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O. Benjamini et al.
Figure 1. Side effects of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Side effects were scored on a 0-5 scale with 0=no side effect.
progressive disease years after previous CLL-directed ther- apy and had no history of autoimmune hemolytic anemia. Both patients tested negative for SARS-CoV-2 antibodies. Their hemoglobin levels improved with corticosteroid ther- apy and recovered to normal after they were given ritux- imab and venetoclax. There was no correlation between the presence or severity of side effects and positive serolog- ical response (Online Supplementary Table S1; Figure 1). Analyses were performed separately for therapy-naïve and treated patients, but still no correlation was found between the presence or severity of side effects and a positive sero- logical response. However, the adverse event rate was found to be statistically higher among treatment-naïve patients than among previously treated and currently treat- ed patients (Online Supplementary Table S2).
Vaccine efficacy
A positive antibody response to the vaccine was evident in only 160 (43%) of all the patients with CLL.
In univariate analysis, the following variables were found to be highly statistically significantly (P<0.001) associated with the lack of development of an immune response to the vaccine: low IgG (<700 mg/dL), low IgM (<40 mg/dL), low IgA (<80 mg/dL), platelet count <150x109/L, hemoglobin below normal value, number of prior therapies for CLL, recent anti-CD20 antibody treatment, and currently being treated with BTK inhibitors or BCL2 inhibitors. A few other variables were found to be statistically significantly (P<0.05) associated, including CIRS score >6, age >70 and trisomy 12. There was no significant difference with regard to gender, comorbidities, FISH results except trisomy 12 or IGHV mutational status. Additional information is available in Table 2.
Multivariate logistic regression was used to predict response to vaccination and determine which variables were independently associated with the response (Table 4). LASSO regularization was used to avoid over-fitting and obtain a simpler model, which retained only the informa- tive variables while disregarding the remaining variables.
The following independent variables were found to be sta- tistically significant: age >70 years, recent treatment with anti-CD20 antibody, ongoing treatment with ibrutinib, IgG <700 mg/dL and IgM <40 mg/dL.
Neutralizing antibodies
Samples from 45 patients at Sheba Medical Center were also tested for the production of neutralizing anti- bodies. A pseudo typed virus system based on VSV was developed for the detection of neutralizing antibodies, instead of using infectious and viable viruses, due to safe- ty concerns. Neutralizing antibodies prevent the pseudovirus from entering the host cells. As shown in Figure 2, the amount of neutralizing antibodies (log trans- formed) is correlated linearly with anti-COVID-19 RBD- IgG titer (r=0.83 and P<0.001). Moreover, as demonstrat- ed in the correlation matrix, 25 of 26 patients with posi- tive IgG were also positive for neutralizing antibodies (the 26th patient was not tested for neutralizing antibod- ies). Similarly, 14 of 17 patients who were negative for anti-COVID-19 IgG were also negative for neutralizing antibodies (the neutralizing antibodies of the remaining 3 patients were not determined). The Choen κ agreement between IgG and neutralizing antibodies was κ=0.75±0.08 (P<0.001) which is indicative of high concor- dance between the two tests.
Vaccine efficacy according to treatment status and type of anti-leukemia therapy given
One hundred fifty eight (42.3%) patients were treatment- naïve and of these 97 (61%) developed an IgG response to the vaccine. The immune response was better in treatment- naïve patients than in previously treated patients and was graded according to CLL disease status (vaccine response better in therapy-naïve patients > complete response > par- tial response > progressive disease) (Figure 3A)
In the treated cohort: an inverse correlation was found between number of lines of prior anti-CLL therapy and the development of a serological response. (Table 2).
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