Rituximab Is Associated with an Increased Risk of Malaria Infection in a Malaria-Endemic Region

Abstract

Rituximab has become a standard of care for the treatment of lymphoproliferative B-cell neoplasms, such as diffuse large B cell lymphoma (DLBCL). As an anti-CD20 monoclonal antibody, rituximab depletes the B lymphocyte compartment and is associated with downstream impairment in humoral immunity and increased risk of infections. While such infections are often bacterial, non-bacterial infections also do occur. Malaria is a vector-borne protozoal infection caused by plasmodium species and is endemic in most parts of sub-Saharan Africa (SSA) where HIV infection is also endemic and an independent risk factor for malaria. Most studies evaluating the safety and efficacy of rituximab were in non-endemic malaria areas with a low prevalence of HIV in the US and Europe. Therefore, the effect of rituximab-induced immunodeficiency on malaria-specific immunity and the risk of malaria among DLBCL in malaria-endemic regions is not well established. The incidence of DLBCL in SSA is increasing due to the growth and aging of the population as well as epidemic levels of HIV infection. The objective of this retrospective study is to evaluate the risk for malaria infection among DLBCL patients treated with standard chemotherapy in Malawi, a malaria-endemic country with high HIV prevalence. We performed a retrospective analysis of 96 patients, aged ≥18 with DLBCL from the Kamuzu Central Hospital (Lilongwe, Malawi) Lymphoma Study, a prospective observational cohort treated with CHOP or R-CHOP 2013-2019. Symptomatic malaria cases were determined by retrospective chart review and defined as individuals with documented positive malaria rapid diagnostic test (MRDT) or peripheral blood film (PBF) during treatment or up to one year of follow-up. Laboratory malaria cases were individuals with positive P. falciparum histidine-rich protein 2 (HRP2) antigenemia using quantitative ELISA at mid-treatment (2 months), completion (4 months), or post-treatment (12 months). HRP2 antigenemia is suggestive of current or very recent P. falciparum malaria infection. Unadjusted odds ratios were calculated for risk factors for malaria using logistic regression. Treatment regimens varied slightly with 59 patients (62%) receiving CHOP, and 37 (38%) receiving R-CHOP. Fourteen of the 96 DLBCL (14.6%) patients developed symptomatic malaria during the treatment period and the remainder remained free of malaria-associated symptoms. Symptomatic malaria was not significantly associated with age, gender, DLBCL stage, number of treatment cycles received, prior history of TB, performance status, HIV infection, or HIV RNA viral load > 1,000 copies. However, among the symptomatic malaria cases, five (36%) received CHOP, and nine (64%) received R-CHOP. Patients treated with R-CHOP were more likely to develop symptomatic malaria than CHOP patients (OR 3.38, 95% CI 1.05-12.26; p=0.03). Thirty-two (24 CHOP, 8 R-CHOP) patients were positive for malaria based on the HRP-2 antigen test and there was no correlation with rituximab treatment. However, HRP-2 antigen concentrations were significantly higher in R-CHOP patients compared to CHOP patients (2.3 OD vs 0.58 OD; p=0.01). To our knowledge, this is the first study to evaluate the effect of rituximab on malaria risk among DLBCL patients treated with chemotherapy in a malaria-endemic region. This study suggests that rituximab increases the risk of symptomatic malaria in adult DLBCL patients. Data investigating the effect of rituximab on malaria-specific antibody production is currently being analyzed. Further studies are needed to determine whether antimalarial chemoprophylaxis should be implemented to improve the comprehensive care of cancer patients residing in malaria-endemic areas.