Blood (2022) 140 (5): 408-409
August 4, 2022:
Life surely has been upended since early in 2020, when the Severe Respiratory Syndrome Coronavirus (SARS-CoV-2) first emerged, heralding the onset of the COVID-19 pandemic. For those with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), the situation has been particularly challenging due to the increased risk of illness from underlying immune compromise compared to the general population. CLL/SLL, a malignancy of B-cells, causes both humoral (B-cell) and cellular (T-cell) immune dysfunction resulting in an overall dysregulation of the immune system and increased risk of and difficulty fighting infection. Furthermore, many therapies implemented to treat CLL/SLL may, in the short term, cause further immunosuppression. In particular, anti-CD20 antibodies such as rituximab or obinutuzumab may severely deplete antibody levels necessary to counter infection.
During the first wave of COVID-19, beginning in February 2020, the overall case fatality rate (CFR) for those with CLL/SLL was reported to be 40% for those hospitalized and 31%-33% overall. Subsequently, the rates have decreased, with one study reporting through February 2021, a CFR of 20% for hospitalized CLL/SLL patients and an overall CFR of 11%. However, over time the virus has continued to evolve. Late in 2021, the omicron variant emerged first as B.1.1.529 and with further mutations subsequently as BA.2 and now has evolved to the BA.5 strain. Overall, the omicron variant has been reported to cause less severe outcomes in the general population, and for CLL/SLL patients, the data is just beginning to emerge. A recently released Israeli study looking at COVID-19 in CLL/SLL patients during the omicron surge from January 2022 to March 2022 reported a CFR of 31% for hospitalized patients and an overall CFR of 14%. And now, a new study out of Denmark presents additional encouraging data for CLL/SLL patients with COVID-19 and provides some reassuring news. But first, some background information is needed before delving into the details of the study.
In December 2020, the first COVID-19 vaccines were released, demonstrating significant efficacy in the general population. However, this was not the case for those with CLL/SLL. Because of the inherent immune depressing effect of CLL/SLL, the ability to make antibodies to fight the virus is blunted, and therefore the response to the vaccine is diminished. The serologic response rate, which measures the ability to generate antibodies following a vaccine, has been reported to be as low as 0% for individuals receiving anti-CD20 antibodies and as high as 80% for those in clinical remission, with an overall response rate of 40%. And for those who do respond to the vaccine, unfortunately, the levels of antibodies levels produced are also low. T-cell immunity is also a factor in fighting COVID-19, and the impact of CLL/SLL on vaccine-initiated T-cell immunity in patients is unclear. However, despite the reduced efficacy, primary vaccination series and booster vaccines still may mitigate against severe disease and prevent death in patients with CLL/SLL and are recommended for all immunocompromised persons. The current COVID-19 vaccine recommendations can be found here: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations/immuno.html
In addition to vaccinations, there is now a very effective COVID-19 preventive therapy for immunocompromised individuals, a dual long-acting monoclonal antibody combination of tixagevimab and cilgavimab known as (Evusheld) which is approved and recommended for patients with CLL/SLL. Though the SARS-CoV-2 virus has mutated and evolved over the past two years, recent data show the efficacy of this agent to omicron BA.5, which is currently the circulating dominant viral strain. More information can be found on the NIH’s Covid-19 Treatment Guidelines: Special Considerations in People Who Are Immunocompromised.
You’ll find this patient-friendly language on our website: Answering the Most Common Questions About COVID-19 Booster Doses and Evusheld for Those with CLL/SLL.
These measures will help to prevent infection and mitigate severe disease. However, there are breakthrough infections, and should that occur, there are now new strategies and novel agents, including the use of steroids, various anti-viral therapies, and several different monoclonal antibodies to treat the illness. It is crucial in interpreting published studies to understand that as the virus has evolved, some therapies have been abandoned due to becoming ineffective, and others started. New treatment paradigms have been employed and will continue to change, as does the virus. Furthermore, what preventive and interventional treatment strategies are used may vary from one country to another and between different institutions.
The data being presented here came from Denmark, where the protocol for all patients with hematologic malignancies is as follows:
- A full primary dose vaccination series against SARS-CoV-2 and the first of two additional booster vaccines in August 2021 and the second in January 2022.
- A single dose of an anti-SARS-CoV-2 monoclonal antibody for anyone testing positive for SARS-CoV-2, whether in or out of the hospital
- Dexamethasone (a steroid), low molecular heparin (blood thinner), and remdesivir (anti-viral) for those patients hospitalized with moderate to severe COVID-19.
- The researchers collected data from the Danish registry for CLL patients with a positive SARS-CoV-2 polymerase chain reaction. As a result, 793 patients were identified for the study.
- The 2-year time frame was divided into 4 periods focusing on the surge of different variants. The BA.2 strain was the dominant variant during the fourth and final period of the study before the emergence of the omicron BA.5 variant.
- The patient data was divided into a cohort extracted from the Danish electronic health record (EHR) of patients having been in the hospital for either CLL or COVID-19 or both and a separate cohort (population) extracted from the CLL Danish database for which the only data available was overall survival. The individuals in the EHR group were older than those in the cohort group.
- The 30-day hospitalization rates for the patients in the EHR cohort declined from 83% in 2021 before the emergence of the omicron variant to 55% when the omicron BA.2 subvariant became dominant, reflecting an improved trend. However, this number may not reflect the exact percentage of hospitalizations for the CLL/SLL community as this data was not available for the younger population cohort and had a better overall survival rate than the EHR.
- Intensive care admissions in the EHR cohort declined from 13% to 0%. This may be partly due to the high vaccination rate, early administration of a monoclonal antibody upon diagnosis, treatment with remdesivir, and administration of oxygen up to 30L/min outside of the ICU.
- The 30-day overall survival in the EHR cohort improved from 83% to 91% when the first omicron variant became dominant but decreased to 77% with the emergence of the BA.2 subvariant.
- The overall survival for the population cohort was 99.2% when the omicron BA.2 variant was dominant.
- When combining the EHR and population cohorts, the 30-day overall survival rates improved from 88.8% early in the pandemic to 98.2% during the BA.2 period.
- The patients who died were older than 70 years of age with at least 1 additional underlying illness such as dementia, diabetes, cardiac, pulmonary disease, or other malignancy.
With preventive measures, early intervention, and in-hospital treatment strategies, this study out of Denmark has shown that the risks of avoiding severe COVID-19 and death are improving. What part each of these interventions played is unknown, but the overall survival rate for CLL patients was 99%. However, some succumbed to the disease and tended to be older with additional underlying comorbidities. Continued efforts are needed to protect the CLL/SLL community, and aggressive and early intervention strategies are especially needed for the most vulnerable individuals. And as the virus continues to mutate, further information will be forthcoming.
Dr. Koffman interviewed the lead researcher, Dr. Carsten Niemann, Associate Professor of Hematology at the University of Copenhagen. Dr. Niemann shared encouraging news and a brighter outlook for those of us with CLL in this interview I hope you will enjoy.
To read the complete original Danish study published in Blood, click on Patients with CLL have a lower risk of death from COVID-19 in the Omicron era. In addition, Dr. Koffman interviewed the lead researcher, Dr. Kirsten Niemann, and we will post that interview soon.
To read the well researched article, click on https://ashpublications.org/blood/article/140/5/407/486044/CLL-and-COVID-19-light-at-the-end-of-the-tunnel – .Yuw3c_FFpOc.twitter
We share in this journey together.
Kim Davidson, MD
Kim Davidson received her Doctor of Medicine degree from the Medical College of Virginia. Following training in Obstetrics, Gynecology, and Family Medicine, she provided medical care and taught for over thirty years until retiring. She is a CLL patient and shares this journey with all of you.