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Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA–mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier.

Primary cutaneous T-cell lymphomas ( CTCLs) was first described in 1991, and in 2008, it was classified as a provisional form of cutaneous T-cell lymphoma by the World Health Organization. This is considered a highly aggressive lymphoma, and because of the rarity and lack of clearly defined diagnostic features, it can represent a considerable diagnostic challenge. Diagnosis of CTCL requires demonstration of the T-cell receptor (TCR) and absence of the TCR. Until recently, no reliable antibody for formalin-fixed paraffin-embedded sections against the TCR existed, and most CTCLs were diagnosed in absence of the TCR- and presence of a compatible cytotoxic immunophenotype (CD4−CD8−, granzyme). However, because some lymphomas are TCR silent and thus not belonging to the -lineage, this approach should not stand alone. We present a case of CTCL that illustrates the difficulties in diagnosing this type of lymphoma both histopathologically and clinically. This case was particularly challenging because the neoplastic T cells displayed immunohistochemical positivity for both TCR- and TCR-. Therefore, TCR- may be aberrantly expressed in CTCL, and positive staining for TCR- alone cannot be used to exclude the diagnosis of CTCL.

Cutaneous T-cell lymphoma (CTCL) is a devastating lymphoid malignancy characterized by the accumulation of malignant T cells in the dermis and epidermis. Skin lesions cause serious symptoms that hamper quality of life and are entry sites for bacterial infection, a major cause of morbidity and mortality in advanced diseases. The mechanism driving the pathological processes that compromise the skin barrier remains unknown. Here, we report increased transepidermal water loss and compromised expression of the skin barrier proteins filaggrin and filaggrin-2 in areas adjacent to TOX-positive T cells in CTCL skin lesions. Malignant T cells secrete mediators (including cytokines such as interleukin 13 [IL-13], IL-22, and oncostatin M) that activate STAT3 signaling and downregulate filaggrin and filaggrin-2 expression in human keratinocytes and reconstructed human epithelium. Consequently, the repression of filaggrins can be counteracted by a cocktail of antibodies targeting these cytokines/receptors, small interfering RNA–mediated knockdown of JAK1/STAT3, and JAK1 inhibitors. Notably, we show that treatment with a clinically approved JAK inhibitor, tofacitinib, increases filaggrin expression in lesional skin from patients with mycosis fungoides. Taken together, these findings indicate that malignant T cells secrete cytokines that induce skin barrier defects via a JAK1/STAT3-dependent mechanism. As clinical grade JAK inhibitors largely abrogate the negative effect of malignant T cells on skin barrier proteins, our findings suggest that such inhibitors provide novel treatment options for patients with CTCL with advanced disease and a compromised skin barrier.

Deregulation of Notch signaling has been linked to the development of T-cell leukemias and several solid malignancies. Yet, it is unknown whether Notch signaling is involved in the pathogenesis of mycosis fungoides and Sézary syndrome, the most common subtypes of cutaneous T-cell lymphoma. By immunohistochemistry of 40 biopsies taken from skin lesions of mycosis fungoides and Sézary syndrome, we demonstrated prominent expression of Notch1 on tumor cells, especially in the more advanced stages. The γ-secretase inhibitor I blocked Notch signaling and potently induced apoptosis in cell lines derived from mycosis fungoides (MyLa) and Sézary syndrome (SeAx, HuT-78) and in primary leukemic Sézary cells. Specific down-regulation of Notch1 (but not Notch2 and Notch3) by siRNA induced apoptosis in SeAx. The mechanism of apoptosis involved the inhibition of nuclear factor-κB, which is the most important prosurvival pathway in cutaneous T-cell lymphoma. Our data show that Notch is present in cutaneous T-cell lymphoma and that its inhibition may provide a new way to treat cutaneous T-cell lymphoma.

Deregulation of Notch signaling has been linked to the development of T-cell leukemias and several solid malignancies. Yet, it is unknown whether Notch signaling is involved in the pathogenesis of mycosis fungoides and Sézary syndrome, the most common subtypes of cutaneous T-cell lymphoma. By immunohistochemistry of 40 biopsies taken from skin lesions of mycosis fungoides and Sézary syndrome, we demonstrated prominent expression of Notch1 on tumor cells, especially in the more advanced stages. The γ-secretase inhibitor I blocked Notch signaling and potently induced apoptosis in cell lines derived from mycosis fungoides (MyLa) and Sézary syndrome (SeAx, HuT-78) and in primary leukemic Sézary cells. Specific down-regulation of Notch1 (but not Notch2 and Notch3) by siRNA induced apoptosis in SeAx. The mechanism of apoptosis involved the inhibition of nuclear factor-κB, which is the most important prosurvival pathway in cutaneous T-cell lymphoma. Our data show that Notch is present in cutaneous T-cell lymphoma and that its inhibition may provide a new way to treat cutaneous T-cell lymphoma.

Daratumumab is an integral part of the treatment of multiple myeloma (MM) but its real-world efficacy has only been described in small cohorts. MAMMOTH is the only large multi-center study that reported the outcomes of CD38-refractory MM. The present study includes a complete, Danish, nation-wide cohort of 635 MM patients who initiated treatment a daratumumab-containing index regimen (IR) prior to 1.1.2019, and describes the outcomes of 472 patients who discontinued their IR until 1.1.2021. Patients received a median of 3 lines of therapy (LOT) prior to the IR. The median time from diagnosis to discontinuation of the IR (T 0) was 4 years. At T 0,73% of patients were quadruple drug class exposed (CE). The median overall survival (mOS) after T 0was 12.2 months in the entire cohort, 15.3 months in double CE, 22.5 months in triple CE, 12.6 months in quadruple CE and 8.3 months in alkylator-bortezomib-carfilzomib-daratumumab-lenalidomide-pomalidomide-exposed patients. After T 0, 79%, 48%, 29%, 17%, 10% and 6% of patients received 1, 2, 3, 4, 5, 6 additional LOT, respectively, achieving overall response rates ranging from 44% to 11% and median time to next treatment (TNT) from 138 to 54 days. In the first subsequent LOT after T 0, 51% of patients were retreated with daratumumab. Despite the lack of benefit in terms response and TNT, daratumumab retreatment was associated with superior OS on multivariate analysis adjusting for age, previous transplantation, IR, drug class exposure at T 0, treating site, time from diagnosis to T 0and presence of cytogenetic high-risk markers. Median OS was 24.6 months in patients retreated with and 11.3 months in patients treated without daratumumab (p<0.0001). In conclusion, patients with MM who discontinue their first daratumumab-containing regimen have a life expectancy of approximately one year. Our results support a rationale behind daratumumab retreatment.

Szabo: Takeda: Consultancy; Sanofi: Consultancy; Janssen: Consultancy.

Andersen: Novo Nordisk: Other: Holds stock in Novo Nordisk; Hologic Deutchland GmbH: Research Funding. Odum:Micreos human Health B.V: Consultancy. Litman:Leo Pharma A/S: Research Funding. Gjerdrum:Nanostring Technologies: Other: Recieves founding from NanoString regarding a B-cell lymphoma research project., Research Funding; Celgene: Other: Celgene has funded the participation in ASH 2019.

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