Risk of Breakthrough COVID-19 Infection May Be High in Population With Hematologic Malignancies


Patients with hematologic malignancies may be at a higher risk for breakthrough infections following full COVID-19 vaccination.

Patients with hematologic cancer are at risk for not producing antibodies following 2 doses of the COVID-19 vaccine and could be at a high risk for breakthrough infections, according to findings from a prospective cohort registry study (NCT04794387) published in Cancer Cell.1

Estimates from the Leukemia & Lymphoma Society (LLS) indicate that approximately 250,000 patients with hematologic malignancies within the United States will not have detectable antibodies following full vaccination with the COVID-19 vaccine. Additionally, findings from the analysis indicated that 75% of patients with hematologic malignancies produced antibodies against COVID-19 following full vaccination. Notably, patients with common B-cell malignancies had the lowest rate of seropositivity (range, 44%-79%). Overall, the seroconversion rate in patients with hematologic malignancies ranged from 46% to 85% following inoculation with both vaccines. Among a cohort of age- and sex-matched immunocompetent controls, the serological response was 100%.

“Although some patients with hematologic malignancies will not mount a full antibody response compared to healthy individuals, vaccines are safe and offer protection to the majority of blood cancer patients,” Gwen Nichols, chief medical officer at the LLS, said in a press release.2 “But not everyone will be protected, and [patients with] blood cancer are at increased risk of serious illness and death from COVID-19. We encourage blood cancer patients to take every measure to protect themselves from COVID-19 by getting vaccinated and continuing to take preventative precautions. This includes wearing a mask, social distancing, and avoiding crowds and poorly ventilated indoor spaces.”

Investigators pulled samples for the study from March 2021 to May 5, 2021. Fourteen-day antibody response was evaluated in 1495 patients who had received the second dose of the vaccine. The median patient age was 68 years (range, 16-110). In total, 652 patients received mRNA-1246 and 793 received BNT162b2 vaccines.

Additional findings from the study indicated that seronegativity was observed in nearly all patients with non-Hodgkin lymphoma, while 64 patients with Hodgkin lymphoma were seropositive. Seronegativity was also noted in 56% of patients with mantle cell lymphoma (MCL), 38% of those with marginal zone lymphoma, 26% of those with Waldenström macroglobulinemia, 22% of those with follicular lymphoma, and 21% of those with diffuse large B-cell lymphoma. Investigators reported that seronegativity was observed in those who had received no therapy within the past 2 years and those who had previously been treated with a number of B-cell–suppressive therapies, including anti-CD20 monoclonal antibodies, BTK inhibitors, and CD19 CAR T-cell therapy.

Moreover, of the 36% of patients with chronic lymphocytic leukemia (CLL) who did not generate spike antibodies, 66 of 235 patients reportedly did not receive therapy within the last 2 years. Investigators believe that disease may directly impair B-cell function. Additionally, high seronegative rates were noted among patients who were receiving treatment with BTK inhibitors, anti-CD20 monoclonal antibodies, or those who received a combination of the aforementioned therapies plus venetoclax (Venclexta).

Conversely, patients with acute myeloid leukemia, acute lymphocytic leukemia, and CLL had seronegativity rates of 9%, 12%, and 2.9%, respectively, as well as 5.3% of those with multiple myeloma. However, no patients with smoldering myeloma were reported as being seronegative.

Investigators assessed differences in response between both COVID-19 vaccines within a population of seronegative malignancies, including MCL, follicular lymphoma, and Waldenström macroglobulinemia (n = 845). The unadjusted logistic regression analysis found patients were more likely to mount an immune response to the mRNA-1273 vaccine vs the BNT162b2 vaccine (OR, 1.50; 95% CI, 1.06-2.06; P = .021; OR, 1.73; 95% CI, 1.12-2.42; P = .001). This was further supported by the regression model with adjustments for age, disease type, gender, vaccine, and cancer group utilizing 2 different models (OR, 1.48; CI, 1.06-2.06; P = 0.021; OR, 1.73; CI, 1.24-2.42; P = 0.001).

“Many patients with hematologic malignancies are at risk of not producing antibodies after two doses of the mRNA SARS-CoV-2 vaccines. Differences in antibody responses between the two mRNA vaccine series are detected in patient populations that have a high seronegative rate. Providers should be aware that a substantial subset of vaccinated blood cancer patients may be at high risk of breakthrough COVID-19 infections. Further studies are needed to assess the status of the immune system in seronegative patients and develop options for protecting this vulnerable population,” the investigators concluded.


  1. Greenberger LM, Saltzman LA, Senefeld JW, et al. Antibody response to SARS-CoV-2 vaccines in patients with hematologic malignancies. Cancer Cell. 2021. doi:10.1016/j.ccell.2021.07.012.
  2. Study from The Leukemia & Lymphoma Society shows COVID-19 vaccine is safe but 25% of blood cancer patients do not produce detectable antibodies. News release. July 22, 2021. Accessed August 25, 2021. https://bit.ly/3zpa9fm
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