My Take on Key Therapy Issues for Patients With CLL During COVID-19

Our understanding of how COVID-19 interacts with chronic lymphocytic leukemia (CLL) is continually evolving as we gain more clinical experience and data. Below, I share my perspective on several important issues specific to patients with CLL during the COVID-19 pandemic, including how and when treatment modifications should be considered; whether gammaglobulin replacement therapy (IVIg) can be used as COVID-19 prophylaxis; the interaction of BTK inhibition with COVID-19; and counseling patients on reducing their risk for COVID-19 infection. 

Treatment Modifications Depend on Local COVID-19 Prevalence
Treatment modifications obviously should take into account the frequency of COVID-19 cases in the patient’s location. In locations with very few COVID-19 cases, the impact on therapy and disruption to medical visits is likely to be minimal, albeit with a heightened sense of caution. However, if the patient lives in an area that currently has a high frequency of COVID-19 cases, then recommendations regarding medical follow-up and care may be drastically different.

For example, as a provider in New York City, my practice was greatly altered when the pandemic peaked in this region in March-April 2020. At that time, my practice changed to predominantly telemedicine for those on active observation and monitoring. I discouraged elective procedures or visits unless medically necessary and encouraged patients to remain at home. If therapy could be delayed, it was. When choosing therapy, we preferred BTK inhibitors because these agents require less monitoring or need for hospitalization compared with other intravenous therapies or venetoclax—although we, of course, took into account the needs and treatment history of the individual patient in the context of potential risk of COVID-19 exposure. Now that the COVID-19 cases have dramatically declined in New York City, office visits have resumed in person with precautionary measures, particularly now that our ability to test for COVID-19 has improved.  

IVIg as COVID-19 Prophylaxis
Many patients with CLL are at an increased risk of infection, but we do not yet know if prophylactic IVIg therapy actually reduces the severity of COVID-19. During the peak of COVID-19 in my practice, I deferred IVIg treatment in my patients at our center, preferring to arrange for them to receive their IVIg therapy at home, if possible.

Using IVIg therapy as prophylaxis is challenged by an ongoing shortage that predates the COVID-19 pandemic. In addition, if we were to use replacement therapy for all patients with CLL and low IgG levels, then most patients would be receiving IVIg at any given time. We do not currently have any data that would support this broad use and, unfortunately, would likely not have enough IVIg for everyone.

Although I find that IVIg therapy is beneficial in many patients with CLL, I believe we need more data specific to its usage as COVID-19 prophylaxis. Furthermore, we would need to balance the potential risk of COVID-19 exposure with the benefits of IVIg therapy. We also currently do not know if patients with CLL will adequately produce antibodies to COVID-19, particularly given that antibody production is affected by certain therapies, let alone the clinical implications of those antibodies that are produced.

BTK Inhibition and COVID-19
Questions have been raised regarding BTK inhibitor use during the COVID-19 pandemic and whether therapy should be discontinued. If the patient is already on BTK inhibitor therapy or even venetoclax and doing well, I recommend continuing that therapy. If a patient is positive for COVID-19 but relatively asymptomatic, then I continue therapy unless they are hospitalized with severe symptoms and unable to take their medication. For my patients receiving intravenous therapy of some form—again depending on their disease circumstances—then there were some for whom I held therapy when our hospital was at its COVID-19 peak.

Preliminary reports have noted that some patients receiving BTK inhibition therapy at the time of their COVID-19 infection avoided severe respiratory complications. Preclinical data also suggest that BTK inhibitors may mitigate severe pulmonary inflammatory complications due to their regulation of signaling and activation of macrophages and demonstrated efficacy in dampening hyperinflammatory immune response in chronic graft-vs-host disease. Indeed, there are several ongoing clinical trials evaluating BTK inhibitors as a potential therapy for COVID-19. We eagerly await these data. 

Recently, Mato and colleagues—including myself—published a retrospective analysis of COVID-19 outcomes in a large series of 198 patients with CLL across 43 international centers. We noted a high mortality rate of 33% and hospital admission occurring in 90% of patients. These hospitalized patients were typically older (median age: 71 vs 58 years in those not admitted) and had comorbidities. Neither CLL-directed therapy nor therapy with a BTK inhibitor appeared to affect survival. There also did not seem to be a difference in survival between those receiving therapy vs active observation. This initial report seems very alarming, but it should be noted that this study population comprised symptomatic patients presenting to their respective medical centers. This analysis likely did not capture many patients who may have been asymptomatic or with mild symptoms of COVID-19 and who did not present for testing or medical attention. Thus, this initial report will require follow-up; hopefully, we will gain a more representative sample of patients with CLL who contracted COVID-19.

A similar report by Scarfò and colleagues from the European Research Initiative on CLL and CLL Campus reported that in 190 patients with CLL and confirmed COVID-19, those who presented with severe vs mild COVID-19 did not differ in rates of comorbidities or hypogammaglobulinemia. There were differences noted in the severity of illness by age and CLL treatment history, with BTK inhibitors in particular appearing to exert a protective effect. Furthermore, in those with severe COVID-19, age did not affect overall mortality.

Counseling on COVID-19
Currently, I advise my patients with CLL to continue practicing safe social distancing, to wear masks, and to avoid unnecessary trips or plane travel. This does not mean that our patients should avoid going outdoors and getting some exercise, as this is important for both psychological and physical well-being. Clearly, both clinician and patient must balance these considerations with the patient’s personal and family circumstances. I further counsel my patients that if they develop any signs or symptoms of an infection, they should contact their provider and receive testing. Again, when counseling patients on COVID-19 and treatment for their CLL, clinicians must take into consideration where they live with respect to COVID-19 prevalence along with the patient’s particular disease circumstances. There is much we are still learning, and our advice will likely evolve over time.

Your Thoughts?
How have your treatment decisions for CLL been affected by the COVID-19 pandemic? Please share your thoughts and experiences in the comments box.

Please also join my colleagues Jacqueline C. Barrientos, MD, MS, on September 24 and Jacob D. Soumerai, MD, on October 15 for interactive live Webinars to discuss the implications of COVID-19 for patients with CLL!