Predictive Factors to Hypogammaglobulinemia and Non-Neutropenic Infection Complications after Rituximab/Chemotherapy Treatment
Authors: Filanovsky Kalman , Shvidel Lev , Shtalrid Mordechai , Haran Michal , Duek Adrian , Berrebi Alain 
Published: October 2019

Abstract
Rituximab is a chimerical human/mouse monoclonal anti-CD20 antibody successfully applied in B-cell lymphoproliferative disorders. The suppression of B-lymphocytes may induce hypogammaglobulinemia and increased risk for infection. These complications are rarely observed as a result of monotherapy with rituximab but have been often noted following combination with aggressive chemotherapy or in the setting of autologous stem cell transplantation (ASCT). In an attempt to study the role of rituximab in induction of hypogamma, we analyzed the frequency of this phenomenon, its possible causes, infectious complications and infection-related mortality in lymphoma patients treated with different chemotherapy regimens with or without rituximab. We analyzed 136 patients who received rituximab concurrently with chemotherapy (R-Chemo) and 46 patients who were treated with chemotherapy only, with follow-up period of up to five years. Following R-Chemo, 17 cases (12.5%) of severe hypogamma (defined as <60% of normal IgG range) were diagnosed, 21 patients (15.5%) had mild and moderate hypogammaglobulinemia, and 16 (12%) were found with decreased IgM alone. Multivariate analysis showed a significant increase of severe hypogamma when >6 doses of rituximab were given. Moreover, rituximab in >8 doses leaded to severe hypogamma in 50% of patients compared to 11.8% in patients treated with <8 doses (p .006) associated with 3 times more infections. The type of chemotherapy regimen didn’t influence development of the hypogamma. Even myeloablative chemotherapy used in combination with rituximab before ASCT slightly increased the rate of severe hypogamma (p .06). Only the combination of fludarabine and rituximab (FR) compared to other Chemo-R, induced non-significant increase of severe hypogammaglobulinemia (21% vs 11%; p .02), severe non-neutropenic infection 19.4% vs 5.0% (p .005) and infection-related mortality 24% vs. 6% (p. 004). Multivariate analysis showed that patients post FR treatment were 6.4 times more prone to have severe infections than post other Chemo-R regimens (95% CI 1.49–27.0). Age and gender of patients, type of lymphoma, bone marrow involvement didn’t affect the immunoglobulin level. We found a strong correlation between the IgG level and frequency of severe infections and mortality from infection (p <.01). Finally, the pre-treatment hypogamma was not found as a risk factor for infection. However, the duration of this phenomenon was found important: patients with severe hypogamma lasted >6 months were 4.5 times more likely to have severe infection (95%CI 1.19–18.5). In conclusion, we emphasized the importance of follow-up on immunoglobulin level in patients receiving rituximab. Hypogammoglobulinemia is not rare and is a clinical important phenomenon, leading to increase in infection and mortality rate in patients receiving R-Chemo. Longer treatment with more than six doses of rituximab significantly increases the incidence of hypogammoglobulinemia. The type chemotherapy regimen, except for fludarabine didn’t affect the incidence of hypogammaglobulinemia and infection rate in our patients.