There has been much excitement about the possibility that BTK inhibitors such as ibrutinib or acalabrutinib might improve outcomes in COVID-19 for all patients ever since Dr. Treon published a retrospective study on his patients with Waldenstrom macroglobulinemia, a B-cell cancer similar to CLL, who did well while on ibrutinib when they contracted COVID-19.
Let’s first review the biology and best treatment options as of today of the typical COVID infection.
In general, therapy for the infection caused by the novel coronavirus SARS-CoV-2 (COVID-19) can be divided into two phases of treatment. The first treatment phase uses drugs specifically to lessen the viral load. The second treatment phase once the virus has taken hold, tries to dampen the exaggerated inflammatory response to the infection, commonly referred to as the cytokine storm. This is where the BTK inhibitors might help.
An antiviral called Remdesivir and monoclonal antibodies directed at the virus’s spike protein are examples of emergency authorized therapies that may work by preventing the virus from taking hold and/or lessening viral replication in the early phase of the illness. They are both generally less helpful when used during the secondary inflammatory stage of the illness, at which point they may even make the patient’s condition worse.
Once the inflammatory process kicks in, therapies that lessen inflammatory damage to the lungs and other vital organs are indicated. That is why the steroid dexamethasone was authorized for COVID-19 treatment, because it has proven to save lives ultimately by reducing inflammation.
However, even though steroids such as dexamethasone are currently the standard immune suppressing drugs being used, they have the undesirable side effect of dampening the body’s ability to control the virus.
Once the inflammatory nature of the second phase of COVID-19 was understood, the race was on for a more targeted anti-inflammatory agent. Among the many candidates considered were the BTK inhibitors, namely ibrutinib and acalabrutinib. These drugs are best known for having revolutionized the care of CLL. But they also have complex effects on the immune system that has been shown to mitigate the cytokine release syndrome (or cytokine storm) as seen with CAR-T therapy.
But isn’t a run-away cytokine storm the exact culprit that is killing patients with COVID-19? Could these same CLL drugs also help COVID-19 patients? For more of the promising pre-clinical and retrospective research studies on this possibility, see this article: Inhibition of Bruton Tyrosine Kinase in Patients with Severe COVID-19.
Hence, the genesis of the prospective CALAVI Phase II trials for Acalabrutinib in Patients Hospitalized with Respiratory Symptoms of COVID-19.
To its credit, this was an open-label randomized clinical trial that compared adding acalabrutinib (Calquence) to best supportive care (BSC), versus BSC alone in patients hospitalized with respiratory complications of COVID-19.
Sadly, the official press release stated, “The addition of Calquence to best supportive care (BSC) did not increase the proportion of patients who remained alive and free of respiratory failure. No new safety signal for Calquence was observed in the trials.” To summarize, this was a negative study and the trial was terminated.
Remember this study was done on all COVID-19 patients, not those with CLL. Most of those in the study would have been expected to recover with only standard BSC. Thus, proving a small benefit might be difficult.
Like so much happening in COVID-19 research, the only information we can go by is the press release at this point. We will learn more when we can review the actual data.
There are still three ongoing trials (either open or opening) that are looking at the use of ibrutinib in COVID-19 patients:
- Ibrutinibfor the Treatment of Patients With B-Cell Malignancies Who Are Infected with Coronavirus Disease 2019 (COVID-19)
- Study of Oral Ibrutinib Capsules to Assess Respiratory Failure in Adult Participants With Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and Pulmonary Injury
- Ibrutinibfor the Treatment of COVID-19 in Patients Requiring Hospitalization
And one with another BTKi not yet approved in CLL, zanabrutinib:
Until we can see all of the data on acalabrutinib, zanabrutinib and ibrutinib, I, for one, am not ready to throw in the towel that a BTKi given at the right time to the right patient with COVID-19 might prove to be lifesaving.
Here is the official press release from AstraZeneca.
We are all in this together.
Brian Koffman MDCM (retired), MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.