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Editorials
It is time to adapt anti-CD20 administration schedules to allow efficient anti-SARS-CoV-2 vaccination in patients with lymphoid malignancies
Caroline Besson
Service d’Hematologie Oncologie, Centre Hospitalier de Versailles, Le Chesnay, 78150, France; UVSQ, Inserm, CESP, 94805, Villejuif, France
E-mail: CAROLINE BESSON - cbesson@ch-versailles.fr doi:10.3324/haematol.2021.279457
Patients with comorbidities are especially sensitive to coronavirus disease 2019 (COVID-19). This is notably true for patients with cancer, including patients with a recent (<5 years) diagnosis of a hematologic malignancy who have a ≥2.5-fold increased risk of death from COVID- 19.1 Patients with non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) share immune-sys- tem deficiencies due to the biological features of NHL/CLL per se (hypogammaglobulinemia, frequent neutropenia, lymphopenia or lymphocytic dysfunction) and to their treatments (chemotherapy, anti-CD20 monoclonal anti- bodies [anti-CD20], Bruton tyrosine kinase [BTK] inhibitors or BCL2 inhibitors), leading to an increased inci- dence and severity of infections. NHL/CLL patients are more likely to develop severe2 and/or prolonged forms of COVID-19.3 The COVID-19-related mortality of NHL patients was shown to increase with age, relapsed/refrac- tory disease and administration of anti-CD20 therapy within 1 year3 while it was shown to be related to age, comorbidities but not with therapy (mainly BTK inhibitors) among CLL patients.4 Therefore, these po- pulations need to be particularly protected against COVID- 19.
Vaccination against severe acquired respiratory syn- drome coronavirus 2 (SARS-CoV-2) was shown to pre- vent COVID-19 in the general population. The efficacy of vaccination in the NHL/CLL population requires further evaluation as immunocompromised patients were excluded from initial studies of SARS-CoV-2 mRNA vac- cines. Only limited data on the efficacy of vaccination in these populations have been published. Herishanu et al.5 studied 167 CLL patients from a single center and report- ed that their antibody response to the BNT162b2 mRNA COVID-19 vaccine was affected by disease activity and by treatments. It decreased from 55.2% in treatment- naive patients to 16.0% in patients on treatment at the time of vaccination. Remarkably, none of the 22 patients exposed to anti-CD20 within less than 12 months before vaccination had an antibody response.5 This raises partic- ular concerns about these drugs.
In this issue of Haematologica, Benjamini et al. report on a larger multicenter series of 373 CLL patients, followed in nine Israeli medical centers, who received two doses of BNT162b2 mRNA COVID-19 vaccine.6 Consistently with the study by Herishani et al.,5 61% of the treatment- naive patients had a serological response to vaccine, com- pared to 23% and 24% among patients on BTK inhibitors or BCL2 inhibitors, and only 5% among patients who received anti-CD20 antibodies during the year before vaccination. Deepening the analysis to clinical and bio- logical factors, they demonstrate that age <70 years, nor- mal IgM (≥40 mg/dL), IgA (≥80 mg/dL) and IgG (≥700 mg/dL) levels, normal hemoglobin level (≥13.5 g/dL for
males or ≥12 g/dL for females) are associated with an antibody response. This allowed the construction of a specific score that predicted response to vaccination.
In the same issue, Gurion et al., analyze the antibody response after vaccination with two doses of BNT162b2 mRNA COVID-19 vaccine of 162 patients with lym- phoma enrolled in two medical centers in Israel.7 Positive serological responses were observed in 51% of the patients. In a multivariate analysis, active lymphoma and administration of anti-CD20 treatment within 1 year before the second dose of vaccine were identified as neg- ative predictors for antibody response. Interestingly, the rate of seropositivity increased according to the time between anti-CD20 administration and vaccination, from 3% within 45 days, to 22% between 45 days and 1 year and to 80% if the vaccine was given more than 1 year after anti-CD20. Remarkably, the last percentage was equal to that of patients never exposed to anti-CD20.
The lack of robust data from large and multicenter cohorts available so far in these high-risk populations ren- ders the present studies of the upmost importance for physicians taking care of NHL/CLL patients worldwide. Two important messages can be drawn from the results reported by these studies. First, patients with NHL/CLL frequently fail to develop an effective humoral response to BNT162b2 vaccine. The striking observation that recent anti-CD20 therapy strongly impairs the develop- ment of antibody response after vaccination should be at the forefront of concerns. The second major information is the identification of other risk factors associated with lack of humoral response in this setting. Besides older age, a risk factor for lack of antibody response, which had already been identified in the general population, some NHL/CLL-specific factors also seem to affect serological response, such as active disease, and, among CLL patients only, lower hemoglobin and/or immunoglobulin levels. The usefulness of the CLL score built with these factors needs to be determined in clinical practice.
The two studies suffer from significant limitations, mostly related to the short follow-up after vaccination (2- 6 weeks and 2-3 weeks after the second dose of vaccine in patients with NHL and CLL, respectively). With longer follow-up, it will be especially important to obtain data on the occurrence of COVID-19 after vaccination in these cohorts of patients. As B-cell depletion may also affect the generation of both B- and T-cell memory responses,8 the serological data should be supplemented by the exploration of T-cell immune responses. Indeed, T-cell immunity has a major role in generating durable protec- tive immunity after viral vaccination. Recent studies, per- formed among non-immunocompromised patients, show that two doses of BNT162b1 can elicit solid CD4+ and CD8+ T-cell responses.9 Although the evaluation of T-cell
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haematologica | 2022; 107(3)