Chronic Lymphocytic Leukemia and a Pandemic: A Bad Combination

If you care for patients with chronic lymphocytic leukemia (CLL), you have undoubtedly seen severe COVID infection. Patients with CLL tend to have impaired cellular and humoral immunity, and studies have shown increased risk for severe COVID-19 infection and death. When the COVID vaccines became available, care providers were anxious to get their patients with CLL vaccinated. However, the effectiveness of COVID vaccination in the CLL population was unknown, as patients with all types of cancer were excluded from the initial clinical trials. A plenary paper published in Blood clarifies this issue.¹ 

The researchers enrolled 167 patients with CLL in a prospective study designed to test the effectiveness of the BNT162b2 mRNA, more commonly known as the Pfizer vaccine. Patients received two doses of the vaccine, 21 days apart. They were tested for antibody titers to the COVID spike protein using a commercially available assay two to three weeks after the second dose. Of the 167 patients with CLL, only 39.5 percent produced detectable anti-spike protein antibodies. In contrast, 52 healthy control patients included in the study had a 100 percent response to vaccination.

The investigators provided more granularity to the data by segregating patients by disease status and likelihood of response to vaccination. A positive response to vaccination occurred in 55 percent (32/58) of treatment-naïve patients, 79 percent (19/24) of patients off therapy and in remission, 30 percent (3/10) of patients off therapy with active disease, and 16 percent (12/75) of patients on active therapy.

They further analyzed the likelihood of response according to the type of therapy being administered. Sixteen percent of patients (8/50) on Bruton's tyrosine kinase (BTK) inhibitors generated a vaccine response, and 14 percent (3/22) on venetoclax plus anti-CD antibody therapy generated a vaccine response.

Importantly, the investigators evaluated the timing of anti-CD20 monoclonal antibody treatment and the likelihood of response to vaccination. Among patients for whom it had been at least 12 months since their last anti-CD20 therapy, 46 percent (25/55) responded to vaccination. In patients where it had been less than 12 months since their last anti-CD20 therapy, zero percent (0/22) responded to vaccination.

What should one do with this information? Here are my thoughts.

1. For your patients with CLL who have been vaccinated, measure their response to vaccination. It becomes easier to give them social distancing and masking advice if you know whether vaccination was effective. It also becomes a bit easier to make treatment decisions.

2. For your patients with CLL who are vaccinated but fail to respond to vaccination, obviously encourage a booster vaccine. We have no data yet on the proportion of non-responders who can be converted with booster vaccination, but I suspect we will have some data in 2022.

3. For your patients with CLL who are unvaccinated, continue to try and convince them to accept the vaccine while being candid about the potential for vaccine failure. Particularly, if the patient is untreated but heading toward treatment in the near future, emphasize how much more difficult successful vaccination becomes once on treatment.

4. For your patients with CLL currently on treatment with a BTK inhibitor who have failed to respond to vaccination, if your patient's disease is well controlled on the BTK inhibitor, consider holding the BTK inhibitor for one to two weeks prior to the booster and two weeks after the booster. There are no data for this approach, but in the absence of data, I see little downside.

5. For your patient on treatment with a venetoclax plus anti-CD20 combination therapy, it is probably best to wait until 12 months from the last anti-CD20 dose before attempting initial vaccination or booster.

Could patients with CLL with no response to initial vaccination or the booster benefit from a fourth dose of the vaccine? We don't know. Could your patient with CLL who failed to respond to vaccination with one product derive benefit from trying a different vaccine? We don't know. Do patients with CLL who have been vaccinated and have no antibody response have some T-cell immunity that is protecting them? We don't know. Hopefully we will get answers to some of these questions in the coming year. If one pauses to reflect on the amount of progress against preventing and treating COVID-19 over the past 18 months, it is truly astounding. Go science!