From the Journals

CLL and COVID-19: Outcome trends and lessons learned



Retrospective data suggest that improvements over time in overall survival (OS) among COVID-19-infected patients with chronic lymphocytic leukemia (CLL) mirror those observed in COVID-19–infected patients in general, but the data also highlight areas for further investigation, according to the researchers.

Dr. Lindsey Roeker, a Hematologist-Oncologist at Memorial Sloan Kettering Cancer Center, New York MSKCC

Dr. Lindsey Roeker

Specifically, “the data highlight opportunities for further investigation into optimal management of COVID-19, immune response after infection, and effective vaccination strategy for patients with CLL,” Lindsey E. Roeker, MD, a hematologic oncologist at Memorial Sloan Kettering Cancer Center, New York, and colleagues wrote in a Nov. 4, 2021, letter to the editor of Blood.

The researchers noted that recently reported COVID-19 case fatality rates from two large series of patients with CLL ranged from 31% to 33%, but trends over time were unclear.

“To understand change in outcomes over time, we present this follow-up study, which builds upon a previously reported cohort with extended follow up and addition of more recently diagnosed cases,” they wrote, explaining that “early data from a small series suggest that patients with CLL may not consistently generate anti–SARS-CoV-2 antibodies after infection.”

“This finding, along with previous reports of inadequate response to vaccines in patients with CLL, highlight significant questions regarding COVID-19 vaccine efficacy in this population,” they added.

Trends in outcomes

The review of outcomes in 374 CLL patients from 45 centers who were diagnosed with COVID-19 between Feb. 17, 2020, and Feb. 1, 2021, showed an overall case fatality rate (CFR) of 28%. Among the 278 patients (75%) admitted to the hospital, the CFR was 36%; among those not admitted, the CFR was 4.3%.

Independent predictors of poor survival were ages over 75 years (adjusted hazard ratio, 1.6) and Cumulative Illness Rating Scale–Geriatric (CIRS) scores greater than 6 (aHR, 1.6).

Updated data for 254 patients diagnosed from Feb. 17 to April 30, 2020, and 120 diagnosed from May 1, 2020, to Feb. 1, 2021, showed that more patients in the early versus later cohort were admitted to the hospital (85% vs. 55%) and more required ICU admission (32% vs. 11%).

The overall case fatality rates in the early and later cohorts were 35% and 11%, respectively (P < .001), and among those requiring hospitalization, the rates were 40% and 20% (P = .003).

“The proportion of hospitalized patients requiring ICU-level care was lower in the later cohort (37% vs. 29%), whereas the CFR remained high for the subset of patients who required ICU-level care (52% vs. 50%; P = .89),” the investigators wrote, noting that “[a] difference in management of BTKi[Bruton’s tyrosine kinase inhibitor]-treated patients was observed in the early versus the later cohort.”

“In the early cohort, 76% of patients receiving BTKi had their drug therapy suspended or discontinued. In the later cohort, only 20% of BTKi-treated patients had their therapy suspended or discontinued,” they added.

Univariate analyses showed significant associations between use of remdesivir and OS (HR, 0.48) and use of convalescent plasma and OS (HR, 0.50) in patients who were admitted, whereas admitted patients who received corticosteroids or hydroxychloroquine had an increased risk of death (HRs, 1.73 and 1.53, respectively).

“Corticosteroids were associated with increased risk of death when the data were adjusted for admission status (HR, 1.8) and the need for mechanical ventilation (HR, 2.0), although they were not significantly associated with survival when the data were adjusted for use of supplemental oxygen (HR, 1.4),” they wrote, also noting that admitted patients treated with corticosteroids in the later cohort did not experience an OS benefit (HR, 2.6).

The findings mirror population-based studies with decreasing CFR (35% in those diagnosed before May 1, 2020, versus 11% in those diagnosed after that date), they said, adding that “these trends suggest that patients in the later cohort experienced a less severe clinical course and that the observed difference in CFR over time may not just be due to more frequent testing and identification of less symptomatic patients.”

Of note, the outcomes observed for steroid-treated patients in the current cohort contrast with those from the RECOVERY trial as published in July 2020, which “may be an artifact of their use in patients with more severe disease,” they suggested.

They added that these data “are hypothesis generating and suggest that COVID-19 directed interventions, particularly immunomodulatory agents, require prospective study, specifically in immunocompromised populations.”

The investigators also noted that, consistent with a prior single-center study, 60% of patients with CLL developed positive anti–SARS-CoV-2 serology results after polymerase chain reaction diagnosis of COVID-19, adding further evidence of nonuniform antibody production after COVID-19 in patients with CLL.

Study is ongoing to gain understanding of the immune response to SARS-CoV-2 vaccination in patients with CLL, they said.

Changing the odds

In a related commentary also published in Blood, Yair Herishanu, MD, and Chava Perry, MD, PhD, of Tel Aviv Sourasky Medical Center called the reduction in mortality over time as reported by Dr. Roeker and colleagues “encouraging and intriguing.”

“One explanation is that the later cohort included a larger proportion of patients with mild symptoms who were diagnosed because of increased awareness of COVID-19 and more extensive screening to detect SARS-CoV-2 over time. That is supported by the lower hospitalization rates and lower rates of hospitalized patients requiring ICU care in the later cohort,” they wrote. “Another possibility is better patient management owing to increasing experience, expanding therapeutic options, and improved capacity of health systems to manage an influx of patients.”

The lower mortality in hospitalized patients over time may reflect better management of patients over time, but it also highlights the significance of “early introduction of various anti–COVID-19 therapies to prevent clinical deterioration to ICU-level care,” they added.

Also intriguing, according to Dr. Herishanu and Dr. Perry, was the finding of increased secondary infections and death rates among corticosteroid-treatment patients.

In the RECOVERY trial, the use of dexamethasone improved survival in patients hospitalized with COVID-19 who received respiratory support. Perhaps the impaired immune reactions in patients with CLL moderate the hyperinflammatory reactions to COVID-19, thus turning corticosteroids beneficial effects to somewhat redundant in this frail population,” they wrote.

Further, the finding that only 60% of patients with CLL seroconvert after the acute phase of SARS-CoV-2 infection suggests CLL patients may be at risk for reinfection, which “justifies vaccinating all patients with CLL who have recovered from COVID-19.”

“Likewise, patients with CLL may develop persistent COVID-19 infection,” they added, explaining that “prolonged shedding of infectious SARS-CoV-2 virus and within-host genomic evolution may eventually lead to emergence of new virus variants.”

Given the high risk of severe COVID-19 disease and impaired antibody-mediated immune response to the virus and its vaccine, a booster dose may be warranted in patients with CLL who fail to achieve seropositivity after 2 vaccine doses, they said.

The available data to date “call for early application of antiviral drugs, [monoclonal antibodies], and convalescent plasma as well as improved vaccination strategy, to improve the odds for patients with CLL confronting COVID-19,” they concluded, adding that large-scale prospective studies on the clinical disease course, outcomes, efficacy of treatments, and vaccination timing and schedule in patients with CLL and COVID-19 are still warranted.

The research was supported by a National Cancer Institute Cancer Center support grant. Dr. Roeker, Dr. Herishanu, and Dr. Perry reported having no financial disclosures.

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