Patients with lymphoma hospitalized for severe COVID-19 infection were at higher risk for prolonged hospital stay and death if they were treated with B-cell–depleting therapies (eg, rituximab, obinutuzumab) within the previous 12 months. The risk of persistent COVID-19 infection was also higher in people older than age 70 and in those with relapsed or refractory disease, according to a retrospective study presented at the 2021 American Association for Cancer Research (AACR) Virtual Meeting: COVID-19 and Cancer.1
These findings related to a mainstay of treatment for lymphoma raise many questions about how to manage patients with lymphoma during the COVID-19 pandemic. Should they receive anti-CD20 treatments, or should treatment be delayed if possible? Should they receive COVID-19 vaccination? These issues have yet to be resolved.
“Patients with lymphoma hospitalized for COVID-19 have high risk of death at 6 months of about 31%. Those with B-cell lymphoma have a high incidence of prolonged evolution of infection. Administration of anti-CD20 therapy within the past 12 months is one of the main risk factors for longer hospitalization and death,” stated lead author Sylvain Lamure, MD, a hematologist at Centre Hospitalier Universitaire (CHU), Montpellier, France.
“After 1 month, 41% of patients who received anti-CD20 monoclonal antibodies were still hospitalized for severe COVID-19 vs 13% not treated with those antibodies.”— Sylvain Lamure, MD
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“Although anti-CD20 monoclonal antibodies improve survival among patients with B-cell non-Hodgkin lymphoma, these treatments induce rapid B-cell depletion, which alters the generation of antibody response to new pathogens, which may impact the clinical course of COVID-19,” he said.
“These findings raise concerns about the management of patients [with B-cell malignancies], especially for maintenance therapy with rituximab or other anti-CD20 treatments. We need standardized guidelines to help us make decisions during the COVID-19 pandemic. Convalescent plasma may turn out to be a treatment for B-cell–depleted patients with persistent COVID-19, but further study is needed. These patients have dysfunctional immunologic memory,” Dr. Lamure commented.
Background and Study Details
Several studies and registries have shown that patients with any type of lymphoma or other hematologic malignancy have a higher incidence of death from COVID-19 compared with other types of cancer. Other risk factors for COVID-19–related mortality include older age and relapsed or refractory disease.
Researchers at CHU conducted a retrospective study of 111 patients with lymphoma hospitalized for COVID-19 at any of the 16 French hospitals in March and April 2020. The goal of the study was to identify factors associated with worse outcomes from COVID-19 in this patient population. The focus was on hospital length of stay longer than 30 days or hospitalization for recurrent symptoms for more than 30 days and death.
“We used length of hospital stay as a proxy for persistent COVID-19,” Dr. Lamure explained.
Eligible patients could have been formerly treated for lymphoma, undergoing current treatment, or had no treatment. Of the 111 patients in the trial, 63 (57%) had previously received B-cell–depleting therapy. The most common type of lymphoma was diffuse large B-cell lymphoma.
After 1 month, 24 patients had died; 55 patients recovered from COVID-19; 31 patients remained hospitalized for COVID-19, and 1 was rehospitalized with recurrent symptoms, for a 29% incidence of persistent COVID-19. There were 14 deaths among the 32 hospitalized patients.
Persistent COVID-19 Cohort
At 6 months, among the 32 patients with persistent COVID-19, 19 had recovered, 4 had ongoing symptoms, and 9 had died. At a median follow-up of 191 days, the 6-month overall survival for the entire cohort was 69%.
The median age of patients with persistent COVID-19 (n = 32) was 64 years (range, 43–87 years), and 63% were male. More than two-thirds (69%) had at least one significant comorbidity. None of the eight patients with T-cell lymphoma included in the study experienced persistent COVID-19 infection.
Among the 32 patients with persistent COVID-19, the median time from the first hospital admission until final discharge was 58 days (range, 31–235 days). The median duration of COVID-19 symptoms was 83 days (range, 32–237 days). A total of 8 patients were treated with corticosteroids and 9 received convalescent plasma; 16 of 17 recovered.
A univariate analysis identified age, comorbidities, histology subtypes, anti-CD20 antibody, or bendamustine treatment within the past 12 months, as well as relapsed or refractory disease, as factors associated with a longer length of stay. A multivariate analysis found that age, comorbidities, anti-CD20 antibody treatment within 12 months, and relapsed or refractory disease were significantly associated with a longer length of stay and with overall survival.
“After 1 month, 41% of patients who received anti-CD20 monoclonal antibodies were still hospitalized for COVID-19 vs 13% not treated with those antibodies,” Dr. Lamure stated.
Caroline Besson, MD, PhD
Senior author of the study, Caroline Besson, MD, PhD, a hematologist at Centre Hospitalier de Versailles and Université de Versailles Saint-Quentin-en-Yvelines, France, commented: “Our findings regarding the impact of anti-CD20 therapy on the course of COVID-19 can contribute to the guidelines for managing lymphoma during the pandemic. Our results also highlight the need for specific therapies for patients with COVID-19 who are B-cell–depleted and for the evaluation of the efficacy and timing of the COVID-19 vaccination in this particular population.”
Discussion Points: More to Learn
Session moderator Solange Peters, MD, PhD, pointed out that the reasons for poorer survival among patients with hematologic malignancies who develop COVID-19 are not fully understood. Dr. Peters is the 2020–2022 European Society for Medical Oncology President and Head of the Medical Oncology Service and Chair of Thoracic Oncology in the Oncology Department at the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Solange Peters, MD, PhD
“The mortality [from COVID-19] is shocking in patients with hematologic malignancies without completely understanding the underlying reasons. It is not clear whether B-cell depletion is the main cause or the only cause of this increased mortality,” she said.
Research suggests that impairment in the adaptive immune system changes the threshold for risk severity, but it is difficult to tease out which changes are the primary contributor. CD8 T cells may be implicated in response to COVID-19 among patients with hematologic malignancies. Dr. Peters asked Dr. Lamure whether CD8 memory T cells had been measured in this retrospective series. Dr. Lamure responded: “Unfortunately, we haven’t done that with this cohort, since it was a retrospective study. We have no idea about T cells in those patients.”
Dr. Peters asked whether treatment with rituximab or obinutuzumab should be delayed in patients with low-grade lymphomas who develop COVID-19. Dr. Lamure responded: “If there are no urgent lymphoma-related symptoms, we can delay treatment a little, but patients with follicular lymphoma benefit from maintenance therapy with rituximab. This is a difficult question to answer. We currently recommend vaccination for COVID-19 before starting rituximab, but this has to be evaluated. The benefit of convalescent plasma is currently explored in another cohort of patients with lymphoma.”
Also, Dr. Peters noted, more evidence is needed to decide whether patients with lymphoma and those with other hematologic malignancies should undergo COVID-19 vaccination, as well as regarding its optimal timing.
DISCLOSURE: Dr. Lamure reported no conflicts of interest. Dr. Besson has received funding from Roche related to this study. Dr. Peters has received honoraria and has had a consultant/advisory role with AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Incyte, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Phosphoplatin Therapeutics, Pfizer, Regeneron, Sanofi, -Seattle Genetics, and Takeda; has received honoraria and was a speaker for an organized public event for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Illumina, Medscape, Merck Sharp and Dohme, Novartis, Pfizer, Prime, Sanofi, and Takeda; and has received honoraria/grants/research support from Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, F. Hoffmann-La Roche, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, and Phoshoplatin Therapeutics.
1. Lamure S*, Dulery R*, Delord M, et al: High incidence of persistent COVID-19 among patients with lymphoma treated with B-cell depleting immunotherapy. AACR Virtual Meeting: COVID-19 and Cancer. Abstract S09-02. Presented February 5, 2021. *contributed equally