Clinical characteristics of COVID-19 and the efficacy of vaccination in patients with hematologic malignancies

Patients with hematologic malignancies are at increased risk of severe forms of COVID-19 and have higher mortality, compared to patients with COVID-19 in the general population. The reasons for this include immunosuppression caused by the underlying hematologic disease and/or anticancer therapy received by these patients, advanced age, but also low levels of seroconversion after vaccination. These patients are also at a higher risk of getting infected because of frequent visits to health care facilities and high exposure to other patients. Results from published studies highlight the importance of prevention strategies in these patients, based on infection control measures and physical distancing, but also on well-timed vaccination. Risk factors which have proven to be crucial for severe forms of COVID-19 are age, the presence of comorbidities, malignancy type, progressive disease, and the type of oncologic therapy that these patients receive. Therefore, patients with hematologic malignancies represent a priority group for vaccination, which is recommended by all international professional associations. Considering that these patients are at risk of not developing an adequate immune response to the vaccine, the issues of determining the optimal time period for receiving the vaccine, the optimal dose, and the capacity of developing an immune response to the vaccine in specific groups of patients with hematologic malignancies, are questions that remain unresolved. Studies have shown that, despite the weak immune response to the vaccine, the mortality of vaccinated patients with hematologic malignancies is significantly lower than the mortality of unvaccinated patients.

This article provides a review of relevant studies which analyze the characteristics, morbidity and mortality of patients with hematologic malignancies and COVID-19 and the role of vaccination in these patients.

INTRODUCTION

Coronavirus disease (COVID-19), caused by the SARSCoV-2 virus, is primarily a respiratory disease, with possible systemic effects. First identified in Wuhan City, in December 2019, in the ensuing months the disease spread worldwide and was declared a pandemic by the World Health Organization (WHO), in March 2020 [1]. As of December 2021, there had been a total of 263 million cases and 5.22 million deaths worldwide [2]. With the growing impact of COVID-19, physicians face additional challenges when it comes to the management and treatment of patients with hematologic malignancies (HM). The incidence of COVID-19 infection in patients with HM ranges between 1 and 3.9% [3]. Patients with hematologic malignancies are considered to be at increased risk of morbidity and mortality from COVID-19, due to immunosuppression caused by the underlying disease and/or anticancer treatment that these patients receive; due to frequent visits to health care facilities and high exposure to other patients; due to advanced age; and finally, due to low levels of seroconversion after vaccination. It is of great importance to estimate the risks related to COVID-19 in hematologic patients, in order to inform and improve clinical decision-making.

MORTALITY RATE IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES AND COVID-19

The largest multicenter studies analyzing patients with hematologic malignancies and COVID-19 reported a mortality rate ranging from 31% to 50% [4],[5],[6],[7]. These results show a substantially higher mortality rate in patients with hematologic malignancies, as compared to the overall population, for which the mortality rate is estimated to be between 0.1% and 9.4% [8], and patients with all cancers, whose mortality rate is estimated at 13% [9]. The majority of patients included in these studies were hospitalized patients. For example, in the largest study analyzing patients with hematologic malignancies and COVID-19, carried out by the European Hematology Association (European Hematology Association Survey - EPICOVIDEHA), which included 3,801 HM patients with COVID-19, 73.1% of patients were hospitalized [7]. The mortality rate in this study was 31.2%. In their multicenter study, Vijenthira et al. reported a mortality rate of 34%, with 77% hospitalized patients [4]. In order to determine the mortality rate among all patients with hematologic malignancies and COVID-19, it is important for studies to collect data on an unselected population of patients.

Yigenoglu et al, from Turkey, are considered to be the closest in estimating the true population mortality risk for patients with hematologic malignancies infected with COVID-19. Based on population-based data from the countrywide Ministry of Health database (188.897 laboratory confirmed COVID-19 patients, including 740 patients with hematologic malignancies), the mortality risk for patients with HM and COVID-19 was estimated to be 13.8% [10]. The risk of death in the control population of this study was 7%. The risk estimate of 13.8%, reported by Yigenoglu et al., is also comparable to the estimated risk of death of 13% in patients with all cancers [9].

According to Vijenthira et al., the mortality rate for hospitalized patients with HM and COVID-19 was 39%, which is substantially higher than in hospitalized patients without malignancy (17.1%) [11]. A significantly lower mortality rate in patients with HM and COVID-19 was observed in the second wave of the pandemic (October – December 2020) (24%), as compared to the first wave of COVID-19 (March – May 2020) (40%) [7]. The improved clinical outcome in the second wave is most likely due to better knowledge of the clinical course of the disease, better protective measures for HM patients, a larger number of asymptomatic/mild cases detected by screening swabs, and improved treatment for COVID-19.

MORBIDITY AND MORTALITY RATES IN PATIENTS WITH SPECIFIC HEMATOLOGIC MALIGNANCIES

In their multicenter study involving 3,801 patients, Pagano et al. reported a larger number of COVID-19 cases among patients with lymphoproliferative disorders, particularly in non-Hodgkin lymphoma patients (1,084 patients, 28.5%) and multiple myeloma patients (684 patients, 18%), which had also been confirmed by previous reports [12],[13], but they also found a large number of COVID-19 cases among patients with acute myeloid leukemia (AML) (497 patients, 12.5%), which is considered a rare malignancy [7].

When it comes to mortality rates from specific hematologic malignancies, multiple studies have shown that patients with myelodysplastic syndrome (MDS) and AML have the highest mortality rates, ranging from 42% – 53%, for MDS, to 40% – 44%, for AML (Figure 1) [5],[6],[7],[14]. Vijenthira et al. observed similar results, with patients with acquired bone marrow failure syndromes (MDS, aplastic anemia) having the highest mortality rate (53%); followed by patients with acute leukemias (41%); patients with myeloproliferative neoplasms, including chronic myeloid leukemia, polycythemia vera, essential thrombocytosis, myelofibrosis (34%); patients with plasma cell dyscrasias, such as multiple myeloma, amyloidosis, smoldering myeloma, monoclonal gammopathy of undetermined significance (33%); and finally patients with lymphomas (32%) and chronic lymphocytic leukemia (31%) [4]. Pagano et al. listed a number of reasons for this occurrence. Firstly, patients with AML/MDS are often over the age of 65, and, as will be mentioned later, advanced age highly correlates with mortality. Furthermore, these patients are also severely immunocompromised, due to the underlying disease and treatments received. Also, treatment delay is often not possible in these patients, due to the urgent need for starting active treatment [7]. This aspect is particularly important, considering that lower mortality was observed in patients who delayed AML treatment [15]. Pagano et al. also observed that, in high-risk MDS patients, treatment with demethylating agents was associated with a particularly high mortality rate, which highlights the role of these agents as being potentially associated with high mortality in AML/MDS patients with COVID-19 [7].

Figure 1. Mortality rate of patients with specific hematologic malignancies according to Pagano et al.

RISK FACTORS RELATED TO SEVERITY AND INCREASED MORTALITY IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES AND COVID-19

As in the general population, increasing age and the presence of comorbidities are highly correlated with mortality in patients with hematologic malignancies and COVID-19 [4],[7],[16]. In their multicenter study, which analyzed the outcomes of over 3,000 patients, Vijenthira et al. observed that patients aged ≥ 60 had a significantly higher risk of dying (47%) than those aged is closely linked to COVID-19 mortality has as yet not been determined. Theories include the possibility that younger individuals are less prone to hyperinflammatory immune response, as compared to older people, as well as the possibility of the significance of the differences in angiotensin-converting enzyme 2 distribution, which may limit viral entry and subsequent inflammation, hypoxia, and tissue injury [17]. Progressive disease, type of malignancy, and type of antineoplastic treatment, as described earlier, have also been linked to higher mortality rates [6]. Patients receiving monoclonal antibody-based therapy had a significantly greater (HR 2.02) risk of death, as compared to those not receiving active antineoplastic treatment, while those receiving active conventional chemotherapy were 50% more likely to die from COVID-19. By contrast, there was significantly lower mortality (53%) among patients receiving hypomethylating agents [4].

Results have shown that the risk of mortality is heterogeneous and cannot be predicted solely on the basis of individual risk factors, such as patient age and the severity of the underlying disease. For example, some elderly patients, with a poor prognosis at the time of diagnosis of COVID-19, did not develop severe disease and they recovered, while 13% of patients younger than 40, with a prognosis of more than 12 months of survival, had a poor outcome [10],[12].

In conclusion, patients with hematologic malignancies and COVID-19 are at increased risk from severe disease and mortality, as compared to COVID-19 patients in the general population. Increasing age, the number of comorbidities, type of malignancy, progressive disease and the type of antineoplastic treatment received are key risk factors for disease severity. The results observed in these studies confirm the frailty of hematologic patients with COVID-19 and highlight the importance of preventing COVID-19 among patients with hematologic malignancy. Evidence-based prevention strategies such as vaccination, infection-control measures, physical distancing, and appropriate shielding advice should be emphasized for hematology patients and the units in which they receive their care.

EFFICACY OF THE SARS-COV-2 VACCINE IN PATIENTS WITH HEMATOLOGIC MALIGNANCIES

In addition to other preventive measures, vaccination against the SARS-CoV-2 virus is the main strategy in the fight against COVID-19. Vaccines aim to induce humoral and cell-mediated immunity against the receptor-binding domain of the spike protein and other viral epitopes of the SARS-CoV-2 virus, which bind to the receptor of the host. To date, there have been 4 approaches to developing SARS-CoV-2 vaccines. The first approach uses the technology of isolating the DNA or messenger RNA (mRNA) of the virus; the second approach uses envelopes of other viruses as vectors for SARS-CoV-2 protein transfer; the third approach is an inactive vaccine; while the fourth approach involves the insertion of protein subunits of the virus antigen [18]. Several vaccines are currently available, while several more from different manufacturers are expected to be approved in the future. So far, the World Health Organization (WHO) has approved 8 vaccines from different manufacturers [19]. Details about the vaccines are shown in Table 1.

Table 1. Types of vaccines against SARS-CoV-2 used in most countries of the world

For almost all vaccines, two doses administered 3 – 12 weeks apart are recommended, while, only for the Ad26.COV2.S vaccine, just one dose is required. Recently, a third dose (i.e., a second dose for the Ad26. COV2.S vaccine) has been recommended for immunocompromised patients by the Centers for Disease Control and Prevention [20].

The efficacy of the vaccine is reflected in the development of a sufficient antibody titer and the development of a T cell response that protects against COVID-19 [21],[22]. In randomized clinical studies, vaccination has been shown to be 72% – 95% effective in protecting against mild to moderate COVID-19, and as much as 86% – 100% effective in protecting against severe COVID-19, in the general population [23].

Highest efficacy is achieved after the administration of two doses of the mRNA1273 vaccine (94.1%) and the BNT162b2 (94.6%) vaccine [22],[24]. The lowest efficacy was observed after the administration of two doses of the BBIBP-CorV vaccine (78.1%) [25]. These data are based on studies in the general population; patients with malignancies were not included.

It is known that patients with hematologic malignancies represent a particularly sensitive group, due to inadequate humoral and cellular immunity, and thus represent a priority group for vaccination. Vaccination against SARS-CoV-2 in hematological patients has been recommended by several scientific associations [26],[27],[28]. Vaccination is recommended for patients with controlled hematologic malignancies (complete or partial remission of the disease), also, 3 months after bone marrow stem cell transplantation, as well as in patients who had previously been infected with the SARS-CoV-2 virus. For patients with poorly controlled hematologic malignancies or patients undergoing chemotherapy, it is necessary to make an individual assessment of the need for vaccination [23].

To date, there has been a small number of publications examining the immune response of hematological patients after vaccine administration. Preliminary results have shown that only 18% – 25% of patients with hematologic malignancies registered seroconversion after the first dose of the BNT162b2 vaccine, while seroconversion was registered in 46.7% patients after the second dose. If the cut-off value of the antibody titer that can effectively neutralize the SARS-CoV-2 virus is examined, the number of hematological patients who achieve immune response is below 2% [29],[30],[31]. The reasons why patients with hematologic malignancies may have a weak immune response are connected to the activity of the malignant disease and the applied immunochemotherapy, which especially affects the B lymphocyte population, but also to the transplantation of hematopoietic cells, which leads to the weakening of the humoral and cellular response [32].

Mallard et al. showed that the factors affecting seropositivity after the administration of the second dose of the BNT162b2 vaccine in hematological patients were the male sex, anti-B cell-targeted treatment in the previous 12 months, and a low CD19 + B cell count. However, a small number of patients without seroconversion had an adequate T cell response to SARS-CoV-2, indicating that, in patients without an adequate humoral response, some protection against the COVID-19 infection may be achieved [31].

A study evaluating the immune response to the BBIBP-CorV vaccine, in patients with malignancy, was recently published, with patients with hematologic malignancies having the worst seroconversion score (61.9%) [33].

A study investigating the mortality of hematological patients after vaccination included 113 patients vaccinated with one or two doses of the vaccine at the time of the study [34]. The majority of patients were men (61.1%) and patients older than 50 years (85.5%). More than 80% of patients were diagnosed with lymphoproliferative disease. Seventy-eight patients (68.1%) were on active treatment or less than three months had passed since their last chemotherapy at the time of diagnosis of the COVID-19 infection. Most of the patients received the mRNA vaccine (BNT162b2, n = 79 (69.9%), mRNA1273, n = 20 (17.7%)), while the remaining 14 (12.4%) received the vector vaccine (ChAdOx1 nCoV-19, n = 10) or the inactivated vaccine (CoronaVac, n = 4). The median time between the latest dose of the vaccine and the diagnosis of COVID-19 infection was 64 days. Seroconversion was analyzed in 40 patients vaccinated with two doses of the vaccine. Seroconversion was achieved in only 13 patients (optimal titer value in 8 patients and weak immune response in 5 patients), while 27 patients did not achieve an immune response. The mortality in vaccinated patients in this study was 12.4%, which is significantly lower than the mortality of unvaccinated hematological patients [34]. Seroconversion in various hematologic malignancies is shown in Figure 2 [35],[36],[37],[38].

Figure 2. Seroconversion in various hematologic malignancies

SARS-COV-2 VACCINE EFFICACY IN SPECIAL POPULATIONS WITH HEMATOLOGIC MALIGNANCIES

Chronic lymphocytic leukemia (CLL)

Herishanu et al. examined seroconversion after the administration of the second dose of the BNT162b2 vaccine in patients with CLL. The study included 167 patients; the median age was 71 years and 67.1% of the patients were men. Seroconversion was registered in only 66 patients (39.5%). The variables associated with the generation of an immune response were the following: the female sex, patients younger than 65 years, early-stage disease (Binet A), patients not on active therapy and/or not receiving anti-CD20 antibodies for 12 months, normal total immunoglobulin levels [39].

Patients actively treated with Bruton’s tyrosine kinase inhibitor and anti-CD20 antibodies had a significantly poorer immune response, after receiving two doses of an mRNA vaccine [40]. It is believed that it takes 9 – 12 months, following the administration of anti-CD20 antibodies, for the reconstitution of B lymphocytes [41].

In patients on active BCL-2 inhibitor therapy, seroconversion did not occur after vaccination in one study [42], and in another study, only two patients out of five had some serological response to vaccination [39].

Multiple myeloma (MM)

Terpos et al. analyzed the concentration of neutralizing antibodies to SARS-CoV-2 on day 22 after the first dose of the BNT162b2 vaccine, in 48 patients (median age 83 years) with multiple myeloma, as compared to controls. Of the 48 patients with MM, 35 patients were on chemotherapy, 4 patients were in remission, and 9 patients were diagnosed with smoldering myeloma. Patients with MM had a significantly lower titer of neutralizing antibodies, compared to the control group (20.6% vs. 32.5%; p < 0.01). A total of 55% of subjects in the control group had a titer above 30%, while only one quarter of the patients with MM achieved this value. Patients who achieved the appropriate antibody titer were in remission of the disease and had a total value of immunoglobulins in the reference range, while the 8 patients in whom seroconversion was not registered had immunoparesis [30]. Another study, by the same authors, compared the titer values of neutralizing antibodies on the 50th day of the BNT162b2 vaccine and 7 weeks after the administration of the first dose of the ChAdOx1 nCoV-19 vaccine, in patients with plasma cell malignancy, as compared to the control group. It was shown that patients with MM had significantly lower titers, as compared to the control group, while the prognostic parameters that proved most significant in case of inadequate immune response were lymphopenia, use of anti-CD38 agents and the male sex [43]. Van Oekelen et al. demonstrated that the factors negatively affecting seroconversion in patients with MM were the following: grade 3 lymphopenia, application of anti-CD38 therapy, and the application of more than 3 treatment lines in patients [38].

Myeloproliferative diseases

A study examining the immune response in myeloproliferative diseases included 42 patients (10 patients diagnosed with myelofibrosis, 15 patients diagnosed with polycythemia vera (PV), and 17 patients diagnosed with essential thrombocythemia (ET)). All patients were on active treatment – 29 patients were on hydroxycarbamide, 8 patients were on ruxolitinib, three on anagrelide, while two patients were on interferon-alpha therapy. Patients with myelofibrosis had a significantly lower seroconversion rate, as compared with patients with PV and ET (60% vs. 93.8%) [44]. It is believed that one of the reasons why patients with myelofibrosis have a poorer immune response to vaccines is the use of ruxolitinib [37],[42].

Non-Hodgkin Lymphoma (NHL)

A study evaluating the immune response after the second dose of an mRNA vaccine in patients with NHL included 147 patients. Of these patients, 47% had an aggressive type of lymphoma, while the rest were diagnosed with indolent lymphoma. A total of 37% of patients were on active treatment with the anti-CD20 antibody regimen (rituximab or obinutuzumab). In 44% of patients, more than 6 months had passed after anti-CD20 antibody administration, and 19% of patients did not receive therapy. The worst immune response was registered in patients on active treatment (7.7% of patients achieved seroconversion), while the best response was registered in patients who had not previously been treated (89% of patients achieved seroconversion). A multivariate analysis showed that lymphopenia and the use of anti-CD20 antibodies were associated with a poorer serological response [45].

CONCLUSION

Interpretation of immune response to vaccination in patients with hematologic malignancies is complex. Age, type of vaccine, underlying disease, applied therapy, and the time elapsed from the last therapy to vaccination must be taken into account.

In summary, mRNA vaccines are recommended in these patients because of the safety profile, but immunosuppression and reduced vaccine immunogenicity must be considered. On the one hand, these patients are at high risk of developing severe forms of COVID-19, but, on the other, they are also at risk of not developing an adequate immune response to the vaccine, due to the already mentioned reasons of immunosuppression. Therefore, the following remains unknown: what is the optimal time for vaccine administration; which dose should be applied; and what is the capacity of developing an immune response to vaccines in certain groups of patients with hematologic malignancy. A small number of studies have shown that, despite a weaker immune response to the vaccine, the mortality of vaccinated patients with hematologic malignancies is significantly lower, as compared to unvaccinated patients. The latest data from the register of the Working Group on Infectious Diseases of the European Hematological Association indicate a significant reduction in mortality in patients with hematologic malignancies after vaccination. Mortality in COVID-19 patients with hematologic malignancies decreased from 31%, in the pre-vaccination period, to 12.4%, in the post-vaccination period. However, it is necessary to conduct clinical studies on the effectiveness of other types of vaccines, but also to administer a third dose to these patients, in order to improve vaccination recommendations in these patients and improve immune response.