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R. Gurion et al.
of anti-CD20 monoclonal antibodies, while this rate was only 3% in patients vaccinated within 45 days after anti- CD20 therapy (Table 4). It is noteworthy that the seropos- itivity rate in the former group was similar to that observed in lymphoma patients who had not received this treatment (i.e., were treated with chemotherapy only or were under “watch-and-wait” management).
None of the 28 patients treated with obinutuzumab developed a serological response in comparison to 62% seronegativity demonstrated in patients treated with ritux- imab within the same time frame.
Levels of SARS-CoV-2 IgG
In a linear regression model, a shorter time period between anti-CD20 therapy and vaccination predicted lower levels of anti-spike IgG and explained the 18% vari- ance in antibody titers, while all other evaluable variables, such as age, gender, lymphoma type and absolute lympho- cyte count had no predictive power. A correlation was revealed between the levels of circulating anti-spike IgG antibodies and the time between the last anti-CD20 treat- ment and vaccination. A significant difference was found between patients never exposed to anti-CD20 therapy (median of 1161 AU/mL; range, 0-15,567) or those receiving these agents more than 12 months prior to vaccination (median of 661 AU/mL; range, 0-15,220), relative to patients treated with these drugs within 12 months before vaccination: 0-45 days (median of 0 AU/mL; range, 0-225); 46-120 days (median of 0.7 AU/mL; range, 0-1575); 121-180 days (median of 0.5 AU/mL; range, 0-234); and 181-365 days (median of 0 AU/mL; range, 0-373 AU/mL) (Figure 1).
In a model taking into account age, gender, absolute lym- phocyte count, disease activity and the time from the last anti-CD20 treatment to vaccination, only the last variable was statistically significant and predicted the titers of IgG antibodies.
Discussion
The current study, evaluating the antibody-mediated response in lymphoma patients who received two doses of BNT162b2 vaccine, showed that only 51% of these individ- uals developed seropositivity. These findings are in line with results of the studies assessing the efficacy of other anti-viral vaccines in the lymphoma setting. Indeed, studies assessing the efficacy of the influenza vaccine demonstrat- ed insufficient humoral immunity and higher rates of overt
Table 4. Serological response compared between patients treated with anti-CD20 monoclonal antibodies and those who did not receive this treatment.
Table 3. Multivariate analysis of factors associated with a lack of sero- logical response.
Variable
Age ≥80 years
ALC ≤1.2x109/L
Active disease
Time between the last anti-CD20 treatment and vaccination
<12 months
Type of lymphoma
P-value Odds Ratio (95% CI)
0.5 2.8 (0.13-61.9)
0.4 2.1 (0.4-10.4) 0.006 11.8 (2-67.6)
<0.001 93 (12.3-704.4)
0.8 1.2 (0.25-6.1)
Time from anti- CD20 therapy to vaccination (days)
N. of N. of patients patients
with positive serology
% of patients with positive serology (CI)
% of patients with negative serology (CI)
97 (85-99) 76 (53-92) 75 (19-99) 86 (42-99) 19 (5-42) 20 (10-32)
95% CI: 95% confidence interval; ALC: absolute lymphocyte count. The IgG variable was removed due to missing data
clinical disease in patients treated with chemotherapy, with only 10% of patients developing a sufficient antibody titer to at least one of the influenza A antigens, as compared to 45% in the control group.24 Moreover, lymphoma patients vaccinated within a randomized trial of the recombinant zoster vaccine administered during or a maximum of 6 months after anti-lymphoma therapy, also showed low lev- els of seropositivity, varying between 20% and 50%.25
Currently available data point to the vital importance of COVID-19 prevention in cancer patients in general and in those with hematologic malignancies in particular.7 Evidence-based prophylactic approaches such as vaccina- tion, have become the top priority measures significantly contributing to infection control. Nevertheless, the pivotal study, demonstrating 95% efficacy of the BNT162b2 vac- cine in COVID-19 prevention, did not include patients with lymphoma. In a single-center Israeli study, examining anti- body-mediated response rates with the Elecsys anti-SARS- CoV-2 S assay in patients with chronic lymphocytic leukemia, positive humoral responses were observed in 52% of patients, compared to 100% in an age- and sex- matched control cohort.26 Notably, the assay used in the lat- ter study differed from the one employed in our analysis.
In the current study, treatment with anti-CD20 mono- clonal antibodies as well as active disease at the time of vaccination emerged as significant predictors of a lack of serological response to BNT162b2. Likewise, the impact of anti-CD20 therapy was evident in the observed titers of anti-spike IgG antibodies, which increased as the time
Figure 1. Correlation between the levels of circulating anti-spike IgG antibodies and the time from the last anti-CD20 treatment to vaccination. Dots represent antibody titer values in arbitrary units (AU); red lines represent medians. ***P<0.0001; **P<0.001; *P<0.01; NS: not statistically significant.
0-45
46-120
121-180
181-365
>366
No anti-CD20 therapy
34 1 3(1-15) 21 5 24(8-47) 4 1 25(1-81) 7 1 14(1-58)
21 17
56 45
81 (58-95) 80 (68-90)
N.: number; CI: confidence interval.
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