Patients with hematological malignancies, such as leukemias, myelodysplastic syndromes, myeloproliferative neoplasms, lymphomas, and multiple myeloma, have an increased risk of infections as a result of disease-related immune dysregulation [19]. In addition, many commonly used treatments may have an immunosuppressive effect, adding to the risk of infection [19]. For example, treatment with B-cell-targeting therapies, resulting in B-cell depletion and/or disruption of the B-cell receptor signaling pathway, may adversely affect the production of antibodies in response to COVID-19 vaccination [20]. B-cell recovery may also be slow in these patients; for example, in lymphoma patients, recovery was shown to remain below normal controls one year after administration of rituximab [21]. In addition, patients undergoing HSCT are at particularly high risk of immunosuppression due to impairment in innate and adaptive immunity [22]. In the case of allogeneic HSCT, patients generally need ongoing immune suppressive therapy to treat and prevent graft-versus-host disease [22]. Although data are limited, preliminary studies suggest patients with hematological malignancies who are receiving CD19-directed CAR T-cell therapy also have a reduced response to COVID-19 vaccines [23].

Seroconversion rates following COVID-19 vaccination have shown to be reduced in patients with hematologic malignancies. An Israeli study in 427 people showed that a lower proportion of those with hematologic malignancies were seropositive after COVID-19 vaccination than in an immunocompetent comparator group (75% vs. 99%; p < 0.001) [24]. Moreover, patients treated for hematologic malignancies (n = 164) had significantly less seropositive responses (e.g., immunochemotherapy (29%); anti-CD20 antibodies (0%); or BCL2 (25%), BTK (40%), or JAK2 (42%) inhibitors; p < 0.001) [24]. In addition, the prospective CAPTURE (COVID-19 antiviral response in a pan-tumor immune monitoring) study showed seroconversion rates following COVID-19 vaccination were lower in 21 patients with haematological malignancies (59%) than in those with solid tumours (85%) [25]. Overall, 81% had received chemotherapy, 48% had received targeted therapy, and 29% had received anti-CD20 therapies in the 12 weeks prior to vaccination. In addition, a study of 121 patients with non-Hodgkin’s lymphoma, including chronic lymphocytic leukemia (CLL), showed an 85-fold reduction in mean anti-SARS-CoV-2 spike immunoglobulin G–binding titers in these patients compared with healthy controls, with seroconversion occurring in only 67% of patients [26]. Overall, 47% of patients had received anti-CD20-directed therapy within one year prior to COVID-19 vaccination. Finally, a systematic review of five studies examining the response to COVID-19 vaccination in a total of 70 patients receiving CAR T-cell therapy, showed a low cumulative humoral response rate of 31% [23].

A number of studies have shown patients with hematologic malignancies are at increased risk of severe outcomes following infection with COVID-19. A study by Mittelman et al. showed that among 32,516 vaccinated patients with hematologic malignancies, the relative risk for COVID-19 infection (1.60; 95% CI, 1.12–2.37) and hospitalization (3.13; 95% CI, 1.68–7.08) was significantly greater, compared with matched controls [27]. Overall, 5107 (15.9%) patients were receiving active treatment for a hematological malignancy. In addition, a study examined data from the VISION Network, which included 20,101 immunocompromised patients aged ≥ 18 years with COVID-19-like illness discharged from 187 hospitals across nine states in the United States [4]. Results showed that in patients with hematological malignancies, vaccine effectiveness against hospitalization was around 74% (95% CI: 62%, 83%), versus 90% (95% CI: 89%, 91%) in immunocompetent patients who had received two doses of an mRNA vaccine two weeks prior to hospitalization. In addition, a study in 2767 patients with non-Hodgkin lymphoma showed those receiving active treatment given within 30 days of COVID-19 diagnosis (n = 195) had more severe outcomes than those not receiving treatment (OR 1.4; 95% CI 1.0, 2.0) [28]. Two large multicenter retrospective studies have also reported high rates of severe COVID-19 disease and mortality in both untreated as well as treated patients with CLL [29,30]. In one of the studies [26], survival rates were not associated with active treatment, whereas in the second study [27], significantly more patients (91/151, 60.3%) in the severe COVID-19 group were off treatment within the last year or had never received treatment for CLL compared with less severe cases (15/39, 38.5%) (p < 0.05). Finally, The Center for International Blood and Marrow Transplant Research (CIBMTR) found that severe COVID-19 disease requiring mechanical ventilation occurred in 45/318 (14%) of HSCT recipients and thirty-day survival was around 67% [22]. Given the increased risk of severe COVID-19 outcomes in patients with hematologic malignancies, broader protection is needed beyond vaccination.