High Incidence of Non-Neutropenic Infections Induced by Rituximab Plus Chemotherapy and Associated with Hypogammaglobulinemia: A Frequently Unrecognized and Easily Treatable Complication.
Authors: Cabanillas Fernando , Pavia Orestes , Rivera Ezequiel 
Published: April 2020

Abstract
In the pivotal single agent Rituximab trial, hypogammaglobulinemia occurred in only 14% of cases and was not considered to be associated with any morbidity. Our experience with the combination of Rituximab plus chemotherapy (R-Chemo) seemed to differ from the single agent experience and suggested that this complication might occur commonly as a consequence of therapy, can lead to significant infectious morbidity and frequently is not recognized by clinicians. We thus analyzed our experience with R-Chemo in 97 patients (median age 58) to determine: 1- frequency and type of non-neutropenic infections (NNI). 2- frequency and type of hypogammaglobulinemia. 3- response to gammablobulin infusion therapy. 4- factors associated with development of NNI. To be considered as NNI, only those cases of bronchitis, sinusitis or pneumonia of acute onset and lasting over two weeks in spite of antibiotics or relapsing immediately after discontinuation of antibiotics, were counted. Others counted as NNI were infections requiring hospitalization in spite of normal neutrophils and Herpes Zoster (H.Z.). We observed a total of 40 episodes of NNI in 19 pts for a total of 19/97 (20%) pts who developed some type of NNI. A Kaplan-Meier cumulative estimate revealed that by 3 years, 43% of pts treated with R-Chemo were projected to have developed at least one NNI. Of the 19 pts with NNI, 15 had Ig levels studied and all 15 had hypogammaglobulinemia. The most frequently affected Ig were IgG (14/15) and IgM (13/14). Ig A was usually spared (only 6/14 cases affected). Types of NNI observed were 18 bronchitis, 16 sinusitis, 4 pneumonias, 3 otitis media, 2 FUOs and 3 H.Z. Some pts had combined episodes of different types of NNI (ex. sinusitis and bronchitis) and 7/19 required hospitalization. Ten pts. received gammaglobulin infusions and all 10 cases responded promptly. Gammaglobulin infusions were given sporadically and only when NNIs recurred; their effect was long lasting, frequently for as long as 6–12 months after administration. We examined sex, age (&lt;60 vs ≥60 ), histology (indolent vs aggressive), type of R-Chemo (Fludara+R vs other Chemo+R) for their correlation with development of NNI. Indolent histology, female sex and Fludara+R significantly correlated with NNI at P&lt;.05 but multivariate analysis first picked Fludara+R followed by female gender as the only 2 independent variables predictive of NNI. Figure 1 below illustrates the cumulative incidence of NNI according to type of R-Chemo regimen.
Figure Figure
Conclusions: 1-Clinicians should be aware of the exceedingly high incidence of NNI and hypogammaglobulinemia associated with R-Chemo, particularly with, but not limited to Fludara+R. 2- This can lead to significant morbidity including hospitalizations and is usually manifested as either bronchitis, sinusitis, pneumonia, otitis media, and non-neutropenic FUO, frequently of delayed onset. 3-Females who receive Fludara-R are particularly prone to develop NNI (incidence is 63% in females vs 10% males, p=.01). 4- Hypogammaglobulinemia leading to NNI is a frequent cause of hospitalization. 5-Treatment with gammaglobulin infusion is very effective and there is no need to repeat it monthly.