Cutaneous Lymphoma Summit 2009

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.

To determine the relationship between the WHO and European Organization for Research and Treatment of Cancer (EORTC) pathologic classifications for primary cutaneous B-cell lymphoma (CBCL) and the implication of this relationship on initial treatment. Patients with primary CBCL treated with radiotherapy were identified retrospectively. Initial biopsy specimens were reviewed by two dermatopathologists and classified according to the EORTC and WHO systems. Primary outcomes were recurrence-free and overall survival. Thirty-four patients were identified; initial biopsy specimens were adequate for classification in 32 patients. Four different composite histopathologic subtypes of lymphoma were identified: 53% (17 of 32) follicle center cell by EORTC and diffuse large B-cell by WHO (FCC/DLB), 25% (eight of 32) follicle center cell by EORTC and follicular by WHO (FCC/Fol), 13% (four of 32) marginal zone by EORTC and WHO (MZ/MZ), and 9% (three of 32) large B-cell of the leg by EORTC and diffuse large B-cell by WHO (Leg/DLB). Five-year relapse-free survival ranged from 62% to 73% for FCC/DLB, FCC/Fol, and MZ/MZ but was 33% for Leg/DLB (P =.6). Five-year overall survival was 100% for FCC/DLB, FCC/Fol, and MZ/MZ but was 67% for Leg/DLB (P =.07). At 5 years, 21% of all patients had developed extracutaneous disease. Two-thirds of primary cutaneous FCC lymphomas by EORTC criteria satisfy WHO criteria for DLB lymphoma. Unlike DLB lymphoma presenting in nodal or noncutaneous sites, these lesions are associated with an indolent course and may be treated with local radiotherapy alone.

The Oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) Demonstrates Broad and Durable Clinical Activity in Relapsed / Refractory Non Hodgkin’s Lymphoma (NHL)

Epstein-Barr Virus Kinase-Targeted Therapy for Primary Central Nervous System Post-Transplant Lymphoproliferative Disorder

The Lugano classification, a modification of the Ann Arbor classification, is recommended as for Hodgkin lymphoma with the exception of the elimination of the A or B classification of symptoms. For Non‐Hodgkin Lymphoma in paediatric patients, the St Jude/Murphy system is recommended. The International Society for Cutaneous Lymphoma, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treat of Cancer have recently published updated staging and guidelines for the management of cutaneous lymphoma. The classification applies to primary cutaneous lymphoma, mycosis fungoides, Sezary syndrome and T and B Cell Cutaneous Lymphoma. The regional lymph nodes are the superficial nodes, i.e., those of head and neck, and the axillary, epitrochlear, inguinal and popliteal nodes.

The Revised European-American Classification of Lymphoid Neoplasms (REAL) classification is based on the principle that each type of lymphoma is a distinct disease defined by morphology, immunophenotypic and genetic features, clinical presentation, and course. If either primary or secondary involvement of the skin is a constant factor, this aspect is considered integral to disease definition. Organ-specific classification schemes, such as that proposed by the European Organization for Research and Treatment of Cancer (EORTC) for cutaneous lymphomas, are not required, and indeed may impede the recognition of common features of diseases involving multiple anatomic sites. The use of multiple classification systems is a step backward, and may lead to confusion among hematologists/oncologists and dermatologists. Nevertheless, cutaneous lymphomas in many instances are distinct. Their natural history is often more indolent than nodal lymphomas, and for that reason they often require different therapeutic approaches. We agree with the efforts of the EORTC classification to emphasize the unique clinical aspects of many cutaneous lymphomas, as this recognition is essential for appropriate clinical management. As has been learned for nodal lymphomas, clinical features play an important role in prognosis and should be used in guiding therapy. For cutaneous lymphomas, the presence or absence of systemic spread is particularly important.

Prognostic Factors in Primary Cutaneous Lymphomas Other Than Mycosis Fungoides and the Sézary Syndrome

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. Up to now, no curative treatment has been established for those cases. In the last few years, several publications have reported durable responses in some patients following allogeneic stem cell transplantation (alloSCT). To compare the efficacy and safety of conventional therapies with allogeneic stem cell transplantation in patients with advanced primary cutaneous T-cell lymphomas. The search strategy included the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (1950 to May 2011), Internet-databases of ongoing trials (www.controlled-trials.com; www.clinicaltrials.gov), conference proceedings of the American Society of Clinical Oncology (ASCO, 2009 to present) and the American Society of Hematology (ASH, 2009 to present). 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, 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 2010 were handsearched. Genetically randomised controlled trials (RCT) comparing alloSCT plus conditioning therapy regardless of agents with conventional therapy as treatment for advanced CTCL were eligible to be included. From eligible studies data would have been extracted by two review authors and assessed for quality. Primary outcome measures were overall survival, secondary criteria were time to progression, response rate, treatment-related mortality, adverse events and quality of life. 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, no randomised trials addressing this question were identified. Nevertheless, prospective genetically randomised controlled trials need to be initiated to evaluate the precise role of alloSCT in advanced CTCL.

To evaluate the clinical relevance of genomic aberrations in primary cutaneous large B-cell lymphoma (PCLBCL). Skin biopsy samples of 31 patients with a PCLBCL classified as either primary cutaneous follicle center lymphoma (PCFCL; n = 19) or PCLBCL, leg type (n = 12), according to the WHO-European Organisation for Research and Treatment of Cancer (EORTC) classification, were investigated using array-based comparative genomic hybridization, fluorescence in situ hybridization (FISH), and examination of promoter hypermethylation. The most recurrent alterations in PCFCL were high-level DNA amplifications at 2p16.1 (63%) and deletion of chromosome 14q32.33 (68%). FISH analysis confirmed c-REL amplification in patients with gains at 2p16.1. In PCLBCL, leg type, most prominent aberrations were a high-level DNA amplification of 18q21.31-q21.33 (67%), including the BCL-2 and MALT1 genes as confirmed by FISH, and deletions of a small region within 9p21.3 containing the CDKN2A, CDKN2B, and NSG-x genes. Homozygous deletion of 9p21.3 was detected in five of 12 patients with PCLBCL, leg type, but in zero of 19 patients with PCFCL. Complete methylation of the promoter region of the CDKN2A gene was demonstrated in one PCLBCL, leg type, patient with hemizygous deletion, in one patient without deletion, but in zero of 19 patients with PCFCL. Seven of seven PCLBCL, leg type, patients with deletion of 9p21.3 and/or complete methylation of CDKN2A died as a result of their lymphoma. Our results demonstrate prominent differences in chromosomal alterations between PCFCL and PCLBCL, leg type, that support their classification as separate entities within the WHO-EORTC scheme. Inactivation of CDKN2A by either deletion or methylation of its promoter could be an important prognostic parameter for the group of PCLBCL, leg type.

Quality of Life in Cancer Patients Undergoing Anticoagulant Treatment for Venous Thromboembolism: The Quavitec Study

Aim This study was aimed to translate an updated European Organization for Research and Treatment of Cancer (EORTC) quality of life module for head and neck (EORTC QLQ-H&N43) in grammatically and conceptually acceptable Marathi language and its linguistic validation.Materials and Methods Approval was obtained from the Institutional Ethics Committee. The permission for translation was obtained from the EORTC translation unit (TU). The EORTC guidelines for the translation were followed to form a translation for pilot testing which was administered to 10 Marathi speaking head and neck squamous cell cancer (HNSCC) patients who gave informed written consent for the participation in the study. Patients were interviewed personally. The final Marathi translation was prepared and sent to EORTC TU for approval. Statistical analysis was performed using SYSTAT version 12 by Cranes software, Bengaluru, Karnataka, India.Results After getting permission, the translation files were received from EORTC TU, including Marathi EORTC QLQ-H&N35 for reference. Two forward translations, reconciled translation, back translations, first interim translation, translation for proof editing, and second interim translation (SIT) were prepared. This SIT was pilot tested in 10 Marathi-speaking HNSCC patients. Each patient was interviewed regarding difficulty in answering, confusing or offensive word, and reframing sentence. The questionnaire was well understood by patients reflecting its linguistic validity. After incorporating the changes as per the patient’s interview, updated translation was prepared and sent to EORTC TU which was accepted and approved by EORTC. The psychometric analysis of pilot testing showed that the questionnaire is acceptable.Conclusion Marathi translation of EORTC QLQ-H&N43 is well accepted and understandable. It can be used for future studies.

Integrative medicine use in patients with cutaneous T-Cell lymphoma: A cross-sectional survey study

BackgroundThe European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 is a core questionnaire designed to evaluate health-related quality of life (HRQoL) of cancer patients participating in international clinical trials. It is available in several languages including Danish. The EORTC QLQ-TC26 is a supplemental module developed for patients with testicular cancer, which can be useful in clinical trials. Despite Denmark holding a high prevalence and incidence of testicular cancer, no Danish translation was previously available. This paper describes the translation process and pilot testing of the Danish translation of QLQ-TC26.MethodsThe English language EORTC QLQ-TC26 was translated into Danish using forward and backward procedures with reconciliation. The translated instrument was assessed in semi structured cognitive interviews in a sample of 10 patients ages 20–56 receiving treatment for testicular cancer.ResultsIn one round of pilot testing, no changes were required for the Danish translation based upon patient comments. The Danish translation was agreed by participants to be both culturally acceptable and semantically comprehensible.ConclusionsThe pilot testing of the Danish translation of the EORTC QLQ-TC26 was performed in one round of patient interviews; these results support the Danish translation as a comparable instrument to the English language version. However, further validation is required to ensure complete equivalency. These results support the use of the EORTC QLQ-TC26 in future clinical trials conducted with Danish-speaking patients.

PURPOSE Low-dose radiation demonstrates efficacy in treating primary cutaneous T-cell lymphomas. This study evaluated the safety and efficacy of low-dose total skin electron beam therapy (TSEBT) regimens in patients with mycosis fungoides (MF). MATERIALS AND METHODS Patients with stage IB to IIB MF received low-dose TSEBT. The primary end point assessed was the overall response rate (ORR). The secondary end points included time to next treatment (TTNT), progression-free survival (PFS), and toxicity. Exploratory patient-reported outcome measures and potential soluble biomarkers were investigated. RESULTS In a study of 118 patients, 38 were in stage IB to IIA and 80 were in stage IIB according to International Society for Cutaneous Lymphomas /European Organisation for Research and Treatment of Cancer (EORTC) TNM classification. Patients had received a median of four previous treatments and were treated with either 12 Gy in eight fractions (65 patients) or 8 Gy in two fractions (53 patients). The ORR was 92% at 3 months. After a median follow-up of 45 months (95% CI, 36 to 54), the median TTNT was 16 months (95% CI, 8 to 24) and the median PFS was 11 months (95% CI, 8 to 14). There was no significant difference in outcome between the radiation regimens. Only 17% reported grade 2 toxicities, and the rate of grade 3 or higher toxicity was 4%. There were no significant differences in toxicity based on radiation dose or fractionation. Participants reported meaningful improvements, including reduced itching and skin disease burden, along with better scores on Skindex-29 and EORTC core quality of life questionnaire assessments. The study identified several prognostic factors and potential biomarkers in a multivariate analysis. CONCLUSION Low-dose TSEBT delivered with 8 Gy or 12 Gy provides significant clinical benefits and shows minimal toxicity. In a multivariate analysis, we identified several prognostic factors and potential biomarkers which could support patient selection.

Primary cutaneous B-cell lymphomas (PCBCL) represent a unique type of extranodal B-cell lymphomas. Recently, the "European Organization for Research and Treatment of Cancer (EORTC)-Cutaneous Lymphoma Study Group" classified PCBCL into two major groups: one with low-grade malignancy and excellent prognosis (follicle center cell lymphoma, immunocytoma/marginal zone B-cell lymphoma) and the other with intermediate malignancy and worse prognosis (large B-cell lymphoma of the leg). The clinical course and the prognosis of both groups clearly distinguish them from nodal lymphomas with similar morphological aspects, thus underlying the need for different treatment modalities. We investigated retrospectively the therapeutic data from 51 patients with PCBCL (40 low grade lymphomas, 11 large B-cell lymphomas). Several treatment modalities were used: total excision, radiotherapy, polychemotherapy, systemic corticosteroids, systemic antibiotics, as well as a variety of combination treatments. Recurrence, dissemination and/or death of the patients were not significantly related to any single treatment modality. In our opinion, the choice of treatment for PCBCL depends on the histologic classification, the number, spread and localization of the infiltrates, and on the general condition of the patient.