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ASH 2020: Dr. Christopher Pleyer Discusses the Effect of Bruton Tyrosine Kinase Inhibitors on the Efficacy of Adjuvanted Recombinant Hepatitis B and Zoster Vaccines in Patients with Chronic Lymphocytic Leukemia (CLL)

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Dr. Christopher Pleyer is a staff physician within the Hematology Branch of the National Heart, Lung, and Blood Institute, as well as an investigator in the Laboratory of Lymphoid Malignancies, both are which are part of the National Institutes of Health (NIH) in Washington, DC.

In this interview, Dr. Koffman and Dr. Pleyer discuss the findings from two studies that were previously mentioned in earlier stages of the trial. Dr. Pleyer looked at immune response rates in CLL patients after receiving the HEPLISAV-B for preventing hepatitis, and the Shingrix vaccine for preventing shingles.

It is important to note that the goal of these studies was to look at how patients with CLL responded to vaccines in general. The COVID-19 vaccine was not part of this study. Here is what we know about the trial design:

  • Both studies were performed independent of one another, and each included approximately 50-60 patients.
  • The studies looked at two newer generation vaccines. The first was the Shingles vaccine called Shingrix. The second was a hepatitis B vaccine called HEPLISAV-B. Both vaccines are highly effective in the general population for inducing immune and antibody responses (at well over 90%).
  • The trial compared the response rates of two specific groups of patients with CLL; patients that were treatment naive (or who have never had treatment for CLL before), and patients who were being treated with either ibrutinib or acalabrutinib.
  • It was already understood going into the trial that BTK inhibitors have complicated effects on the immune system, and many CLL patients are on these medications long term. For more information on the effects of BTK inhibitors on the immune system, read here.
  • Study participants were given the standard vaccines (as approved by the FDA) three months apart. Then three months after the last vaccine dose, antibody responses were measured.


For those CLL patients in the treatment naïve group:

  • Patients with CLL who were previously untreated (treatment naïve) were able to create antibodies 28% of the time when given the hepatitis B vaccine. So nearly ¾ of patients did not make antibodies against hepatitis B.
  • Treatment naïve patients were able to create antibodies 60% of the time when given the shingles vaccine.
  • For comparison, the normal response rate found in healthy patients when given these vaccines is approximately 90-95%.
  • The shingles vaccine had a better response rate, but it was still much less than the response we would expect to find in healthy patients when given Shingrix.
  • It is hypothesized that the reason why CLL patients had a higher antibody response to the shingles vaccine versus the hepatitis B vaccine is that shingles is a form of the varicella-zoster virus, which is the same virus that causes chickenpox in childhood. After someone has previously been exposed to varicella-zoster, it never goes away and hides away dormant in the nerve endings throughout adulthood. With age and immunosuppression, the virus can get reactivated and cause shingles (a painful rash). The thinking is that patients responded better to the shingles vaccine because they had previously been exposed to the same virus that causes shingles as children, and had some form of a memory response when given the vaccine.
  • In contrast, the hepatitis B virus is something that patients in the study had never been previously exposed to, making it unknown and foreign to these patient’s immune system. Therefore, with the hepatitis B vaccine, there was no memory response that could take place, making it more difficult to mount an immune response.

For those CLL patients in the BTK inhibitor group (ibrutinib or acalabrutinib):

  • Patients with CLL who were on BTK inhibitors were able to create antibodies to the shingles vaccine only 40% of the time following the shingles vaccine. Statistically speaking, the difference between a 60% response rate in those who were treatment naïve and a 40% response rate in those on a BTKi is not considered that much of a difference in a clinical trial.
  • The big surprise was that CLL patients on BTK inhibitors had virtually no immune response after being given the hepatitis B vaccine, with only 4% (one patient) out of the entire study population responding.
  • There are some subsets of antibodies, particularly IgA, that do increase over time after treatment with a BTK inhibitor begins. There is also a correlation between CLL patients who have a higher IgA level and having lower risk of infections.
  • Since IgA is an antibody that is secreted in higher amounts in the mucosal areas of the body (including the mouth and respiratory tract), and upper respiratory infections are a common problem in CLL patients, having even a small increase in IgA levels after treatment with BTK inhibitors begin may still provide some level of protection against infections.


  • The overall message from these studies is that CLL patients can respond to vaccines. Although the response rate (particularly to the hepatitis B vaccination) was lower than what we had hoped for, some immunity is better than no immunity.
  • It is still extremely important to get vaccinated, even if some with CLL are not able to produce an immune response.
  • The findings of this study reinforce the need for more specific research that investigates how CLL patients will respond to vaccines. More specifically, studies are needed that not only look at the overall immune response to the COVID-19 vaccine, but also compare the findings of patients that are treatment naïve, patients that are on BTK inhibitors, and patients that are on other novel therapies (such as venetoclax or other BCL-2 inhibitors).
  • More information will be forthcoming from this study at a later date. Particularly concerning how long the antibody response lasts after vaccination in CLL patients, if booster shots might be beneficial, and information surrounding T-cell responses to vaccines in those with CLL. This information is critical to understand, so stay tuned.

The biggest question at the forefront of everyone’s mind right now is, “Will the COVID-19 vaccination work in CLL patients?”

We can hypothesize and translate the findings of this study to the COVID-19 vaccine which leads one to conclude that there are legitimate concerns, especially for patients who are on BTK inhibitors. However, the honest answer is that we just do not know the answer to this question until multiple in-depth studies can be performed.

Information on current and upcoming clinical trials directed towards filling the critical data gap concerning immune system response rates in those who receive the COVID-19 vaccine can be found on CLL Society’s website. Information will be updated as more COVID-19 trials become available.

Visit to read the actual ASH abstract on this clinical trial and study all of the details.

Watch Dr. Brian Koffman, Chief Medical Officer and Executive Vice President of CLL Society, interview Dr. Christopher Pleyer concerning his research presented at ASH 2020:

For more information on clinical trials, please visit the CLL Society Website.

Thank you for reading this summary and watching this interview.

Keep learning, be kind, and stay well!

Robyn Brumble, MSN, RN
Director of Scientific Affairs
CLL Society