Introduction
This module features expert answers to a selection of questions asked by learners at live Webinars focused on important emerging data related to the intersection of chronic lymphocytic leukemia (CLL) and the COVID-19 pandemic. Topics range from optimizing treatment selection, managing toxicities, and mitigating COVID-19 risk for patients with CLL to leveraging established CLL therapies for treatment of patients with COVID-19. The perspectives below are adapted from live expert answers provided by Jacqueline Barrientos, MD, MS; Nicole Lamanna, MD; John Pagel, MD, PhD; and Jacob D. Soumerai, MD.

COVID-19 Outcomes in Patients With CLL

Do patients with CLL have worse outcomes if they develop COVID‑19?

Nicole Lamanna, MD:

Preliminary data from a single center in Spain suggest that hospitalized patients with active hematologic malignancies have worse outcomes than those in remission or under observation only.¹ Regarding CLL specifically, Scarfò and colleagues² published a retrospective study of 190 European patients with CLL and confirmed COVID-19 in July 2020. This study reported a higher mortality rate among hospitalized patients with CLL vs the general Italian population (32.5% vs 13.4%, respectively). That being said, the patients with CLL had several risk factors for severe COVID-19: They were older, with a median age of 72 years at the time of COVID-19 diagnosis, and approximately three quarters had at least 1 comorbidity. Another report by myself and colleagues also noted a high mortality rate, 33%, in 198 patients with CLL.³ The median age was 70. While these initial reports were during the first wave of the pandemic in the spring when many patients remained home and were not tested (or had limited access to testing at that time), these numbers are still startling. As more patients with CLL are currently being tested, hopefully the mortality numbers will not appear as drastic as those initially reported.

In my current experience, I will underscore that many patients with CLL have had COVID-19 and have done well. Unfortunately, the contrary is also true. I have had several patients with CLL who suffered from increased morbidity and mortality due to their illness with COVID-19. Given what I observed in my New York City–based practice from March through June 2020, regrettably, I had lost more patients with CLL to COVID‑19 during that time than I had to the disease itself in many years. I will feel more at ease when we have an effective vaccine and therapeutics to treat the virus successfully in my CLL patients.

Are data available on COVID-19 outcomes in younger patients with CLL?

Jacob D. Soumerai, MD:
Unfortunately, our data are very limited now. Most of the available observational data are derived from hospitalized patients with COVID‑19 because, earlier in the pandemic, healthier patients often stayed home and were not tested for COVID-19. This skews our sample toward patients with more severe COVID-19.

In my Boston practice, I have had a number of patients with CLL, including younger patients, who have developed COVID-19. Thankfully, the vast majority has done well. My anecdotal experience is that our available observational data likely overestimate the risk of poor COVID-19 outcomes in most patients with CLL. That being said, I think that reality likely lies somewhere between my positive anecdotal experience and the published data on severe cases.

I counsel my patients that there are likely to be differences in COVID-19 risk within the heterogeneous population of individuals with CLL. This population is inclusive of a broad spectrum of patients such as those who had received multiple courses of chemoimmunotherapy years ago, patients on their third course of a targeted agent now, patients receiving first‑line therapy with venetoclax and obinutuzumab or a BTK inhibitor, and patients who have never needed—and will likely continue to never need—therapy due to low disease burden. Unfortunately, we do not yet have the data to support my assumption that risk varies among these patient groups.

Would it be possible for CLL-associated lymphocytosis to counteract COVID-19–associated lymphopenia in patients with CLL who are not receiving treatment?

Jacob D. Soumerai, MD:
That is an interesting question. I am unaware of any data on this interaction. I would hypothesize that COVID-19–associated lymphopenia has a greater effect on normal B-cells than malignant B-cells.

Minimizing Risk and Treating COVID-19 in Patients With CLL

When seeing patients in person, do you perform mandatory COVID‑19 screening at the visit or only for patients with possible (eg, symptomatic) COVID-19?

John Pagel, MD, PhD:
Currently, we do not know the optimal approach for screening patients for COVID-19, although ASCO does offer guidelines on screening that are based on expert judgment of what is rational and appropriate.⁴ It is obviously important to know whether your patients have COVID-19 when they are going to be treated for CLL. We presently do not recommend that patients be tested if they lack COVID-19 symptoms. Patients without symptoms or possible COVID-19 exposure can come in as long as they are masked and rigorously follow distancing and handwashing guidance.

How would you counsel your patients with CLL about their risk of COVID-19 related to wearing masks, travelling on planes, and exercising outdoors?

Nicole Lamanna, MD:
This is the most common question I discuss with my patients because so many patients want to know what they can and cannot safely do. Given my experience and observations during this pandemic, I tell my patients that I do not recommend them travelling on planes. I recommend appropriately wearing masks and to practice social distancing. I do think they should exercise outdoors if they have a safe area, such as their backyard, or live in a neighborhood where they can take a walk while maintaining appropriate social distancing. Exercising is clearly good for their physical and mental well-being, so I tell my patients to get out and about, but just be cautious and use common sense.

I am concerned about the risk of increased exposure as states have started reopening. Obviously, the COVID‑19 pandemic has had a devastating impact on the economy and everyone’s mental health, and it is understandable that people are desperate to have a break, get out, and socialize. Unfortunately, we can clearly see that SARS-CoV-2 infections are increasing across the United States⁵—making it all the more important for patients with CLL to continue social distancing, quarantining at home, and minimizing travel and exposure.

Are patients with CLL at greater risk for becoming infected with SARS-CoV-2?

Nicole Lamanna, MD:
I do not believe that patients with CLL are at a higher risk of contracting SARS-CoV-2; indeed, I think that most people have the same risk of contracting the infection depending upon their risk of exposure. However, as discussed previously, patients with CLL are certainly at a higher risk of developing complications from COVID-19.

When would you hold therapy in a patient with CLL who has asymptomatic COVID‑19?

Jacob D. Soumerai, MD:
If the patient is receiving CLL treatment and has asymptomatic COVID-19, I would be inclined to continue therapy for their CLL. However, I would consider holding therapy if the patient were experiencing therapy‑related adverse events (eg, uncontrolled cytopenias) that could place him or her at risk for developing severe COVID-19 or related sequelae.

Would you recommend thromboprophylaxis in a patient with CLL, severe COVID-19 status, and a platelet count > 100 x 10⁹/L?

Jacqueline Barrientos, MD, MS:
To provide some brief context for this question, patients with COVID-19 are at elevated risk for thromboembolic events even after recovery from the infection.⁶ My answer depends on the individual situation. Much of the available guidance would state that low‑dose thromboprophylaxis should be considered, and I would recommend consulting the guidelines regularly updated on the ASH Web site.⁷

In my center, we have institutional guidelines and we offer patients who have been hospitalized with COVID-19 the opportunity to participate in a clinical trial to better understand this question as this is an evolving field. Pharmacologic thromboprophylaxis with in-patient unfractionated heparin/low molecular weight heparin (LMWH) is indicated unless patients have an absolute contraindication with perceived high-risk factors for bleed or an IMPROVE Bleed Score of 7 or more. Extended thromboprophylaxis with a direct oral anticoagulant (DOAC) or LMWH is indicated in high-risk patients (IMPROVE VTE score of 4 or more or age > 60 and elevated D-dimer greater than 2 times the upper limit of normal) unless patients have ABSOLUTE contraindications ie, active bleeding, a recent history of bleed (within 3 months), severe thrombocytopenia (platelet count < 50,000/mL), dual antiplatelet therapy, active cancer (especially gastrointestinal cancer), a history of bronchiectasis or pulmonary cavitation, or an IMPROVE Bleed score of 7 or more). Depending on the patient’s comorbidities (renal disease, bleeding risks, etc) they may receive the anticoagulant enoxaparin at 40 mg once per day (or the thromboprophylaxis dose of a DOAC) for at least 1 month. Some of my pulmonary colleagues have continued thromboprophylaxis until the D-dimer levels returned to normal. Since the initial COVID peak, our institution created the Coronavirus Related Outpatient Work Navigators (CROWN) program, which is designed for patients with symptoms that range from moderate to severe, and offer a way to treat people in the lowest-risk environment possible while also protecting hospital capacity if a second surge of COVID-19 cases develops. When patients are discharged from the hospital, they are referred to this practice as these patients may have particular needs that would not be addressed in a traditional practice setting.

Is there a benefit to early administration of convalescent plasma in patients with COVID-19 rather than waiting for the development of severe symptoms?

Nicole Lamanna, MD:
An ongoing question with all the COVID-19 therapies under investigation, from the IL-6 receptor antagonist tocilizumab to steroids to convalescent plasma, is the importance of timing. Waiting to administer treatment until patients are intubated or on high-flow oxygen due to COVID-19 lung damage may miss the window when treatment could have prevented the inflammatory response and fibrosis.⁸ I suspect that timing is quite important, although again we need more data. Timing may also explain why a treatment worked well in one patient who had early disease with mild symptoms, whereas it was ineffective in a patient who had already progressed to more severe COVID-19.

Regarding convalescent plasma specifically, my experience is limited. Its use in my institution was limited during the height of the initial outbreak because there were many restrictions, even though donations were available.

Are there any known risks or benefits from IVIg for patients with CLL who have recovered from COVID-19?

John Pagel, MD, PhD:
Once patients have recovered, we hope that they will have developed their own antibodies against SARS‑CoV‑2. Some patients with CLL and COVID-19 may not mount an adequate long‑term IgG response. Indeed, a single-center retrospective analysis reported that anti–SARS-CoV-2 IgG development occurred in 67% of patients with CLL vs nearly 100% of immunocompetent patients.⁹ However, the clinical implications of an inadequate IgG response remain to be determined.

I do think that most patients will generate sufficient immune response, but if a patient were profoundly hypogammaglobulinemic, I would probably continue administering IVIg. I consider the risk to be relatively low and I would encourage subcutaneous administration.

Should the high-dose quadrivalent flu vaccine be administered to patients with CLL who are younger than 60 years of age?

Jacob D. Soumerai, MD:
There are data on the efficacy of flu vaccines in patients with CLL and specifically those receiving a BTK inhibitor. Flu vaccination seems to be effective in this population, although there is ongoing debate on whether there is decreased efficacy in some patients with CLL as well as with specific therapies (eg, ibrutinib).^10,11 The efficacy of other common vaccines in CLL has been investigated as well.¹²

The FDA has only approved the high-dose quadrivalent flu vaccine for individuals who are aged 65 years or older.¹³ For younger patients, if they are not receiving therapy, I would not administer the high‑dose flu vaccine. I would recommend the high-dose flu vaccines for patients who are receiving treatment and/or are older.

Selecting Treatment for CLL in the COVID-19 Era

Is active surveillance still the optimal approach for patients who do not have a definitive reason to start treatment for CLL during the COVID-19 pandemic?

Jacqueline Barrientos, MD, MS:
Yes. There are no data to support starting therapy for patients with high‑risk CLL (ie, 17p deletion, TP53 mutation, or unmutated IGHV) because although there can be a PFS benefit, there is no survival advantage.¹⁴ There are, however, several early intervention phase III trials planned or ongoing for patients with high-risk disease in the United States, such as the EVOLVE CLL/SLL Study¹⁵ evaluating venetoclax plus obinutuzumab and the GLLC-EARLY¹⁶ trial evaluating acalabrutinib.

In the era of COVID-19, we hold off therapy as long as possible because treatment-related toxicities could potentially lead to a hospitalization, and if the patient lives in an area with high COVID-19 prevalence, that could result in a worse outcome.

Jacob D. Soumerai, MD:
Yes. Even when there is no longer a COVID-19 pandemic, we probably do not need to start therapy if the patient does not meet International Workshop on CLL (iwCLL) criteria—although bear in mind that the iwCLL criteria are not a perfect line in the sand. There are patients who are borderline.

For example, one of my patients had stopped initial therapy with a BTK inhibitor due to adverse events and, given that the disease was in CR, opted for a treatment‑free interval until the disease re‑emerged. The disease has now re‑emerged and her lymphocyte doubling is every 6 months, but she is not quite meeting the criteria. Under normal circumstances, I would consider her as someone not needing to start treatment today but who would need it soon, so I might have started treatment to try and prevent future complications. But in the context of a global pandemic and where treatment is not clearly indicated, I think it is important to avoid healthcare exposures and reduce traffic to the hospital. Therefore, I would not start treatment now.

Would you recommend BTK inhibitors over other therapies for CLL?

Nicole Lamanna, MD:
In a CLL patient who requires therapy and taking into account the incidence of COVID-19 in one’s area, I consider BTK inhibitors easier to initiate in some respects than a venetoclax‑based combination, which requires monitoring for tumor lysis syndrome.¹⁷ Patients receiving venetoclax could be at a greater risk for COVID-19 exposure if they require hospitalization to monitor for tumor lysis. Patients receiving BTK inhibitor therapy generally require monitoring with only bloodwork and can discuss via telemedicine visits.

A key question is whether patients with CLL would have better outcomes on a BTK inhibitor vs other therapies if they develop COVID-19. Some observational data have suggested that treatment with ibrutinib may improve COVID-19 outcomes in patients with CLL. In a retrospective study of 190 patients with CLL and confirmed COVID-19, the odds for being hospitalized for COVID-19 were significantly lower in patients on ibrutinib vs another CLL therapy or being off therapy (odds ratio: 0.44; 95% CI: 0.20-0.96; P < .05).² However, a retrospective analysis of 198 patients with CLL and symptomatic COVID-19 by Mato and colleagues¹⁸ reported no difference in survival for those on a BTK inhibitor vs not receiving a BTK inhibitor. In addition, a recent press release indicated that the randomized phase II CALAVI trials—randomizing patients to acalabrutinib vs best supportive care in patients hospitalized with respiratory symptoms of COVID-19—did not meet the primary endpoint of increasing the proportion of patients who remained alive and free of respiratory failure.

Does the COVID-19 pandemic make you more reluctant to use venetoclax over BTK inhibitors in relapsed/refractory CLL?

Jacqueline Barrientos, MD, MS:
In general, yes. When we were at the peak of the pandemic in New York and our hospital system had on average 3500 hospitalized patients with COVID-19, I was recommending ibrutinib or acalabrutinib to nearly all my patients who required therapy because of the ease of use and monitoring considering that we were able to send phlebotomists to the patients’ homes and we could do telehealth visits when in-person visits were too risky. However, there are still some patients for whom BTK inhibitors would not be appropriate. For example, I had a patient who had suffered spontaneous intracranial bleeds and I was concerned that another hemorrhagic stroke could be fatal. Given that BTK inhibitors are associated with the risk of major hemorrhage, I recommended venetoclax.^19,20 Even though she was high risk, we administered venetoclax outpatient because of the COVID-19 pandemic under strict close observation and monitoring—the patient agreed to come to our infusion center to get IVF the day before, the day of the dosing, and the day after. We monitored the labs the day before (they had to be perfect), she would take the dose at home at 6:00 am and then come to the infusion center and get post 4-,8-,12-, and 24-hour laboratories which we would process stat. We agreed that any abnormalities that would not correct would prompt us to admit her to the hospital. We were able to successfully dose escalate her to 400 mg daily over 5 weeks without any hospitalizations.

Given the risk of cardiac events with ibrutinib, under what conditions is ibrutinib still preferred over acalabrutinib?

Jacqueline Barrientos, MD, MS:
We are still waiting for mature data from head-to-head phase III clinical trials comparing ibrutinib vs acalabrutinib. In the meantime, I think the decision rests on patient preference after we review the data. For example, we have more mature data for patients with del(17p) or TP53 mutations that have been treated with ibrutinib and I mention this to the patients. We discuss the side effect profile that we know from the trials and real-world studies and take into consideration the patient’s comorbidities. Some patients prefer once-daily dosing with ibrutinib compared with twice-daily dosing with acalabrutinib, so I work with the patient’s preference.

Clinical Considerations Surrounding BTK Inhibition and COVID-19 in Patients With CLL

Are the positive preliminary outcomes with acalabrutinib for severe COVID-19 reported in the National Cancer Institute case series applicable to patients with CLL?

Jacob D. Soumerai, MD:
This question refers to a June 2020 report on preliminary clinical outcomes in 19 patients without CLL who received acalabrutinib for 10-14 days to treat severe COVID-19.²¹ Oxygenation, inflammation measures (ie, C-reactive protein, IL-6), and lymphopenia improved and/or normalized in most patients over the treatment course, with 8 out of 11 patients on supplemental oxygen being discharged to room air and 4 out of 8 patients on mechanical ventilation being extubated.

This observational dataset did not include patients with CLL. Thus, do these data apply to patients with CLL? We know that patients with CLL have immune dysregulation that may interfere with BTK inhibitor action, so it is possible that the results obtained with BTK inhibition for COVID-19 may be different in patients with hematologic malignancies. Additional data are sorely needed.

In a patient with CLL and COVID‑19, when would be the best time to initiate a BTK inhibitor?

John Pagel, MD, PhD:
Based on the data, I would start the BTK inhibitor as soon as there is an indication for CLL therapy, but I would not necessarily start unless that indication is present. In the modern era, most patients will receive a BTK inhibitor upfront. Observational data do suggest that BTK inhibition improves outcomes in patients with CLL and COVID-19, but these were patients who were already receiving BTK inhibitors to treat their CLL.²

A related question is whether we should use prophylactic BTK inhibition to prevent COVID-19 by starting before a patient has symptoms or a reason to begin CLL therapy. I do not think we have sufficient information to support that approach, and I would discourage clinicians from using BTK inhibitors as COVID-19 prophylaxis in patients with CLL and no indication for CLL therapy.

What are your thresholds for involving cardio‑oncology care in patients newly started on a BTK inhibitor?

Jacqueline Barrientos, MD, MS:
I have a very, very low threshold for involving cardio-oncology in patients at higher risk for atrial fibrillation or other cardiac events (eg, those with uncontrolled hypertension, older patients with severe vascular issues). Back when I was participating in phase I trials for BTK inhibitors, I actually knew more about the cardiotoxicities than the cardio‑oncology specialists. Fortunately, they are catching up and many younger cardiologists are very interested in understanding how BTK inhibitors affect the heart. In our center, we have recruited a clinician who is interested in this area and I send all my patients, even those with minimal concerns, for evaluation.

Should we stop ibrutinib if COVID‑19 is suspected or diagnosed in a patient with CLL?

Nicole Lamanna, MD:
Personally, I do not stop ibrutinib or other oral agents (ie, another BTK inhibitor or venetoclax) as long as patients’ COVID-19 symptoms are mild and they are otherwise doing well at home. There are ongoing studies evaluating the use of BTK inhibitors in treatment of COVID‑19, although data are emerging and limited.

If they develop severe complications, and are admitted to the hospital, one needs to weigh whether discontinuation of their therapy is appropriately warranted at that time (ie, holding BTK inhibitor because they may undergo a procedure, have cardiac complications, coagulations issues, or are intubated, etc). We have limited data to suggest what would be the correct practice at this point.

How do you administer a BTK inhibitor in intubated patients?

Jacob D. Soumerai, MD:
This is a really pertinent question. We need data on the pharmacokinetics of nasogastric administration of BTK inhibitors. There have been case reports on successful nasogastric administration of ibrutinib to a comatose patient²² as well as to a patient with a swallowing disorder.²³

Acalabrutinib is a weak base and requires acidic conditions to dissolve. After evaluating a number of sodas and juices, standard Coca-Cola containing phosphoric acid only as an acid regulator (eg, Diet Coke and Coke Zero) has been shown to allow a rapid drug dissolution and is recommended in preparing nasogastric suspension for patients who are intubated.²¹

What are the indications to discontinue BTK inhibition in patients with CLL and COVID‑19?

Jacob D. Soumerai, MD:
Patients with COVID‑19 can develop atrial fibrillation during acute hospitalization.²⁴ Thus, I would stop the BTK inhibitor if the patient develops cardiac arrhythmias. I would also stop if the patient were developing coagulopathy in the hospital. I would consider stopping the BTK inhibitor in a patient who is developing a bacterial superinfection.

Unfortunately, we do not have robust data to tell us whether we should continue or stop ibrutinib. I would encourage discussing these issues in tumor boards to ensure that you have established potential institutional guidance for discontinuation.

Jacqueline Barrientos, MD, MS:
I can relate what I have done with one of my patients. This patient had previously been hospitalized for severe pneumonia associated with Klebsiella pneumoniae requiring 2 intubations within the past 2 years. He developed COVID-19 while receiving zanubrutinib off label but did not have any symptoms beyond 1 day of fever and a loss of smell and taste that lasted for 3 weeks, so I continued him on zanubrutinib.

I decided to continue him on zanubrutinib because, before Treon and colleagues²⁵ reported their case series on BTK inhibition potentially protecting against lung injury in hypoxic patients with COVID-19, I had on my service the first patient on a clinical trial involving ibrutinib who developed COVID-19. I spoke with the trial sponsor and advocated for him to continue on ibrutinib based on preclinical data. We continued him on ibrutinib and, although he did not require hospitalization, he was quite ill for approximately 4 weeks with high fevers. I grew concerned and told him to hold the ibrutinib just to see what would happen; however, he felt so much more miserable that, within 24 hours, he asked me to restart. I cleared restarting ibrutinib with the trial sponsor, and he eventually recovered from COVID-19 and is now doing well. Therefore, I decided not to stop zanubrutinib in the patient with a history of severe pneumonia.

In my practice, as long as the patient does not have any risk for bleeding events or cardiac events and is younger, I would continue therapy. But if the patient has severe vasculopathy, I would stop therapy. This is because COVID-19 can cause myocardial issues and I have seen “Kawasaki in adults”—essentially, a postinflammatory syndrome in patients with COVID-19. Specifically, I was consulted on a case of a 42‑year‑old patient (not with CLL) whose ejection fraction went from normal to approximately 10% in the setting of a SARS-CoV-2 infection (remarkably without any cough or flu-like symptoms), but was able to regain his heart function after appropriate therapy.

PI3K Inhibition in Patients With CLL and COVID-19

Are there any data on use of PI3K inhibitors in patients with CLL and COVID-19?

Jacob D. Soumerai, MD:
No. I would be nervous about giving a PI3K inhibitor to a patient with COVID-19 because this drug class is associated with rare cares of pneumonitis.²⁶ There are no compelling preclinical data for use of PI3K inhibitors in COVID-19. I would stop a PI3K inhibitor in a patient admitted with COVID-19 or presenting with symptoms consistent with COVID-19.

Have you had any experience with continuing or discontinuing PI3K inhibitors in patients who develop COVID-19?

Jacqueline Barrientos, MD, MS:
I would be hesitant to start a PI3K inhibitor in a patient who lives in an area with a high prevalence of COVID-19. Unfortunately, I had 2 patients who were receiving PI3K inhibitors when they developed COVID-19 and both died, even though we discontinued the PI3K inhibitor, so I have always wondered if the drug contributed to their outcomes as patients with CLL have a difficult time if they develop severe COVID-19. I have seen too many autoimmune complications from PI3K inhibitors (eg, pneumonitis, colitis) and would not elect to use this drug class when trying to manage COVID-19.

Implications of COVID-19 Vaccination in Patients With CLL

If a COVID-19 vaccine becomes available, will it be useful in patients with CLL?

John Pagel, MD, PhD:
I highly anticipate and am hopeful that a COVID-19 vaccine will be effective in our patients with CLL. These therapies will be initially genetic material (mRNA)–based vaccines, and this type of vaccine will unlikely be risky in a patient with CLL. Nonetheless, most all CLL patients will likely be appropriate for the vaccine, while taking into account both their disease and their CLL therapy.

When a COVID-19 vaccine is approved, would you suggest that patients with CLL receive the vaccine?

Jacqueline Barrientos, MD, MS:
I tell all my patients that once we have the data for the COVID-19 vaccines available for our review, I will discuss these data with them. Based on the press releases, I am very optimistic that these vaccines will be efficacious against COVID-19.

Has there been any research on administering a COVID-19 vaccine in immunocompromised patients such as those with CLL?

John Pagel, MD, PhD:
To date, I am unaware of any ongoing trial for immunocompromised patients or patients with CLL specifically.