Low-Dose Total Skin Electron Beam Therapy As Part Of A Multimodality Regimen For Treatment Of Sezary Syndrome Clinical, Immunologic, And Molecular Analysis

Importance Sezary 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-gamma. Design, Setting, and Participants This 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-gamma, and low-dose TSEBT. Main Outcomes and Measures To 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 Sezary 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-gamma 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-gamma 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 Relevance We 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.This case series discusses 3 patients with Sezary syndrome who were treated with low-dose total skin electron beam therapy as part of a multimodality systemic regimen.Question What treatment options are available for patients with Sezary syndrome (SS) that is resistant to multiple treatments? Findings This case series describes 3 patients with treatment-refractory SS who received low-dose total skin electron beam therapy (TSEBT) as part of a multimodality systemic regimen for treatment of SS and who experienced long-term clinical remissions; additional investigations demonstrated reversal of the immune dysfunction characteristic of SS. Meaning The combination regimen of low-dose TSEBT with immunotherapy should be considered for further use and study in patients with refractory SS; given the good tolerability of low-dose TSEBT, it would be a valuable addition to SS management if proven to be effective.