COVID-19 Severity in CLL Correlates With 3 Disease Characteristics

The severity of coronavirus disease 2019 increases with age in patients with chronic lymphocytic leukemia. However, age and the existence of comorbidities may not impact death from COVID-19, according to results from a retrospective international study.

The severity of coronavirus disease 2019 (COVID-19) increases with age in patients with chronic lymphocytic leukemia (CLL). However, age and the existence of comorbidities may not impact death from COVID-19, according to results from a retrospective international study published in Leukemia.

The study was conducted through a collaboration between the European Research Initiative on CLL (ERIC) and CLL Campus. Study results came from a survey completed by 121 investigators at 118 sites around the world. Of the survey responder, 58 investigators confirmed that there were COVID-19 cases in their CLL cohort. The majority of the cases were identified in Europe (74%), followed by Asia (13.6%), Latin America (4.2%), Africa (3.4%), Canada (2.5%), and Australia (1.7%). Altogether, 156 cases of COVID-19 in patients with CLL were reported from a pool of 15,083 patients. COVID-19 cases were symptomatic and required hospitalization in 141 patients. Preventative measures for SARS-CoV-2 were reported by all but 0.8% of the sites.

“To the best of our knowledge, we present here the largest European series of patients with CLL infected by SARS-CoV-2 and experiencing COVID-19. Among the European cases (96.8% of the total) included in this project, almost 90% originated from Italy and Spain, hence mirroring the dynamics of the SARS-CoV-2 pandemic in Europe with Italy being the first country in a number of infected individuals followed by Spain, with a lower incidence,” wrote the study authors led by Paolo Ghia, MD, PhD of the Università Vita-Salute San Raffaele.

Patient data in the study was stratified by clinical and biological characteristics, like age, comorbidities, and gender. Secondly, patient data were stratified by the severity of COVID-19 and finally, by antileukemic treatment. The median age of patients assessed was 72 years (range, 48-94). The majority of patients were male (n = 126), and more patients (96%) were diagnosed with CLL than small. Lymphocytic leukemia (SLL, 3%). At the time of screening, 145 patients (76%) had comorbidities for which the mean was 2 (range, 1-9). The comorbidities found included hypertension (54%), diabetes mellitus (24%) chronic obstructive pulmonary disease (6%), cardiovascular conditions (29%), respiratory illness (14%), and other malignancies (12%). In terms of antileukemic treatment history, 38.6% of patients were previously untreated, 61.4% received prior treatment. The majority of patients (62%) had either 1 prior line of therapy or 2 prior lines (30%).

Diagnosing and Managing COVID-19 in Patients With CLL

COVID-19 in patients with CLL manifested as fever in 87% of patients, respiratory symptoms in 49%, and dyspnea in 48%. In other cases, the symptoms of COVID-19 were fatigue (17%), diarrhea (12%), myalgias/arthralgias (10%), headache (7%), nausea/vomiting (3%), and abdominal pain (2%).

In terms of disease management, 11% of patients were at-home confinement. Among the hospitalized patients with COVID-19 and CLL, 10% were hospitalized without the need for oxygen and 59% were hospitalized and required oxygen. The remaining 20% of patients were hospitalized under intensive care.

To manage both COVID-19 and CLL symptoms, antivirals were administered to 50% of patients, hydroxychloroquine, or a similar drug was administered to 76%, azithromycin was given to 47%, and interleukin (IL) 6/IL6R monoclonal antibodies were administered to the 23% of patients.

The outcome of management and treatment was COVID-19 resolution for most patients (51%), but 19% were still under medical care, and 30% of patients died, according to the most recent data. Forty-eight (31.8%) patients had 1 prior line of therapy, and 25.2% had 2 or more prior lines.

Dispositive in terms of whether COVID-19 was severe or nonsevere was characterized. A total of 151 patients were reported as having severe disease and 39 were reported as nonsevere. In the severe group, most patients were above 65 years of age, and male with a median time between CLL diagnosis and COVID-19 diagnosis of 88 days. Regarding treatment for CLL, most patients were previously treated (57.3% versus not untreated (42.7%), and 39.7 had been treated for CLL within the last 12 months. About thirty-one percent of subjects received only 1 prior line of therapy. Just over 25% of them received 2 or more prior lines of therapy. More than 2 comorbidities were observed in 30.5% of patients in the severe group and 69.5% had 2 or fewer comorbidities. Hypogammaglobulinemia was reported in more than half of the patients (55%).

In patients with nonsevere COVID-19, the median age was below 65 years for most patients (56.4%) and above 65 years for the remaining subjects. The population was predominantly male (71.9%). The median time between CLL diagnosis and COVID-19 diagnosis was 71 days in this group. In terms of prior treatment, 23.1% of patients were previously untreated and 76.9% were previously treated. The majority of patients (61.5%) had been treated for CLL within the last 12 months and 35.9% of them had 1 prior line of therapy while the remaining 41.0% had 2 or more prior lines. Greater than 2 comorbidities were reported in 30.8% of the group and 69.2% had less than 2 comorbidities. A total of 23 patients (67.6%) were reported as having hypogammaglobulinemia, while the remaining 11 patients did not have this diagnosis.

At the time of COVID-19 diagnosis, 34.2% of patients were receiving treatment for CLL, which was a Bruton’s tyrosine kinase inhibitor for 67.7%, a venetoclax (Venclexta) regimen for 13.8%, idelalisib (Zydelig) for 4.6%, chlorambucil (Leukeran) combined with obinutuzumab (Gazyva) in 4.6%, bendamustine plus rituximab (Rituxan) for 3.1%, and another therapy of chemotherapy or steroids for the remaining 6.2% of patients.

The outcome of COVID-19 in these patients was that 63.6% of the severe population was alive at data cutoff versus 97.4% of the nonsevere population (P <.00001). A total of 55 patients with severe COVID-19 or 36.4% of the severe COVID-19 population died. Only 1 patient in the nonsevere COVID-19 cohort died.

Overall Ghia et al found COVID-19 manifestations to be in line with previous reports, despite that older age correlated with the severity of COVID-19. It was written, “The presence of

3 or more comorbidities was not significantly different in patients hospitalized with severe versus nonsevere disease; moreover, the presence of hypogammaglobulinemia, a frequent laboratory finding in CLL, did not show a relevant impact on the clinical course of COVID-19 patients, probably underscoring the relevance of the inflammatory reaction rather than the viral replication (and the capacity to clear it by antibody-mediated immune response) in shaping the severity of the disease.”

How Manifestations Predict COVID-19 Outcomes in Patients with CLL

When comparing patients with severe COVID-19 who were hospitalized and/or admitted to the intensive care unit to patients with nonsevere COVID-19 who were confined at home, there were no differences in relation to gender or patients having multiple comorbidities of hypogammaglobulinemia.

There were significant differences, however, in relation to patients’ age, history of treatment for CLL, and mortality. Ghia et al noted that this conclusion was drawn from the facts that more patients (74%) of the severe group versus 43.6% in the nonsevere group were above the age of 65 years (P <.05). Also, patients with severe COVID-19 were more likely to be off CLL treatment within the last year (60.3%) compared with only 39.5% of patients with nonsevere COVID-19.

There was also a significant difference in the hospitalization rate between the severe group and nonsevere group which appeared dependent on the type of CLL treatment patients had received. Specifically, 1.6% of patients who received ibrutinib were hospitalized due to COVID-19, as were 1.8% of patients on venetoclax and 4.2% of those who received chemoimmunotherapy. Notably, patients treated with chemoimmunotherapy had a higher risk of hospitalization compared with those treated with ibrutinib (Odds ratio [OR], 2.77; 95% CI 1.51-5.10; P <.01). Treatment with chemoimmunotherapy was also more likely to lead to hospitalization for COVID-19 when compared with venetoclax treatment (OR, 2.77; 95% CI 1.02-5.54; <.05). Overall, the ibrutinib-treated patients were less likely to be hospitalized compared with patients receiving other CLL-specific treatment or those who were off treatment (OR, 0.44; 95% CI 0.20-0.96; P <.05).

“The potential impact of CLL-specific treatments on the course of COVID-19 still needs to be fully elucidated, with international guidelines suggesting careful evaluation of pros/cons of treatment interruption, in particular in patients on targeted agents,” wrote Ghia et al.

The death rates observed in the study were significantly higher among patients with severe COVID-19 compared with patients with nonsevere COVID-19 (P <.00001). Age was not a determining factor of death among these patients.

“This evidence is pointing to the fact that when severe COVID-19 occurs, it is probably the underlying leukemic disease with the typical immune dysregulation that predisposes to a dismal outcome, leveling off the death risk and overcoming the effect of age and other comorbidities,” Ghia et al wrote in conclusion.


Chia P, Scarfo L, Chatzikonstaninou, 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. Published online July 09, 2020.