Impact of Clonal T-LGL Populations in Peripheral Blood on Clinical Outcomes in Cutaneous T-Cell Lymphoma

Background: Cellular immunity plays a crucial role in the progression of cutaneous T-cell lymphoma (CTCL). In the early stages of the disease, the presence of reactive CD8+ T-cells is beneficial. However, as the disease advances, immune responses tend to diminish. Notably, clonal T large granular lymphocyte (T-LGL) proliferation has been observed in a range of malignancies and is associated with more favorable outcomes in Sézary Syndrome (SS). This study aims to explore the clinical features and survival outcomes of patients (pts) with mycosis fungoides (MF) and SS who exhibit clonal T-LGL populations.

Methods: We prospectively identified 79 pts at Moffitt Cancer Center (MCC) CTCL Multidisciplinary Clinic with peripheral T-LGL proliferations confirmed by flow cytometry and T-cell receptor (TCR) gene rearrangement. Custom multicolor flow cytometry included 25 T-cell, B-cell, and NK-cell markers. TCR gene rearrangement was detected using multiplex polymerase chain reaction (PCR) and capillary electrophoresis. Clinical characteristics and detailed molecular annotations were described using descriptive statistics, and survival outcomes were estimated using Kaplan-Meier methods.

Results: Among the 79 pts examined, 71 were diagnosed with confirmed CTCL, comprising 54 with MF, 14 with SS (including 4 cases of MF transformed to SS), two with lymphomatoid papulosis, and one with primary cutaneous anaplastic large cell lymphoma (ALCL). Immunohistochemical analysis of skin biopsies revealed no evidence of T-LGL population infiltration. Our primary focus was on the MF and SS groups (n=68). The median ages for these cohorts were 61 years for MF and 67 years for SS, with ages ranging from 19 to 89 years. The majority of pts were male, with a male-to-female ratio of approximately 2:1. Within the MF group, there were 42 white pts (78%), nine Black pts (17%), four Hispanic pts (7%), and three Asian pts (6%). In the SS group, there were 11 white pts (79%), two Black pts (14%), and one Hispanic patient (7%). Most cases of MF were in the early stages, with 50% in Stage IA and 41% in Stage IB, while 24% of pts were diagnosed at Stage B1.

Notably, no pts developed neutropenia or splenomegaly attributable to clonal T-LGL populations. These clonal T-LGL cells were characterized as CD8+, CD57+, TCR alpha-beta+, and CD16-. TCR peak analyses revealed distinct clonotypes between blood and skin samples in all 11 pts examined. NGS testing performed on 12 pts identified no STAT3 or STAT5b mutations. The size of the T-LGL clones ranged from 0.1 to 1.6 x 10⁹ cells/L, with the majority falling below 0.5 x 10⁹ cells/L. Among the 54 pts with longitudinal follow-up, 49 (91%) exhibited persistent T-LGL populations for at least six months, with one patient with SS maintaining persistence for 12 years.

T-LGL populations may present at diagnosis or gradually emerge after treatment, exhibiting a dynamic relationship with circulating Sézary cells. Pts with clonal T-LGL proliferation demonstrated excellent clinical outcomes irrespective of disease stage. For MF patients, five patients died (four from disease) at a median follow-up of six years. In primary SS patients, all but one (who succumbed to COVID) were alive and achieved complete blood responses to ECP or mogamulizumab after a median follow-up of seven years. Despite these promising outcomes, managing skin disease remained challenging, with nine patients experiencing large cell transformations. Unfortunately, four of these patients died despite systemic therapies and radiation.

Single-cell TCR and RNA analyses of two patients confirmed monoclonal or oligoclonal T-LGL proliferation with dominant clonotypes. These T-LGLs exhibited a CD8+ effector T-cell phenotype with elevated levels of cytotoxic markers, including granzyme H and perforin-1.

Conclusion: Our study reveals that clonal T-LGL proliferation in patients with MF and SS is linked to excellent blood responses and survival rates, with notable benefits in SS. T-LGL populations were dynamically correlated with circulating Sézary cells, yet did not precipitate symptoms commonly associated with T-LGL leukemia. However, managing skin disease remains a significant challenge. Further exploration of T-LGL populations and their cytotoxic mechanisms could yield valuable insights into potential therapeutic targets for CTCL.