Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin–restricted mycosis fungoides. Early diagnosis of SS is therefore key to achieving enhanced therapeutic responses. However, the lack of a biomarker (s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+T cells, CD164+ and CD164− CD4+ T cells isolated from patients with high circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox and miR -214 was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164−CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3 and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker.
Cutaneous T-cell lymphoma (CTCL) represents a diagnostic challenge because of its large symptomatic overlap with other common skin conditions such as atopic dermatitis (AD) and psoriasis. Dupilumab has offered promising results in AD treatment; however, concerns exist that its use may exacerbate undiagnosed CTCL. We present a patient with CTCL and concomitant AD who experienced improvement in both CTCL blood involvement and AD following the addition of dupilumab therapy.
IMPORTANCE Sézary syndrome (SS) is an advanced form of cutaneous T-cell lymphoma with few long-term remissions observed. OBJECTIVE To profile 3 patients with SS who have experienced long-term remission following the addition of low-dose total skin electron beam therapy (TSEBT) to systemic regimens of extracorporeal photopheresis, bexarotene, and interferon-γ. DESIGN, SETTING, AND PARTICIPANTSThis is a retrospective case series with additional investigations of patient-donated samples to assess therapeutic response. The study was conducted at the University of Pennsylvania Cutaneous Lymphoma Clinic and follows 3 patients with stage IVA1 CD4 + SS who presented to the clinic between November 1, 2009, and November 1, 2017, and who had a history of SS that was refractory to multimodality systemic therapy prior to receiving low-dose TSEBT.INTERVENTIONS Patients were treated in a multimodality fashion with combined extracorporeal photopheresis, bexarotene, interferon-γ, and low-dose TSEBT. MAIN OUTCOMES AND MEASURESTo characterize treatment responses in these patients, the extent of skin disease was measured with the modified severity weighted assessment tool. Blood disease was measured with flow cytometric assessments of Sézary cell count, CD4:CD8 ratio, and high throughput sequencing of the T-cell receptors. To assess for restoration of immune function, we measured markers of immune exhaustion, including PD-1 (programmed cell death 1), TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains), CTLA4 (cytotoxic T-lymphocyte-associated protein 4), TOX (thymocyte selection-associated high mobility group box protein), and Foxp3 (forkhead box P3) on circulating CD4 and CD8 T cells, along with production capacity of interferon-γ by lymphocytes following activation stimuli.RESULTS Following administration of low-dose TSEBT and maintenance of the other therapies, remissions ranged from 24 to 30 months, with complete responses in 2 patients ongoing. Markers of immune exhaustion including PD-1, TIGIT, CTLA4, TOX, and Foxp3 were significantly reduced from baseline following TSEBT, along with enhanced production capacity of interferon-γ by lymphocytes following activation stimuli. High throughput sequencing demonstrated near-complete eradication of the circulating clone among 2 of 3 patients with stable levels in 1. CONCLUSIONS AND RELEVANCEWe describe 3 patients who achieved long-term clinical and molecular remissions following low-dose TSEBT as part of a multimodality regimen for treatment of SS. As long-term remissions in SS are uncommon, this approach demonstrates promise, and clinical trials should be considered.
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