key: cord-0686598-6jizc32i authors: Mittelman, Moshe; Magen, Ori; Barda, Noam; Dagan, Noa; Oster, Howard S.; Leader, Avi; Balicer, Ran title: Effectiveness of the BNT162b2mRNA Covid-19 Vaccine in Patients with Hematological Neoplasms in a Nationwide Mass Vaccination Setting date: 2021-10-20 journal: Blood DOI: 10.1182/blood.2021013768 sha: bc38cbf73c3c8bfe90ff4edc2ee253e16e8bd012 doc_id: 686598 cord_uid: 6jizc32i Evidence regarding the effectiveness of covid-19 vaccine in patients with impaired immunity, is limited. Initial observations suggest a lower humoral response in these patients. We evaluated the relative effectiveness of the mRNA BNT162b2 vaccine in patients with hematological neoplasms compared to matched controls. Data on patients with hematological neoplasms after two vaccine doses were extracted and matched 1:1 with vaccinated controls. Subpopulation analyses focused on patients receiving therapy for the hematological neoplasm, patients without treatment who are only followed, and recipients of specific treatments. The analysis focused on covid-19 outcomes from day 7 through 43 following the second vaccine dose: Documented covid-19 infection by PCR; Symptomatic infection; Hospitalizations; Severe covid-19 disease and covid-19-related death. Of a population of 4.7 million insured people, 32,516 patients with hematological neoplasms were identified, of whom 5,017 were receiving therapy for an active disease. Vaccinated patients with hematological neoplasms, compared with vaccinated matched controls, had an increased risk of documented infections (RR 1.60, 95% confidence interval [CI] 1.12-2.37), symptomatic covid-19 (RR 1.72, 95% CI 1.05-2.85), covid-19 related hospitalizations (RR 3.13, 95% CI 1.68-7.08), severe covid-19 (RR 2.27, 95% CI 1.18-5.19) and covid-19 related death (RR 1.66, 95% CI 0.72-4.47). Limiting the analysis to patients on hematological treatments showed a higher increased risk. This analysis shows that vaccinated patients with hematological neoplasms, in particular patients on treatment, suffer from covid-19 outcomes more than vaccinated individuals with intact immune system. Ways to enhance covid-19 immunity in this patient population, such as additional doses, should be explored. Evidence regarding the effectiveness of covid-19 vaccine in patients with impaired immunity, is limited. Initial observations suggest a lower humoral response in these patients. We evaluated the relative effectiveness of the mRNA BNT162b2 vaccine in patients with hematological neoplasms compared to matched controls. Data on patients with hematological neoplasms after two vaccine doses were extracted and matched 1:1 with vaccinated controls. Subpopulation analyses focused on patients receiving therapy for the hematological neoplasm, patients without treatment who are only followed, and recipients of specific treatments. The analysis focused on covid- 19 Limiting the analysis to patients on hematological treatments showed a higher increased risk. This analysis shows that vaccinated patients with hematological neoplasms, in particular patients on treatment, suffer from covid-19 outcomes more than vaccinated individuals with intact immune system. Ways to enhance covid-19 immunity in this patient population, such as additional doses, should be explored. Mass vaccination campaigns against covid-19 are conducted worldwide. The mRNA-based vaccines were proven to be effective in randomized clinical trials, preventing covid-19 in the range of 94% to 95% 1,2 and in a real-life setting. 3 Vaccinated individuals experienced a reduced rate of all studied outcomes compared to unvaccinated controls. 3 Patients with solid tumors and hematological neoplasms, suffering from impaired immunity, are at particular risk with higher morbidity and mortality. [4] [5] [6] [7] Unfortunately, data on the vaccination effectiveness in this patient population are still limited. Israel's national policy has encouraged all patients with malignancies to be vaccinated. Thus, most patients with hematological neoplasms in Israel received two consecutive doses of the BNT162b2 mRNA covid-19 vaccine (Pfizer), administered 21 days apart, as a standard of care through the national vaccination program. Preliminary reports have suggested a low seroconversion rate in vaccinated patients with hematological neoplasms compared with healthy controls, 7-15 but were not powered to assess covid-19-related outcomes. These observations raise concerns regarding the outcomes of covid-19 exposure in such vaccinated patients. Whether the lower seroconversion rates in this patient population are associated with lower clinical effectiveness remains to be determined. The primary aim of this study was to test the relative effectiveness of the BNT162b2 mRNA covid-19 vaccine in patients with hematological neoplasms compared with vaccinated matched controls. The secondary aims were to study the vaccination effect in certain subgroups of hematological neoplasms, as well as the effect in patients receiving specific hematological treatments. Setting: The base population for this study was the population of Clalit Health Services (CHS), the largest health care organization in Israel, which insures 4.7 million people (52% of the population). Patient population: Of 1,583,251 CHS members who were vaccinated before February 28, 2021, 37,899 were eligible for the study and 32,516 were matched to unvaccinated controls ( Figure 1 ). Patients were eligible to be included in the exposed group of patients with hematological neoplasms if they fulfilled one of the following criteria: 1) Documented diagnosis of a hematological neoplasm (according to International Classification of Diseases, ninth edition (ICD9) codes or Clalit diagnostic criteria) during the 6 months preceding data extraction, with or without chemotherapy or biologic therapy; 2) Documented diagnosis of hematological neoplasm and a referral to an inpatient or outpatient clinic and/or day-care for administration of hematological treatment during the 6 months preceding data extraction; 3) Patients receiving active chemotherapy and/or biologic therapy that is used exclusively for hematologic patients (See supplements for a list of diadnoses of hematological neoplasms and treatments). The patient population with hematological neoplasms was further divided into patients receiving therapy for the hematological neoplasm or patients without hematological treatment. Patients on therapy were defined as patients presently receiving, or have recently (≤ 6 months) received, biologic therapy or chemotherapy for the hematological neoplasm. Patients without treatment were defined as patients who are followed but not treated -either treated in the past (>6 months) or never required active treatment. We used data collected between December 20, 2020 and Ethics: This study was approved by the CHS institutional review board. Overall, 32,156 individuals with a hematological neoplasm met the inclusion criteria and served as the exposed group in this study (Figure 1 ), which was matched to vaccinated controls without hematological neoplasm. 3.09, 10.81, 8.97, and 19 .31, respectively. Whether the reason for the higher relative risk in patients receiving treatment is the treatment, the more advanced disease, associated with impaired immunity, or the more frequent hospital visits, remains unclear. The trend of increased risk was similar for lymphoma and active myeloma. Vaccinated patients with hematological neoplasms treated with erythropoietin or rituximab were also shown to be at a relatively higher risk. It is likely that the more advanced anemia and hematological neoplasm requiring erythropoietin treatment, usually myelodysplastic syndromes, is responsible for the increased risk to develop covid-19 complications. Our results of decreased vaccine effectiveness in patients with hematological neoplasms correlate with preliminary reports suggesting that these patients fail to produce high titers of anti-SARS-CoV-2 antibodies. 7,14,20 Avivi et al. 11 and Van Okelen et al. 8 However, these preliminary reports demonstrating a reduced humoral immune or cellular response after mRNA vaccination among patients with hematological neoplasmsincluded a relatively small number of patients, thus still require further large-scale confirmation. In addition, it is difficult to interpret anti-covid-19 seroconversion into clinical efficacy, nor that we know the required titer of neutralizing antibodies to confer clinical immunity. 7 Finally, the role of cellular immunity in covid-19-infection is still unclear, with preliminary data suggesting abnormalities in these vulnerable patients. 22, 23 All these point to a gap in correlating impaired immune responses to vaccination in patients with hematologic neoplasms with covid-19 incidence and its complications. The current study was performed in an attempt to fill this gap of knowledge, regarding the practical effectiveness of the vaccines in this patient population. Such evidence might lead to applicable therapeutic strategies and a paradigm shift. Our study has several limitations. A retrospective study, based on electronic medical records, might be associated with difficulties in identifying the right patient subpopulations, as well as heterogeneity of the studied group (all types of lymphoma, for example). The number of individuals for some parameters, and especially the number of events, might be too small to allow for meaningful comparisons. Also, no comparison was performed in this study to unvaccinated individuals. Having serology results could be beneficial in interpretation of the data. In addition, one has to take into consideration that controls, respectively. The difference (risk ratio, RR) between the patient and control groups is even more prominent than that of figure 2. 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