COVID-19 severity and mortality in chronic lymphocytic leukemia (CLL) patients

With recent publications in two well respected and influential peer reviewed journals, BLOOD and NATURE, we are finally getting some robust data on the outcomes in CLL patients who have contracted COVID-19.

The data are retrospective and were collected in collaborative efforts across several institutions.

While the results are not good, we need to keep in mind that there remain more unknowns than knowns and more questions than answers.

CLL Society wants to not only highlight the major findings, but to also provide some perspective on these data and share comments from the investigators. I urge you to read this article to the end.

The two published surveys are similar, but there are some significant differences.

Let’s first look at the retrospective international (mostly European) multicenter study of 190 patients published in NATURE on July 9, 2020: COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus.

Takeaways:

• Data were inputted by the CLL doctors about their patients with confirmed CLL who tested positive for COVID-19.
• 90% were hospitalized.
• 79% of those hospitalized presented with severe COVID-19, defined as needing oxygen and/or intensive care admission.
• Severe COVID-19 was more common in those > 65 years old.
• Hospitalizations were less frequent for those on ibrutinib, a BTK inhibitor.
• Age and comorbidities did not impact the mortality rate. This is surprising.
• The overall mortality rate was 30% for all the patients and 32.5% among those in hospital.

Next we will exam the retrospective data from 198 CLL patients (50% US, 29% Spain, 15% UK, 4% other European countries) published in BLOOD: Outcomes of COVID-19 in Patients with CLL: A Multicenter, International Experience.

Takeaways:

• The same percentage of patients, 9 out of 10, required hospitalization.
• 37% of those symptomatic CLL patients hospitalized had died by the time data were collected (median follow up of 16 days) while another 25% remained in hospital, and as the paper indicates, this suggests that “case fatality rate for inpatients in this series will rise beyond 37%.”
• There was no difference in overall survival for patients who have received CLL-directed therapy versus the “watch and wait” population. This was not unexpected.
• Most patients had their BTKi or Bruton tyrosine kinase inhibitors, such as ibrutinib or acalabrutinib, treatment suspended, so the numbers were small for those who stayed on them, but there was a statistically non-significant trend towards better survival for that group.
• In this series, older age and comorbidities did increase the mortality risk.

Conclusions:

There is no doubt about it. We CLL patients don’t want to get a severe case of COVID-19 because odds are good that we will need to be hospitalized and our mortality rate is unacceptably high.

And it does seem that all stages of disease, even untreated CLL, puts us at increased risk. How our risk compares to others of similar age or with the same types of comorbidities (other illnesses such as diabetes or hypertension or heart disease) is not fully answered, but the data suggests that the CLL itself is an independent and significant risk factor for dying from COVID-19 or its complications.

The difference between the BTKi data in the two trials may be explained by the fact that 80% had stopped taking their BTKi in Dr. Mato’s survey published in BLOOD. We discuss the reasons why these drugs might help COVID-19 in this article: Ibrutinib and Acalabrutinib for COVID-19.

Why older age and comorbidities did not increase the risk in the E.R.I.C. results published in NATURE is not clear. This is inconsistent with our understanding about COVID-19.

There are many more details and data points available for study in the full articles themselves. These are freely accessible through the hyperlinks above.

But there is much to learn from just these highlights.

The first lesson comes from the number two author of the BLOOD series, Dr. Lindsey Roeker, a third-year hematology fellow at Memorial Sloan Kettering Cancer Center:

“I agree that this paper should give pause to the CLL community. Until we understand CLL patients’ risk of contracting COVID-19 (determining incidence was not the intent of this project, but does remain an important consideration), I think this serves as an important reminder to practice hand hygiene, social distancing, and being conservative with mask wearing, etc. in order to minimize risk of contracting COVID-19, as the fatality rate is high among those who require hospitalization”.

What Dr. Roeker is telling us is consistent with what the CLL Society has been saying from the beginning. It is best to do all that we can to avoid the SARS-CoV-2 virus.

For general guidelines on how to do this, visit our COVID-19 page with links to the CDC and more. The American Society of Hematology (ASH) gives this advice about CLL treatment during the pandemic to its doctor community, but we can learn from it too. Dr. John Pagel offers us these helpful specific pointers to keep us immune-compromised patients remain protected during the COVID-19 pandemic.

Dr. Roeker is also reminding us that we don’t know the true incidence of SARS-CoV-2 infections. Many CLL patients may be asymptomatic or have very mild disease with some folks never having been tested. Some may have a positive test, but not inform their oncologist and just handle it at home. Some may not mount an adequate antibody response, so testing produces a false negative.

Dr. Anthony Mato of Memorial Sloan Kettering Cancer Center, the lead investigator, goes further in this short video interview:

He summarizes the collaborative research and future plans. He does emphasize that we don’t know the denominator, the true number of CLL patients with COVID-19. Many of us know a few CLL friends who have gotten through the infection relatively unscathed, who do not show up in these series.

I give the last words to Dr. John Byrd:

“The very important article by Dr. Mato and colleagues represents a collected case series with a unique snapshot of COVID-19 cases in CLL early in the pandemic.  The death rate in this study clearly brings pause and nervousness to patients with CLL along with their families and also health care providers.   I believe it probably does not get worse than these numbers and at this time is globally better.  Why is this?    Several new approaches have come forward that have been shown to be effective against either the virus directly or also reversing the systemic and lung inflammation caused by this.  Physicians have also learned to manage it better.  There is also a plethora of clinical trials available at this time with new therapies that offer promise.  Many of these trials are randomized where a new treatment is compared to standard therapy approach because a good number of COVID-19 patients can improve on their own (even without special intervention).   Some of these are good trials whereas others have fewer supporting data.   How can you sort through this if COVID strikes you?

Just like treatment management of CLL, it is important for patients to involve experts in their disease to be part of guiding strategies to avoid covid-19 and also how to treat it if acquired.   Collectively, I personally believe increased knowledge and disease specific management will result in improved results for CLL and other blood cancer patients getting COVID-19”.

Dr. Byrd reminds us these data were collected early in the pandemic. Patients are doing better now as we can better manage the disease.

Stay safe. Stay strong. We are all in this together.

Brian Koffman MDCM (retired), MS Ed

Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.