Julia Scarisbrick

Final Results From a Multicenter, International, Pivotal Study of Romidepsin in Refractory Cutaneous T-Cell Lymphoma

PURPOSE The primary objective of this study was to confirm the efficacy of romidepsin in patients with treatment refractory cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS This international, pivotal, single-arm, open-label, phase II study was conducted in patients with stage IB to IVA CTCL who had received one or more prior systemic therapies. Patients received romidepsin as an intravenous infusion at a dose of 14 mg/m(2) on days 1, 8, and 15 every 28 days. Response was determined by a composite assessment of total tumor burden including cutaneous disease, lymph node involvement, and blood (Sézary cells). RESULTS Ninety-six patients were enrolled and received one or more doses of romidepsin. Most patients (71%) had advanced stage disease (≥ IIB). The response rate was 34% (primary end point), including six patients with complete response (CR). Twenty-six of 68 patients (38%) with advanced disease achieved a response, including five CRs. The median time to response was 2 months, and the median duration of response was 15 months. A clinically meaningful improvement in pruritus was observed in 28 (43%) of 65 patients, including patients who did not achieve an objective response. Median duration of reduction in pruritus was 6 months. Drug-related adverse events were generally mild and consisted mainly of GI disturbances and asthenic conditions. Nonspecific, reversible ECG changes were noted in some patients. CONCLUSION Romidepsin has significant and sustainable single-agent activity (including improvement in pruritus) and an acceptable safety profile, making it an important therapeutic option for treatment refractory CTCL.

Survival Outcomes and Prognostic Factors in Mycosis Fungoides/Sézary Syndrome: Validation of the Revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer Staging Proposal

PURPOSE We have analyzed the outcome of mycosis fungoides (MF) and Sézary syndrome (SS) patients using the recent International Society for Cutaneous Lymphomas (ISCL)/European Organisation for Research and Treatment of Cancer (EORTC) revised staging proposal. PATIENTS AND METHODS Overall survival (OS), disease-specific survival (DSS), and risk of disease progression (RDP) were calculated for a cohort of 1,502 patients using univariate and multivariate models. RESULTS The mean age at diagnosis was 54 years, and 71% of patients presented with early-stage disease. Disease progression occurred in 34%, and 26% of patients died due to MF/SS. A significant difference in survival and progression was noted for patients with early-stage disease having patches alone (T1a/T2a) compared with those having patches and plaques (T1b/T2b). Univariate analysis established that (1) advanced skin and overall clinical stage, increased age, male sex, increased lactate dehydrogenase (LDH), and large-cell transformation were associated with reduced survival and increased RDP; (2) hypopigmented MF, MF with lymphomatoid papulosis, and poikilodermatous MF were associated with improved survival and reduced RDP; and (3) folliculotropic MF was associated with an increased RDP. Multivariate analysis established that (1) advanced skin (T) stage, the presence in peripheral blood of the tumor clone without Sézary cells (B0b), increased LDH, and folliculotropic MF were independent predictors of poor survival and increased RDP; (2) large-cell transformation and tumor distribution were independent predictors of increased RDP only; and (3) N, M, and B stages; age; male sex; and poikilodermatous MF were only significant for survival. CONCLUSION This study has validated the recently proposed ISCL/EORTC staging system and identified new prognostic factors.

Diagnosis and management of acute graft-versus-host disease

A joint working group established by the Haemato‐oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Bone Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of acute graft‐versus‐host disease. This guideline includes recommendations for the diagnosis and grading of acute graft‐versus‐host disease as well as primary treatment and options for patients with steroid‐refractory disease. The goal of treatment should be effective control of graft‐versus‐host disease while minimizing risk of toxicity and relapse.

Molecular cytogenetic analysis of cutaneous T-cell lymphomas: identification of common genetic alterations in Sézary syndrome and mycosis fungoides

Background Data on genome‐wide surveys for chromosome aberrations in primary cutaneous T‐cell lymphoma (CTCL) are limited.

U.K. consensus statement on the use of extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease

Extracorporeal photopheresis (ECP) has been used for over 30 years in the treatment of erythrodermic cutaneous T‐cell lymphoma (CTCL) and over 20 years for chronic graft‐versus‐host disease (cGVHD). The lack of prospective randomized trials has led to different centres having different patient selection criteria, treatment schedules, monitoring protocols and patient assessment criteria. ECP for CTCL and cGVHD is available only at six specialized centres across the U.K. In the recent Improving Outcomes Guidance the National Institute for Health and Clinical Excellence endorsed the use of ECP for CTCL and because of the complexity of treatment supported its use in specialized centres and also suggested the need for expansion of this service. In 2005 consultants and senior nurses from all U.K. sites and from Scandinavia formed a Photopheresis Expert Group. This group’s first aim was to produce a consensus statement on the treatment of CTCL and cGVHD with ECP using evidence‐based medicine and best medical practice, in order to standardize ECP eligibility, assessment and treatment strategies across the U.K.

Guidelines on the use of extracorporeal photopheresis

After the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T‐cell lymphoma was published in 1983 with its subsequent recognition by the FDA for its refractory forms, the technology has shown significant promise in the treatment of other severe and refractory conditions in a multi‐disciplinary setting. Among the major studied conditions are graft versus host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection and inflammatory bowel disease.

Bexarotene therapy for mycosis fungoides and Sézary syndrome

Background  Bexarotene (Targretin®) is a synthetic retinoid which is licensed for the treatment of advanced refractory cutaneous T‐cell lymphoma (CTCL).

Diagnosis and management of chronic graft-versus-host disease.

A joint working group established by the Haemato‐oncology subgroup of the British Committee for Standards in Haematology (BCSH) and the British Society for Bone Marrow Transplantation (BSBMT) has reviewed the available literature and made recommendations for the diagnosis and management of chronic graft‐versus‐host disease (GvHD). This guideline includes recommendations for the diagnosis and staging of chronic GvHD as well as primary treatment and options for patients with steroid‐refractory disease. The goal of treatment should be the effective control of GvHD while minimizing the risk of toxicity and relapse.

Prognostic factors, prognostic indices and staging in mycosis fungoides and Sézary syndrome: where are we now?

Mycosis fungoides is the most prevalent form of primary cutaneous T‐cell lymphoma. Patients frequently present with early‐stage disease typically associated with a favourable prognosis and survival of 10–35 years, but over 25% may progress to advanced disease with a median survival < 4 years, and just 13 months in those with nodal involvement. Sézary syndrome presents in advanced disease with erythroderma, blood involvement and lymphadenopathy. The Bunn and Lamberg staging system (1979) includes stages IA–IIA (early‐stage disease) and IIB–IVB (advanced‐stage disease) and provides prognostic information, but some patients with tumour‐stage disease (IIB) have a worse prognosis than those with erythrodermic‐stage (III). Conversely, patients with plaque‐stage (IB) folliculotropic mycosis fungoides may have a worse outcome than those with tumour‐stage (IIB). The more recent staging system of the European Organisation for the Research and Treatment of Cancer/International Society for Cutaneous Lymphoma has been designed to reflect tumour burden at different sites. However, this staging system has not been validated prospectively for prognosis. Furthermore, this staging system does not include a detailed measurement of skin tumour burden, as indicated by the modified skin weighted severity assessment tool. This assessment measures body surface area of disease and is weighted to record patch, plaque and tumour to produce a numerical value from 0·5 to 400 and is an established endpoint for clinical studies. Nor does this staging include clinicopathological features associated with a poor prognosis such as folliculotropism. Here we review the clinical, haematological, pathological and genotypic parameters outside the staging system, which may affect survival in mycosis fungoides and Sézary syndrome. Most studies are retrospective and single centre. The identification of poor prognostic factors may be used to develop a prognostic index to use alongside staging, which may be of benefit in mycosis fungoides/Sézary syndrome to identify patients with a potentially poor prognosis.

U.K. consensus statement on safe clinical prescribing of bexarotene for patients with cutaneous T‐cell lymphoma

Background  Bexarotene is a synthetic retinoid from the subclass of retinoids called rexinoids which selectively activate retinoid X receptors. It has activity in cutaneous T‐cell lymphoma (CTCL) and has been approved by the European Medicines Agency since 1999 for treatment of the skin manifestations of advanced‐stage (IIB–IVB) CTCL in adult patients refractory to at least one systemic treatment. In vivo bexarotene produces primary hypothyroidism which may be managed with thyroxine replacement. It also affects lipid metabolism, typically resulting in raised triglycerides, which requires prophylactic lipid‐modification therapy. Effects on neutrophils, glucose and liver function may also occur. These side‐effects are dose dependent and may be controlled with corrective therapy or dose adjustments.