Hypogammaglobulinaemia and Infectious Toxicity Related with the Use of Maintenance Strategies with Rituximab in B Lymphomas
Authors: García Mañó Lucia , Bento Leyre , Martinez-Serra Jordi , Salar Antonio , Sanchez Raga Jose Maria , Herráez Inés , Ruiz-de Gracia Silvia , García-Recio Marta , Ferraro Mariana , Garcia Francesc , Besalduch Juan , Sampol Antonia , Gutierrez Antonio 
Published: November 2019

Abstract
Introduction
The use of maintenance treatment with rituximab in B lymphomas has improved the results in terms of progression free survival in follicular lymphoma (PRIMA trial). This improvement has been seen in other types of indolent lymphomas including chronic lymphatic leukemia or specific cases of aggressive lymphomas with or without low grade associated component. However, the rituximab maintenance, even though is a well-tolerated strategy, is not free of toxicity. Our objective is reporting the rituximab toxicity associated to the maintenance with rituximab in a series of B-cell lymphomas treated with immunochemotherapy in first line in Hospital Son Espases (HUSE) and Hospital del Mar (HM).
Methods and materials
To avoid selection bias, we retrospectively identified from the Pharmacy registries of HUSE and HM those patients who had been treated with rituximab maintenance between 2002 and 2014 in first line of induction treatment with conventional immunotherapy or immunochemotherapy. Second lines or more intensive treatments were excluded. We obtained information about diagnosis, prognostic and outcome in all the patients, including levels of immunoglobulins as well as the seriousness of infections or other related side effects. Polymorphisms FcgRIIIa were analyzed using RT-PCR and sequencing.
Results
With the previous criteria 82 patients were included. Table 1 shows the diagnostic characteristics and the treatment of the patients. The median of age was 65 years; most cases were follicular lymphoma treated with R-CHOP or R-B and receiving maintenance with rituximab every 2 months (66%). Table 2 describes toxicity related to rituximab maintenance: hypogammaglobulinaemia IgG, IgA or both in the 27%, 21% and 11% of the cases respectively. When we analyzed the role of polymorphisms of FcgRIIIa we found that the patients with homozigous polymorphism VV were exempt of hypogammaglobulinaemia IgG or IgA. Moreover the polymorphism FF was associated meaningfully with a greater incidence of hypogammaglobulinaemia IgA (p=0.022). Only the 8% of the cases of hypogammaglobulinaemia needed treatment with intravenous immunoglobulins and only 6% had grade 3-4 infections. 21% of the patients treated with rituximab maintenance developed grade 3-4 neutropenia, generally reversible with the administration of G-CSF and without serious infections. Increase of mortality was not observed related with the presence of hypogamaglobulinaemia IgG (p=0.34), IgA (p=0.59) or both (p=0.59) or grade 3-4 neutropenia secondary to rituximab (p=0.38).
Conclusions
Between one-quarter or one-fifth of the patients who received maintenance therapy with rituximab during 2 years associate hypogammaglobulinaemia IgG, IgA and/or neutropenia as toxicity. Nevertheless these complications are generally mild, without related severe infections or increase of mortality.
Table 1. Clinical characteristics of the series Median of age 65 (27-85) Sex 41 (50%) / 41 (50%) ECOG PS >1 7 (9%) Type of lymphoma:- Folicular lymphoma- DLBCL- CLL/SLL- Marginal lymphoma- Mantel cell lymphoma- Other 46 (56%)13 (16%)8 (10%)6 (7%)5 (6%)4 (5%) Stage III-IV 71 (87%) B symptoms 29 (35%) Induction treatment:- R-CHOP/R-CVP- R-B- Rituximab alone- Schema with Fludarabine-R- Intensive schemas- Others 50 (61%)13 (16%)9 (11%)4 (5%)3 (4%)3 (4%) Type of maintenance (2 years):- Every 2 months- Every 3 months- Every 6 months (4 weeks) 54 (66%)15 (18%)1 3 (16%)
Table 2. Rituximab maintenance attributable toxicity Polimorphism FcgRIIIA Type of toxicity Total FF FV VV p Hypogammaglobulinaemia- IgG- IgA- Double IgG + IgA 22 (27%)17 (21%)9 (11%) 7 (23%)11 (37%)3 (10%) 15 (31%)6 (12%)6 (12%) 0 (0%)0 (0%)0 (0%) 0.340.0220.74 Treatment with immunoglobulins iv 7 (8%) 3 (10%) 4 (8%) 0 (0%) 0.79 Grade 3-4 infections: 5 (6%) 2 (7%) 3 (6%) 0 (0%) 0.87 Grade 3-4 neutropenia: 17 (21%) 8 (27%) 8 (17%) 1 (25%) 0.59

Disclosures
No relevant conflicts of interest to declare.