Page 48 - Haematologica Vol. 110 - January 2025

PERSPECTIVE ARTICLE
pathogenically and prognostically remain elusive. Rheumatoid arthritis is the most frequent autoimmune disorder associated with T-LGLL, being reported in approx- imately 20% of patients across different case series.39,40 However, it is possible that several rheumatoid arthritis-re- lated cases resemble but do not fully meet the diagnostic criteria41,42 for T-LGLL. The genesis of this association is still controversial, particularly regarding whether the de- tectable T-cell clones in this concurrent disease are the result or the cause of the immune-inflammatory associat- ed events.40 Whatever their origin, these expanded clones have been shown to contribute to the pathogenesis of rheumatoid arthritis. In fact, cytotoxic CD8+ lymphocytes targeting citrullinated proteins have been recently demon- strated in patients with rheumatoid arthritis.43 These cells are clonally expanded and highly express cytotoxic and synovium-trafficking molecules, likely mediating synovitis and joint tissue destruction.
T-LGLL has also been reported to coexist with solid neo- plasms, including prostate, breast, lung, melanoma, col- orectal, and kidney tumors, as well as neuropathies, im- munodeficiency (e.g., hypogammaglobulinemia, common variable immune deficiency, CVID) and following solid organ transplantation (allogeneic HSCT), as reported by Bareau et al.44 and Viny et al.45
The question of whether these clonal proliferations repre- sent an independent indolent form of T-LGLL or whether they come from a highly exaggerated benign T-cell response to the antigenic stimulation provided by the accompanying disorder is still under discussion. A distinctive feature of T-LGLL is its well-known association with robust immune responses, such as after viral infections (Epstein-Barr virus, hepatitis C virus, human T-cell lymphotropic virus type I/ II) and rheumatoid arthritis.46,47 In cases in which neoplasia co-occurs, the expansion of LGL is likely the result of a seemingly unstoppable stimulation by tumor antigens. This hypothesis is tantalizing and is supported by rare reports of LGL expansions resolving after the primary disease has disappeared.45,48-50
T-cell clones in other hematologic disorders
T-cell clones are also detectable in several hematologic conditions including bone marrow failure syndromes, acute and chronic leukemias, as well as plasma cell dyscrasias, Hodgkin and non-Hodgkin lymphomas, and immune throm- bocytopenia. A retrospective systematic survey of different hematologic disorders that have been associated with T-LGLL is beyond the scope of this paper and compre- hensive reviews on the matter have already been provided by Zhang et al.50 and more recently by Bravo-Perez et al.51 Similar to what has been discussed for non-hematologic disease states, it is conceivable that these expanded clones
G. Semenzato et al. result from a chronic immune response triggered by im-
munogenic antigens or molecules expressed by neoplastic cells in relevant malignant hematopoietic disorders. We herein want to focus on a few selected circumstances that might provide insights into the intricate nature of these cell proliferations. The following examples may elucidate the stimuli that potentially drive T-cell clones and might trigger the evolution of T-CUS.
First of all, consider the setting of premalignant conditions. Interestingly, multiple precursor states are sometimes detectable concurrently, including MBL with T-LGLL,52,53 clonal hematopoiesis with T-LGLL,54 T-CUS with MGUS,55 and MGUS with T-LGLL.56,57 These co-occurrences serve as proof of concept that the entire hematopoietic system is under antigenic pressure, potentially leading to multi-com- partment disorders. Fluctuations in clonal dynamics58,59 and evidence of multi-clonal MBL,60 MGUS,57 and T-CUS2 are consistent with the hypothesis of chronic antigen-driven immune responses resulting from a strong and extensive reactive process that occurs prior to the stepwise acqui- sition of genomic alterations. These findings also indicate that the antigen drive likely underlies cell expansions, acting in an environment-specific context that over time may be progressively established by additional, secondary pervasive mutations.
Peripheral expansion of clonal cytotoxic T lymphocytes de- rived from the graft in the initial stages of allogeneic HSCT immune recovery is a well-known physiological event,61 with such clonal expansions persisting beyond the early transplantation period. The presence of persistent immu- nodominant T-cell clonotypes following allogeneic HSCT is significantly more frequent in those patients who developed cytomegalovirus reactivation and/or acute graft-versus-host disease, a finding which suggests a reactive cell expansion. The absence of STAT3 mutations in CD3-sorted populations and the declining longitudinal kinetics further support the benign nature of these clones.62 Moreover, Mohty et al.63 demonstrated that a subset of allotransplanted patients achieved long-term complete remission concomitant with or following LGL expansion, suggesting that these cells could represent effector lymphocytes which may participate in graft-versus-leukemia activity.
Several studies have documented a marked peripheral large granular lymphocytosis after treatment with dasati- nib,64,65 a second-generation multi-tyrosine kinase inhibitor currently used in chronic myeloid leukemia (CML). Clonal lymphocytes were already present at diagnosis, persisted at low levels during first-generation tyrosine kinase inhib- itor therapy, and expanded during dasatinib treatment.66 In addition to the intended inhibition of BCR-ABL1 kinase, dasatinib also inhibits other kinases, including SRC and TEC that behave as major regulators of immune responses.67 By inhibiting distinct off-target kinases in immune effec- tor cells, dasatinib may restore the function of anergic, exhausted leukemia-specific clonal cytotoxic preexisting
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