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Simple Summary: The clonal expansions of large granular lymphocytes are frequently detected in a wide spectrum of hematological and immune diseases. This clinical overlap, especially in patients with unexplained cytopenia, makes their diagnostic classification particularly challenging. Herein, we aim to elucidate the boundaries between LGL leukemia (LGLL) and LGL clonal expansions. We also discuss the relevance of LGL clone detection in the diagnostic algorithm, as they might acquire different pathogenetic roles according to the diverse clinical setting. Clonal expansions of large granular lymphocytes (LGL) have been reported in a wide spectrum of conditions, with LGL leukemia (LGLL) being the most extreme. However, the boundaries between LGLL and LGL clones are often subtle, and both conditions can be detected in several clinical scenarios, particularly in patients with cytopenias. The intricate overlap of LGL clonal expansion with other disease entities characterized by unexplained cytopenias makes their classification challenging. Indeed, precisely assigning whether cytopenias might be related to inadequate hematopoiesis (i.e., LGL as a marginal finding) rather than immune-mediated mechanisms (i.e., LGLL) is far from being an easy task. As LGL clones acquire different pathogenetic roles and relevance according to their diverse clinical settings, their detection in the landscape of bone marrow failures and myeloid neoplasms has recently raised growing clinical interest. In this regard, the current availability of different diagnostic techniques, including next generation sequencing, shed light on the relationship between LGL clones and cytopenias, paving the way towards a better disease classification for precision medicine treatments. Herein, we discuss the clinical relevance of LGL clones in the diagnostic algorithm to be followed in patients presenting with cytopenias, offering a foundation for rational management approaches. [ABSTRACT FROM AUTHOR]

Simple Summary: TRBC1 expression analysis by flow cytometry (FCM) has been recently proved to be a useful, simple and fast approach to assessing Tαβ-cell clonality. The aim of this study was to validate the utility of this assay specifically for the diagnosis of T-cell clonality of T-large granular lymphocytic leukemias (T-LGLL), as more mature polyclonal Tαβ large granular lymphocytes (Tαβ-LGL) show broader TRBC1+/TRBC1− ratios vs. total Tαβ cells. Our results showed that a TRBC1-FCM assay is also a fast and easy method for detecting T-cell clonality in T-LGLL based on altered (increased or decreased) percentages of TRBC1+ Tαβ cells of LGL expansions (i.e., with lymphocytosis) suspected of T-LGLL, whereas in the absence of lymphocytosis (or in TαβCD4-LGLL), the detection of increased absolute cell-counts of more precisely defined subpopulations of T-LGL expressing individual TCRVβ families is required. Flow cytometric (FCM) analysis of the constant region 1 of the T-cell receptor β chain (TRBC1) expression for assessing Tαβ-cell clonality has been recently validated. However, its utility for the diagnosis of clonality of T-large granular lymphocytic leukemia (T-LGLL) needs to be confirmed, since more mature Tαβ cells (i.e., T-LGL normal-counterpart) show broader TRBC1+/TRBC1− ratios vs. total Tαβ cells. We compared the distribution and absolute counts of TRBC1+ and TRBC1− Tαβ-LGL in blood containing polyclonal (n = 25) vs. clonal (n = 29) LGL. Overall, polyclonal TRBC1+ or TRBC1− Tαβ-LGL ranged between 0.36 and 571 cells/μL (3.2–91% TRBC1+ cells), whereas the clonal LGL cases showed between 51 and 11,678 cells/μL (<0.9% or >96% TRBC1+ cells). Among the distinct TCRVβ families, the CD28− effector-memory and terminal-effector polyclonal Tαβ cells ranged between 0 and 25 TRBC1+ or TRBC1− cells/μL and between 0 and 100% TRBC1+ cells, while clonal LGL ranged between 32 and 5515 TRBC1+ or TRBC1− cells/μL, representing <1.6% or >98% TRBC1+ cells. Our data support the utility of the TRBC1-FCM assay for detecting T-cell clonality in expansions of Tαβ-LGL suspected of T-LGLL based on altered percentages of TRBC1+ Tαβ cells. However, in the absence of lymphocytosis or in the case of TαβCD4-LGL expansion, the detection of increased absolute cell counts by the TRBC1-FCM assay for more accurately defined subpopulations of Tαβ-LGL-expressing individual TCRVβ families, allows the detection of T-cell clonality, even in the absence of phenotypic aberrations. [ABSTRACT FROM AUTHOR]