Prior Rituximab Reduces the Effectiveness of COVID-19 Vaccination in Lymphoma

Treatment with rituximab prior to COVID-19 vaccination nearly halved the number of patients with B-cell non-Hodgkin lymphoma who developed blocking antibodies following COVID-19 vaccination compared with healthy controls.

Ronald Levy, MD

Ronald Levy, MD

Treatment with rituximab (Rituxan) prior to COVID-19 vaccination nearly halved the number of patients with B-cell non-Hodgkin lymphoma who developed blocking antibodies following COVID-19 vaccination compared with healthy controls, according to findings from a study that were published in Blood Cancer Discovery.1

The results showed that 55% of patients with lymphoma (n = 126) developed blocking antibodies following mRNA vaccination vs 100% of controls (n = 20; P < .001). Moreover, similar vaccine responses were found in treatment-naïve patients and controls.

“This finding is likely to be practice-changing,” senior study author Ronald Levy, MD, the Robert K. and Helen K. Summy Professor at Stanford School of Medicine, said in a press release.2 “We found that antibody responses to the COVID-19 vaccine were blunted in people who received rituximab up to a year before vaccination. But if they were vaccinated prior to treatment, most responded and were able to hold on to that response during their rituximab treatment.”

To better understand why patients with lymphoma develop poor responses to COVID-19 vaccination, investigators evaluated blocking antibodies, total anti-spike immunoglobulin, and spike-specific memory B cells in the peripheral blood of 126 patients with lymphoma and 20 age-matched healthy controls 1 and 4 months following COVID-19 vaccination.

Patients were enrolled between February 1, 2021, and June 30, 2021.

Samples were collected from all 146 individuals 1 month after their last vaccine dose (median, 28 days) and from 128 individuals 4 months following their last vaccine dose (median, 127 days). Almost all individuals received an mRNA-based COVID-19 vaccine.

Regarding disease histology, 70% of patients had follicular lymphoma or diffuse large B-cell lymphoma. Of the 126 patients with lymphoma, 17 had no prior treatment, 31 had received a CD20-directed antibody within the prior 6 months, 65 had not received treatment at least 6 months prior to vaccination, 12 were receiving a BTK inhibitor, and 1 was receiving lenalidomide (Revlimid) monotherapy.

Approximately half of patients who were receiving a BTK inhibitor at the time of vaccination without prior or current CD20-directed treatment developed blocking antibodies (n = 5/12).

Notably, the time since last CD20-directed treatment was a significant independent predictor of vaccine response. Among 9 patients who had received a CD20-directed antibody within 1 month prior to vaccination, 0 developed responses to the vaccine. Additionally, 0 of the 31 patients who were treated with a CD20 antibody within 6 months prior to vaccination developed blocking antibodies. However, 76% of previously but not recently treated patients developed blocking antibodies.

Conversely, patients who started CD20-directed treatment shortly after achieving a vaccine-induced antibody response generally maintained that response during treatment.

To better understand the duration of the impact of CD20-directed therapy on vaccine response, investigators evaluated patients who had received prior CD20-directed treatment (n = 100). The time since the last anti-CD20 dose ranged from 1 week to 17.5 years before vaccination.

A significant association between the time interval and blocking antibody response was reported (Spearman coefficient, 0.59; P < .0001). The likelihood of vaccine response remained low until at least 12 months following the last CD20-directed treatment.

Similar findings were reported in a subset of 16 patients who received a CD20-targeted antibody alone without prior or current chemotherapy.

“When we compared the effects of chemotherapy or other drugs, we found that it was mainly recent rituximab treatment that limited a person’s response to the vaccines,” Levy said.

Further results indicated that 15 of the 126 patients had been completely vaccinated against COVID-19 before starting treatment with rituximab. Ten of these patients developed a blocking antibody response to the virus. In 6 of these patients, that response lasted at least 4 months after starting rituximab.

“It’s so important to give people the chance to mount an effective immune response to vaccinations, particularly now,” Levy said. “There has been controversy in the field about the value of continuing rituximab treatment after the initial therapy because doing so has not been shown to help these patients live longer. Our study suggests this practice of extended treatment should probably be abandoned in the COVID era.”


  1. Shree T, Shankar V, Lohmeyer JJk, et al. CD20-targeted therapy ablates de novo antibody response to vaccination but spares pre-established immunity. Blood Cancer Discov. Published online ahead of print January 6, 2022. doi:10.1158/2643-3230.BCD-21-0222.
  2. Prior treatment with cancer drug likely renders COVID-19 vaccine ineffective, study finds. News release. Stanford Medicine. February 2, 2022. Accessed February 3, 2022.
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