Sequential monitoring reveals shifts in Sézary cell immunophenotype correlated with disease progression. Three PB samples were collected at different disease stages from SS case 11. (A) The initial sample, isolated 6 months after diagnosis. MFC analysis showed 1 homogeneous tumor population characterized by the diminished expression of CD3 surface antigen. (B) The second PB sample was collected 16 months after diagnosis. At that time, the patient had experienced disease progression, and systemic treatment with CHOEP chemotherapy was initiated. Herein, the tumor population increased from 30% to 90% of the total CD4⁺ T-cell population, but this expansion was primarily based on the (dramatic) emergence of a novel Sézary cell tumor population characterized by a distinct immunophenotypic profile (CD3^loCD4^lo in combination with CD26^negCD7^negCD2^lo) as compared with the preexisting tumor population, which was detectable but proportionally decreased over time. Treatment was insufficiently effective and was switched to mogamulizumab, a monoclonal antibody targeting CCR4. (C) At third sampling, 19 months after the first sample and now under treatment with mogamulizumab, the initial CD3^lo tumor population was no longer detectable, and the newly emerged CD3^loCD4^lo tumor population was abundantly present compromising >90% of total CD4⁺ T cells.