ORLANDO – The histone deacetylase inhibitor romidepsin showed significant single-agent activity in patients with relapsed or refractory peripheral T-cell lymphoma, investigators reported at the annual meeting of the American Society of Hematology.
In a phase II trial, 130 patients with various subtypes of relapsed/refractory peripheral T-cell lymphoma (PTCL) who received romidepsin (Istodax) had a complete response rate of 13% as determined by an independent review committee (IRC) of radiologists and hematologists, and 16% as judged by study investigators.
Overall objective responses (a composite of complete responses [CR], complete responses unconfirmed [CRu] and partial responses [PR]) were 26% according to the IRC, and 29% according to investigators, said Dr. Bertrand Coiffier, professor of hematology at Hospices Civils de Lyon (France).
The agent "warrants further investigation as front-line therapy in these patients in combination with chemotherapy," Dr. Coiffier said.
Romidepsin is approved in the United States for patients with cutaneous T-cell lymphoma that has relapsed after at least one prior systemic therapy. The drug has demonstrated activity against PTCL in phase I and II trials conducted by the National Cancer Institute, and it has received fast-track status from the Food and Drug Administration for PTCL, as well as an orphan-drug designation in the United States and Europe.
Peripheral T-cell lymphoma is the overall term for a heterogeneous group of non-Hodgkin’s lymphomas arising from clonal proliferation of mature post-thymic lymphocytes. These malignancies tend to be clinically aggressive, respond poorly to chemotherapy, have high relapse rates, and are associated with poor long-term survival.
"We don’t have any standard of care for these patients, and we need to find new drugs," said Dr. Coiffier.
The open-label, single-arm trial involved 130 patients from centers in Australia, France, Germany, Spain, and the United States. Histologies included PTCL not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase (ALK)–anaplastic large cell lymphoma (ALCL), ALK-positive ALCL (if stem-cell transplant had failed), enteropathy-type TCL, subcutaneous panniculitis-type TCL, extranodal natural killer/T-cell lymphoma nasal type, and transformed mycosis fungoides.
All patients had relapsed/refractory disease following at least one prior systemic therapy (median 2), and either measurable disease according to International Workshop Criteria or measurable cutaneous disease.
The patients received romidepsin 14 mg/m2 in a 4-hour intravenous infusion on days 1, 8, and 15 of a 28-day cycle for a total of six cycles. Patients who responded to the drug could receive additional treatment cycles at their discretion and that of the investigators. Responses were assessed after every 2 cycles, with follow-up every 2-3 cycles.
The primary end point was the complete response rate as determined by the IRC. It found that 34 patients (26%) had objective responses, and that 17 of these (13% of all patients) were CR (10 patients) or CRu (7 patients). An additional 17 had partial responses, 32 (25%) had stable disease, and 64 (49%) either had progressive disease or were not evaluable.
At the time of the presentation, the median duration of complete responses had not been reached according to the IRC analysis (range less than 1 month to more than 26.3 months). The median duration of objective responses (CR, CRu, and PR) was 12 months. Median time to objective response was 2 months, time to CR was 4 months, and time to progression was 6 months.
Complete responses were seen in 14% of 49 patients whose disease was refractory to the most recent therapy, Dr. Coiffier noted. As of the data cutoff date of March 31, 2010, 9 of the 17 patients with a CR/CRu continued to receive the drug, 5 discontinued it (1 of these patients went on to transplant), and 3 had disease progression, following response durations of 12, 2.2, and 1.9 months.
Treatment-emergent adverse events occurred in nearly all patients (96%). Events occurring in 20% or more of patients included nausea (59%), fatigue (41%), vomiting (38%), thrombocytopenia (38%), diarrhea (35%), pyrexia (34%), neutropenia (30%), anorexia (28%), constipation (28%), anemia (23%), and dysgeusia (21%). Grade 3 or 4 adverse events occurred in 86 patients (66%), and included pyrexia (7%), pneumonia (5%), vomiting (5%), and sepsis (5%). In all, 22 patients (17%) withdrew because of side effects.
There were eight patient deaths within 30 days of the last drug dose: three from progressive disease and five from infections. One patient died from a probable treatment-related case of sepsis and multiple organ failure.
Eight patients had electrocardiographic abnormalities, four of which were prolongation of the QTc interval. None of these patients had concurrent symptoms of either syncope or other cardiac adverse events at the time of the reported abnormality, Dr. Coiffier noted.