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R. Gurion et al.
2.09 and 12.16, depending on the type of malignancy and whether the disease has been actively treated within the months preceding the infection.5,6,8,9 Both non-Hodgkin lym- phoma per se and prior chemotherapy with or without anti- CD20 monoclonal antibodies have been suggested to con- tribute to patients’ reduced survival and prolonged hospital- ization following infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2).10-13
The damage the pandemic inflicted on multiple health- care systems which collapsed as a result of the high inci- dence of respiratory illness and intensive care demand, mostly due to the severity of COVID-19, led to an acceler- ated Food and Drug Administration approval of several anti-SARS-CoV-2 vaccines, following the successful com- pletion of phase III studies. Among them was the BNT162b2 mRNA vaccine, which was demonstrated to have an efficacy of 95% in disease prevention in the pivotal phase III study. While the trial included approximately 40,000 volunteers, patients with active cancer were not enrolled into the study.14
Promptly after the Food and Drug Administration approval, this vaccine was approved by the Israeli Ministry of Health (December 2020), and vaccination was initiated at a large scale nation-wide level, with around 70% of the population aged 16 years and above having been fully vac- cinated by April 2021. In addition, vaccination of potential- ly immunocompromised populations was started, includ- ing patients with hematologic conditions, despite the lack of good quality efficacy data for these patients, but in accor- dance with recommendations by hematologic and infec- tious disease agencies around the world.15-17
The rationale for this action had been the emerging data regarding the high infection-related morbidity and mortali- ty among these patients, especially during the periods of peak virus spread, along with the probable low risk of vac- cine-induced complications. However, at the physiological level, it is unclear whether patients with lymphoma will be able to generate good quality immune responses to this vac- cine, since the response to any vaccine requires interactions between various compartments of the immune system, many of which are compromised by the lymphoprolifera- tive disease itself,11 but even more so, by the chemo- immunotherapy regimens used for the treatment of these diseases.18,19 The lower prevalence and slower evolution of a humoral response to SARS-CoV-2 infection observed in this population of patients20,21 insinuate that this might be the case with humoral responses to the vaccine as well22.
The objectives of this study were to evaluate the rates of anti-spike (anti-S) antibody responses to the BNT162b2 vaccine among lymphoma patients and to identify patient- and treatment-related factors influencing the antibody responses.
Methods
This was a non-interventional cross-sectional study conducted at two medical centers in Israel: Rambam Health Care Campus, Haifa (RMB) and Rabin Medical Center, Petach Tikva (RMC). All the procedures involved in this study were in accordance with the ethical standards of the institutional review boards of the two cen- ters (approvals: # 0883-20-RMB; 1087-20-RMC) and with the 1964 Helsinki Declaration and its later amendments. All patients signed the informed consent form.
The inclusion criteria were: age ≥18 years, the diagnosis of a
lymphoproliferative disease, including Hodgkin and non-Hodgkin lymphoma according to the World Health Organziation 2016 clas- sification23 and no known history of COVID-19 infection. Study participants were divided into the following two groups: (i) patients who received treatment, including chemotherapy or immunochemotherapy, i.e., monoclonal antibodies, tyrosine kinase inhibitors or immunomodulatory drugs, within 12 months prior to anti-COVID-19 vaccination; and (ii) patients with indolent lymphoma who were under "watch-and-wait" management before anti-COVID-19 vaccination.
All patients were vaccinated with two doses of BNT162b2 vac- cine, 21 days apart, and were followed at hematology clinics. Blood samples were drawn 4±2 weeks after the second dose of vaccine and were evaluated for anti-spike SARS-CoV-2 antibodies. The SARS-CoV-2 IgG II Quant (Abbott©) assay was performed as per manufacturer’s instructions for quantitative measurement of IgG antibodies against the spike protein of SARS-CoV-2. The test result was considered positive if the IgG level was ≥50 AU/mL. The patients’ baseline characteristics, collected from institutional electronic medical records, included each patient's demographics, comorbidities, lymphoma characteristics, duration, type and the first and last dates of anti-cancer treatment as well as disease activ- ity before vaccination. Laboratory data such as complete blood count and serum protein electrophoresis before vaccination were also documented. The primary outcome was the rate of seroposi- tivity for anti-spike antibodies.
Statistical considerations
We analyzed patients’ characteristics using frequencies (per- centages) for categorical variables and median (range) for continu- ous variables. A logistic regression model with the exp(β) was applied as an estimator of an OR and the 95% confidence interval (95% CI) around it to define the baseline variables that predict negativity of a serological response to SARS-CoV-2 vaccine. We used the likelihood ratio of the receiver operator characteristics curves and area under the curve to define the optimal cutoff for continuous variables. Univariate and multivariate logistic regres- sion analyses were performed to evaluate potential predictors of seronegativity. To predict anti-spike IgG levels, we fitted a multi- ple-variable linear regression model based on: age, gender, lym- phoma type, absolute lymphocyte count and time from the last anti-CD20 monoclonal antibody treatment to vaccination. Stepping method criteria for entry and removal were 0.05 and 0.2, respectively. The Kruskal-Wallis test was used to compare medi- ans of antibody titers. To generate 95% CI around proportions, we used the binomial approximation of the normal distribution. Statistical analyses were performed using SPSS software (version 27, SPSS inc. Chicago, IL, USA) and GraphPad Prism version 6.0 software (GraphPad Software, San Diego, CA, USA).
Results
Patients’ characteristics
A total of 162 lymphoma patients who received two doses of the BNT162b2 vaccine between January and April, 2021 were included in the study. The median age of partic- ipants was 65 years (interquartile range, 52-73), 55% were males, 142 (88%) had non-Hodgkin lymphoma, including indolent and aggressive disease and the remaining 20 (12%) had Hodgkin disease. Reported comorbidities included dia- betes mellitus (19%), ischemic heart disease (11%), and other malignancies (17%). Most (55%) of the patients received first-line anti-lymphoma therapy, while about 17% were under "watch-and-wait" management. The most
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haematologica | 2022; 107(3)