COVID-19 vaccination in patients on rituximab: a survey of lymphoma physicians at NCI designated cancer centers

SARS-CoV2 is a novel betacoronavirus that emerged in 2019 and has resulted in a global pandemic of coronavirus disease 2019 (COVID-19) [1]. COVID-19 can cause progressive respiratory failure, which has resulted in millions of deaths worldwide. Three vaccines to prevent COVID-19 were granted emergency use authorization (EUA) by the Food and Drug Administration, two RNA platform technology (mRNA-1273, Moderna (Cambridge, MA); and BNT162b2, Pfizer, New York, NY) and one adenovirus vector vaccine (Ad.26.COV2.S, Johnson and Johnson, New Brunswick, NJ) [1]. Individuals with hematologic malignancy and recent exposure to chemotherapy are at particularly high risk of severe COVID-19 [2]. Rituximab is a monoclonal antibody against CD20, expressed on the surface of both normal and malignant mature B-cells. Rituximab is a highly effective treatment for patients with B-cell lymphomas, and has been evaluated as long-term maintenance after initial therapy for mantle cell lymphoma (MCL) and indolent lymphomas, such as follicular lymphoma (FL). In patients with MCL following autologous stem cell transplant (ASCT), there is an overall survival (OS) benefit with maintenance rituximab (MR) [3]. A prolonged progression-free survival (PFS) benefit with MR in patients with FL treated with bendamustine and rituximab has led to widespread use despite the lack of OS benefit [4]. In contrast, MR for patients with MCL after induction with bendamustine and rituximab, did not show a PFS or OS benefit [5]. Multiple studies have demonstrated an impaired immunological response to vaccines after treatment with rituximab, both in patients with rheumatologic disorders and lymphoma [6–14]. Treatment with rituximab results in complete depletion of peripheral blood B-cells within 72 h, although plasma cells and antibody titers are not affected [13]. In several studies, rituximab resulted in decreased antibody production to influenza and pneumococcal polysaccharide vaccines [6,7]. This impaired response lasts at least 6 months, with some studies demonstrating ongoing effect at 7–9 months [10]. The lack of antibody response is most strongly demonstrated for primary antigen exposure, whereas some studies showed preservation of response to recall antigens, such as those in prior year influenza vaccines [14]. While plasma cells and existing antibody levels are not affected by rituximab, there is a prolonged decrease in memory B-cells, which results in decreased IgM production to antigen exposure, even 6–10 months after rituximab [12]. Although most of the data on the effect of rituximab on vaccine response is in relation to antibody production, studies have also shown an effect on cellular immunity. T-cell responsiveness after influenza and tetanus toxoid vaccines is decreased in rituximab treated patients, but this improved after 5 months [8,11]. In addition, T-cell dependent recall responses were preserved after rituximab, whereas T-cell dependent primary antigen response was decreased [9]. There is also emerging evidence that the novel mRNA platform vaccines to prevent COVID-19 are less effective in patients with recent exposure to anti-CD20 therapy. In a study of 167 patients with CLL, 0/22 (0%) receiving anti-CD20 therapy in the past 12 months had a detectable antibody response to BNT162b2, compared to 25/55 (45.5%) of those who received anti-CD20 therapy more than 12 months prior to vaccination [15]. Also of note, within the group that was vaccinated more than 12 months after exposure to anti-CD20 therapy, there was no association between antibody response and time since treatment. An additional study in five patients with rheumatologic disease on rituximab showed that the presence of CD19þ cells at the time of BNT162b2 vaccination was predictive of antibody response [16]. T cell response to vaccination was not impaired in this study. The variable benefit of MR in patients with lymphoma, the risk of severe COVID-19 in patients with hematologic malignancies, along with the potential for lack of vaccine efficacy in patients receiving rituximab, has led to significant uncertainty about whether to hold rituximab