COVID-19 Pandemic Highlights Underrecognized Vulnerability of Patients With CLL

At the onset of the pandemic, hematology/oncology physicians were challenged in counseling patients with serious underlying malignant conditions about their risk for severe disease due to COVID-19. Certain patient populations were at greater risk than others, such as those who recently underwent allogeneic bone marrow transplant; however, the danger to other high-risk populations was opaquer. Emerging data identify the unique risks that patients with chronic lymphocytic leukemia (CLL) face across all stages of the disease spectrum in the setting of COVID-19 exposure, specifically the reduced response to currently available vaccines. Given the sizable prevalence of CLL in the United States (estimated at 195,129 cases in 2018),¹ an understanding of these risks is important to optimally educate and treat patients with CLL as the pandemic remains a formidable threat with deaths exceeding 3 million worldwide.²

Clinicians have long known about the innate immune defects associated with CLL,³ and these arguably have never been highlighted more strongly than during the COVID-19 pandemic. Multiple abnormal cellular and humoral responses in CLL lead to defects in the immune response, including active COVID-19 infection and reduced response to vaccines.^3,4 Results from 2 large multicenter studies have demonstrated increased rates of more severe COVID-19 infection and mortality in patients with CLL.^5,6 One of these studies included 198 patients with CLL who received a diagnosis of COVID-19. Investigators found that rates of hospital and intensive care unit admissions, intubation, and mortality were similar in patients on active therapy compared with those being treated with observation or a “watch and wait” approach; the overall case mortality rate was approximately 30%.5 These data from the initial year of the pandemic were very sobering for physicians and patients.

In terms of COVID-19 response, investigators have observed that rates of seroconversion to measurable levels of antibodies against the COVID-19 spike protein are significantly lower for patients with CLL compared with patients with solid tumors and among those with other types of hematologic malignancies. For example, in a study (NCT04794387) sponsored by the Leukemia & Lymphoma Society, investigators evaluated outcomes for patients with hematologic malignancies treated with the full COVID-19 vaccine series of BNT162b2 (PfizerBioNTech) or mRNA-1273 (Moderna).⁷ Seropositivity to the spike protein was observed in 64.2% of patients with CLL compared with 95.1% of patients with multiple myeloma and 98.5% of patients with Hodgkin lymphoma (Figure 1⁷). The lowest rates of seroconversion to the vaccine were among patients with CLL treated with B-cell–depleting therapies: obinutuzumab (Gazyva; 18.1%), Bruton tyrosine kinase (BTK) inhibitors (42.9%-50%), and venetoclax (Vencexta; 39.3%) (Figure 2⁷).

Further, investigators reported low rates of seroconversion to the COVID-19 vaccine in a prospective Israeli study (NCT04746092) of 167 patients with CLL; the overall antibody response rate to vaccine was 39.5%.⁸ Low rates of antibody response to the vaccine in the setting were reported in patients treated with BTK inhibitors (16.0%) and venetoclax (13.6%), and were highest in patients who obtained clinical remission after treatment (79.2%) and those who were previously untreated (55.2%).⁸

Investigators at Roswell Park Comprehensive Cancer Center in Buffalo, New York, suggest that the ability to generate an antibody response to the COVID-19 vaccine may begin to improve by 9 months following completion of B-cell–depleting therapy for CLL. Retrospective data showed an improvement in antibody response from 11% in patients with active B-cell–directed therapy within 9 months of vaccination to 88% in patients who received no prior treatment or whose treatment was last administered more than 9 months prior to vaccination.⁹

These data must be interpreted through the lens of rapidly evolving clinical experience as the COVID-19 pandemic continues. Rates of seroconversion are lower for patients with CLL, but we have yet to know whether this will translate into proportionally higher rates of hospitalization, morbidity, and death from COVID-19 infection. Additional investigative efforts are needed to determine whether these rates correlate among patients with CLL who are vaccinated but not able to seroconvert by a measured antibody response and to stratify patients who develop “breakthrough infections” even after achieving a measurable antibody response.

Because the spike protein antibody only measures the humoral immunity, it is unclear to what extent cellular immunity may be promoted with the vaccine, as the full spectrum of immune response cannot be quantified by a single measure of humoral response. However, based on the previously defined humoral and cellular immune defects innate to CLL, it is reasonable to extrapolate the possibility of a less robust immune response applied to nonhumoral mechanisms as well.

As we navigate this rapidly changing landscape, it is helpful to have some guiding principles for the treatment of patients with CLL:

Given the higher rates of vaccine antibody response in the absence of recent B-cell–depleting therapy, counsel patients to complete a COVID-19 vaccination series prior to initiation therapy (ie, BTK inhibitors, venetoclax, monoclonal antibody therapy).

The measurement of antibody response to the COVID-19 spike protein is a single measure of humoral response and does not account for the T-cell response and the remainder of the complex immune cascade. Therefore, low or negative COVID19 antibodies should not discourage the recommendation for a third COVID-19 vaccination dose (with BNT162b2 or mRNA-1273) or the recommendation for CLL patients at risk of not generating a measurable antibody response to receive vaccination.

Data concerning increased risk for severe COVID-19 infection and lower rates of protection from infection with the COVID-19 vaccine are compelling and relevant talking points in educating patients and families about the importance of maintaining appropriate precautions after completing a COVID-19 vaccination series.

Given the lower rates of seroconversion among vaccinated patients with CLL, it is important to counsel patients on the importance of COVID-19 testing if symptoms develop or documented COVID-19 exposure to allow for possible administration of casirivimab and imdevimab (REGEN-COV [Regeneron]) early in the disease course.

These data and recommendations will evolve as the pandemic continues. As clinicians, we are tasked with educating ourselves and our patients on these emerging data. It is critical to be mindful of managing risks present among our most vulnerable populations, which includes all individuals with CLL regardless of their treatment or remission status.

References

1. Cancer stat facts: leukemia — chronic lymphocytic leukemia (CLL). National Cancer Institute Surveillance, Epidemiology, and End Results Program. Accessed October 21, 2021. bit.ly/3pqmSvS
2. The true death toll of COVID-19. World Health Organization. Accessed October 21, 2021. bit.ly/3B24nA7
3. Tadmor T, Welslau M, Hus I. A review of the infection pathogenesis and prophylaxis recommendations in patients with chronic lymphocytic leukemia. Expert Rev Hematol. 2018;11(1):57-70. Published correction in Expert Rev Hematol. 2018 Jan;11(1):ix.
4. Ravandi F, O’Brien S. Immune defects in patients with chronic lymphocytic leukemia. Cancer Immunol Immunother. 2006;55(2):197-209. doi:10.1007/s00262-005-0015-8
5. Mato AR, Roeker LE, Lamanna N, et al. Outcomes of COVID-19 in patients with CLL: a multicenter international experience. Blood. 2020;136(10):1134-1143. doi:10.1182/blood.2020006965
6. Scarfo L, Chatzikonstantinou T, Rigolin GM, et al. 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. Leukemia. 2020;34(9):2354-2363. doi:10.1038/s41375-020-0959-x
7. Greenberger LM, Saltzman LA, Senefeld JW, Johnson PW, DeGennaro LJ, Nichols GL. Antibody response to SARS-CoV-2 vaccines in patients with hematologic malignancies. Cancer Cell. 2021;39(8):1031-1033. doi:10.1016/j.ccell.2021.07.012
8. Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood. 2021;137(23):3165-3173. doi:10.1182/blood.2021011568
9. Ghione P, Gu JJ, Attwood K, et al. Impaired humoral responses to COVID-19 vaccination in patients with lymphoma receiving B-cell-directed therapies. Blood. 2021;138(9):811-814. doi:10.1182/blood.2021012443