Mogamulizumab-associated rash - Case series and review of the literature.

Mogamulizumab, a monoclonal antibody directed against CC chemokine receptor 4, is approved as a second-line treatment of mycosis fungoides and Sézary syndrome. One of the most common side effects is mogamulizumab-associated rash (MAR), which can present in a variety of clinical and histological types. Clinically, it can be difficult to differentiate between MAR and progression of the underlying disease, so histological examination is crucial for clinicopathological correlation. Current data analyses suggest that MAR is more common in patients with Sézary syndrome and is associated with a significantly better response to treatment, making the distinction from disease progression particularly important. The management of MAR depends on its severity, and therapy may need to be paused. This article presents three cases from our clinic and reviews the current literature on MAR. It emphasizes the importance of understanding MAR in the management of patients with cutaneous lymphomas.

Therapy of necrobiotic xanthogranuloma - case series and review of the literature.

Necrobiotic xanthogranuloma is a rare disease that is part of the non-Langerhans cell histiocytoses. It is characterized by yellowish skin lesions, which are typically periorbitally localized. Extracutaneous manifestations of all organs are possible and can cause potentially life-threatening complications. The disease also belongs to the facultative paraneoplasias and is often associated with paraproteinemia. These aspects should be considered regarding further diagnostics. Due to the rarity of the disease, there are no standardized guidelines for therapy so far. The combination of prednisolone and chlorambucil as well as intravenous immunoglobulins seem to be effective therapeutic options. We present four cases from our clinic as well as the current results of the literature in this mini-review and would like to highlight the therapeutic challenge as well as the need for the development of guidelines.

Ultrahypofractionated Low-Dose Total Skin Electron Beam in Advanced-Stage Mycosis Fungoides and Sézary Syndrome.

PURPOSE: The aim of this study was to assess the safety and efficacy of an ultrahypofractionated low-dose total skin electron beam therapy (TSEBT) regimen in patients with advanced mycosis fungoides (MF) or Sézary syndrome (SS). METHODS AND MATERIALS: In this multicenter observational study from 5 German centers, 18 total patients with MF or SS underwent TSEBT with a total dose of 8 Gy in 2 fractions. The primary endpoint was the overall response rate. RESULTS: Fifteen of 18 patients with stage IIB-IV MF or SS were heavily pretreated with a median of 4 prior systemic therapies. The overall response rate was 88.9% (95% confidence interval [CI], 65.3-98.6), with 3 complete responses (16.9%; 95% CI, 3.6-41.4). At a median follow-up period of 13 months, the median time to next treatment (TTNT) was 12 months (95% CI, 8.2-15.8), and the median progression-free survival was 8 months (95% CI, 2-14). A significant reduction in the modified severity-weighted assessment tool, total Skindex-29 score (Bonferroni-corrected P < .005), and all subdomains (Bonferroni-corrected P < .05) was observed after TSEBT. Half of the irradiated patients (n = 9) developed grade 2 acute and subacute toxicities. One patient had confirmed grade 3 acute toxicity. Chronic grade 1 toxicity has been observed in 33% of patients. Patients with erythroderma/SS or prior radiation therapy appear at higher risk of skin toxicities. CONCLUSIONS: TSEBT with 8 Gy in 2 fractions achieves good disease control and symptom palliation with acceptable toxicity, greater convenience, and fewer hospital visits.

Impact of blood involvement on efficacy and time to response with mogamulizumab in mycosis fungoides and Sézary syndrome.

BACKGROUND: Cutaneous T-cell lymphomas (CTCL) are rare types of non-Hodgkin lymphoma, which present in skin. Mycosis fungoides (MF) and Sézary syndrome (SS) are subtypes which make up two-thirds of all CTCL cases. The phase 3 MAVORIC study (NCT01728805) compared mogamulizumab to vorinostat in MF and SS patients, with post hoc data showing a trend for higher efficacy in mogamulizumab-treated patients as baseline blood tumour burden increases. OBJECTIVES: The aim of this study was to use updated post hoc analyses in order to examine the efficacy of mogamulizumab and vorinostat in MF patients when stratified by baseline blood involvement and to determine what factors affect time-to-global and time-to-skin response to inform clinical follow-up. METHODS: Post hoc analyses were carried out using data from MAVORIC. Overall response rate (ORR), progression-free survival (PFS) and time-to-next-treatment (TTNT) data were used to assess efficacy in patients with MF. Time-to-global response (TTR) was examined by disease subtype, by blood involvement in MF patients, and time-to-skin response was examined by blood involvement in MF patients. RESULTS: Numerically superior results were seen for ORR, PFS and TTNT in mogamulizumab-treated patients with MF compared with vorinostat, with a trend for outcomes improving with increasing baseline blood class. Statistically significant results for mogamulizumab compared with vorinostat were seen for MF B1 pts for PFS (8.43 vs. 2.83 months, p = 0.003) and TTNT (11.9 vs. 3.13 months, p = 0.002), and for MF B2 pts for ORR (46.2 vs. 9.1 months, p = 0.033). CONCLUSIONS: In mogamulizumab-treated MF patients, ORR and PFS were seen to improve with increasing blood involvement, which led to improved TTNT. TTR was more predictable for mogamulizumab-treated MF patients with blood involvement, and skin response may take longer than previously reported in some patients.

Mogamulizumab Combined with Extracorporeal Photopheresis as a Novel Therapy in Erythrodermic Cutaneous T-cell Lymphoma.

BACKGROUND: Primary cutaneous T-cell lymphomas (CTCLs) are rare lymphoproliferative malignancies characterized by significant morbidity and mortality in advanced disease stages. As curative approaches apart from allogeneic stem cell transplantation are lacking, establishing new treatment options, especially combination therapies, is crucial. METHODS: This retrospective study included 11 patients with SS or MF receiving therapy with mogamulizumab in combination with ECP from four European expert centers. The response rates in the skin and blood as well as treatment use and adverse events (AE) were described. RESULTS: 8/11 patients (73%) showed an overall response (OR) in the skin. The mean mSWAT decreased from 98.2 ± 40.8 to 34.6 ± 23.8. The overall response rate (ORR) in the blood was 64% with two complete responses. During combination therapy, the mean number of Sézary cells decreased from 3365.3 × 106/L before treatment to 1268.6 × 106/L. The mean minimum known period without progress was 7.2 months in the skin and 7.6 months in the blood. The most common AEs were mogamulizumab-associated rash (MAR) (45.5%), anemia (27.3%), lymphocytopenia (27.8%), and infusion related reaction (16.7%). No AE led to treatment discontinuation. CONCLUSIONS: Our study presents the combination of mogamulizumab and ECP as an effective therapy in the blood and skin in CTCL with good tolerability, similar to mogamulizumab monotherapy.

Chlormethin-Gel zur Behandlung der Mycosis fungoides: Ein Expertenkonsens aus Deutschland, Österreich und der Schweiz (DACH-Region) zum Therapiemanagement.

HINTERGRUND: Chlormethin-Gel ist in Europa zur Therapie von Patienten mit Mycosis fungoides in allen Krankheitsstadien zugelassen. Die optimalen Behandlungsregime hinsichtlich Frequenz, Dosierung, Kombinations- oder Erhaltungstherapien sind noch nicht vollständig etabliert. METHODIK: Zehn in der Erforschung und Behandlung kutaner T-Zell-Lymphome erfahrene Experten aus Deutschland, Österreich und der Schweiz (DACH-Region) wurden schriftlich zu Indikation, Anwendungsfrequenz, Beurteilung des Therapieerfolgs, Begleittherapie, Nebenwirkungen, Kombinationstherapien in späteren Krankheitsstadien, Erhaltungstherapie und Adhärenz im Rahmen der Therapie der Mycosis fungoides mit Chlormethin-Gel befragt. Die strukturiert aufbereiteten Ergebnisse der Umfrage wurden in einer Konsensuskonferenz diskutiert und Empfehlungen zum Management der Therapie mit Chlormethin-Gel entwickelt. ERGEBNISSE: Wesentlich für die Therapie mit Chlormethin-Gel ist ein individuelles, symptomorientiertes Therapiemanagement. Systemische Nebenwirkungen des Wirkstoffs sind wegen der fehlenden systemischen Verfügbarkeit bei topischer Anwendung unwahrscheinlich. Die häufig auftretende allergische oder irritativ-toxische Kontaktdermatitis kann durch eine Anpassung des Therapieregimes, Therapiepausen sowie nebenwirkungsspezifische und unterstützende Maßnahmen häufig beherrscht werden. Ein einschleichender Therapiebeginn mit Anwendung von Chlormethin-Gel jeden zweiten Tag kann die Tolerabilität wesentlich verbessern, insbesondere wenn die Therapie alternierend mit topischen Kortikosteroiden erfolgt. SCHLUSSFOLGERUNGEN: Die Anwendung von Chlormethin-Gel bei Mycosis fungoides wird durch die begleitende Kontaktdermatitis häufig eingeschränkt. Mit einem geeigneten Therapie- und Nebenwirkungsmanagement können vermeidbare Therapieabbrüche verhindert werden und mehr Patienten von der Therapie profitieren.

Kutane Angiosarkome: molekulare Pathogenese und neue therapeutische Ansätze.

Das kutane Angiosarkom (CAS) ist ein hochaggressiver maligner Tumor mit schlechter Prognose. Das primäre, spontane CAS (pCAS) und das sekundäre, mit einer Bestrahlung oder einem Lymphödem assoziierte CAS (sCAS) unterscheiden sich klinisch sowie molekular. Die Amplifikation/Überexpression von Myc ist ein charakteristisches, wenn auch nicht ausschließliches Merkmal von sCAS, während der Verlust von TP53 selektiv bei pCAS vorkommt. Detaillierte molekulare Analysen mit modernen Multi-Omics-Ansätzen haben gezeigt, dass sowohl pCAS als auch sCAS eine erhebliche molekulare Heterogenität aufweisen. Die betroffenen Gene und ihre molekularen Regulatoren sind mögliche therapeutische Zielstrukturen. Darüber hinaus kann das pCAS in Cluster mit hoher Mutationsrate und/oder ausgeprägten Entzündungssignaturen eingeteilt werden, die als Grundlage für die künftige Stratifizierung von pCAS-Patienten in immuntherapeutischen klinischen Studien dienen können. Während die Aufklärung der der Erkrankung zugrunde liegenden molekularen Veränderungen zügig voranschreitet, verläuft die Entwicklung daraus abgeleiteter neuer Therapien für das CAS jedoch bisher eher langsam. Dennoch wurden einige über die Standardtherapien wie Operation und Radiochemotherapie hinausgehende klinische Studien zu neuen Behandlungsmöglichkeiten initiiert. Dazu gehören zielgerichtete Therapien gegen VEGF und VEGFR1-3 wie Bevacizumab und Pazopanib, sowie ß-Adrenozeptorenblocker wie Propranolol. Derzeit werden auch Immuntherapien entwickelt, unter anderem unter Verwendung der Immuncheckpoint-Inhibitoren Pembrolizumab und Nivolumab sowie des Anti-RANKL-Antikörper Denosumab.

The optimal use of chlormethine gel for mycosis fungoides: An expert consensus from Germany, Austria and Switzerland (DACH region).

BACKGROUND: In Europe chlormethine gel is licensed for the management of patients with mycosis fungoides of all stages. However, the optimal regimen regarding frequency and dosing as well as combination and maintenance therapy is not well established. METHODS: Ten experts experienced in research and management of cutaneous T-cell lymphomas from Germany, Austria, and Switzerland (DACH region) were asked in written form to report on indication for chlormethine gel, frequency of use, monitoring, concomitant therapies, adverse effects, combination therapies in later stages of the disease, maintenance therapy, and adherence to this therapy for mycosis fungoides. The structured answers were discussed in a consensus conference and recommendations were developed. RESULTS: Essential for therapy with chlormethine gel is an individualized and symptom-oriented management. Because of the lack of systemic resorption of topically administered chlormethine gel, systemic adverse events are unlikely. An allergic or irritative-toxic contact dermatitis is common but manageable with adaptation of the regimen, interruption of administration, and symptom-specific supportive measurements. A step-up initial approach with application of chlormethine gel every other day is associated with a better tolerability, especially if it is alternated with topical corticosteroids. CONCLUSIONS: The use of chlormethine gel in the management of mycosis fungoides is often limited by a concomitant contact dermatitis. An adequate therapeutic regimen and the management of adverse effects can preclude an unnecessary withdrawal of therapy so that more patients can benefit from this treatment option.

Cutaneous Angiosarcomas: Molecular Pathogenesis Guides Novel Therapeutic Approaches.

Cutaneous angiosarcoma (CAS) is a highly aggressive cancer with a poor prognosis. Primary, spontaneous CAS (pCAS) and secondary, post-irradiation- or lymphedema-associated CAS (sCAS) are clinically, but also molecularly distinct. Myc amplification/overexpression is a characteristic, although not exclusive feature of sCAS, while loss of TP53 selectively occurs in pCAS. Detailed molecular analyses with modern multi-omics approaches have revealed that both pCAS and sCAS exhibit considerable molecular heterogeneity. Affected genes and their molecular regulators including a plethora of microRNAs may serve as future drug targets. Furthermore, pCAS could be subdivided into clusters with high tumor mutational burden and/or high tumor inflammation signatures providing a rationale for the stratification of pCAS patients in future immunotherapeutic clinical studies. Development of novel treatment regimens guided by these molecular alterations, however, cannot fully keep up with the pace of their discovery due to the low incidence of the disease. Nevertheless, beyond conventional surgery and chemoradiotherapy, clinical trials investigating novel treatment options have been initiated including targeted therapies against VEGF and VEGFR1-3 such as bevacizumab and pazopanib, and ß-adrenoreceptor blockers such as propranolol. Finally, immunotherapies are being developed including immune checkpoint inhibitors pembrolizumab and nivolumab as well as anti-RANKL antibody denosumab.

[Single-center retrospective analysis of extracorporal photopheresis in clinical practice : Peripheral venous compared to central venous access]. / Unizentrische, retrospektive Analyse der praktischen Durchführung der extrakorporalen Photopherese : Periphervenöser und zentralvenöser Zugang im Vergleich.

BACKGROUND: Extracorporal photopheresis (ECP) was shown to be effective without severe side effects in the treatment of cutaneous T cell lymphoma (CTCL) and graft versus host disease (GvHD). However, only few studies investigated the practical aspects of ECP. METHODS: Treatment protocols of 2038 ECP procedures in 52 patients (CTCL, n = 29; GvHD, n = 15; other, n = 8) were evaluated. The patients were treated with the UVAR® XTS™ ECP system (Therakos, Inc. Johnson & Johnson, Raritan, NJ, USA) between 2001 and 2010. All patients started with a peripheral venous access. During the course of treatment 7 patients were treated via a port and 4 via a central venous catheter. RESULTS: In all, 1765 (86.6%) treatments were performed with a peripheral venous access; 239 (11.7%) ECPs were done via a port and 34 (1.7%) via a central venous catheter. The peripheral venous access showed a higher flow rate and longer photoactivation time. ECPs via port lead to higher UV-irradiated volumes, longer treatment times and higher differences in systolic blood pressure. The following side effects were observed: being unwell (n = 13), hypo- (n = 13) and hypertension (n = 7), vertigo (n = 4), headache (n = 4), shortness of breath (n = 4), fever (n = 3) and metallic taste (n = 3). Technical complications such as problems with venous access (9.6%) occurred in 385 (18.9%) treatments. CONCLUSIONS: Peripheral venous access should be preferred for ECP treatments.

Histology and Serum Cytokine Responses in an Imported Rickettsia slovaca Infection, Germany.

Rickettsia slovaca, a spotted fever group rickettsial pathogen, causes a syndrome consisting of scalp eschar and neck lymphadenopathy following tick bite. We analyzed the histologic skin reaction in the eschar, showing a prominent eosinophilic infiltration, as well as the presence of B lymphocytes and CD4- and CD8-positive T cells. Examination of the serum cytokine responses over time demonstrated an initial proinflammatory cytokine elevation followed by normalization.

Evaluation of Immunophenotypic and Molecular Biomarkers for Sézary Syndrome Using Standard Operating Procedures: A Multicenter Study of 59 Patients.

Differentiation between Sézary syndrome and erythrodermic inflammatory dermatoses can be challenging, and a number of studies have attempted to identify characteristic immunophenotypic changes and molecular biomarkers in Sézary cells that could be useful as additional diagnostic criteria. In this European multicenter study, the sensitivity and specificity of these immunophenotypic and recently proposed but unconfirmed molecular biomarkers in Sézary syndrome were investigated. Peripheral blood CD4(+) T cells from 59 patients with Sézary syndrome and 19 patients with erythrodermic inflammatory dermatoses were analyzed for cell surface proteins by flow cytometry and for copy number alterations and differential gene expression using custom-made quantitative PCR plates. Experiments were performed in duplicate in two independent centers using standard operating procedures with almost identical results. Sézary cells showed MYC gain (40%) and MNT loss (66%); up-regulation of DNM3 (75%), TWIST1 (69%), EPHA4 (66%), and PLS3 (66%); and down-regulation of STAT4 (91%). Loss of CD26 (≥80% CD4(+) T cells) and/or CD7 (≥40% CD4(+) T cells) and combination of altered expression of STAT4, TWIST1, and DNM3 or PLS3 could distinguish, respectively, 83% and 98% of patients with Sézary syndrome from patients with erythrodermic inflammatory dermatoses with 100% specificity. These additional diagnostic panels will be useful adjuncts in the differential diagnosis of Sézary syndrome versus erythrodermic inflammatory dermatoses.

Aggressive primary cutaneous B-cell lymphomas show increased Angiopoietin-2-induced angiogenesis.

Primary cutaneous large B-cell lymphomas, leg type (PCLBCL/LT) are primary cutaneous B-cell lymphoma (PCBCL) with an intermediate prognosis. Therefore, antracycline-based polychemotherapy combined with rituximab has been recommended as first-line treatment. Yet, despite this regimen, the 5-year survival rate remains 50-66% only. Angiogenesis, the formation of a vascular network, is essential for the pathogenesis of nodal lymphomas. So far, no study has analysed angiogenesis and its key factors in PCLBCL/LT. The present study was aimed at characterizing angiogenesis in PCLBCL/LT to identify the angiogenic molecules as potential therapeutic targets. The intra-tumoral microvessel density (MVD) was assessed by immunohistochemical studies of CD20 and CD31. The MVD was higher in PCLBCL/LT compared with indolent PCBCL. Analyses of open-source microarray data showed correlation between the angiogenic molecule angiopoietin-2 (Ang-2) and pan-endothelial cell markers. ELISA studies determined a shift between Ang-2 and Ang-1 towards Ang-2 in the peripheral blood of PCLBCL/LT patients. Immunofluorescence costainings against the Ang receptor Tie2/angiogenic integrins/CD34 revealed that the vasculature in both aggressive and indolent PCBCL tumors harbours an endothelial cell subpopulation with reduced expression of Tie2. In contrast, the alternative Ang-2 binding partners, angiogenic integrins, are strongly expressed in PCBCL. In line with these findings, downstream targets of Ang-2-integrin signalling, that is phosphorylation of focal adhesion kinase at Tyr397, and sprouting angiogenesis are enhanced in PCLBCL/LT. Our data present Ang-2 as a promising therapeutic target and anti-angiogenic therapy as a new line in treatment of PCLBCL/LT as a hitherto intractable disease.

Cutaneous tumor cell load correlates with survival in patients with Sézary syndrome.

BACKGROUND: Sézary syndrome (SS) is defined by the triad of erythroderma, generalized lymphadenopathy and more than 1 000 circulating Sézary cells/µl in the peripheral blood. PATIENTS AND METHODS: We screened the cutaneous lymphoma registry of our department for SS patients to identify clinical features of SS besides the defining criteria and to correlate them with disease survival. RESULTS: 24 SS patients were analyzed retrospectively. The mean age was 65 years with 62 % male patients. The median follow-up time was 32.5 months with an estimated 5-year overall survival rate of 76 %. All patients complained about itching and presented with palmoplantar keratoderma. 62.5 % had nail involvement, 21 % alopecia, 12.5 % ectropion, 4 % prurigo nodularis, 8 % localized and 8 % generalized skin tumors, including leonine facies. In addition, 33 % had infections and also 33 % had venous thromboembolism. We identified cutaneous tumor cell load as a significant prognostic marker for SS. None of the other parameters were associated with disease specific survival. CONCLUSIONS: Clinically SS is characterized by various presentations beyond erythroderma. The cutaneous tumor cell load in SS is strongly associated with outcome and survival. We demonstrate a high risk for venous thromboembolism in SS patients who might benefit from anti-coagulation therapies.