Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium

ABSTRACT Background Advanced-stage mycosis fungoides (MF)/Sezary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. Patients and methods This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). Results Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. Conclusion This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach

Clinical diversity and treatment approaches to blastic plasmacytoid dendritic cell neoplasm: a retrospective multicentre study

BACKGROUND Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive type of hematologic precursor malignancy primarily often manifesting in the skin. We sought to provide a thorough clinical characterisation and report our experience on therapeutic approaches to BPDCN. METHODS In the present multicentric retrospective study, we collected all BPDCN cases occurring between 05/1999 and 03/2018 in 10 secondary care centres of the German-Swiss-Austrian cutaneous lymphoma working group. RESULTS A total of 37 BPDCN cases were identified and included. Almost 90% of the patients had systemic manifestations (bone marrow, lymph nodes, peripheral blood) in addition to skin involvement. The latter presented with various types of cutaneous lesions: nodular (in more than 2/3) and bruise-like (in 1/3) skin lesions, but also maculopapular exanthema (in circa 1/6). Therapeutically, 22 patients received diverse combinations of chemotherapeutic regimens and/or radiotherapy. Despite initial responses, all of them ultimately relapsed and died from progressive disease. Eleven patients underwent hematopoietic stem cell transplantation (HSCT; autologous HSCT n=3, allo-HSCT n=8). The mortality rate among HSCT patients was only 33.33% with a median survival time of 60.5 months. CONCLUSION Our study demonstrates the clinical diversity of cutaneous BPDCN manifestations and the positive development observed after the introduction of HSCT

Phenotypic plasticity of malignant T cells in blood and skin of a Sézary syndrome patient revealed by single cell transcriptomics

$\bf Background:$ Sézary Syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphomas (CTCL). In SS patients, malignant T cells are circulating through the blood and cause erythroderma. $\bf Objective:$ To compare the transcriptome of single cells in blood and skin samples from a patient with advanced SS. $\bf Methods:$ We utilized combined single cell RNA and T-cell receptor (TCR) sequencing (scRNA-seq). $\bf Results:$ We scrutinized the malignant T cells in blood and skin in an unbiased manner without pre-sorting of cells. We observed different phenotypes of the same monoclonal malignant T-cell population, confirmed by TCR sequencing and inferred copy number variation analysis. Malignant T cells present in the circulating blood expressed genes resembling central memory T cells such as $\it CCR7$, $\it IL7R$ and $\it CD27$. In the skin, we detected two major malignant T-cell populations: One subpopulation was closely related to the malignant T cells from the blood, while the other subpopulation expressed genes reminiscent of skin resident effector memory T cells including $\it GZMB$ and $\it NKG7$. Pseudotime analysis indicated crucial transcriptomic changes in the transition of malignant T cells between blood and skin. These changes included the differential regulation of $\it TXNIP$, a putative tumor suppressor in CTCL, and the adaptation to the hypoxic conditions in the skin. Tumor cell proliferation in the skin was supported by stimulating interactions between myeloid cells and malignant T cells. $\bf Conclusions:$ Using scRNA-seq we detected a high degree of functional heterogeneity within the malignant T-cell population in SS and highlighted crucial differences between SS cells in blood and skin