a median of 3 (1–11) prior therapies. These included PUVA in 15 patients, interferon in 8, bexarotene in 13, denileukin diftitox in 6, oral steroids in 6, topical nitrogen mustard in 7, or cytotoxic chemotherapy in 15. Disease extent at time of enrollment included 6 patients with tumor stage, 6 with generalized erythroderma and 3 with Sézary syndrome. Three patients, all with Sézary syndrome, achieved a complete response and five patients had partial responses for an overall response rate of 30%. With patients continuing to respond, the median duration of response is 18 (6–48) months. Partial responses were observed in patients with plaque/patch stage (1), generalized erythroderma (1), and tumor stage disease (3). An additional five patients had stable disease with a median duration to date of 6 months (4–14). Two patients had unconfirmed partial responses, three patients were not evaluable for response, one patient is too early to evaluate for response and seven patients had documented progression of disease. Overall depsipeptide was well tolerated, the main toxicities observed were nausea, taste changes, fatigue, neutropenia, thrombocytopenia. Non-specific ST-T wave changes were noted by ECG, without changes in cardiac function. No evidence of cardiac damage has been detected by serial echocardiograms, MUGA scans or troponin assays. Eight patients with objective responses receiving depsipeptide were followed for 12 to 53 months without evidence of cumulative toxicity. Induction of histone acetylation of more than two-fold was observed in paired samples of PBMNCs obtained from 9 of the 18 individual patients tested. RT-PCR analysis of MDR-1 demonstrated unchanged expression in tumor biopsies taken from 8 patients at the time of tumor progression when compared to prior to treatment initiation. While it is generally recognized that patients with Sézary syndrome are more refractory to available therapies, remarkably all patients enrolled with Sézary syndrome achieved a complete response to single agent depsipeptide. In conclusion, depsipeptide is the first of a new generation of histone deacetylase inhibitors to demonstrate consistent clinical activity with durable responses achieved in patients with CTCL. Patients are being accrued to a replicate arm for the purpose of confirming the observed response rate.