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Monoclonal gammopathy defines distinct clinical subsets in chronic lymphocytic leukemia across therapeutic eras

Year: 2025

Type: article

Abstract: ABSTRACT: Monoclonal gammopathy (MG) in chronic lymphocytic leukemia (CLL) portends heterogeneous outcomes, yet its molecular drivers and therapeutic implications remain undefined. In this retrospective analysis of 2075 patients with CLL (1999-2024), MG was detected in 18.47% cases, with immunoglobulin M (IgM) (8.18%), IgG (8.09%), light-chain (1.14%), and IgA (1.06%) subtypes demonstrating divergent clinicogenomic profiles. Patients with IgA-MG were older at diagnosis, whereas those with IgG-MG had a younger age and a higher frequency of mutated immunoglobulin heavy-chain variable (IGHV). In contrast, IgM-MG was associated with unmutated IGHV, elevated lactate dehydrogenase and β2-microglobulin levels, higher frequencies of TP53 aberrations, and enrichment of MYD88, BIRC3, and DDX3X mutations. IgG-MG was associated with shorter time-to-first treatment (TTFT) only, whereas IgM-MG correlated with significantly inferior TTFT, progression-free survival, and overall survival. Subgroup analyses revealed that the adverse prognostic impact of MG was pronounced in IGHV-mutated CLL but attenuated in unmutated cases. Prognostic discrimination by the CLL-International Prognostic Index (CLL-IPI) remained robust regardless of MG status. Notably, patients with IgM-MG did not experience significant survival benefit from targeted therapy compared with conventional regimens. These findings demonstrate that MG subtypes, particularly IgM-MG, define biologically and clinically distinct subsets of CLL. Given the limited efficacy of Bruton tyrosine kinase inhibitors in IgM-MG, immunofixation-based MG profiling may inform risk-adapted treatment strategies and personalized therapy selection.

Source: Blood Advances

DOI: 10.1182/bloodadvances.2025017057