Results from a pivotal, open-label, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma after prior systemic therapy.
ABSTRACT Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee.
Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%).
Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.
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ABSTRACT: Peripheral T-cell lymphomas (PTCLs) are a diverse family of lymphoid neoplasms with poor prognosis. They represent approximately 6-10% of non-Hodgkin lymphomas with significant geographic variation. The median age at diagnosis varies with histology, however the majority of patients with PTCL are in their fifth or sixth decade of life. Until recently clinical development of new agents for PTCL was slow due to difficulties in making the correct diagnosis, lack of uniform classification and combination of rarity and biologic diversity of the group. In the last 5 years, significant advances were made to overcome these obstacles, leading to the approval of three new agents for relapsed and refractory PTCL by the Food and Drug Administration, based on well conducted prospective studies. Pralatrexate, a unique antifol, was the first agent granted approval, followed by romidepsin, a histone deacetylase inhibitor, and brentuximab vedotin, an immunoconjugate. Owing to the unique nature of these agents, durable responses were seen in patients with highly refractory disease, and some of these responses are long lasting after discontinuation of therapy. Accumulating data indicate that these novel agents have little cumulative toxicity and can be administered continuously to patients who are not candidates for consolidative stem-cell transplantation (SCT), with little impact on quality of life. They might also provide a new salvage option for patients eligible for SCT with no impact on autologous stem-cell collection or subsequent engraftment. New studies are underway to evaluate efficacy and safety of new agents in combination regimens for both newly diagnosed and relapsed/refractory PTCL. Several other investigational drugs showed promise in recent trials. This review focuses on novel therapies for T-cell lymphomas, their place in current treatment paradigms and future directions.Therapeutic advances in hematology. 06/2013; 4(3):173-87.
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ABSTRACT: OPINION STATEMENT: Peripheral T-cell lymphomas (PTCL) are a group of uncommon and heterogeneous malignancies arising from a postthymic or mature T-lymphocyte. The treatment of PTCL remains a challenging endeavor. Compared with the more common aggressive B-cell lymphomas, more patients with PTCL will be refractory to initial therapy and those who achieve responses often will have shorter progression-free survival. Despite retrospective data that suggest that anthracycline-based multiagent chemotherapy regimens may not provide a benefit compared with nonanthracycline regimens, nonanthracycline-based regimens, with the notable exception of L-asparaginase regimens for extranodal NK/T-cell lymphoma, have been disappointing so far. Based on phase II evidence and subset analyses available, we believe that the addition of etoposide to standard regimens and consolidation of first remissions with autologous stem cell transplantation (autoSCT) provides the best outcome in patients with PTCL and currently use CHOEP followed by ASCT for eligible patients with the common PTCL subtype: PTCL-NOS, AITL, and ALK negative ALCL. For those with ALK-positive ALCL standard CHOP or CHOEP is appropriate with consideration of ASCT only for those with high-risk disease. Other strategies to incorporate additional agents, such as with dose-adjusted EPOCH or sequential CHOP-ICE regimens are logical options; however, they lack the supporting literature of CHOEP. Whereas the above recommendation is our current off-protocol approach, with the possible exception of low risk ALK positive ALCL, none of these choices is supported by strong enough data to supplant a well-conceived clinical trial as the truly preferred strategy in PTCL. The novel agents, romidepsin, pralatrexate, and brentuximab vedotin, are currently approved in the relapsed/refractory setting. These agents are being studied as additions or substitutions for other agents in up-front multiagent chemotherapy regimens. In the relapsed/refractory setting, both pralatrexate and romidepsin remain well-studied choices with some patients achieving a response with durability. Clinical trials of new agents in PTCL continue to be a valuable option and an important part of routine patient management as progressive disease often is seen. Lastly, we believe patients with relapsed/refractory PTCL should be considered for allogeneic stem cell transplantation if a suitable response is demonstrated and a willing donor is available.Current Treatment Options in Oncology 04/2013; · 2.42 Impact Factor
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ABSTRACT: Treatment of relapsed/refractory T cell neoplasms represents an unmet medical need. We recorded, retrospectively, data on 20 consecutive adult patients with T cell neoplasms (8 T cell lymphoma not otherwise specified (T-NOS), 4 angioimmunoblastic (AILT), 3 prolymphocytic leukemia (T-PLL), 3 advance-stage mycosis fungoides (MF) or Sézary syndrome (SS), and 2 T cell large granular lymphocytic leukemia (T-LGL)), treated with bendamustine. Partial (PR) and complete response (CR) rates were reached in nine (45 %) and two (10 %) patients, respectively, including three PR in T-NOS, one CR in AILT, three PR in T-PLL, two PR in MF/SS, and one CR and one PR in T-LGL lymphoma. The 6 months estimated progression free and overall survival was 44 and 67 %, respectively. Grade 3-4 neutropenia and thrombocytopenia were registered in 44 and 25 % of cases. Four patients developed major infectious complications. At a median follow-up of 6 months (range 1-18), 13 patients are alive and 7 patients died all because of lymphoma progression. Bendamustine deserves further investigation in patients with T cell neoplasms.Annals of Hematology 04/2013; · 2.87 Impact Factor