Incidence of Infections and Prophylaxis Practice, in Two Cohorts of Patients of Autoimmune Disorders of Hematological Interest or Non-Hodgkin Lymphoma Treated with Rituximab
Authors: Perrone Salvatore , Tomasello Riccardo , Raso Simona , Annibali Ombretta , Tafuri Mariantonietta , Mattana Marta , Soriano Tania , Fanciullo David , Assanto Giovanni Manfredi , Pedone Giacinto Luca , Baldacci Erminia , Santacroce Eugenio , Ingrascì Manuela Giuseppa , Biglietto Mario , Cammarata Claudia , Totaro Matteo , Ligia Silvio , Fattizzo Bruno , Santoro Cristina , Siragusa Sergio , Napolitano Mariasanta 
Published: December 2024

Introduction Rituximab is a chimericanti-CD20 monoclonal antibody, largely employed in the treatment of B-cell non-Hodgkin lymphomas and in several autoimmune diseases. Indeed, rituximab can cause profound B cell depletion and reduce the title of immunoglobulin and autoreactive antibodies. However, the presence of hypogammaglobulinemia increases the risk of infections in patients (pts) treated with rituximab, and reports of increased severity and mortality from COVID-19 infection, especially during pandemics, have been reported. Currently, there are limited data on patients with autoimmune disorders of hematological interest (AID), such as autoimmune hemolytic anemia (AIHA), acquired hemophilia (AHA), and immune thrombocytopenic purpura (ITP). Methods We performed a retrospective, multicentric study to compare two cohorts of patients treated with rituximab for indolent non-Hodgkin lymphoma (iNHL) or AID between March 2014 and March 2024, aiming to evaluate the incidence and characteristics of infections and common antimicrobial prophylaxis administration practices. We collected chart data from six Italian hematologic centers. Results. We identified 206 pts, 90 had iNHL while 116 AID, of these 46 pts had AIHA, 13 AHA, and 57 ITP. The patients' characteristics can be briefly resumed: 96 (47%) were male, 110 female (53%); the median age at diagnosis was 55 years. After the treatment with rituximab that was given at 375mg/m2 in most cases, 29 pts (14%) developed hypogammaglobulinemia. The majority of patients (70%) received a Pneumocystis jirovecii pneumonia (PJP) prophylaxis for a median duration of 9 months, the choice of PJP prophylaxis with trimethoprim/sulfamethoxazole was driven by center-specific policies. Indeed, no cases of PJP occurred, independently of receiving prophylaxis or not. Infectious complications occurred in 46 pts (22%); CTCAE grade was I in 16 pts, II in 24 pts, III 7 pts, IV in 4 pts. Rate of infections categorized by diagnosis (AID = autoimmune disease was 20% while for iNHL was 24% (P-value not significant (0.48)). At the end of 1 year observation after rituximab 23 pts, (15%) died; of these only 5 deaths (2%) were considered related to infection.
The effects of predictor variables on the risk of infectious complications were Age lower than 65 years 0.73 (-1.43-0.02), while hypogammaglobulinemia appears to increase risk of infection 1.34 (0.51-2.18). Patients with AID had less infections than iNHL 0.4 ( -0.32- 1.12).
Discussion
In this large multi-centric retrospective study, we captured the Italian real-life prevalence of infections, prophylaxis, and mortality rate in patients treated with rituximab for AID and iNHL. We confirmed that patients with AID have an increased risk of infections similar in patients with iNHL. The incidence of infections in AID is quite high; therefore, the administration of only anti PYP prophylaxis, may not be sufficient. On the contrary, also patients who did not receive PJP prophylaxis did not had increased PJP infections, so questioning its utility. Zadro in 2023 reported an increased mortality rate secondary to infections for AID in AIHA the 6-month cumulative incidence of hospitalization with a discharge diagnosis of infection was 18.3%. Our incidence of infections of 22% was similar to what is reported in literature and by Zadro et al. The differences in the rate of infections in two cohorts, albeit not statistically significant, may depend on several confounding factors: corticosteroid exposure (that was constantly given to the group of patients with AID) and radiotherapy exposure in some iNHL patients. Our study has many limitations due to its retrospective design. In conclusion, further research is warranted in the field, a prospective study will allow to better define the occurrence of infections, related to rituximab in patients affected with AID.