High incidence of non-neutropenic infections induced by rituximab plus fludarabine and associated with hypogammaglobulinemia: a frequently unrecognized and easily treatable complication

Background: Rituximab is associated with low incidence of hypogammaglobulinemia and little morbidity. Our experience with the combination of rituximab + chemotherapy suggested the opposite. Patients and methods: We analyzed our experience with rituximab plus chemotherapy in 97 patients to determine: frequency and type of non-neutropenic infection (NNI); frequency and type of hypogammaglobulinemia; response to gammaglobulin therapy; and factors associated with NNI. Results: We observed 40 episodes of NNI in 19 of 97 (20%) patients. By 3 years, 43% of patients treated with rituximab + chemotherapy were projected to have developed at least one NNI. Of 19 with NNI, 15 had Ig levels studied and all 15 had hypogammaglobulinemia. Most frequently affected Ig were IgG (14 of 15) and IgM (13 of 14). IgA was usually spared (six of 14 cases affected). NNIs observed were 18 bronchitis, 16 sinusitis, four pneumonias, three otitis media, two fevers of unknown origin (FUOs) and three herpes zoster. Hospitalization was required in seven of 19. Ten received gammaglobulin infusions and all responded promptly. Gammaglobulin was given only when NNIs recurred. We examined sex, age, histology, type of rituximab-chemotherapy (fludarabine + rituximab versus other chemotherapy + rituximab) for correlation with NNI. Conclusions: Indolent histology, female sex and fludarabine + rituximab significantly correlated with frequency of NNI but multivariate analysis picked fludarabine + rituximab followed by female gender as the only two independent variables predictive of NNI.