Purpose: Romidepsin is a histone deacetylase inhibitor (HDI) approved for the treatment of both cutaneous and peripheral T-cell lymphoma (CTCL and PTCL). During development, a thorough assessment of cardiac toxicity was conducted.Experimental Design: A phase II single-agent nonrandomized study of romidepsin was conducted in patients with CTCL or PTCL who had progressed after at least 1 prior systemic therapy.Results: Results for the first 42 patients enrolled on the NCI 1312 phase II study of romidepsin in CTCL or PTCL showed no cardiac toxicity based on serial electrocardiograms (ECG), troponins, and MUGA scans/echocardiograms. The cardiac assessments reported herein confirm the safety of romidepsin among 131 enrolled patients, while supporting a role for electrolyte replacement. Heart rate increased an average 11 bpm following romidepsin infusion; there was no evidence of increased arrhythmia. Criteria for potassium/ magnesium replacement were met before 55% of 1365 romidepsin doses; an association with hypoalbuminemia was confirmed. We propose a mechanism for ST segment flattening and depression, the most common ECG abnormalities observed: HDI-induced alteration of the activity or expression of K ATP channels. In addition, examination of the variants of the active transporter of romidepsin, ABCB1, showed a trend toward smaller heart rate changes in the peri-infusion period among wild-type than variant diplotypes.Conclusions: We conclude that in the context of appropriate attention to electrolyte levels, the data support the cardiac safety of romidepsin.

Summary Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T-cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the National Cancer Institute 1312 trial, demonstrating long-term disease control and the ability to retreat patients relapsing off-therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third-line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3.5 months to 10 years; in four of six patients, re-initiation of treatment led to disease regression. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics-mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T-cell lymphoma, but suggests a complex mechanism of action.

Summary The use of allele‐specific quantitative polymerase chain reaction to identify KIT D816V in the peripheral blood of adults with mastocytosis has been reported to have value in the diagnosis, assessment of disease burden and management of this disease. To examine the value of this assay in children with cutaneous manifestations of mastocytosis, we assessed data on 65 patients with all variants of paediatric‐onset mastocytosis, including those known to have systemic disease, to correlate KIT mutation status with clinical findings, serum tryptase levels and bone marrow histopathology. We found that KIT D816V was not identified in the peripheral blood of children known to have only cutaneous disease (specificity 100%) but was found in those known to have both cutaneous and systemic/probable systemic disease (sensitivity of 85·2%). These findings were the basis of the development of an algorithm to assist in the decision for when to perform a bone marrow biopsy in children presenting with cutaneous manifestations of mastocytosis.