Multilineage lymphoid clonal hematopoiesis: a cross-sectional, correlative analysis of plasma cell dyscrasias and large granular lymphocytic leukemia.

Clonal expansions in large granular lymphocytic leukemia (LGLL) may arise in response to immune dysregulation in the context of other hematologic malignancies. This study aimed to investigate the co-occurrence of LGLL and plasma cell dyscrasias (PCDs) to assess its prevalence, features, and potential underlying mechanisms. We conducted a cross-sectional study involving 2064 PCD cases and 534 LGLL cases. Of the 534 LGLL cases, 20% co-occurred with PCD, while LGLL was present in 2% of the 2064 PCD cases. Among 117 patients with both conditions, PCDs were predominantly associated with IgM M-protein, while LGLL patients had increased NK-cell proliferation and fewer mutations in STAT3/5B. The co-occurrence was linked to a higher incidence of autoimmune conditions, B-cell neoplasms, and more severe immune-mediated cytopenias. In symptomatic PCD/LGLL patients with low plasma-cell infiltration, B-cell-targeted therapies outperformed immunosuppression, suggesting humoral involvement. Correlation with biological parameters revealed elevated interleukin-6 and inhibitory effects of sera of symptomatic PCD/LGLL patients on hematopoietic cells. Our findings suggest an association between PCD and LGLL, characterized by distinct features that may have significant implications for clinical management. These results highlight the importance of considering hematologic co-occurrences in clinical practice and warrant further investigation into the molecular mechanisms linking these conditions.