The Outcomes of Covid-19 in Patients with CLL during the Omicron Sub-Variants Surge

Introduction: Patients with chronic lymphocytic leukemia (CLL) infected with SARS-CoV-2 are at increased risk of severe Covid-19 and death, because of an impaired immune system and suboptimal immunity after vaccination. Despite recent studies, the outcomes of patients with CLL infected with the Omicron sub-variants are not fully elucidated.

Methods: In this single-center retrospective study, we analyzed the clinical outcomes of CLL patients infected with SARS-CoV-2 from December 2021 through July 2022. The entire cohort was divided into three groups according to the SARS-CoV-2 variants dominating periods in Israel; period #1, since December 15^th, 2021 until March 13^th, 2022 (B.1.1.529, BA.1), period #2, since March 14^th until June 5^th, 2022 (BA.2) and period #3, since June 6^th until July 24^th, 2022 (BA.5).

Results: A total of 90 patients were included in this study (Table 1). The median age was 72 years (range 39-93) and 66 were males (73.3%). Thirty-four patients (37.8%) were treatment naïve, 45 (50.0%) on active treatment (28 treated with Bruton's tyrosine kinase inhibitors [BTKi], 16 with venetoclax+anti-CD20 therapy, and 1 with venetoclax monotherapy), and 11 (12.2%) previously treated. Eighty-seven patients (96.7%) had Covid-19-related symptoms, most commonly fatigue (n=50, 55.6%), followed by cough (n=43, 47.8%) and fever (n=37, 41.1%). Eighty-five patients (94.4%) were vaccinated with at least 3 doses of the BNT162b2 mRNA vaccine.

During the study's follow-up period (median=120 days, range 4-221), 2 patients (2.2%) were re-infected with SARS-CoV-2. The severity of Covid-19 on detection was mild in 78 patients (86.7%) and moderate/severe in 12 patients (13.3%). Forty-eight patients (53.3%) were treated with oral antiviral drugs or monoclonal antibodies (40 with paxlovid, 7 with molnupiravir and 1 with casirivimab/imdevimab) outside the hospital. Nine patients developed mild Covid-19 despite administration of pre-exposure prophylaxis with tixagevimab/cilgavimab (median=49 days [range, 7-102] prior to infection). Twenty-seven patients (30.0%) were hospitalized, 15 (55.6%) of them due to severe/critical Covid-19. The median time from SARS-CoV-2 diagnosis to hospitalization was 9 days (range, 0-36). Fifteen hospitalized patients (55.6%) required oxygen support and 2 (7.4%) eventually needed mechanical ventilation. Nine patients (33.3%, 9/27) were readmitted because of persistent SARS-CoV-2 infection, including 6 patients (66.7%) who were hospitalized twice and 3 patients (33.3%) three times. Four patients with persistent Covid-19 after a course of antiviral therapy were subsequently successfully treated with paxlovid and remdesivir. The overall 30-day mortality due to Covid-19 was 6.7% (6/90, 22.2% [6/27] of the hospitalized patients).

In comparison between the 3 different time periods (Figure 1), both the hospitalization and death rates were higher in the period #1 (hospitalization rate of 42.9% [21/49] vs. 20.0% [5/25] vs. 6.3% [1/16] in period #1, #2, and #3, respectively and a mortality rate of 12.2% [6/49] in period #1 compared with 0% [0/25] in period #2 and 0% [0/16] in period #3). In univariate analysis, the independent variables associated with hospitalization included: period #1 (OR=4.4, 95% CI 1.6-12.3; p=0.007), active anti-CLL therapy (OR=3.8, 95% CI 1.3-8.9; p=0.021), and fever (OR=3.7, 95% CI 1.4-9.4; p=0.012).

Conclusions: In patients with CLL, the rates of hospitalization and mortality due to Covid-19 were lower during the BA.2 and BA.5 sub-variants dominating period compared to the period dominated by the Omicron (B.1.1.529) and the BA.1 sub-variant. The improved outcomes may be attributed to better clinical management (e.g. pre-exposure prophylaxis and antiviral therapies) and viral strain properties.

Herishanu:Medison: Honoraria; BeiGene: Honoraria; Janssen: Honoraria; AbbVie: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria.