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CLL COVID: Updates
Updates on BTKi Therapy for COVID-19 and Considerations for Patients With CLL

Released: December 16, 2020

Expiration: December 15, 2021

Jacqueline Barrientos
Jacqueline Barrientos, MD, MS
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Update on BTK Inhibitors in the Treatment of COVID-19
Preliminary data from off-label use of BTK inhibitors demonstrated promising outcomes in patients with COVID-19. The CALAVI and CALAVI US trials are open‑label, multicenter phase II trials evaluating the safety and efficacy of acalabrutinib with best standard of care for patients who had a diagnosis of COVID-19. Adult patients with confirmed SARS-CoV-2 infection and COVID-19 pneumonia requiring hospitalization with oxygen saturation < 94% or requiring supplemental oxygen were randomized 1:1 to receive either best standard of care plus acalabrutinib or best standard of care plus placebo for patients who were hospitalized but not on mechanical intubation or in the ICU. Unfortunately, we do not have the actual data from the trials available at this time, but we know from a recent press release that the trials did not meet the primary endpoint of the proportion of patients alive and free of respiratory failure on Day 14. This is disappointing as we were hoping to use this drug as a companion to the best standard of care for a patient diagnosed with COVID-19 to prevent severe complications. This highlights the importance of randomized placebo-controlled trials, which are the gold standard to evaluate the efficacy of any new therapy or intervention for patients. Our knowledge of COVID-19 is rapidly changing and we still don’t know enough about the disease to know what will or will not work. To me, it was a reasonable attempt to try a drug that was already available and to see if that would benefit patients with a COVID-19 diagnosis. At this point, there is no consensus on BTK inhibitor management if a patient who is taking the drug gets infected with SARS CoV-2. In our practice, we continue the patients on the drug unless there are other complicating events (eg, active arrhythmias or bleeding). Most of the available data for these cases are retrospective without randomized trials of continuing vs stopping the drug, so at present, we evaluate potential risks vs benefits on an individual basis.

Trials investigating the role of other BTK inhibitors, ibrutinib and zanubrutinib, are ongoing. It is possible that the CALAVI trials started a little bit earlier than the other BTK inhibitor trials, enabling an earlier data read out. It will be interesting to learn the results of those data, because acalabrutinib is a second-generation BTK inhibitor with higher selectivity, so I wonder if perhaps ibrutinib, given its known potential for off-target effects and ability to modulate T cells and NK function, may have different activity than acalabrutinib in patients with COVID-19.

COVID-19 Outcomes in Patients With CLL
Mato and colleagues, in their publication from a multicenter analysis of COVID-19 outcomes in 198 patients with CLL across 43 international centers, included patients receiving ibrutinib and those not receiving ibrutinib. Survival did not appear to be affected by CLL-directed therapy nor by therapy with a BTK inhibitor, but this was based on data between February 17, 2020 and April 30, 2020—ie, early in the pandemic. At the time, we didn’t even know if the use of steroids was effective, and many of our patients were ultimately intubated early. Now we know that steroids improve survival. We also know that intubation should be avoided as much as possible and instead we employ high-flow oxygen. Our center has in place an ambulatory protocol for patients with a diagnosis of COVID-19 and they can be visited at home by a nurse who provides medications as needed, including the newly approved monoclonal antibodies, if indicated. These monoclonal antibody therapies are administered via IV infusion in an ambulatory setting with all appropriate safety monitoring procedures in place.

We also have much greater access to testing, so we can diagnose patients earlier than when tests were not widely available and our limited supplies forced us to triage which patients to test. I believe that early detection can lead to a decrease in contagion as patients can isolate and prevent more contagion. Also early intervention and maximizing outpatient management of patients with COVID-19 could prevent the overwhelming influx of patients to the emergency rooms that we saw during the first wave of the disease.

COVID-19 is a heterogeneous disease and can behave very differently in our patients with CLL. CLL is also a heterogenous disease, as some patients can be on active surveillance for many years and never require any intervention and other patients have multiple previous lines of therapy, including chemoimmunotherapy, making them more susceptible to infection. Similarly, COVID-19 is a heterogenous disease and can behave differently in our patients with a CLL diagnosis. We still cannot predict who is likely to develop more severe symptoms with COVID-19. We have had some patients who probably had asymptomatic COVID-19 disease based on positive antibody testing and known exposure. Likewise, we have had symptomatic patients who had difficulty clearing the infection based on prolonged positivity to PCR antigen testing.

I have had a handful of patients with CLL who didn’t seroconvert the antibody testing for several weeks. In these regards, we are not sure whether these antibodies are protective, as there have been reports of SARS CoV-2 reinfection.

SARS-CoV-2 Vaccination for Patients With CLL
The key issue for our patients with CLL is that many patients have a compromised immune system. Even before the COVID-19 pandemic, several patients with hypogammaglobulinemia due to CLL required monthly IVIG infusions to minimize their risk of developing a severe infection. As such, I wonder whether the vaccine will effectively lead to the production of neutralizing antibodies in patients with these characteristics or in patients recently treated with immunosuppressive chemoimmunotherapy. Although the preliminary press releases have shown that these novel mRNA vaccines have > 95% efficacy, my concern is that we don’t have the data available yet to understand whether the trials enrolled patients with CLL. It will be very interesting to learn the population demographics from the vaccine trials. Given that each one of these vaccines employs a different technology to produce it, is there one vaccine that should be used preferably on patients with a CLL diagnosis? We currently avoid live vaccines in patients with CLL due to the theoretical risk for severe infection. Luckily, most of the vaccines in development for COVID-19 are not live vaccines. Currently, only one vaccine is authorized by the FDA and recommended to prevent COVID-19, the Pfizer-BioNTech COVID-19 vaccine. This vaccine is a type of mRNA vaccine, it contains material from the virus that causes COVID-19 that gives our cells instructions to produce a protein that is unique to the virus so that our immune systems are able to recognize the protein and prevent future severe complications from COVID-19. There are still several questions that remain unanswered until the data are available. I recently reached out to a colleague in the UK inquire about his experience since the UK approved the vaccine before the US, and he confirmed that he had vaccinated an elderly patient with CLL without any complications. My hospital just vaccinated the first American this morning, a critical care nurse in the frontlines, so I am eager to see how the vaccination efforts go over the next few weeks. Hopefully when more data and longer follow-up are available, we will be able to offer consensus guidelines for best practices in our patients with CLL.

Your Thoughts?
Do you think the vaccines will be effective in patients with CLL? Will you recommend that all of your patients be vaccinated? Please leave your thoughts in the comment box below.

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