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Largest Study to Date Demonstrates Most Blood Cancer Patients Benefit From a Third Primary Dose of mRNA COVID-19 Vaccine

Study supports the Centers for Disease Control and Prevention (CDC) recommendation for immunocompromised adults  

Rye Brook, N.Y., December 13, 2021 – While one in four blood cancer patients do not produce detectable antibodies after their first two doses of the COVID-19 vaccine, 43% of them will produce antibodies after a third dose, according to new data from The Leukemia & Lymphoma Society (LLS). For some patients with blood cancer, the third dose led to antibody levels seen in healthy adults. This was confirmed by measuring levels of detectable antibodies to the spike protein in SARS-CoV-2 before and after the third dose of the mRNA COVID-19 vaccines. Results from the study, the largest of its kind to date, also demonstrate that blood cancer patients who had at least some antibodies after the first two doses are likely to produce large amounts after the third vaccination. 

“Our data shows a clear benefit of giving blood cancer patients three primary vaccine doses, but there is still a large portion of patients who will remain at risk even with the additional dose,” says Lee Greenberger, Ph.D., LLS chief scientific officer. In this study, about 20% (139/699) of blood cancer patients still had no measurable COVID-19 antibodies after the third dose. The results, which were reported Saturday at the American Society of Hematology (ASH) Annual Meeting in Atlanta, are from the largest pool of blood cancer patients reported to date.

Vaccines stimulate production of anti-spike antibodies, which can block entry of the COVID-19 virus into human cells. Having these antibodies appears to offer protection from getting sick or having severe disease. However, for many blood cancer patients, their antibody levels may not be as strong as those in fully vaccinated, healthy adults – making them more susceptible to a COVID-19 breakthrough infection.

The data reported by LLS are from the LLS National Patient Registry, which has been tracking COVID-19 vaccine response among more than 11,000 blood cancer patients since February 2021. LLS previously reported findings from first and second dose vaccination, as well as a smaller study with third vaccination in near real-time, to help blood cancer patients and their oncologists make informed decisions about vaccines and other measures they can take to avoid infection. 

The larger pool of data in the current study, from 699 patients, provides more robust information about how the third COVID-19 mRNA dose works in patients with all types of blood cancer (Figure 1). The study does not include information about response to Johnson & Johnson vaccines.

The study was weighted to include more patients with blood cancers that deplete the immune system’s B-cells, which are responsible for making antibodies. Patients with these types of cancer, including chronic lymphocytic leukemia, diffuse large B-cell lymphomas, follicular lymphomas, marginal zone lymphomas, mantle cell lymphomas, and Waldenstrom’s Macroglobulinemia, are less likely to develop antibodies. In patients that failed to make antibodies to the initial vaccination, the antibody response after the third vaccination ranged from 0%-48%.

In contrast, the remaining participants had myeloid forms of leukemia, Hodgkin’s lymphoma and multiple myeloma, all of which tend to respond more favorably to initial vaccinations as well as the third vaccination. Detectable antibody rates in these patients ranged from 75% to 100%. 

“These results are consistent with the CDC’s recommendation for immunocompromised adults, demonstrating the value of a third mRNA vaccine dose for blood cancer patients as part of the primary vaccination series, with a booster dose six months later,” says Gwen Nichols, M.D., LLS chief medical officer. “But blood cancer patients also need to remember that they are among the nearly three million Americans with weakened immune systems who may not get optimal vaccine protection. We encourage blood cancer patients to continue to layer on additional precautions, like mask wearing and social distancing.”

Some cancer treatments blunt vaccine response, but one might actually boost it

B-cell depleting treatments, including Bruton tyrosine kinase (BTK) inhibitors and anti-CD20 antibody treatments, are essential for treating certain types of cancer but they blunt immune response either while patients are on therapy, or in the case of anti-CD20 antibody, even many months after the therapy is completed. Among chronic lymphocytic leukemia patients (320 in this study), who are commonly treated with these therapies, 65% who had no therapy for the previous two years produced antibodies to the third vaccine. However, among those who received BTK inhibitors and anti-CD20 antibody treatments within the last two years, just 23% to 41% produced third-dose antibodies.

In contrast, patients who receive antibody infusions as part of their normal blood cancer therapy may get an unexpected benefit. Intravenous immunoglobulin, or IVIG, is often given to patients on BTK inhibitors or anti-CD20 antibodies, or who have had certain CAR T-cell treatments, to replace antibodies not produced by their own B-cells. The level of COVID anti-spike antibodies in IVIG, which is derived from blood plasma donors, has increased dramatically as more of the U.S. population has either had COVID-19 or been vaccinated.

In this study, some of the patient who were treated with IVIG infusion had unusually high levels of antibodies after a third vaccine dose, including some who were made no detectable antibodies after the first two doses. While the researchers cannot rule out that the large increase in antibodies was due solely to the third vaccine, IVIG infusions are likely to play a role.

Blood cancer patients should be proactive in seeking COVID-19 vaccination and care

Blood cancer patients should follow the CDC vaccination recommendations. But because they may not get optimal vaccine protection, they should continue to wear masks, social distance, avoid poorly ventilated and crowded spaces, and encourage those around them to get vaccinated to avoid infection.

Blood cancer patients should also alert their oncologist immediately if they come in contact with someone who has COVID-19 or if they test positive for the virus. Antibody therapy can help reduce the risk of getting sick or having serious complications from COVID-19, but treatment must start as soon after exposure as possible. In addition, FDA this week authorized a new monoclonal antibody cocktail that can be used to prevent COVID-19 in in immunocompromised patients who do not mount an adequate antibody response to vaccination.

While a lack of measurable antibodies likely means these patients have little or no protection from vaccines, vaccines can stimulate the immune system in other ways. Further studies are underway by LLS and others to evaluate other ways the immune system may respond to vaccination, such as by activating T-cells.


Figure 1

Antibody Response

For more information about the LLS COVID-19 Response Program and its supporters, visit this link:


About the LLS National Patient Registry 

The LLS National Patient Registry, a project of the Michael J. Garil Patient Data Collective, was created to honor the memory of Michael Garil, who was diagnosed with acute lymphoblastic leukemia in 1974 at the age of 7. His parents, Ethel and Bernard Garil, have generously supported the creation of the LLS National Patient Registry to gather vital information from a large pool of people affected by blood cancers. The current trial was conducted under IRB review with electronic consent of patients. Data were de-identified before being analyzed for vaccine results, and all patient records are held in strict confidence.

About this study

The current study includes 699 patients enrolled in the LLS National Patient Registry who had a third COVID-19 vaccination between June and September 2021. Seventy-five percent of the patients in the study had forms of cancer known to blunt immune response to COVID-19 vaccines and to COVID-19 infection. 

The median patient age was 68 years; 55% were female and 95% identified as white. In accordance with CDC recommendations, most patients received the same vaccine (Pfizer-BioNTech or Moderna) for their third dose as they did for the first two. The study does not include information about response to the Johnson & Johnson vaccine because nearly all of the patients in the registry received Moderna or Pfizer vaccines.

About The Leukemia & Lymphoma Society

The Leukemia & Lymphoma Society® (LLS) is a global leader in the fight against cancer. The LLS mission: Cure leukemia, lymphoma, Hodgkin's disease and myeloma. LLS funds lifesaving blood cancer research around the world, provides free information and support services, and is the voice for all blood cancer patients seeking access to quality, affordable, coordinated care.

Founded in 1949 and headquartered in Rye Brook, New York, LLS has regional offices throughout the United States and Canada. To learn more, visit Patients should contact the LLS Information Resource Center at (800) 955-4572, Monday through Friday, 9 a.m. to 9 p.m. ET.

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Irene Tung
The Leukemia & Lymphoma Society
(718) 414-7910