Romidepsin in the Treatment of Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma (CTCL): The New York University Cancer Center Experience

Romidepsin, a histone deacetylase (HDAC) inhibitor has demonstrated overall response rates in CTCL of 35% in 2 separate phase 2 studies [enrolling 71 patients (pts) at 8 centers and enrolling 96 pts at 33 institutions worldwide] and is approved by the United States FDA for the treatment of CTCL in patients with progressive, persistent, or recurrent disease on or following at least 1 prior systemic therapy. Reports of clinical efficacy and toxicity outside the context of clinical trial are absent. Here, we report the largest single center experience of romidepsin in the treatment of relapsed or refractory CTCL following approval of the drug.

Between June 2010 and June 2011, 11 pts with Mycosis Fungoides (MF) and Sezary syndrome (SS), the two predominant subtypes of CTCL, who had adequate organ function, ECOG PS 0 or 1 and who had failed 1 prior systemic therapy, were treated with single agent, romidepsin. Patients received romidepsin at a dose of 14 mg/m2 on days 1, 8, and 15 every 28 days. Response was measured with a quantitative composite which included skin involvement [severity-weighted assessment tool (SWAT) or erythroderma scale], lymph node involvement (CT or MRI scans), and blood involvement (circulating Sézary cells assessed by flow cytometry). Pruritus in pts with CTCL was assessed using a 10-point scale; relief defined as reduction of pruritus score of 3 points in pts with baseline score 3. ECGs were obtained (pre-/post-infusion on all treatment days in cycle 1, and on day 1 of subsequent cycles) to evaluate for potential cardiac toxicity. Serum Mg, Ca and K levels were measured with each treatment and supplementation given as necessary.

Ten pts (5 men and 5 women) with MF (Stages IB-IVA, 6 pts had advanced stage disease i.e ≥IIB) and 1 pt with SS with median age of 73 (59-77), median number of prior therapies 3 (1-8) were treated with a median of 4 cycles (1-12) of romidepsin. Nine pts received at least 2 cycles of therapy. Overall response rate (ORR) [CR (complete response) plus PR (partial response)] was 70% by composite assessment in the 10 assessable pts including 4 CR's and 3 PR's with 3 pts demonstrating disease progression. Treatment in 1 pt was discontinued due to concern for cardiovascular toxicity that was probably not treatment related. For these 10 pts, the median duration of response was 32 weeks (20-46) with ongoing responses in 4 of them (20-44 weeks).Of the 7 responders, 4 continue to maintain their response despite discontinuation of the drug with a mean of 21 weeks (4-42), 2 pts relapsed within 8 weeks of discontinuation of treatment and were retreated with romidepsin with subsequent achievement of similar response as with initial treatment and 1 pt continues to receive treatment. Three of the 7 responders, had received prior treatment with other HDAC inhibitors including vorinostat, panobinostat and belinostat. All 7 responders had prutitus relief. Median time to response was 6 weeks (3.5-8) and median time to progression was 38 weeks (27-42).The most frequent drug-related adverse events (AEs) (all grades, all cycles) were generally mild and included: nausea (50%; none with grade 3), fatigue (50%; none with grade 3) and decreased platelets (40%; none with grade 3). On review of 166 ECGs performed on the 11 pts, small clinically insignificant prolonged QT interval and corrected prolonged QTc interval was observed in only 1 pt. No pts had QTcF values>480 milliseconds and there was no change from baseline of > 20 milliseconds. The ECG values were not associated with functional cardiovascular changes or symptoms and did not lead to discontinuation of drug in any patient.

In our single-center experience, romidepsin has greater ORR (70%, including 40% CR and 30% PR) than what has been reported in the phase II studies (ORR of 35%, including 6% CR and 28% PR) with comparable patient populations. Drug-related AEs were generally mild and consisted of GI disturbances and thrombocytopenia none of which were ≥ grade 3 compared to the 12% grade 3 and 4 toxicity observed in the phase 2 studies. We noted no clinically significant cardiovascular AEs in our pts in contrast with the previous phase 2 trials. Our experience also suggests that resistance to one HDAC inhibitor should not preclude treatment with romidepsin in CTCL pts.

No relevant conflicts of interest to declare.