How to Provide the Needed Protection from COVID-19 to Patients with Hematologic Malignancies

Severe COVID-19 and death from COVID-19 have become preventable conditions in areas of the world with sufficient supply of highly active COVID-19 vaccines. However, this is not true for everyone, as many patients with hematologic malignancies have impaired responses to the COVID-19 vaccinations and require extra attention to protect them from COVID-19 (1, 2). These patients have an increased risk of complications and death from COVID-19 infection due to both their diagnosis frequently altering the function of B and T lymphocytes important for protection from the virus, and also by frequently receiving therapies that further damage lymphocytes, such as chemotherapy, corticosteroids, anti-CD20 antibodies, anti-CD38 antibodies, BTK inhibitors, stem cell transplantation, and chimeric antigen receptor (CAR) T-cell therapies. These factors have resulted in patients with hematologic malignancies being particularly vulnerable to COVID-19, making it imperative to provide them as much additional protection as possible once the COVID-19 vaccines first became available (3).

We reviewed the literature to gather information on the seroconversion rates in patients with hematologic malignancies after receiving a COVID-19 vaccine. We selected 18 series that provided anti–SARS-CoV-2 spike protein IgG seroconversion rates after full COVID-19 vaccination detailed by hematologic malignancy diagnosis, with at least 20 patients per group (Fig. 1; Supplementary Table S1; refs. 2, 4–19). The literature review also included six additional series that are not included in Fig. 1: three due to sampling of serum antibodies before achieving full vaccination as evidenced by lower seroconversions in the healthy control group compared with the rest of the series (20, 21) and three that did not provide breakdown of the data according to different histologic diagnoses (22, 23). There are a lot of variables that were not uniform in these series. For example, the type of COVID-19 vaccine and the timing of antibody analysis related to receiving the vaccine administration varied, with most analyzing samples obtained at 1 or 3 months after the full vaccination. In series that reported samples obtained at different time points, we report on the latest one. Important variables related to the hematologic malignancy, including being on active therapy, the type of therapy, being on watchful waiting before therapy, or having completed therapy, varied among the series and diagnoses. As a comparison, we provide the rates of seroconversion of healthy subjects from the series that included concomitant testing, which in some cases were age-matched controls (4, 6, 10, 12, 13, 15, 17, 19, 24). The combined healthy subject group adds to 729 individuals, with seroconversion rates between 98% and 100% (Fig. 1; Supplementary Table S1), suggesting that these series adequately tested for anti–SARS-CoV-2 spike protein seroconversion at the time when healthy subjects would have responded to the vaccine.

Despite the important caveats resulting from the variability in these series, there are general trends in the data. Patients with chronic lymphocytic leukemia (CLL) have a particularly low rate of seroconversion after COVID-19 vaccination, ranging from 39% to 71% in the reported series (2, 5–9). A similarly low rate of seroconversion is evident in series reporting on patients with non-Hodgkin lymphoma (NHL), ranging from 42% to 75% (2, 4, 8, 13, 14, 16–19, 24). One series reported on patients with Waldenstrom macroglobulinemia (WM) with a 74% seroconversion rate (2). These results of low seropositivity in some series while higher in others are likely to be related to the treatments that the patients were receiving at the time of analysis and in particular the time since receiving therapy for the hematologic malignancy (13, 25). For example, patients with NHL recently treated with anti-CD20 were less likely to develop serologic response to a COVID-19 vaccine, with the rate of seropositivity in one series being 3% in patients vaccinated within 45 days from the last anti-CD20 administration, increasing to 80% in patients vaccinated over 1 year after stopping this therapy (18). Patients with NHL and CLL on BTK inhibitors also have a lower seropositivity after COVID-19 vaccination—in one series from 40% for patients on this targeted therapy to 73% for patients with the same diagnosis but being monitored for their disease without active therapy at the time of COVID-19 vaccination (23).

Patients with multiple myeloma were reported to have a seroconversion rate between 65% and 95% (2, 4, 8, 10, 12–15). Variability in these series may be related to patient's age, level of hypogammaglobulinemia, number of lines of therapy for myeloma, and in particular being on treatment with an anti-CD38 antibody, anti-BCMA therapy, or corticosteroid therapy, all of which were significant factors resulting in lower seroconversion rates in the different series (8, 10, 12, 13, 15). Rates of COVID-19 vaccination response were close to healthy subjects in patients with acute leukemia, chronic myelogenous leukemia (CML), and myelodysplastic syndromes (MDS; refs. 2, 4, 10). This may reflect the enrollment being skewed to patients who had been previously successfully treated for acute leukemia and low enrollment of patients on active chemotherapy, and the use of non–B-cell toxic therapies for the treatment of patients with CML, MDS, and acute myeloid leukemia.

Experience with similar low seroconversion rates in patients with hematologic malignancies when receiving vaccinations for other viral infections, in particular when on certain therapies (26), has led to the testing of higher doses of the vaccine, different formulations, and repeated rounds of immunization (27, 28). During the COVID-19 pandemic, some patients without seroconversion after receiving the full initial vaccination have received subsequent immunizations (sometimes referred to as boosters, but may not be the adequate term for persons who did not respond to the first set of vaccination). Initial data from a prospective registry from The Leukemia & Lymphoma Society provide evidence that a third vaccine administration resulted in seroconversion in 21 of 38 patients (55%) who had not seroconverted with the initial round of immunization (29). In this report, most patients who were receiving anti-CD20 therapy or who had completed this therapy within the past 6 months, as well as patients on BTK inhibitors, failed to seroconvert even with the third COVID-19 vaccine administration. In another report, an additional dose of BNT162b2 also increased the anti-spike antibody levels above the predicted protective threshold in 48% of recipients of allogeneic hematopoietic stem cell transplants (30). Overall, even with a third vaccination, approximately half of the patients with hematologic malignancies who did not have seroconversion continue to have no antibody response to the COVID-19 vaccine.

Not all COVID-19 vaccine antibody responses are neutralizing antibodies to the SARS-CoV-2. virus. The quantitation of anti–SARS-CoV-2 spike protein IgG antibodies may not correctly measure protection to the virus and in particular to the Delta variant, which is the current prevalent variant in the United States. Data from patients with hematologic malignancies who had undergone CAR T-cell therapy or stem cell transplantation in the past demonstrated that higher spike antibody titers were associated with higher neutralization activity to the SARS-CoV-2 virus, with the 3-month levels of virus-neutralizing antibodies being lower than to the spike protein (77% compared with 87%; ref. 4). Similarly, in another series, levels of neutralizing antibodies to the SARS-CoV-2 virus at 3 months from COVID-19 vaccination were only 26% in patients with hematologic malignancies compared with 93% in concurrent healthy donors, and both were lower than the anti–SARS-CoV-2 spike protein quantitation, which was 89% overall for patients with hematologic malignancies (pooling data from patients with different leukemias, lymphomas, and myeloma) and 100% for the concurrent healthy controls (13). Neutralizing antibody levels were lowest for patients with CLL, frequently those on therapy with anti-CD20 or BTK inhibitors, and highest in patients with multiple myeloma, the majority of whom were on lenalidomide maintenance therapy, which parallels the levels of anti-spike antibody levels but with lower frequency (13). Therefore, the detection of anti–SARS-CoV-2 spike seroconversion rates overestimates the presence of neutralizing antibodies to the virus, raising concerns that patients with hematologic malignancies are at higher risk than what the commercial antibody tests suggest.

COVID-19 vaccination can provide benefit by inducing both antibody and T-cell responses to the SARS-CoV-2 virus. Because antibody responses are easier to measure with multiple commercial assays, it is logical that the field has focused on reporting serologic responses to the vaccination. Reliably detecting T-cell responses after COVID-19 vaccination is done in research settings, with a lot less information on the frequency of T-cell responses and their clinical significance. Patients with hematologic malignancies who survived the SARS-CoV-2 infection despite having low antibody levels were shown to have robust CD8⁺ cytotoxic T-cell responses to the virus (31). There were still lower levels of CD4⁺ T helper responses in these patients, which raises concerns about the ability of patients with hematologic malignancies to mount an adequate memory response to the virus after infection or vaccination. Studies in mouse models of SARS-CoV-2 demonstrate that both humoral and cellular adaptive immunity contribute to viral clearance in the setting of primary infection. Furthermore, convalescent mice or mice that receive mRNA vaccination are protected from both homologous infection and infection with a SARS-CoV-2 variant. In these mouse models, protection was largely mediated by antibody response and not T-cell immunity (32). Studies of antibody and T-cell responses to COVID-19 vaccination in patients with hematologic malignancies provide evidence that low antibody and T-cell responses are frequently associated (8), but in some cases, patients with low anti–SARS-CoV-2 spike protein antibody response had high T-cell responses to SARS-CoV-2 T-cell epitopes. Therefore, despite the known importance of T-cell responses to the virus, it seems correct to continue to analyze the serologic response to COVID-19 vaccination following anti–SARS-CoV-2 spike IgG antibodies as a main measure of protective immunity to the virus. However, it is acknowledged that further research is needed for the development of robust assays for T-cell responses to the virus that can be applied to larger series of patients and to define which levels of anti-spike antibodies convey protection to COVID-19.

The combined information makes it clear that patients with hematologic malignancies, in particular if they are on therapy with anti-CD20, anti-CD38, anti-BCMA, BTK inhibitors, JAK inhibitors, BCL2 inhibitors, chemotherapy, or corticosteroids, may not achieve sufficient levels of neutralizing antibodies to SARS-CoV-2 even after repeated administration of COVID-19 vaccines (2, 8, 13, 29). Therefore, it is imperative that these patients are provided additional means of protection to the virus. After reviewing the evidence, we have the following recommendations to maximize the protection of vulnerable patients with hematologic malignancies during the current phase of the COVID-19 pandemic.

One set of recommendations is focused on patients with hematologic malignancies. Despite the risks during the COVID-19 pandemic and the detrimental effects of many treatments on protection to the virus, patients with hematologic malignancies should receive the treatments for their condition. In some cases, the start of the treatment could be delayed to allow for initial or booster COVID-19 vaccination. To deliver patients' treatments safely, health care providers should offer patients COVID-19 testing before starting on B-cell–depleting therapies and surveillance COVID-19 testing during the therapy. Despite not being recommended for the general population, checking anti–SARS-CoV-2 spike protein antibody levels after COVID-19 vaccination would be warranted in patients with hematologic malignancies to discern patients who had or did not have seroconversion with the vaccine. This recommendation would require further research to determine which levels of anti-spike proteins would be considered to be protective to the COVID-19 disease. Research is also urgently needed to test different COVID-19 vaccine formulations, doses, repeated rounds of immunization, and heterologous boosting in patients with hematologic malignancies without seroconversion after standard COVID-19 vaccination. Passive immunity prophylaxis, with the administration of anti–COVID-19 monoclonal antibodies, convalescent serum, or serum from vaccinated persons, could be a way to protect immunocompromised patients who cannot avoid exposure. Early experience using convalescent plasma in patients with hematologic malignancies with COVID-19 suggests that it decreases the mortality rates of patients with the most severe disease (33). Therefore, if patients with hematologic malignancies are infected with SARS-CoV-2, they should be promptly offered treatment with monoclonal antibodies and convalescent plasma and with antiviral therapies.

Another set of recommendations pertains to the people around the patients with hematologic malignancies, in particular, their physicians, nurses, caretakers, and close house contacts. Health care systems that take care of patients with hematologic malignancies should have a mandate for 100% vaccination of all staff and should post the information publicly so that patients can be well-informed on the immunization status of their caretakers. It is hard to think that health care workers who are not vaccinated by choice could be taking care of patients whom they are voluntarily putting at risk of severe complications and death from COVID-19. With the increasing evidence that protective immunity to COVID-19 decreases over time after vaccination, there should be priority administration of additional doses for caregivers and health care workers taking care of patients with hematologic malignancies. Patients with hematologic malignancies, their caregivers, and health care workers should continue to use face masks, socially distance, and avoid close contact with unvaccinated individuals; the only unvaccinated people in the society right now should be children under 12 years old for whom the safety of COVID-19 vaccines has not yet been established. Household contacts should be offered frequent COVID-19 testing, in particular if there are children in the house (Fig. 2).

The evidence of low seroconversion rates, correlated with low virus-neutralizing antibodies and suboptimal antiviral T-cell responses in patients with hematologic malignancies, raises questions about public policy. Even if high levels of herd immunity are achieved in society, it would still leave behind a population of vulnerable patients with immunosuppression where there could be evolution of the virus into new variants with increased virulence that could result in second waves of infections in the population that was immune to the prior SARS-CoV-2 variants (34). The emergence of SARS-CoV-2 variants has already been observed in COVID-19–infected patients with hematologic malignancies, especially in those patients with long-term infections (34). An argument should be made to invest in surveillance programs in patients with hematologic malignancies receiving B- or T-cell–directed therapies, with frequent testing of the patients and caregivers.

In conclusion, patients with certain hematologic malignancies are particularly vulnerable during the COVID-19 pandemic, and require additional measures to protect them from this and other viral infections to allow them to proceed with the treatment of their malignancies.

A. Ribas reports personal fees from 4C Biomed, Appia, Apricity, Arcus, Highlight, Compugen, ImaginAb, ImmuneSensor, MapKure, Merus, Rgenix, Lutris, PACT Pharma, Pluto, Synthekine, Tango, Advaxis, CytomX, RAPT, Isoplexis, Kite/Gilead, Amgen, Apexigen, AstraZeneca, Merck, Novartis, Sanofi, and Vedanta, and grants from Agilent and Bristol Myers Squibb outside the submitted work. M.V. Dhodapkar reports other support from Janssen, Roche/Genentech, and Lava Therapeutics outside the submitted work. K.M. Campbell reports personal fees from Tango Therapeutics, PACT Pharma, and personal fees and other support from Geneoscopy LLC outside the submitted work. F.E. Davies reports personal fees from Celgene, Bristol Myers Squibb, Janssen, Takeda, Sanofi, GlaxoSmithKline, and Oncopeptide outside the submitted work. No disclosures were reported by the other authors.

This article reflects discussions that originated in the AACR Hematologic Malignancies Task Force, from which this subgroup of coauthors were self-selected to define the scope of the manuscript, invite additional authors, and contribute to generation of first and subsequent drafts, as well as the final version. The authors thank R. Tamari and D.J. Chung for sharing the data from their series before publication. A. Ribas is supported in part by funds from NCI R35 CA197633, the Parker Institute for Cancer Immunotherapy, and the Ressler Family Fund. M.V. Dhodapkar is supported in part by funds from NCI R35 CA197603 and The Leukemia & Lymphoma Society.