Waldenstrom's macroglobulinemia (WM) is a rare B-cell lymphoma defined by immunoglobulin (Ig) M monoclonal gammopathy and lymphoplasmacytic cell bone marrow infiltration. Prior to 2015, rituximab and chemoimmunotherapy (CIT) were mainstays of therapy. Bruton tyrosine kinase inhibitors (BTKis), ibrutinib and zanubrutinib, subsequently expanded frontline options. Current preferred regimens include bendamustine and rituximab, ibrutinib with/without rituximab, and zanubrutinib. Infectious complications are a significant morbidity in WM. A prior study showed a 3.4-fold higher infection risk in WM patients vs controls (Lund 2014). Baseline hypogammaglobulinemia (low IgA/G) is seen in up to 78% of patients, often worsening with rituximab or CIT (Treon 2004). Chronic lymphocytic leukemia (CLL) demonstrates similar hypogammaglobulinemia. Sun et al (2015) reported that CLL treatment with ibrutinib was associated with IgA recovery and reduced rate of infections, suggesting partial humoral immune reconstitution. We hypothesized that BTKis may have similar effects in WM.

We conducted a retrospective, single-institution study of 45 WM patients. Exclusion criteria were regular plasmapheresis, disease transformation, and insufficient lab data. Median age at diagnosis was 68 years (45–91 years). In patients for whom IPSS-WM could be calculated (n=38), a greater proportion of high-risk cases were in BTKi and CIT groups. 31.1% of patients were treated with CIT, 26.7% with BTKis and 42.2% with rituximab. Median baseline IgM levels were highest in the BTKi group (3571.5 mg/dL), compared with rituximab (1647 mg/dL) and CIT (1674 mg/dL). Most patients were MYD88-mutated and CXCR4-wildtype. 82.2% of patients achieved partial or very good partial responses. 11.1% had stable or progressive disease, all treated with rituximab. No BTKi-treated patients required subsequent therapy. In contrast, 52.6% of rituximab- and 28.6% of CIT-treated patients progressed. Median time to next therapy was 2.99 years for rituximab and 2.24 years for CIT.

Baseline median IgA levels were: BTKi 45.5 mg/dL, rituximab 73 mg/dL, and CIT 60 mg/dL (normal 70–400 mg/dL). At 24 months, IgA increased 33% in BTKi- and 9.6% in rituximab-treated patients but declined 36.7% in the CIT group. IgG declined similarly across all groups (20.2–21.5%). Infections were most frequent within the first 6 months of treatment. In the CIT group, 71.4% experienced infections (n=21; 61.9% grade 2, 23.8% grade 3). In the rituximab group, 68.4% had infections (n=24; 70.8% grade 2, 8.3% grade 3). Only 50% of BTKi patients experienced infections (n=9; 77.8% grade 2, 11.1% grade 3). Respiratory (46.3%) and urinary tract (27.8%) infections were most common. Infections were more frequent in those with declining IgA.

While the etiology for increased infection risk in WM is multifactorial, impaired humoral immunity and hypogammaglobulinemia plays a key role. Prior studies reported persistent or worsening Ig deficits with rituximab or CIT; eg. Treon et al (2004) reported baseline IgA/G deficiencies in 76.1-78.2% of patients, which worsened to 86.9-89.1% post-therapy. BTKi trials did not report Ig levels, though ASPEN showed similar infection rates with ibrutinib and zanubrutinib. Sun et al (2015) found that ≥50% increases in IgA long-term were associated with reduced infections in CLL, though no clear association was found for IgG/M. Acalabrutinib therapy showed similar trends, suggesting class-wide effect.

In our cohort, BTKi treatment was associated with the greatest increase in IgA and lowest rate of infections. Rituximab therapy demonstrated a modest rise in IgA levels. CIT significantly reduced IgA levels, with the most severe infections. These results are consistent with prior studies indicating that treatment with BTKis is associated with decreased risk of infection over time due to partial immune reconstitution. The mechanism of increased IgA production with BTKi therapy is unclear, though may be related to reduction in aberrant IgM-producing clones. Increases in IgA with rituximab were more evident at 24 months, which may be due to waning immunosuppression over time. Combining BTKis with rituximab may improve long-term humoral immunity, though with risk of early immunosuppression.

Limitations of this study include its retrospective design, small sample size, and lack of data on T-cell subsets. Future prospective studies are needed to further elucidate the immunologic effects of BTKi therapy in WM.

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2025
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