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Letters to the Editor
Dissociated humoral and cellular immune responses after a three-dose schema of BNT162b2 vaccine in patients receiving anti-CD20 monoclonal antibody maintenance treatment for B-cell lymphomas
The anti-CD20 monoclonal antibodies rituximab (R) and obinutuzumab (O) are used as maintenance therapy every two months for two-three years in patients with follicular lymphoma (FL) and mantle cell lymphoma (MCL). This strategy improves event-free survival (EFS) and/or overall survival (OS) after immunochemotherapy in responding patients.1-3 Severe forms of COVID-19 with prolonged carriage of the virus in patients on R maintenance have been reported due to a significant alteration of humoral immunity in this context.4,5 Therefore, during the COVID-19 epidemic, clinicians are faced with the question of whether to discontinue main- tenance therapy or not. The Pfizer/BioNTech RNA vac- cine BNT162b2 (Comirnaty®) has shown efficacy and safety data in all age groups and against several variants. 6,7 The specificities of mRNA vaccines also suggest that they may induce a better T lymphocyte response.8
The aim of our study was to evaluate the post-vaccina- tion humoral and T cell response based on the serological data and enumeration of interferon gamma (IFNγ)-pro- ducing T cells in response to SARS-COV-2 specific anti- gens (Elispot assay) in a group of patients with a long- term anti-CD20 antibody lymphoma treatment.
Patients with lymphoma receiving or initiating their maintenance therapy by anti-CD20 antibodies (R or O) and treated in a single center - Centre Henri Becquerel, France - were selected. The study protocol was approved by the local and national ethics committees (Internal Review board N° 2106B and Comité de Protection des Personnes, Ile de France IV, registered as number NCT04918940 at clinical.trial.gov) and written informed consent was obtained. Serologies and Elispot assays were repeated between D21-D28 after the first vaccination (V1), one month after the second vaccination (V2) and 1 month after the third vaccination (V3).
Twenty patients were enrolled in this study: 16 FL (80%); 3 MCL (15%); 1 Marginal Zone Lymphoma (5%) between 21 May 2021 and 1 July 2021. They received three doses of BNT162b2 vaccine after the initial phase of immunochemotherapy, in a steady state regarding lymphoma status (Table 1), during the maintenance phase. Ten patients were treated with R and ten with O. It should be noted that, in order to vaccinate patients as quickly as possible, the vaccine injections were carried out without any time interval rules with respect to the anti-CD20 antibody injections. The median number of R or O infusions received during the maintenance phase at the time of the first vaccination was four infusions (range 0-15, Table 1). The B-cell depletion was profound for all patients with no detectable CD19+/CD20+ cells. T-cell counts also indicated a low rate of both CD4+ and CD8+ T cells in 12/17 (70%) and 9/17 (53%) cases, respectively. Conversely, NK CD56+CD16+ cells were in the normal range in 16/17 (94%) cases (Table 2). With a median fol- low-up of 96 days (range 75-150), no COVID-19 infec- tion was detected in the cohort.
The anti–SARS-CoV-2 post-vaccine antibody response against the spike protein (RBD) was centrally assessed using the ARCHITECT SARS-Cov-2 IgG II Quant (Abbott) CMIA test, with titers >50 arbitrary units (AU) per milliliter considered positive (measurement interval: 6.8–80,000 AU/ml; positive agreement, 99.4%; negative agreement, 99.6%). At baseline, antibodies against the
SARS-CoV-2 virus spike protein were detected in 1/17 patients (5.9%, patient n°7, discussed hereafter). After one, two and three vaccine injections, all except this patient remained below the threshold of 50 AU/ml, indi- cating that the humoral response is deeply impaired in this cohort and does not seem improved by a triple-injec- tion schedule. Therefore, the positivity rate one month after the third injection in this cohort remained unchanged at 5% (1/20 tested patients) with no addition- al responder. Of note, antibody titers only increase after vaccination in patient n°7 despite the fact that, as with other patients, no CD19+/CD20+ B-cells were detectable by cytometry. This male FL patient was treated initially by O-chlorambucil as a first-line treatment. He developed a COVID-19 disease after the first cycle (C1-D8) of this treatment. Other than oxygen therapy, no intensive care was required but the infection led to the postponement of immunochemotherapy for two months. The patient was thereafter treated by R-CHOP (six cycles). This led to the patient receiving one infusion of binutuzumab and six infusions of rituximab before his first vaccine injec- tion.
Contrasting with the deep alteration of the humoral response to SARS-COV-2 vaccination, we demonstrated
Table 1. Population clinical features
Age (years) Median (q1-q3) Min-max
Sex Male
Female
Lymphoma subtype MCL
MZL FL
Maintenance antibody Rituximab Obinutuzumab
Time between first vaccination and last chemotherapy cycle (days)
Median (q1-q3) Min-max
Number of cycles (R/O) received before first vaccination
Median (q1-q3) Min-max
Disease status at the time of vaccination Complete remission
Partial response
Progressive disease
Study population (n=20)
65.5 (58.5-74) 46-77
7 (35%) 13 (65%)
3 (15%)
1 (5%) 16 (80%)
10 (50%) 10 (50%)
243.5 (131-430) 0-781
4.0 (2-8) 0-15
18 (90%) 2 (10%)
0
7 (35%) 6 (30%) 3 (15%) 2 (10%) 2 (10%)
1 (5%) 19 (95%)
Chemotherapy performed before maintenance O-CHOP x 6
R-CHOP x 6
O-Bendamustine x 6
Lenalidomide /rituximab (R2) x 9 R-CHOP/R-HAD
COVID status before vaccination Proven COVID
No history of previous infection
Patients with active or uncontrolled lymphoma diseases were excluded. FL: follicu- lar lymphoma; MCL: Mantle cell lymphoma; MZL: Marginal Zone lymphoma; O: obinutuzumab; R:rituximab; R-CHOP: Rituximab, Cyclophosphamide, Doxorubicin, Prednisolone and Vincristine; R-HAD: Rituximab, high-dose Ara-C and dexametha- sone.
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