Prognostic Significance of Monoclonal Gammopathy in Chronic Lymphocytic Leukemia Under Different Therapeutic Backgrounds

Background: Approximately 10-20% of chronic lymphocytic leukemia (CLL) patients present with monoclonal immunoglobulinopathy (M-protein) at diagnosis, while 20-50% exhibit hypogammaglobulinemia (hypo-γ). However, the prognostic implications of M-protein and hypo-γ remain inconclusive, especially in the context of targeted therapies. There is a paucity of research on whether immunoglobulin levels guide treatment decisions.

Methods: We conducted a retrospective analysis of 2,075 CLL patients diagnosed at our institution from January 2000 to January 2024. All the patients had their serum immunoglobulin levels tested at diagnosis, with 1,223 undergoing immunofixation electrophoresis. We collected baseline clinical data, including cytogenetic abnormalities and IGHV mutation status. Data on first-line treatment regimens, time to first treatment (TTFT), progression-free survival (PFS), and overall survival (OS) were also analyzed.

Results: Among the patients, 226 (18.47%) tested positive for M-protein, with including xx (8.18%) with IgM-type, 99 (8.09%) with IgG-type, 14 (1.14%) with light chain-type, and 13 (1.06%) with IgA-type M-protein. Patients with M-protein were predominantly male and more likely to present with hepatosplenomegaly, anemia, hypoalbuminemia, elevated lactate dehydrogenase (LDH), increased β2-microglobulin (β2MG), and advanced disease stage. Patients with different M-protein types exhibited distinct characteristics. For instance, patients with IgA-M-protein were often older than 65 years at diagnosis, while patients with IgG-M-protein were younger, had a higher proportion of IGHV-mutated cases, and fewer TP53 abnormalities. Conversely, patients with IgM-M-protein were more often IGHV-unmutated, associated with TP53 deletions, and exhibited elevated LDH and β2MG levels. M-protein was also significantly correlated with the preferential use of IGHV segments, with M-protein-positive patients more likely to use V3-15.

Patients with IgM-type or λ light chain-type M-protein at diagnosis had significantly worse TTFT, PFS, and OS compared to patients without M-protein. However, survival was similar between patients with IgG or IgA-type M-protein and those without M-protein. Interestingly, when stratifying M-protein-positive patients by light chain type into κ and λ groups, analysis revealed that λ-type patients had inferior TTFT, PFS and OS, compared to patients without M-protein, while κ-type patients showed no significant differences in outcome.

Patients were categorized into traditional chemotherapy, immunotherapy, and targeted therapy groups based on their first-line treatment. Results indicated that M-protein status did not significantly impact PFS or OS in patients treated with traditional chemotherapy or immunotherapy. However, in the targeted therapy group, patients with M-protein experienced significantly worse PFS and OS than those without M-protein. No significant differences in survival were observed among the three treatment groups for patients with M-protein, while patients without M-protein demonstrated a significant survival advantage with targeted therapy compared to non-targeted regimens.

Furthermore, apart from the presence of M-protein, our analysis revealed that different immunoglobulin levels variably impacted prognosis. Patients with elevated IgM levels (>3.04 g/L) had significantly worse TTFT, PFS, and OS, whereas those with elevated IgG and IgA levels did not show significant outcome differences. Low immunoglobulin levels, whether decreased IgM (<0.46 g/L), IgG (<7.51 g/L), or IgA (<0.7 g/L), were associated with shorter TTFT but did not affect PFS or OS.

Conclusion: CLL patients with M-protein exhibited distinct clinical features and outcomes. Patients with M-protein may not significantly benefit from BTK inhibitor therapy, indicating a need for tailored therapeutic approaches.