Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium

ABSTRACT Background Advanced-stage mycosis fungoides (MF)/Sezary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. Patients and methods This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). Results Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. Conclusion This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach

CD25 Expression Is Correlated with Histological Grade and Response to Denileukin Diftitox in Cutaneous T-Cell Lymphoma

Denileukin diftitox (Ontak®), a recombinant fusion protein of diphtheria toxin and ligand, IL-2, binds to the IL-2 receptor, is internalized, and causes cell death. Denileukin diftitox was approved for the treatment of cutaneous T-cell lymphomas (CTCLs) with CD25+ expression. We prospectively stained lesional skin biopsy specimens from 113 mycosis fungoides and Sézary Syndrome patients for activation markers CD25 and CD30 to correlate expression with clinical tumor-node metastasis (TNM) stage, histologic grade, and response to denileukin diftitox. High expression was defined as positivity of ≥20% of lesional T-cells using immunohistochemistry (IHC). CD25 and CD30 expression was more common in lesions from advanced patients (P=0.04 and 0.002, respectively). Advanced TNM (T3 or T4) was significantly associated with intermediate-grade (P=0.002) and large-cell transformation histology (P=0.04). Of interest, clinical responses were observed in 78.5% of patients with high CD25 expression versus 20% with low to undetectable CD25 expression (P=0.01) among 24 patients receiving standard 5-day infusions of denileukin diftitox at 18μg/kg/day. These data suggest that high CD25 expression by IHC is associated with advanced CTCL and with clinical response to denileukin diftitox therapy

CD25 Expression Is Correlated with Histological Grade and Response to Denileukin Diftitox in Cutaneous T-Cell Lymphoma

Denileukin diftitox (Ontak®), a recombinant fusion protein of diphtheria toxin and ligand, IL-2, binds to the IL-2 receptor, is internalized, and causes cell death. Denileukin diftitox was approved for the treatment of cutaneous T-cell lymphomas (CTCLs) with CD25+ expression. We prospectively stained lesional skin biopsy specimens from 113 mycosis fungoides and Sézary Syndrome patients for activation markers CD25 and CD30 to correlate expression with clinical tumor-node metastasis (TNM) stage, histologic grade, and response to denileukin diftitox. High expression was defined as positivity of ≥20% of lesional T-cells using immunohistochemistry (IHC). CD25 and CD30 expression was more common in lesions from advanced patients (P=0.04 and 0.002, respectively). Advanced TNM (T3 or T4) was significantly associated with intermediate-grade (P=0.002) and large-cell transformation histology (P=0.04). Of interest, clinical responses were observed in 78.5% of patients with high CD25 expression versus 20% with low to undetectable CD25 expression (P=0.01) among 24 patients receiving standard 5-day infusions of denileukin diftitox at 18μg/kg/day. These data suggest that high CD25 expression by IHC is associated with advanced CTCL and with clinical response to denileukin diftitox therapy

Cutaneous Lymphoma International Consortium Study of Outcome in Advanced Stages of Mycosis Fungoides and S\ue9zary Syndrome: Effect of Specific Prognostic Markers on Survival and Development of a Prognostic Model

Abstract PURPOSE: Advanced-stage mycosis fungoides (MF; stage IIB to IV) and S\ue9zary syndrome (SS) are aggressive lymphomas with a median survival of 1 to 5 years. Clinical management is stage based; however, there is wide range of outcome within stages. Published prognostic studies in MF/SS have been single-center trials. Because of the rarity of MF/SS, only a large collaboration would power a study to identify independent prognostic markers. PATIENTS AND METHODS: Literature review identified the following 10 candidate markers: stage, age, sex, cutaneous histologic features of folliculotropism, CD30 positivity, proliferation index, large-cell transformation, WBC/lymphocyte count, serum lactate dehydrogenase, and identical T-cell clone in blood and skin. Data were collected at specialist centers on patients diagnosed with advanced-stage MF/SS from 2007. Each parameter recorded at diagnosis was tested against overall survival (OS). RESULTS: Staging data on 1,275 patients with advanced MF/SS from 29 international sites were included for survival analysis. The median OS was 63 months, with 2- and 5-year survival rates of 77% and 52%, respectively. The median OS for patients with stage IIB disease was 68 months, but patients diagnosed with stage III disease had slightly improved survival compared with patients with stage IIB, although patients diagnosed with stage IV disease had significantly worse survival (48 months for stage IVA and 33 months for stage IVB). Of the 10 variables tested, four (stage IV, age > 60 years, large-cell transformation, and increased lactate dehydrogenase) were independent prognostic markers for a worse survival. Combining these four factors in a prognostic index model identified the following three risk groups across stages with significantly different 5-year survival rates: low risk (68%), intermediate risk (44%), and high risk (28%). CONCLUSION: To our knowledge, this study includes the largest cohort of patients with advanced-stage MF/SS and identifies markers with independent prognostic value, which, used together in a prognostic index, may be useful to stratify advanced-stage patients