Cutaneous Lymphoma Task Force Research Articles

Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC

AbstractThe number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

Epi-O-02 - International Cutaneous Lymphomas Pandemic Section (ICLYPS) analysis of CTCL outcomes during COVID-19

At the onset of the COVID-19 pandemic, the United States Cutaneous Lymphoma Consortium (USCLC) and the European Organisation for Research and Treatment of Cancer Cutaneous Lymphoma Task Force (EORTC-CLTF) developed emergency guidelines for the management of patients with cutaneous lymphomas (CLs) during the pandemic. These emergency protocols were intended to ensure patient safety and called for dose modifications, treatment delays and treatment interruptions as necessary to minimize exposure risks to COVID-19. Because there are no established maintenance protocols for CLs, the impact of such delays or interruptions on disease outcomes was not known. The ISCL created an International Cutaneous Lymphomas Pandemic Section (ICLYPS) to collect data from the institutions around the world to assess the impact of these changes on patients’ outcomes and to determine if these measures were effective in preventing infection. We summarize the outcomes from a preliminary cohort of patients from Brazil, Greece, Italy, Spain, Switzerland, the UK and the US. Actively managed patients with an established diagnosis of CL from March to October 2020 were included according to the Institutional Protection of Human Subjects guidelines at the respective centers. We included 149 patients in this retrospective review. The average age was 61.88 years (range: 22–95). 2 patients (1.3%) had diagnoses of CD30+ lymphoproliferative disorders (LyP and pcALCL), 112 (75.2%) had mycosis fungoides (MF), and 35 (23.5%) had Sézary syndrome (SS). 77 patients (68.7%) had stages IA–IIA MF, 23 (20.5%) had Stage IIB MF, 6 (5.4%) had stage III MF, and 41 (27.5%) had Stage IV disease, of which 6 had Stage IV MF (5.4%) and 35 had SS (23.5%). Treatment was delayed for more than half (53.0%) of the patients for a mean of 3.2 months (range: 10 days to 10 months). Treatment delay was associated with a significant risk of disease relapse or progression across all stages (65.8% vs 32.9%, p<0.00001). During follow up, 6 patients (4%) died due to disease progression, including 3 patients with Stage IIB MF, one with Stage IVB MF, and two with SS. Twenty-eight patients (18.8%) had a confirmed COVID-19 infection during the capture period. Two of these cases were definitive hospital-acquired infections following prolonged hospital admission, while the remaining contracted the virus through community exposures. There were no outpatient office-acquired infections. Three of the 26 patients who contracted COVID-19 died of the infection (2 SS and 1 LyP, mean age: 80, range: 66–89). The ICLYPS analysis has revealed that treatment interruptions and delays during the COVID-19 pandemic resulted in significantly worse outcomes in patients with CLs as compared to those who did not experience treatment interruptions. No outpatient office-acquired infections were reported in this extensive review, and patients with CLs who developed COVID-19 did not do worse than expected according to their risk factors. Effective safety measures and protocols can prevent transmission of COVID-19 at physicians’ offices. Interruption of therapy leads to negative clinical outcomes and should be avoided, especially in the setting of advanced disease, as the risk of contracting COVID-19 in the outpatient setting did not outweigh the risk of morbidity and mortality due to disease progression. Ensuring continuity of treatment and maintenance therapy appears to be critical to avoiding life-threatening disease progression.

Primary cutaneous peripheral T-cell lymphoma, not otherwise specified: results of a multicentre European Organization for Research and Treatment of Cancer (EORTC) cutaneous lymphoma taskforce study on the clinico-pathological and prognostic features.

Cutaneous peripheral T-cell lymphoma, not otherwise specified (PTL NOS) is an aggressive, but poorly characterized neoplasm. The European Organization for Research and Treatment of Cancer cutaneous lymphoma taskforce (EORTC CLTF) investigated 33 biopsies of 30 patients with primary cutaneous PTL NOS to analyse their clinical, histological, immunophenotypic features and outcome. Retrospective analysis of clinical data and histopathological features by an expert panel. Cutaneous PTL NOS manifested clinically either with solitary or disseminated rapidly grown ulcerated tumours or disseminated papulo-nodular lesions. Histologically, a mostly diffuse or nodular infiltrate in the dermis and often extending into the subcutis was found. Epidermotropism was rarely present and only mild and focal. Unusual phenotypes were frequent, e.g. CD3+ /CD4- /CD8- and CD3+ /CD4+ /CD8+ . Moreover, 18% of the cases exhibited an aberrant expression of the B-cell marker CD20 by the tumour cells. All solitary tumours were located on the limbs and presented a high expression of GATA-3 but this did not correlate with outcome and therefore could not serve as a prognostic factor. The prognosis was shown to be generally poor with 10 of 30 patients (33%) dying of lymphoma within the follow-up of 36months (mean value; range 3-144). The survival rates were 61% after 3years (CI, 43-85%) and 54% after 5years (CI, 36-81%). Small to medium-sized morphology of tumour cells was associated with a better outcome than medium to large or large tumour cells. Age, gender, clinical stage, CD4/CD8 phenotype and GATA-3 expression were not associated with prognosis. Chemotherapy was the most common treatment modality, but surgical excision and/or radiotherapy may represent an appropriate first-line treatment for solitary lesions. Cutaneous PTL NOS shows an aggressive course in most patients independent of initial presentation, age and phenotype. Cytomorphology was identified as a prognostic factor. The data indicate a need for more effective treatment modalities in PTL NOS.

The evolving field of Dermato-oncology and the role of dermatologists: Position Paper of the EADO, EADV and Task Forces, EDF, IDS, EBDV-UEMS and EORTC Cutaneous Lymphoma Task Force.

The incidence of skin cancers has been increasing steadily over the last decades. Although there have been significant breakthroughs in the management of skin cancers with the introduction of novel diagnostic tools and innovative therapies, skin cancer mortality, morbidity and costs heavily burden the society. Members of the European Association of Dermato-Oncology, European Academy of Dermatology and Venereology, International Dermoscopy Society, European Dermatology Forum, European Board of Dermatovenereology of the European Union of Medical Specialists and EORTC Cutaneous Lymphoma Task Force have joined this effort to emphasize the fundamental role that the specialist in Dermatology-Venereology has in the diagnosis and management of different types of skin cancer. We review the role of dermatologists in the prevention, diagnosis, treatment and follow-up of patients with melanoma, non-melanoma skin cancers and cutaneous lymphomas, and discuss approaches to optimize their involvement in effectively addressing the current needs and priorities of dermato-oncology. Dermatologists play a crucial role in virtually all aspects of skin cancer management including the implementation of primary and secondary prevention, the formation of standardized pathways of care for patients, the establishment of specialized skin cancer treatment centres, the coordination of an efficient multidisciplinary team and the setting up of specific follow-up plans for patients. Skin cancers represent an important health issue for modern societies. The role of dermatologists is central to improving patient care and outcomes. In view of the emerging diagnostic methods and treatments for early and advanced skin cancer, and considering the increasingly diverse skills, knowledge and expertise needed for managing this heterogeneous group of diseases, dermato-oncology should be considered as a specific subspecialty of Dermatology-Venereology.

Survival in Mycosis Fungoides and Sezary Syndrome: How Can We Predict Outcome?

Early-stage mycosis fungoides (MF) has been associated with long survival. A recent meta-analysis including 6,279 patients with MF and Sezary syndrome found that about 10-20% of stage IB patients don't survive 5 years, whereas patients with advanced-stage MF and Sezary syndrome have a 5-year survival chance of about 20-60%. Identifying prognostic markers to better identify those at risk of limited survival may allow improved management choices and this, coupled with newer treatments, could improve survival.

Brentuximab Vedotin (BV) and Lenalidomide (Len) in Relapsed and Refractory (r/r) Cutaneous (CTCL) and Peripheral (PTCL) T-Cell Lymphomas; A Planned Interim Analysis of Phase II Trial

Background: Patients with r/r tumor stage CTCL and/or PTCL have a poor prognosis. BV is currently FDA approved for CD30 positive CTCL and anaplastic large cell lymphoma (ALCL) with single agent activity in additional PTCL subtypes. Len also has single agent activity in patients with r/r CTCL/PTCL. The safety of the combination was established in a phase I trial in patients with r/r diffuse large B-cell lymphoma. Methods: We conducted a single-institution phase II trial to determine the safety and efficacy of BV+Len combination in patients with r/r CTCL/PTCL. Simon's 2-stage optimal design was followed to test the null hypothesis of overall response rate (ORR) ≤0.3 versus the alternative hypothesis of ORR≥0.5. Patients with ≥ 1 line of systemic therapy or 2 lines of skin directed therapy, at least stage IB (for CTCL), and no prior progression on BV were eligible regardless of CD30 staining. All patients were treated with BV 1.2 mg/kg IV and Len 20 mg PO daily q3 weeks for a maximum 16 cycles. After 7 patients were treated, we reduced Len to 10 mg given safety/tolerability concerns. Responses are assessed by the International Society for Cutaneous Lymphomas and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (ISCL/EORTC) Global response criteria (for CTCL) and Cheson year criteria (for PTCL). The effect of treatment on quality of life is assessed by Skindex-16. Results: As of July 1, 2019, 17 subjects were treated; 10 (59%) with mycosis fungoides (MF), 2 (12%) with Sezary syndrome (SS), 2 (12%) with CD30+ lymphoproliferative disorder, and 3 (18%) with PTCL. Median age was 60 (49-90) years and 76% were males. CD30 was completely negative (&lt;1%) in 3 (18%) of patients and median CD30 staining (by immunohistochemistry) was 7.5% (range 1-75%). Of 12 patients with MF/SS, 5 (42%) had evidence of large cell transformation at accrual. Of 14 patients with CTCL, median baseline mSWAT was 54.5 (range 4.4-190). Median number of prior therapies was 5 (range 1-9). Grade 3 adverse events (AEs) were reported in 11/17 patients; including neutropenia (4), thrombocytopenia (1), bronchitis (1), dyspnea (1), abdominal pain (2), vertigo (1), , DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome (1), urinary tract infection (1), and tumor flare (2). Median number of cycles received was 4 (range 1-17). Best response in 14 evaluable patients were 2 (14%) complete response, 3 (21%) partial response, and 8 (57%) stable disease with ORR of 33% (95% confidence interval:12-62%). Of 17 patients, 5 (29%) remain on treatment, and 12 (71%) discontinued treatment because of disease progression (7; 58%), AEs (4; 33%), or patient preference (1; 2%). Median duration of response was 3.2 (range 2.5-13) months. Of note, 7/14 patients (50%) patients with CTCL had &gt;50% reduction in their Skindex-16 scores after a median of 2 cycles (range 1-3). Conclusions: BV + Len is combination is safe and efficacious in a heavily pre-treated patients with T-cell lymphomas. Len doses higher than 10 mg daily are poorly tolerated and associated with excess tumor flare. Recruitment of both CTCL and PTCL patients for this trial is ongoing. Disclosures William: Guidepoint Global: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Grantier:Pharmacyclics LLC and Janssen Oncology: Other: Advisory Board. Hoffman:Pharmacyclics LLC and Janssen Oncology: Other: Advisory Board. Baiocchi:Prelude: Consultancy. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Christian:Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Acerta: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Cephalon: Research Funding; Merck: Research Funding; Janssen: Research Funding; Millennium Pharmaceuticals Inc: Research Funding. Maddocks:BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Brentuximab vedotin is being used off-label for CD30 negative peripheral and cutaneous T-cell lymphoma. Lenalidomide is being used off-label for both conditions (within a phase II clinical trial)

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Primary cutaneous lymphomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Standardization of regimens in Narrowband UVB and PUVA in early stage mycosis fungoides: position paper from the Italian Task Force for Cutaneous Lymphomas.

UV-based (PUVA and narrowband UVB) phototherapy is broadly and commonly used in the treatment of Cutaneous T-cell Lymphomas (CTCL), yet unfortunately, the evidence for the efficacy of these treatments is based only on case series or prospective but non-randomized studies. Therefore, no internationally approved guidelines exist and no standardization of schedules has been proposed. Recently, consensus guidelines have been published by the United States Cutaneous Lymphoma Consortium. The aim of this study was to review the biological and clinical evidences on PUVA and NB-UVB in CTCL and to critically evaluate acceptability and feasibility of these guidelines in the real-life setting from the perspective of the Cutaneous Lymphoma Task Force of the Italian Lymphoma Foundation (Fondazione Italiana Linfomi, FIL).

Histopathological and immunophenotypical criteria for the diagnosis of Sézary syndrome in differentiation from other erythrodermic skin diseases: a European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force Study of 97 cases.

Patients with erythrodermic disease are a diagnostic challenge regarding the clinical and histological differential diagnosis. To evaluate histopathological and immunohistochemical diagnostic markers for Sézary syndrome. Ninety-seven erythrodermic cases [Sézary syndrome (SS), n = 57; erythrodermic inflammatory dermatoses (EIDs), n = 40] were collected by the EORTC Cutaneous Lymphoma Task Force histopathology group. Evaluation criteria were (i) epidermal and dermal changes; (ii) morphology of the infiltrate; (iii) immunohistochemical analysis of marker loss (CD2, CD3, CD4, CD5 and CD7); (iv) bystander infiltrate by staining for CD8, FOXP3 and CD25; and (v) expression of Ki-67, CD30, PD-1 and MUM-1. The workshop panel made a correct diagnosis of SS in 51% of cases (cutaneous T-cell lymphoma 81%) and of EID in 80% without clinical or laboratory data. Histology revealed a significantly increased degree of epidermotropism (P < 0.001) and more intraepidermal atypical lymphocytes (P = 0.0014) in SS biopsies compared with EID. Pautrier microabscesses were seen only in SS (23%) and not in EID (P = 0.0012). SS showed significantly more dermal cerebriform and blastic lymphocytes than EID. Immunohistochemistry revealed a significant loss of CD7 expression (< 50%) in 33 of 51 (65%) cases of SS compared with two of 35 (6%) EID (P < 0.001). The lymphocytic infiltrate in SS skin samples was found significantly to express PD-1 (P = 0.0053), MUM-1 (P = 0.0017) and Ki-67 (P < 0.001), and showed less infiltration of CD8(+) lymphocytes (P < 0.001). A multivariate analysis identified CD7 loss, increased numbers of small cerebriform lymphocytes, low numbers of CD8(+) lymphocytes and increased proliferation (Ki-67(+) lymphocytes) as the strongest indicators for the diagnosis of SS. A number of different histological and immunophenotypical criteria are required to differentiate between SS and EIDs.

Aggressive epidermotropic cutaneous CD8+ lymphoma: a cutaneous lymphoma with distinct clinical and pathological features. Report of an EORTC Cutaneous Lymphoma Task Force Workshop

Aggressive epidermotropic cutaneous CD8(+) lymphoma is currently afforded provisional status in the WHO classification of lymphomas. An EORTC Workshop was convened to describe in detail the features of this putative neoplasm and evaluate its nosological status with respect to other cutaneous CD8(+) lymphomas. Sixty-one CD8(+) cases were analysed at the workshop; clinical details, often with photographs, histological sections, immunohistochemical results, treatment and patient outcome were discussed and recorded. Eighteen cases had distinct features and conformed to the diagnosis of aggressive epidermotropic cutaneous CD8(+) lymphoma. The patients typically present with widespread plaques and tumours, often ulcerated and haemorrhagic, and histologically have striking pagetoid epidermotrophism. A CD8(+) /CD45RA(+) /CD45RO(-) /CD2(-) /CD5(-) /CD56(-) phenotype, with one or more cytotoxic markers, was found in seven of 18 patients, with a very similar phenotype in the remainder. The tumours seldom involve lymph nodes, but mucosal and central nervous system involvement are not uncommon. The prognosis is poor, with a median survival of 12 months. Examples of CD8(+) mycosis fungoides, lymphomatoid papulosis and Woringer-Kolopp disease presented the typical features well documented in the CD4(+) forms of those diseases. Aggressive epidermotropic cutaneous CD8(+) lymphoma is a distinct lymphoma that warrants inclusion as a distinct entity in future revisions of lymphoma classifications.

Cytotoxic Variant of Mycosis Fungoides with CD8+ CD56+ Phenotype: A Case Report and Review of Literature.

Mycosis fungoides (MF) is the most common cutaneous Tcell lymphoma. Approximately 50% of all primary cutaneous lymphomas are MF[1]. These lymphomas are comprised of epidermotropic collections of small- to medium-sized T lymphocytes with cerebriform nuclei. The neoplastic cell shows a mature CD3+, CD4+, CD45RO+, CD8– memory T-cell phenotype. However, rarely, MF with a CD4–, CD8+ cytotoxic T-cell phenotype has been reported[2-5]. The World Health Organization (WHO)-European Organization for Research and Treatment of Cancer (EORTC) classification for cutaneous lymphomas describes three types of cutaneous lymphomas that express CD56: 1) subcutaneous panniculitis-like T-cell lymphoma, 2) extranodal natural killer (NK)/T-cell lymphoma, nasal type, and 3) CD4+/CD56+ hematodermic neoplasm (blastic NKcell lymphoma)[1]. However, the report does not mention, MF with CD56 expression. Earlier in 2003, a report by the EORTC cutaneous lymphoma task force workshop described cytotoxic/natural killer cell cutaneous lymphomas and divided them into eight categories[6]. One of these categories was the CD56+, cytotoxic variant of MF. This report presents a rare CD8+, CD56+ variant of MF having the cytotoxic phenotype.

Allogeneic stem cell transplantation versus conventional therapy for advanced primary cutaneous T-cell lymphoma

Primary cutaneous T-cell lymphomas (CTCL) belong to the group of non-Hodgkin lymphomas and usually run an indolent course. However, some patients progress to advanced tumour or leukaemic stages. To date, there is no cure for those cases. In the last few years, several publications reported durable responses in some patients following allogeneic stem cell transplantation (alloSCT). This is an update of a Cochrane review first published in 2011 and updated in 2013. To compare the efficacy and safety of conventional therapies with allogeneic stem cell transplantation in patients with advanced primary cutaneous T-cell lymphomas. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1), MEDLINE (1950 to January 2013), Internet-databases of ongoing trials, conference proceedings of the American Society of Clinical Oncology (ASCO, 2009 to July 2013) and the American Society of Hematology (ASH, 2009 to July 2013). We also contacted members of the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force to check for ongoing study activities. We handsearched citations from identified trials and relevant review articles. In addition, we handsearched randomised controlled trials from the European Group for Blood and Marrow Transplantation (EBMT) and International Conference on Cutaneous T-cell Lymphoma, ASCO and ASH up to July 2013. Trials eligible for inclusion were genetically randomised controlled trials (RCTs) comparing alloSCT plus conditioning therapy (regardless of agents) with conventional therapy as treatment for advanced CTCL. Two review authors would have extracted data from eligible studies and assessed their quality. The primary outcome measure was overall survival; secondary outcomes were time to progression, response rate, treatment-related mortality, adverse events and quality of life. We did not identify any randomised controlled trials from the updated search in January 2013. In 2011, we found 2077 citations but none were relevant genetically or non-genetically randomised controlled trials. All 41 studies that were thought to be potentially suitable were excluded after full text screening for being non-randomised, not including CTCL or being review articles. We planned to report evidence from genetically or non-genetically randomised controlled trials comparing conventional therapy and allogeneic stem cell transplantation. However, we did not identify any randomised controlled trials addressing this question. Nevertheless, prospective genetically randomised controlled trials need to be initiated to evaluate the precise role of alloSCT in advanced CTCL.

Étude rétrospective de 23 cas de lymphomes cutanés primitifs suivis l’EHU d’Oran entre 2009–2012

Several reviews and guidelines on the management of mycosis fungoides and Sézary syndrome (MF/SS) have been published; however, treatment strategies for patients with MF/SS vary from institution to institution and no European consensus has yet been established. There are few phase III trials to support treatment decisions for MF/SS and treatment is often determined by institutional experience. In order to summarise the available evidence and review ‘best practices’ from each national group, the European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force met in September 2004 to establish European guidelines for the treatment of MF/SS.This article reviews the treatment regimens selected for inclusion in the guidelines and summarises the clinical data for treatments appropriate for each stage of MF/SS. Guideline recommendations are presented according to the quality of supporting data, as defined by the Oxford Centre for Evidence-Based Medicine. Skin-directed therapies are the most appropriate option for early-stage MF/SS and most patients can look forward to a normal life expectancy. Patients with advanced disease should be encouraged to participate in clinical trials and maintenance of quality of life should be paramount.

Efficacy and safety of bexarotene combined with psoralen-ultraviolet A (PUVA) compared with PUVA treatment alone in stage IB-IIA mycosis fungoides: final results from the EORTC Cutaneous Lymphoma Task Force phase III randomized clinical trial 21011 (NCT00

Psoralen plus ultraviolet A (PUVA) is the standard treatment for early stages of mycosis fungoides. There have been no adequate randomized controlled trials with sufficient power comparing this modality with other therapies. To assess disease response and to compare the response rates of patients treated with PUVA alone or PUVA and bexarotene. EORTC 21011 (NCT 00056056) was a randomized phase III study comparing combined bexarotene (Targretin(®) ) and PUVA vs. PUVA alone in patients with stage IB and IIA mycosis fungoides (MF). The primary endpoint was the overall response rate [complete clinical response (CCR) plus partial response (PR)]. The study was prematurely closed due to low accrual after 93 of 145 required patients (65%) were randomized. Of the 93 randomized patients, 87 started treatment, 41 received PUVA and 46 received PUVA + bexarotene. Total UVA doses received were 107 J cm(-2) (range 1·4-489·9) in the PUVA arm vs. 101·7 J cm(-2) (0·2-529·9) in the combination arm. The safety profile was acceptable with few grade 3-4 toxicities observed in either arm. More drop-outs due to toxicity were observed in the combination arm compared with the PUVA-alone arm. The best overall response (CCR + PR) rate was 71% for PUVA alone and 77% for the combination arm (P = 0·57). The median duration of response was 9·7 months for PUVA vs. 5·8 months for the combination arm (P = 0·33). CCR was seen in 25 patients of whom 10 received PUVA alone (CCR 22%) and 15 received combination therapy (CCR 31%) (P = 0·45). CCR was sustained in 25% of patients regardless of therapy. There was a trend towards fewer PUVA sessions needed to achieve CCR in the combination arm (median 22) compared with the PUVA arm (median 27·5) (P = 0·11). Similarly, a trend towards lower UVA dose required to achieve CCR in the combination arm (median 55·8 J cm(-2) ) compared with the PUVA arm alone (median 117·5 J cm(-2) ) (P = 0·5) was observed. No significant difference in response rate or response duration was observed in this study. However, there was a trend towards fewer PUVA sessions and lower UVA dose required to achieve CCR in the combination arm (PUVA + bexarotene) but this did not achieve statistical significance due to insufficient power.

Time course, clinical pathways, and long‐term hazards risk trends of disease progression in patients with classic mycosis fungoides

Mycosis fungoides (MF) is an indolent primary cutaneous T-cell lymphoma. To the authors' knowledge, no data currently are available regarding the evolution over time of the risk of developing specific pathways of disease progression. This retrospective study analyzed 1422 patients with MF who were diagnosed and followed from 1975 through 2010 in 27 Italian Study Group for Cutaneous Lymphoma centers. The primary objectives were to ascertain the time course, pathways, and hazards risk trends of cutaneous/extracutaneous disease progression; to evaluate whether different tumor-lymph node-metastasis-blood (TNMB) stages have different pathways of disease progression; and to analyze differences between tumor-stage and erythrodermic MF with regard to clinical onset, disease evolution, and prognosis. The secondary objective was to provide a further validation for the revised International Society for Cutaneous Lymphomas and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (ISCL/EORTC) classification. The median follow-up was 14.5 years; stage progression occurred in 29.7% of patients and blood involvement was the most frequent extracutaneous site of disease progression. Patients with stage IA to stage IB disease demonstrated a steady low annual incidence of disease progression to tumor-stage (1%-2%); patients with stage IIA disease had a higher risk within the first years (up to 9.4%). Erythroderma evolved with a significantly higher frequency from patches/plaques (13.9%/28.2%) than tumors (P = .028 and P = .013, respectively). Hazards rates of extracutaneous involvement were low (< 1%). The T-score was found to be associated with extracutaneous involvement site, tumor-stage disease with lymph node/visceral lesions, and erythroderma with blood involvement. TNMB classification and stage progression resulted as independent prognostic variables being detected on multivariate analysis; the type of extracutaneous involvement was found to affect survival . The data from the current study support the need for a stage-tailored follow-up, suggest that the classification of tumor-stage disease at a stage below erythroderma could be modified, and offer a further validation for the revised TNMB classification.

Molecular Markers of Early-Stage Mycosis Fungoides

The lack of a specific marker differentiating early mycosis fungoides (eMF) from benign inflammatory dermatitis presents significant difficulties in the assessment and management of suspected MF patients, which often leads to delayed diagnosis and improper medical approaches. To address this, an investigation was carried out to characterize positive identification markers for eMF by comparing eMF lesions with healthy skin and benign inflammatory dermatitis, using high-throughput genomic transcription profiling. A total of 349 genes were differentially expressed in eMF lesions compared with normal skin. These genes belong to pathways associated with inflammation, immune activation, and apoptosis regulation. Most of them (N=330) also demonstrated significant upregulation in chronic dermatitis, making them nonideal markers for eMF. Among them, 19 genes with specific enrichment in eMF lesions were identified that showed no significant upregulation in chronic dermatitis. Two of them, TOX and PDCD1, showed high discrimination power between eMF lesions and biopsies from benign dermatitis by RNA expression. Furthermore, TOX demonstrated highly specific staining of MF cells in eMF skin biopsies in immunohistochemistry and immunofluorescence, including the early epidermotropic cells in Pautrier's microabscesses. This study demonstrates the potential of eMF-enriched genes, especially TOX, as molecular markers for histological diagnosis of eMF, which currently is a major diagnostic challenge.

Efficacy and safety of bexarotene combined with psoralen/ultraviolet A light (PUVA) compared to PUVA treatment alone in stage IB-IIa mycosis fungoides (MF): Final results from EORTC cutaneous lymphoma task force (CLTF) phase III clinical trial 21011.

8076 Background: Skin-directed treatment with methoxsalen (PUVA) is the current treatment standard in stage IB-IIA MF. A combination of PUVA and bexarotene might be of additional clinical benefit for MF stage I/II patients (pts). Methods: EORTC 21011 was a randomised, open label phase III study comparing combined bexarotene and PUVA versus PUVA alone in pts with stage IB and IIA MF. Study primary endpoint was response (complete clinical + partial response, CCR+PR) rate; secondary endpoints: cumulative dose of UVA and number of PUVA sessions necessary to achieve a CCR, duration of CCR, time to relapse, safety and percentage of drop-outs. Results: The study recruited stage IB/IIA MF pts and was prematurely closed due to low accrual after 93/145 required pts (65%) were randomized; 45 to PUVA, 48 to PUVA+bexarotene. Median number of PUVA weeks were 12 (1-17) in PUVA vs. 10.5 (1-16) in combination arm. Total UVA doses were 107J/cm2 (1.4-489.9) in PUVA vs. 101.7J/cm2 (0.2-529.9) in combination arm. Few grade 3-4 toxicities were observed in both arms (liver enzyme elevation, neutropenia, anemia, increased cholesterol, photosensitivity, pruritus, rash, hypertriglyceridemia). Best overall response (CCR/PR) rate was 71.1% (33/45) for PUVA alone and 77.1% (37/48) for combination arm (p-value=0.57). The median of duration of response was 9.6 for PUVA vs 5.8 months for combination arm (p value=0.33). CCR was seen in 25 pts, 10 in PUVA (CCR 24%) and 15 in combination therapy (CCR 33%) (pvalue=0.45). Similarily, a lower UVA dose was required to achieve a CCR in the combination arm (median of 55.8 J/cm2) compared to the PUVA arm (median of 117.58 J/cm2) (p value=0.5). Conclusions: No significant difference in response rate was observed in this study. There was a trend towards fewer PUVA sessions and lower UVA dose to achieve CCR in the PUVA/bexarotene combination arm (median of 27.5 vs. 22,p-value = 0.11) but this did not achieve statistical significance due to insufficient power. The safety profile was acceptable, as there were only few grade 3-4 toxicities observed in both arms.

Major achievements of the EORTC Cutaneous Lymphoma Task Force (CLTF)

This article describes the achievements of the Cutaneous LymphomaTask Force (CLTF) over the recent decade in their goal to optimize classification and response criteria and establish new treatment options for patients suffering from cutaneous T-cell lymphomas (CTCL). Collaborative work with the International Society of Cutaneous Lymphoma (ISCL) and the United States Cutaneous Lymphoma Consortium (USCLC) has led to publication of pivotal manuscripts proposing revised staging proposals for Mycosis fungoides (MF)/Sézary syndrome (SS) and also non MF/SS primary cutaneous lymphomas as well as the recent publication of a proposal for defining endpoints in MF/SS.

Cutaneous T-Cell Lymphomas: A Review of New Discoveries and Treatments

Treatment regimens of patients with CTCL vary widely based on clinician preference and patient tolerance. Skin directed therapies are recommended for patients with early stage IA and IB MF, with combinations used in refractory cases. While no regimen has been proven to prolong survival in advanced stages, immunomodulatory regimens should be used initially to reduce the need for cytotoxic therapies. In more advanced stages of disease, treatment efforts should strive for palliation and improvement of quality of life. With many new therapies and strategies on the horizon, the future looks promising for CTCL patients. Unfortunately, other than allogeneic HCT, there are no potential curative therapies for CTCL. Clinical trials are currently underway to identify new therapies to improve quality of life for patients, and researchers are hard at work to identify novel pathways and genes for prognostication and as targets for therapies. Importantly, collaborative clinical trials to enhance rates of accrual need to be conducted, and improved interpretation of data via standardizing end points and response criteria should be an emphasis. Recently, the International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer (EORTC) met to develop consensus guidelines to facilitate collaboration on clinical trials. These proposed guidelines consist of: recommendations for standardizing general protocol design; a scoring system for assessing tumor burden in skin, lymph nodes, blood, and viscera; definition of response in skin, nodes, blood, and viscera; a composite global response score; and a definition of end points. Although these guidelines were generated by consensus panels, they have not been prospectively or retrospectively validated through analysis of large patient cohorts.

Clinical End Points and Response Criteria in Mycosis Fungoides and Sézary Syndrome: A Consensus Statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer

Mycosis fungoides (MF) and Sézary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin's lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with MF or SS.