Introduction: Sézary Syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma involving diffuse erythroderma (T4) and leukemic disease (B2). Prognosis is poor, with 5-year overall survival ranging from 30-50%. A unique cohort of patients diagnosed with B2 (high blood tumor burden) leukemic disease without erythroderma has previously been described. However, little is known about these patients' clinical features and prognosis.

Methods: A retrospective study of SS patients diagnosed after 1/1/2010 was conducted at the University of Pennsylvania. Patients with B2 disease with or without T4 disease at diagnosis were identified. B2 disease was defined as positive blood T-cell receptor clonality and Sézary cell count ≥1,000 cells/µl by flow cytometry (CD4+/CD7- or CD4+/CD26-). T4 was defined as erythroderma involving ≥80% body surface area (BSA). Fisher's exact test and Wilcoxon rank-sum test were used for statistical significance. Patients with HTLV-I/II and B2 disease utilizing only percentages of lymphocytes/elevated CD4:CD8 ratio criteria were excluded as per modified ISCLC/USCLC/EORTC criteria. T0/B2 patients were diagnosed based on Sézary immunophenotype and were ruled out for other diagnoses (e.g. T-PLL, T-LGLL, ATLL).

Results: Two cohorts of patients with B2 disease were identified: 21 patients without erythroderma (non-erythrodermic SS, neSS) and 79 classic SS patients (T4/B2 stage at diagnosis, cSS). There were no significant differences in age (70 and 71.5 years), race (76% and 74% white, 24% and 25% black) or absolute Sézary cell count at diagnosis (2,225 vs 2,812 cells/µl) for neSS versus cSS, respectively. A significantly greater proportion of neSS patients were female (76.2% vs 44.3%, p = 0.0034), but significantly fewer had N2/3 nodal disease (4.8% vs 43.4%, p=0.0002). One neSS patient had visceral disease pathologically confirmed in the liver (M1) at diagnosis. This did not occur in the cSS patient cohort.

Of the neSS patients, 3 had no skin involvement (T0), 6 had patch/plaque disease <10% BSA (T1a/b), and 13 had patch/plaque disease >10% BSA (T2a/b). Pruritus was reported in 55% (11/20) of patients at diagnosis. With a median follow-up of 5 years, 3 patients later developed erythroderma (T4). Among these patients, the median time to T4 disease was 1.9 years after B2 diagnosis. Median follow-up for the 18 patients who never developed erythroderma was 4.5 years. Interrogation of 9 neSS patient samples for cancer-associated mutations showed known disease-associated variants in TP53 (n=3), PTEN (n=1), DNMT3A (n=1) and EGR2 (n=1).

The median number of systemic treatments for neSS patients was similar to cSS patients (3.5 vs 3). Among the neSS patient cohort, systemic treatments included extracorporeal photopheresis (ECP)(n=16), bexarotene (n=11), interferon (IFN)(n=8), mogamulizumab (n=8), romidepsin (n=4), brentuximab vedotin (BV)(n=3), pembrolizumab (n=3), chemotherapy (n=1), methotrexate (n=1) and clinical trial (n=1). None underwent hematopoietic stem cell transplant. Four underwent surveillance/topical-only treatment without systemic therapy. Radiation was commonly used, with 4 patients receiving localized radiation, 4 receiving total skin electron beam therapy, and 4 receiving narrow-band UV phototherapy. ECP was the most common first-line therapy. Of the 3 patients who later developed erythroderma, treatments prior to developing T4 disease included ECP (n=3), IFN (n=3), bexarotene (n=3), BV (n=2) and mogamulizumab (n=1).

When compared to the cSS patients, outcomes were significantly better for neSS patients. 2-year overall survival (OS) for neSS vs cSS was 100% (18/18) versus 74% (54/73) (p = 0.0275). 5-year OS was 100% (11/11) versus 34.5% (19/55) (p<0.0001).

Conclusions: Non-erythrodermic patients with B2 disease (T0-2/B2, neSS) had a significantly better prognosis compared to classic SS patients with erythroderma (T4/B2, cSS). neSS patients received multiple systemic treatments; however, 4 patients with minimal skin disease were managed with surveillance or skin-directed therapy alone. Only 3 neSS patients (9.6%) later developed erythroderma. Although neSS patients were more often women and less likely to have nodal disease at diagnosis, other clinical characteristics including age, race and Sézary cell count at diagnosis were similar to cSS patients. Further exploration into mechanisms driving these clinical differences and the optimal management of this unique cohort of patients is needed.

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2025
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