Blood cells with clonal abnormalities linked with neoplasia have been observed in not only otherwise healthy individuals, but also in patients with a preexisting hematological malignancy or its precursor state (HM/preHM). A notable example is the co-occurrence of large granular lymphocyte leukemia (LGL) with B-cell neoplasms or monoclonal B-cell lymphocytosis (BCN/MBL), plasma-cell neoplasms or monoclonal gammopathies of uncertain significance (PCN/MGUS), and myeloid neoplasms or clonal hematopoiesis (MN/CH). While these associations have been previously noted, including in our own series [1,2,3], their exact prevalence, degree of overlap and implications have not been systematically analyzed. Understanding this form of clonal overlap may help uncover shared pathogenetic mechanisms and clarify which clone is driving clinical manifestations such as cytopenia.

Here, we assessed the epidemiology of LGL in association with other HM/preHM using a bidirectional, cross-sectional approach. First, we implemented a HM/preHM-forward strategy by screening individuals with MN/CH, PCN/MGUS, and BCN/MBL for the presence of LGL or T-cell clonopathy of uncertain significance (TCUS). A retrospective review of 2115 MN/CH, 2064 PCN/MGUS, and 1672 BCN/MBL cases revealed concurrent LGL/TCUS in 3%, 2%, and 2% of individuals, respectively. Analysis of large meta-analytic validation cohorts from the NIH All of Us Research Program confirmed that LGL/TCUS was consistently observed at a frequency of ~1% across each of the three other HM/preHM. Among individuals evaluated for all four hematological clonopathies, multiple entities co-occurred in 42% of cases. The most frequent overlap was noted between PCN/MGUS and MN/CH and/or CLL/MBL, whereas LGL/TCUS exhibited the highest rate of co-occurrence with other HM/preHM. Cytopenia was present in 54% of cases. Multiple clonal overlap implied a greater risk of cytopenia (OR 7, P<.01).

We then conducted a reverse LGL-forward analysis, focusing on patients with LGL to assess the presence of coexisting HM/preHM. In a cohort of 388 LGL cases, 58% had at least one additional clonal hematologic condition: MN/CH in 33%, PCN/MGUS in 31%, and BCN/MBL in 15% of cases. Doublets, triplets, and quadruplets were present in 39%, 15% and 4% cases, respectively. Compared to patients with sole LGL diagnosis, those with coexisting HM/preHM exhibited distinct clinical and molecular profiles, including a higher frequency of autoimmune manifestations beyond rheumatoid arthritis (P=.05), lower LGL counts (P=.05), lower rate of STAT3 mutations (P<.01), and more frequent mutations in TET2, DNMT3A, and other MN/CH-related genes (P<.01). The co-occurrence of HM/preHM also conferred a higher risk of both cytopenia of any type (P=.02), and immune-mediated cytopenia including antibody-mediated cytopenia and bone marrow failure (P<.01).

Further we dissected the relative contribution of each coexisting clone to cytopenia in LGL and showed that MN/CH was independently associated with a higher risk of cytopenia of any type (OR 5, P<.01). In contrast, BCN/MBL and PCN/MGUS were specifically linked to anemia (OR 2, P=.03) and immune-mediated cytopenia (OR 2, P=.03), suggesting a role for humoral mechanisms related to B-cell clones. Clinical chart reviews of LGL patients with concurrent BCN/MBL or PCN/MGUS indicated that 11% exhibited manifestations likely attributable to the B-cell clone, all of them showing M-protein. While 27% met criteria for active lymphoma/myeloma, the remaining 73% qualified as monoclonal gammopathies of clinical significance. Importantly, response rates were markedly high for B-cell-targeted agents (88% vs 42% for other treatments), supporting the idea that manifestations in this subset may be driven predominantly by the B-cell clone.

Our findings demonstrate that LGL frequently co-occurs with other HM/preHM entities in both diagnostic directions. In the LGL setting, this co-clonality is not incidental but associated with distinct clinical and molecular characteristics. Importantly, coexisting HM/preHM confers increased risk for cytopenia, especially with MN/CH, and for immune-mediated cytopenia, particularly when a B-cell clone is present. Our work supports systematic screening for additional clonal hematologic conditions in patients with LGL and suggests that interactions between multiple clonal populations may shape disease phenotype and clinical outcomes.

Acknowledgements: AAMDSIF, NIH All of Us Research Program.

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2025
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