Christiane Querfeld

Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome): Part II. Prognosis, management, and future directions

Both mycosis fungoides (MF) and Sézary syndrome (SS) have a chronic, relapsing course, with patients frequently undergoing multiple, consecutive therapies. Treatment is aimed at the clearance of skin disease, the minimization of recurrence, the prevention of disease progression, and the preservation of quality of life. Other important considerations are symptom severity, including pruritus and patient age/comorbidities. In general, for limited patch and plaque disease, patients have excellent prognosis on ≥1 topical formulations, including topical corticosteroids and nitrogen mustard, with widespread patch/plaque disease often requiring phototherapy. In refractory early stage MF, transformed MF, and folliculotropic MF, a combination of skin-directed therapy plus low-dose immunomodulators (eg, interferon or bexarotene) may be effective. Patients with advanced and erythrodermic MF/SS can have profound immunosuppression, with treatments targeting tumor cells aimed for immune reconstitution. Biologic agents or targeted therapies either alone or in combination--including immunomodulators and histone-deacetylase inhibitors--are tried first, with more immunosuppressive therapies, such as alemtuzumab or chemotherapy, being generally reserved for refractory or rapidly progressive disease or extensive lymph node and metastatic involvement. Recently, an increased understanding of the pathogenesis of MF and SS with identification of important molecular markers has led to the development of new targeted therapies that are currently being explored in clinical trials in advanced MF and SS.

Sézary syndrome: Immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC)

Sézary syndrome (SS) has a poor prognosis and few guidelines for optimizing therapy. The US Cutaneous Lymphoma Consortium, to improve clinical care of patients with SS and encourage controlled clinical trials of promising treatments, undertook a review of the published literature on therapeutic options for SS. An overview of the immunopathogenesis and standardized review of potential current treatment options for SS including metabolism, mechanism of action, overall efficacy in mycosis fungoides and SS, and common or concerning adverse effects is first discussed. The specific efficacy of each treatment for SS, both as monotherapy and combination therapy, is then reported using standardized criteria for both SS and response to therapy with the type of study defined by a modification of the US Preventive Services guidelines for evidence-based medicine. Finally, guidelines for the treatment of SS and suggestions for adjuvant treatment are noted.

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

PURPOSE Advanced-stage mycosis fungoides (MF; stage IIB to IV) and Sézary 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.

Alemtuzumab for relapsed and refractory erythrodermic cutaneous T-cell lymphoma: a single institution experience from the Robert H. Lurie Comprehensive Cancer Center

We present the results of an open-label clinical trial and the clinical use of alemtuzumab in 19 heavily pretreated patients with advanced erythrodermic cutaneous T-cell lymphomas (CTCL) (erythrodermic mycosis fungoides and Sézary syndrome). Ten patients received alemtuzumab intravenously using an escalating dose regimen with a final dose of 30 mg three times weekly for 4 weeks followed by subcutaneous administration for 8 weeks. Nine patients were treated with only the SQ or IV dosing. The overall response rate was 84%, with 9 (47%) complete and 7 (37%) partial remissions. The median follow-up was 24 months (range, 6 to 62+ months). Median overall survival was 41 months whereas median progression free survival was 6 months. Minimal residual disease by T-cell gene rearrangement studies was detected in 11 patients who achieved complete response and partial response. Toxicities included myelosuppression and infections; however, the majority of side effects were of Grade 2 in severity and transient. One patient was diagnosed with a concurrent lymphoma (mantle cell lymphoma) 6 months after completing alemtuzumab therapy. Alemtuzumab is particularly effective in patients with erythrodermic CTCL with acceptable toxicities. Combined strategies with alemtuzumab may achieve molecular remissions with longer response durations.

Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1

Bullous pemphigoid is a rare immune-related adverse event after anti–PD-1/PD-L1 immune checkpoint treatment and may be mediated by both T-cell and B-cell responses. Early referral to dermatology for accurate diagnosis and management is recommended. Monoclonal antibodies (mAb) targeting immune checkpoint pathways such as cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed death 1 (PD-1) may confer durable disease control in several malignancies. In some patients, immune checkpoint mAbs cause cutaneous immune-related adverse events. Although the most commonly reported cutaneous toxicities are mild, a subset may persist despite therapy and can lead to severe or life-threatening toxicity. Autoimmune blistering disorders are not commonly associated with immune checkpoint mAb therapy. We report a case series of patients who developed bullous pemphigoid (BP), an autoimmune process classically attributed to pathologic autoantibody formation and complement deposition. Three patients were identified. Two patients developed BP while receiving the anti–PD-1 mAb nivolumab, and one while receiving the anti–PD-L1 mAb durvalumab. The clinicopathologic features of each patient and rash, and corresponding radiologic findings at the development of the rash and after its treatment, are described. Patients receiving an anti–PD-1/PD-L1 mAb may develop immune-related BP. This may be related to both T-cell– and B-cell–mediated responses. Referral to a dermatologist for accurate diagnosis and management is recommended. Cancer Immunol Res; 4(5); 383–9. ©2016 AACR.

Primary cutaneous lymphomas: a review with current treatment options.

Primary cutaneous T- and B-cell lymphomas are a heterogenous group of diseases with varied clinical presentations and prognosis. The use of new molecular, histological, and clinical criteria have enhanced the recognition of primary cutaneous T- and B-cell lymphomas. Compared to their nodal counterpart they have a different clinical behavior and therefore require a different treatment approach. Independent predictive factors identified clinically, histologically, and by immunopheno- and immunogenotyping are essential to assess the appropriate treatment for each subtype. The European Organization for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Study Group provide a classification of cutaneous lymphomas taking into account of the histological and molecular features. Based on this classification we will provide a summary of the current medical literature in diagnosis, treatment, and prognosis for primary cutaneous lymphomas with emphasis on new treatment strategies.

Primary cutaneous B-cell lymphomas: Part II. Therapy and future directions

The choice of therapy for primary cutaneous B-cell lymphoma (PCBCL) relies on correct histopathologic classification and the exclusion of systemic disease. In part II of this continuing medical education article, we will review the available therapies for the different types of PCBCL. Primary cutaneous follicle center lymphoma (PCFCL) and primary cutaneous marginal zone lymphoma (PCMZL) are indolent tumors with an excellent prognosis. They are managed similarly with local therapy, such as radiotherapy or surgical excision, for isolated disease and observation for asymptomatic multifocal presentations. Relapses are common in both PCFCL and PCMZL, but overall survival remains excellent. Primary cutaneous diffuse large B-cell lymphoma (both leg type and other) has a much poorer prognosis than indolent PCBCL, and it often requires an aggressive approach with radiation therapy and/or multiagent chemotherapy. Investigational approaches hold promise for the treatment of these malignancies, particularly primary cutaneous diffuse large B-cell lymphoma.

Primary cutaneous B-cell lymphomas: Part I. Clinical features, diagnosis, and classification

Primary cutaneous B-cell lymphomas (PCBCLs) are defined as lymphomas with a B-cell phenotype that present in the skin without evidence of systemic or extracutaneous disease at initial presentation, after adequate staging. In non-Hodgkin lymphomas, the skin is the second most common site of extranodal involvement after the gastrointestinal tract. PCBCLs are histologically very similar to their nodal counterparts, and these histologic similarities can lead to confusion about both therapy and prognosis. This article will summarize the clinical, pathologic, and diagnostic features of the 3 main types of PCBCL: primary cutaneous follicle center lymphoma, primary cutaneous marginal zone lymphoma, and primary cutaneous diffuse large B-cell lymphoma, leg-type, and the appropriate evaluation and staging procedures for each of these entities.

Outcome of patients treated with a single-fraction dose of palliative radiation for cutaneous T-cell lymphoma.

PURPOSE Cutaneous T-cell lymphoma (CTCL) is a radiosensitive tumor. Presently, treatment with radiation is given in multiple fractions. The current literature lacks data that support single-fraction treatment for CTCL. This retrospective review assesses the clinical response in patients treated with a single fraction of radiation. METHODS AND MATERIALS This study reviewed the records of 58 patients with CTCL, primarily mycosis fungoides, treated with a single fraction of palliative radiation therapy (RT) between October 1991 and January 2011. Patient and tumor characteristics were reviewed. Response rates were compared using Fishers exact test and multiple logistic regressions. Survival rates were determined using the Kaplan-Meier method. Cost-effectiveness analysis was performed to assess the cost of a single vs a multifractionated treatment regimen. RESULTS Two hundred seventy individual lesions were treated, with the majority (97%) treated with ≥ 700 cGy; mean follow-up was 41.3 months (range, 3-180 months). Response rate by lesion was assessed, with a complete response (CR) in 255 (94.4%) lesions, a partial response in 10 (3.7%) lesions, a partial response converted to a CR after a second treatment in 4 (1.5%) lesions, and no response in 1 (0.4%) lesion. The CR in lower extremity lesions was lower than in other sites (P=.0016). Lesions treated with photons had lower CR than those treated with electrons (P=.017). Patients with lesions exhibiting large cell transformation and tumor morphology had lower CR (P=.04 and P=.035, respectively). Immunophenotype did not impact response rate (P=.23). Overall survival was significantly lower for patients with Sézary syndrome (P=.0003) and erythroderma (P<.0001). The cost of multifractionated radiation was >200% higher than that for single-fraction radiation. CONCLUSIONS A single fraction of 700 cGy-800 cGy provides excellent palliation for CTCL lesions and is cost effective and convenient for the patient.

Management of cutaneous T cell lymphoma: new and emerging targets and treatment options

Cutaneous T cell lymphomas (CTCL) clinically and biologically represent a heterogeneous group of non-Hodgkin lymphomas, with mycosis fungoides and Sézary syndrome being the most common subtypes. Over the last decade, new immunological and molecular pathways have been identified that not only influence CTCL phenotype and growth, but also provide targets for therapies and prognostication. This review will focus on recent advances in the development of therapeutic agents, including bortezomib, the histone deacetylase inhibitors (vorinostat and romidepsin), and pralatrexate in CTCL.