LGL Clonal Expansion and Unexplained Cytopenia: Two Clues Don't Make an Evidence

Abstract

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.

Keywords: LGLL; bone marrow failure syndromes; clonality; cytopenias; large granular lymphocytes.

Figure 1

Morphology of a large granular lymphocyte. May–Grunwald Giemsa staining of large granular lymphocytes in the PB of a patient with LGL leukemia. Magnification: optical microscope 1000×.

Figure 2

Coexistence of LGL and myeloid clones. Different scenarios can be hypothesized to explain the peculiar concurrence of LGL clones with myeloid diseases. (A) Common age-related mechanisms occurring in the BM compartment (for instance genetic lesions or inflammatory stimuli) might be involved in the pathogenesis of both conditions, i.e., LGL clonal expansion and myeloid disease. (B) LGL expansion might represent an immune reaction to the presence of aberrant HSCs. (C) A cytotoxic LGL clone might exert a pathogenetic role, causing damage in the myeloid compartment and favoring the development of a myeloid disease. Note: BM, bone marrow; HSC, hematopoietic stem cells; LGL, large granular lymphocytes. The figure was created with Biorender.com.

Figure 3

Diagnostic analyses recommended in case of unexplained cytopenia(s) and evidence of T- or NK-LGL clonal expansion. Note: Each test represents a mere hint towards a diagnostic definition and it is not enough for establishing a precise diagnosis. Germline tissue is intended as non-hematopoietic tissue (such as skin fibroblasts, nails, or buccal swab, according to local practice). MDS, when a specific subgroup is not specified, requires a specific diagnostic work-up in order to define features necessary for classification, according to the fifth WHO classification [20]. Abbreviations: AMT, amegakaryocytic thrombocytopenia; AA, aplastic anemia; BMFS, bone marrow failure syndromes; GoF, Gain of Function CCUS, clonal cytopenia(s) of undetermined significance; DTA, DNMT3A-TET2-ASXL1; DCT, direct Coombs test; GM, germline; IEI(s), inborn errors of immunity; LGLL, large granular lymphocytic leukemia; MDS, myelodysplastic neoplasms; MDS-h, hypoplastic MDS; MDS-IB, MDS with increased blasts; PNH, paroxysmal nocturnal hemoglobinuria; PB, peripheral blood; PRCA, pure red cell aplasia; t-NGS, targeted next generation sequencing; VAF, variant allele frequency. This arrow (↑) indicates an increase, while the other one (↓) a decrease. The table was created with Biorender.com.