IgA and IgG hypogammaglobulinemia in Waldenström's macroglobulinemia.

Background Hypogammaglobulinemia is common in Waldenstrom's macroglobulinemia. The etiology of this finding remains unclear, but it has been speculated to be based on tumor-induced suppression of the 'uninvolved' immunoglobulin production Design and Methods We evaluated the incidence of IgA and IgG hypogammaglobulinemia in 207 untreated patients with Waldenstrom's macroglobulinemia and investigated the associated clinicopathological findings and impact of therapy. We also sequenced eight genes (AICDA, BTK, CD40, CD154, NEMO, TACI, SH2D1A, UNC) implicated in immunoglobulin deficiency in 19 Waldenstrom's macroglobulinemia patients with IgA and/or IgG hypogammaglobulinemia. Results At baseline 63.3%, 58.0% and 49.3% of the 207 patients had abnormally low serum levels of IgA, IgG, or both. No association between IgA and IgG hypogammaglobulinemia and disease burden, serum IgM levels, beta(2)-microglobulin, International Prognostic Scoring System score, or incidence of recurrent infections was observed, although the presence of adenopathy and/or splenomegaly was associated with a lower incidence of hypogammaglobulinemia. Lower IgA and IgG levels were associated with disease progression in patients managed with a 'watch and wait' strategy. IgA and/or IgG levels remained abnormally low despite response to treatment, including complete remissions. A missense mutation in the highly conserved catalytic site of UNG was observed in a patient with hypogammaglobulinemia, warranting further study of this pathway in Waldenstrom's macroglobulinemia. Conclusions IgA and IgG hypogammaglobulinemia is common in Waldenstrom's macroglobulinemia and persists despite therapeutic intervention and response. IgA and IgG hypogammaglobulinemia does not predict the risk of recurrent infections in patients with Waldenstrom's macroglobulinemia, although lower levels of serum IgA and IgG are associated with disease progression in Waldenstrom's macroglobulinemia patients being managed with a 'watch and wait' strategy.