Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy

Hematology, Centre Hospitalier Lyon-Sud, 69310 Pierre-Benite, France.
Journal of Clinical Oncology (Impact Factor: 18.43). 02/2012; 30(6):631-6. DOI: 10.1200/JCO.2011.37.4223
Source: PubMed


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.

Download full-text


Available from: Henry Miles Prince, Nov 22, 2015
    • "In this study we adopted a " piggyback " approach (Nwaka and Hudson, 2006) to extend these findings, focussing on four HDAC inhibitors (Fig. 1) that are clinically approved for cancer. Vorinostat (SAHA; Sigma Aldrich, USA), romidepsin (FK228; Selleck Chemicals, USA), and belinostat (Beleodaq; Spectrum Pharmaceuticals , Inc., USA) have been approved for the clinical treatment of cutaneous or peripheral T-cell lymphoma (Grant et al., 2007; Prince and Dickinson, 2012; Thompson, 2014) and are undergoing clinical trials for various other cancers, including prostate and epithelial ovarian cancers (Garcia-Manero et al., 2008; Modesitt et al., 2008; Molife et al., 2010; Coiffier et al., 2012). Vorinostat and belinostat are hydroxamate-based pan-inhibitors of class I and II mammalian HDACs (Grant et al., 2007; Steele et al., 2011), while romidepsin is a cyclic tetrapeptide pro-drug (Sandor et al., 2002; Byrd et al., 2005) and has some HDAC isoenzyme-selectivity for class I mammalian HDACs (Prince and Dickinson, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Histone deacetylase (HDAC) enzymes work together with histone acetyltransferases (HATs) to reversibly acetylate both histone and non-histone proteins. As a result, these enzymes are involved in regulating chromatin structure and gene expression as well as other important cellular processes. HDACs are validated drug targets for some types of cancer, with three HDAC inhibitors clinically approved. However, they are also showing promise as novel drug targets for other indications, including malaria and other parasitic diseases. In this study the in vitro activity of four anti-cancer HDAC inhibitors was examined against parasites that cause malaria and trypanosomiasis. Three of these inhibitors, suberoylanilide hydroxamic acid (SAHA; vorinostat®), romidepsin (Istodax®) and belinostat (Beleodaq®), are clinically approved for the treatment of T-cell lymphoma, while the fourth, panobinostat, has recently been approved for combination therapy use in certain patients with multiple myeloma. All HDAC inhibitors were found to inhibit the growth of asexual-stage Plasmodium falciparum malaria parasites in the nanomolar range (IC50 10–200 nM), while only romidepsin was active at sub-μM concentrations against bloodstream form Trypanosoma brucei brucei parasites (IC50 35 nM). The compounds were found to have some selectivity for malaria parasites compared with mammalian cells, but were not selective for trypanosome parasites versus mammalian cells. All compounds caused hyperacetylation of histone and non-histone proteins in P. falciparum asexual stage parasites and inhibited deacetylase activity in P. falciparum nuclear extracts in addition to recombinant PfHDAC1 activity. P. falciparum histone hyperacetylation data indicate that HDAC inhibitors may differentially affect the acetylation profiles of histone H3 and H4.
    International Journal for Parasitology: Drugs and Drug Resistance 06/2015; 2012(3). DOI:10.1016/j.ijpddr.2015.05.004 · 3.29 Impact Factor
  • Source
    • "Analog kwasu foliowego 111 29% 11% 10 miesięcy Romidepsin [32] Inhibitor deacetylazy histonowej 130 25% 15% 17 miesięcy Alisertib [33] "
    [Show abstract] [Hide abstract]
    ABSTRACT: Peripheral T-cell lymphoma (PTCL) is relatively uncommon disorder representing only 8–15% of all non-Hodgkin lymphoma. The nodal types of PTCL, which include PTCL not otherwise specified, anaplastic large cell lymphomas (ALCLs), and angioimmunoblastic T cell lymphoma, are a heterogenous group of diseases that are challenging to treat. Although the outcome of patients with PTCL, with the exception of ALK-positive ALCL, is worse than that of patients with B cell lymphomas, they are treated similarly with the CHOP or CHOP-like regimens. The best treatment option for patients who responded to conventional chemotherapy remains undefined. Several prospective phase II studies support autologous hematopoietic stem cell transplantation as consolidation of first response for PTCL. Allogeneic transplant is usually reserved for relapsed disease. In addition, a variety of new drugs were registered in relapsed disease and are being studied in the upfront setting. This review summarizes the standard of care and new treatment options for the most common aggressive PTCL.
    Acta haematologica Polonica 03/2015; 46(2). DOI:10.1016/j.achaem.2015.02.016
  • Source
    • "However, a subsequent ad-hoc revision of the MVA with the inclusion of the use of RT as a variable was the most applicable method to evaluate the potential role of RT in this setting while accounting for other factors. Since 2009, four drugs have gained regulatory approval for the treatment of PTCL (O'Connor et al, 2011, 2013; Coiffier et al, 2012; Pro et al, 2012). Although two of these approvals "
    [Show abstract] [Hide abstract]
    ABSTRACT: Current prognostic models for peripheral T-cell lymphoma (PTCL) have multiple limitations, and questions exist regarding applicability to current patients. We utilized the Surveillance Epidemiology and End Results (SEER)-18 database to evaluate factors affecting overall survival (OS) of PTCL in the modern era and identified 8802 patients between 2000–2010. Most subtypes of PTCL increased in incidence during the study period. In univariate analyses, age >55 years, black race, advanced stage, absence of extra-nodal disease, omission of radiation therapy (RT) and high-risk histology each predicted inferior OS (P < 0·0001). Multivariate analysis (MVA) demonstrated that hepatosplenic, enteropathy-associated and extra-nodal Natural Killer/T cell histologies, each had hazard ratios >1·5 (P ≤ 0·0001) for death. Further, age ≥55 years, black race and advanced stage maintained their significance in the MVA (P < 0·0001 each). Based on the significant factors, a prognostic model was constructed and subsequently validated in an independent cohort. The new model incorporated age, stage, histology and race, with an OS ranging from 9 months (highest risk group) to 120 months (lowest risk group). In summary, this is the largest study of PTCL patients in the modern era that provides risk stratification utilizing a new prognostic model that can be incorporated into future prospective clinical trials.
    British Journal of Haematology 11/2014; 168(5). DOI:10.1111/bjh.13202 · 4.71 Impact Factor
Show more