Claus-Detlev Klemke

Cutaneous lymphomas in Germany: an analysis of the Central Cutaneous Lymphoma Registry of the German Society of Dermatology (DDG).

Background: Primary cutaneous lymphomas form a heterogenous group of lymphatic neoplasias.They manifest themselves on the skin and are the second most frequent group of non‐Hodgkin lymphoma (NHL) following gastrointestinal lymphomas.The number of epidemiologic studies is small due to limited availability and limited comparability on population‐based data.

The diagnosis of Sézary syndrome on peripheral blood by flow cytometry requires the use of multiple markers

Backgroundu2002 Diagnosis of Sézary syndrome (SS)‐defining blood involvement is hampered by the lack of Sézary cell‐specific markers and nonspecific morphology of the tumour cells.

High-throughput mutation profiling of CTCL samples reveals KRAS and NRAS mutations sensitizing tumors toward inhibition of the RAS/RAF/MEK signaling cascade.

Cutaneous T-cell lymphomas (CTCLs) are malignancies of skin-homing lymphoid cells, which have so far not been investigated thoroughly for common oncogenic mutations. We screened 90 biopsy specimens from CTCL patients (41 mycosis fungoides, 36 Sézary syndrome, and 13 non-mycosis fungoides/Sézary syndrome CTCL) for somatic mutations using OncoMap technology. We detected oncogenic mutations for the RAS pathway in 4 of 90 samples. One mycosis fungoides and one pleomorphic CTCL harbored a KRAS(G13D) mutation; one Sézary syndrome and one CD30(+) CTCL harbored a NRAS(Q61K) amino acid change. All mutations were found in stage IV patients (4 of 42) who showed significantly decreased overall survival compared with stage IV patients without mutations (P = .04). In addition, we detected a NRAS(Q61K) mutation in the CTCL cell line Hut78. Knockdown of NRAS by siRNA induced apoptosis in mutant Hut78 cells but not in CTCL cell lines lacking RAS mutations. The NRAS(Q61K) mutation sensitized Hut78 cells toward growth inhibition by the MEK inhibitors U0126, AZD6244, and PD0325901. Furthermore, we found that MEK inhibitors exclusively induce apoptosis in Hut78 cells. Taken together, we conclude that RAS mutations are rare events at a late stage of CTCL, and our preclinical results suggest that such late-stage patients profit from MEK inhibitors.

Oral aprepitant in the therapy of refractory pruritus in erythrodermic cutaneous T‐cell lymphoma

MADAM, Primary cutaneous lymphomas represent the second most common extranodal non-Hodgkin lymphomas. According to the WHO-EORTC classification of primary cutaneous lymphomas, mycosis fungoides (MF) and Sézary syndrome (SS) are the most common types of cutaneous T-cell lymphoma (CTCL). In patients with CTCL, pruritus is often severe and has a significant impact on quality of life. Especially in advanced stages (e.g. erythrodermic MF or SS), patients commonly report an ill-defined, severe, and diffuse pruritus that prevents them from sleeping and functioning. Due to a lack of major antipruritic capacity of emollients, topical steroids or oral antihistamines in CTCL, other treatment options have been discussed, such as gabapentin and mirtazapine, as well as naltrexone and amitriptyline. Substance P is an important mediator of pruritus. An increase in the expression of its receptor, neurokinin-1, has been reported on keratinocytes in pruritic skin diseases. Aprepitant, an oral neurokinin-1 receptor antagonist, has recently been described as a potential antipruritic treatment in different skin diseases, including erlotinib-induced pruritus in patients with tumours as well as in patients with CTCL. This prospective, open-label study includes five patients with erythrodermic CTCL (three with SS and two with erythrodermic MF) in whom pruritus was the main symptom and could not be controlled with conventional antipruritic treatments. The patients comprised three men and two women, mean age 61 (range 51–68) years. The diagnosis was established according to the WHO-EORTC classification of cutaneous lymphomas and the criteria of the International Society of Cutaneous Lymphomas. The study was conducted according to the ethical guidelines at our institution and the Helsinki declaration. Patients were treated with aprepitant 125 mg on day 1 and 80 mg on days 2 and 3 in 2-week repetitions for a median time of 15 weeks (range 6–24) and a median number of 7 therapy cycles (range 3–12). The median time between the diagnosis of CTCL and initiation of aprepitant was 25 months (range 10–67). Previous antipruritic therapies included a combination of antihistamines, gabapentin, mirtazapine, naltrexone or amitriptyline, without effect. During aprepitant treatment, all patients were instructed to continue with their previous antipruritic therapy, and their regular CTCL treatment was not modified (for details see Table 1). The severity of pruritus was assessed using a visual analogue scale (VAS), in which a score of 0 indicates no pruritus and a score of 10 indicates the worst pruritus imaginable. The quality of life was measured by the Dermatology Life Quality Index (DLQI) questionnaire (range 0–30, higher scores indicate worse outcome). A response was defined as > 50% reduction, no response < 25% and a partial remission between 25% and 50% reduction of the VAS compared with baseline. The overall response rate to the aprepitant therapy was 80%, with four of five patients demonstrating a good response and only one of five patients no response. The mean ± SD VAS score at the beginning of the study was 9Æ8 ± 0Æ4 and after intervention 4Æ3 ± 3Æ4 (P = 0Æ125; Fig. 1). The mean ± SD DLQI score at the beginning of the study was 20Æ4 ± 5Æ2 and decreased after intervention to 12Æ4 ± 8Æ1 (P = 0Æ0625; Fig. 1). In the responder group a first reduction of the VAS and DLQI was seen after one cycle of aprepitant therapy, with further decrease at follow up. Oral aprepitant was well tolerated and no side-effects were observed. However, no effects were seen on erythroderma or on reduction of the Sézary cell count. In summary, our clinical case series demonstrates that aprepitant is a safe, well-tolerated and effective drug for the therapy of severe pruritus in patients with erythrodermic CTCL who had not responded to previous therapies. Therefore, we suggest including an escalation scheme for the treatment of pruritus in the treatment guidelines for patients with CTCL. Aprepitant was developed and approved in 2003 as an antiemetic agent in chemotherapy-induced nausea and vomiting. The administration is usually for 3 days only, but also long-term application for up to 8 weeks was reported without major side-effects. We decided to use the more cost-effective standard dosage of aprepitant for 3 days only with repetition every 2 weeks. Interestingly, an improvement of pruritus was already observed after the first cycle of therapy and was stable over 2 weeks, suggesting no loss of efficiency using the standard dosage every 2 weeks. It was recently reported by another group that used aprepitant against pruritus in patients with solid tumours that pruritus relapsed after 3 days without treatment. However, the pathogenesis of pruritus in patients with erythrodermic CTCL and solid tumours might be different. It would be important to confirm the optimal dosage of aprepitant in the treatment regimen of pruritus of different BJD British Journal of Dermatology

Lack of T-Cell Receptor–Induced Signaling Is Crucial for CD95 Ligand Up-regulation and Protects Cutaneous T-Cell Lymphoma Cells from Activation-Induced Cell Death

Restimulation of previously activated T cells via the T-cell receptor (TCR) leads to activation-induced cell death (AICD), which is, at least in part, dependent on the death receptor CD95 (APO-1, FAS) and its natural ligand (CD95L). Here, we characterize cutaneous T-cell lymphoma (CTCL) cells (CTCL tumor cell lines and primary CTCL tumor cells from CTCL patients) as AICD resistant. We show that CTCL cells have elevated levels of the CD95-inhibitory protein cFLIP. However, cFLIP is not responsible for CTCL AICD resistance. Instead, our data suggest that reduced TCR-proximal signaling in CTCL cells is responsible for the observed AICD resistance. CTCL cells exhibit no PLC-gamma1 activity, resulting in an impaired Ca(2+)release and reduced generation of reactive oxygen species upon TCR stimulation. Ca(2+) and ROS production are crucial for up-regulation of CD95L and reconstitution of both signals resulted in AICD sensitivity of CTCL cells. In accordance with these data, CTCL tumor cells from patients with Sézary syndrome do not up-regulate CD95L upon TCR-stimulation and are therefore resistant to AICD. These results show a novel mechanism of AICD resistance in CTCL that could have future therapeutic implications to overcome apoptosis resistance in CTCL patients.

Short German guidelines: Cutaneous lymphomas

Journal compilation

European Organisation for Research and Treatment of Cancer consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome – Update 2017

In order to provide a common standard for the treatment of mycosis fungoides (MF) and Sézary syndrome (SS), the European Organisation for Research and Treatment of Cancer-Cutaneous Lymphoma Task Force (EORTC-CLTF) published in 2006 its consensus recommendations for the stage-adapted selection of management options for these neoplasms. Since then, the understanding of the pathophysiology and epidemiology of MF/SS has advanced, the staging system has been revised, new outcome data have been published and novel treatment options have been introduced. The purpose of the present document is to update the original recommendations bearing in mind that there are still only a limited number of controlled studies to support treatment decisions for MF/SS and that often treatment is determined by institutional experience and availability. This consensus on treatment recommendations was established among the authors through a series of consecutive consultations in writing and a round of discussion. Recommended treatment options are presented according to disease stage, whenever possible categorised into first- and second-line options and supported with levels of evidence as devised by the Oxford Centre for Evidence-Based Medicine (OCEBM). Skin-directed therapies are still the most appropriate option for early-stage MF, and most patients can look forward to a normal life expectancy. For patients with advanced disease, prognosis is still grim, and only for a highly selected subset of patients, prolonged survival can be achieved with allogeneic stem cell transplantation (alloSCT). There is a high need for the development and investigation in controlled clinical trials of treatment options that are based on our increasing understanding of the molecular pathology of MF/SS.

Genomic loss of the putative tumor suppressor gene E2A in human lymphoma

Loss of E2A, observed in more than 70% of patients with Sézary syndrome, which is a subtype of T cell lymphoma, results in altered expression of genes potentially relevant to oncogenesis.

Jessner’s Lymphocytic Infiltration of the Skin: A CD8+ Polyclonal Reactive Skin Condition

Background: Jessner’s lymphocytic infiltration of the skin (JLIS) is a clinically and histologically distinct disease entity. Conflicting results have been reported concerning its differentiation from cutaneous lupus erythematosus and polymorphous light eruption, its relationship to palpable migratory arciform erythema and its classification as a B-cell or a CD4+ T-cell lymphoproliferative disease. Objective: Our study was performed in order to re-evaluate JLIS clinically and by immunohistochemical and molecular analyses. Methods: Stringent inclusion/exclusion criteria were used to collect a cohort of 34 patients with JLIS that did not overlap with lupus erythematosus or polymorphous light eruption. Clinical data were analysed, and immunohistochemical and molecular studies were performed including TCR-γ PCR GeneScan software analysis of tissue and peripheral blood samples. Results: In the majority of the patients, the lesions consisted only of papules and plaques while in 12% annular lesions were also seen. The lesions were found on the face (38%), on the trunk and arms (50%) or at both sites (12%). Immunohistochemical analyses revealed a clear predominance of T cells in all patients, and of CD8+ T cells in 77% of the patients. As judged by TCR-γ PCR GeneScan analysis, 98 and 79% of the tissue and peripheral blood samples, respectively, showed a polyclonal T-cell population; identical T-cell clones were not detected concomitantly in both the skin and the peripheral blood of the same patient. Conclusions: JLIS occurs at 2 major predilection sites, that is the face and trunk. Therefore introduction of palpable migratory arciform erythema as a separate entity is not justified. The lymphoid infiltrates are dominated immunohistochemically by CD8+ T cells that do not show clonality on molecular analysis. Thus, JLIS represents a characteristic CD8+ polyclonal reactive skin condition.

Brief S2k guidelines--Cutaneous lymphomas.

Rudolf Stadler, Chalid Assaf, Claus-Detlev Klemke, Dorothee Nashan, Michael Weichenthal, Reinhard Dummer, Wolfram Sterry (1) Department of Dermatology, Johannes Wesling Klinikum, Minden, Germany (2) Department of Dermatology, HELIOS Klinikum, Krefeld, Germany (3) Department of Dermatology, Venereology, and Allergology, Mannheim University Hospital, Germany (4) Department of Dermatology, Dortmund Hospital, Germany (5) Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein (UKSH), Campus Kiel, Germany (6) Department of Dermatology, Zurich University Hospital, Switzerland (7) Department of Dermatology, Venereology, and Allergology, Charite – Universitatsmedizin Berlin, Germany