The extensive Danish testing strategy and the access to the nationwide collection of PCR data made it possible to present COVID-19 data among CLL patients treated with venetoclax. The highest rate of positive PCR tests in Denmark was 33.99% in February 2022 and the average positive rate during the entire pandemic was estimated to be 5.03% (https://ourworldindata.org/coronavirus/country/denmark). The testing frequency was particularly high among patients who were at high risk for developing severe COVID-19 illness, including patients with hematologic malignancies. We present real-world data from a single-institution observational study of COVID-19 infections in an unselected CLL/SLL cohort treated with venetoclax. The clinical presentation in our cohort is comparable to similar studies, except for a relatively high rate of patients with unmutated IGHV and TP53 disruption. Almost all patients (98%) had received a full COVID-19 vaccination program. Among patients with available assessments of vaccine antibody responses, an adequate response could be demonstrated in 47%. This is consistent with a recent study reporting a serological response in > 40% of patients treated with venetoclax but humoral responses to vaccines were significantly higher in treatment-naïve CLL patients [17]. The incidence of COVID-19 in our cohort was 44%, in accordance with the general Danish population between March 2020 and March 2023 (54%) (https://www.sst.dk/da/corona/Status-og-materiale/Coronatal). Most patients presented with COVID-19 during the Omicron era (75%) and 25% of the patients developed severe/critical COVID-19 disease. Dose reductions of venetoclax were slightly more frequent in the group of patients with COVID-19 infection. The distributions of baseline clinical features were similar in patients with and without COVID-19 infection. Half of the COVID-19 patients were hospitalized but no ICU admissions were registered. Other studies of CLL patients and COVID-19 show similar hospitalization rates but notable higher ICU admission rates at 19–22% [6, 7]. Routine PCR testing at our center could have made early detection and intervention with antiviral antibodies more likely. This may have contributed to the low ICU admission rate.
The 30-day mortality rate was found to be lower than expected with only two deaths (4%), both occurring in patients with severe comorbidities as the primary cause of death. We observed a similar 30-day mortality rate of 6% in CLL patients not being treated with venetoclax and the survival probability at 90 days was not significantly different between the venetoclax-treated and venetoclax-naïve cohorts. However, higher mortality rates of 19–33% among CLL patients have been reported in other studies [3, 18]. In a recent large clinical trial of first-line venetoclax combinations, COVID-19 was detected in a small subgroup with 4/45 (9%) deaths in venetoclax-treated patients with COVID-19 and 2/10 (20%) deaths in chemoimmunotherapy-treated patients [11]. These mortality rates are higher compared to our data, but the study was primarily conducted during the start of the pandemic. In a recent Danish nationwide study, a CLL cohort with a positive SARS-CoV-2 PCR test and a subgroup of CLL patients tested positive at hospital test sites presented with a 30-day mortality rate of 2% and 23%, respectively [4]. The 30-day mortality of the total cohort was 4.7%, which is comparable to the findings of our study. The low mortality rates may partly be explained by most patients in both studies being diagnosed with SARS-CoV-2 in the late period of the pandemic. In this period, better treatment opportunities with antiviral antibodies were available and the milder Omicron BA.1 variant was dominant. The hospitalization rate in the Danish population-based study was slightly higher (68%) compared to our data (46%) [4]. The rates of ICU admission were 8.5% and 0%, respectively despite our cohort being characterized by patients with more severe CLL according to Binet stage, unmutated IGHV and TP53 disruption status. This comparison, therefore, points towards a generally mild course of COVID-19 infections among patients treated with venetoclax.
In our study, patients in ongoing venetoclax treatment required more intensive treatment with antiviral antibodies, antiviral drugs and antibiotics compared to patients with COVID-19 after discontinuation of venetoclax. In general, infections are relatively common in patients treated with venetoclax. Multiple studies had shown grade 3–4 infection rates at estimated 20% in patients during treatment, most frequently pneumonia, sepsis or febrile neutropenia [9, 19]. Furthermore, cytopenia including neutropenia are one of the most common grade 3–4 adverse events related to venetoclax [20]. However, our real-life data has shown that infections with COVID-19 generally has a mild and manageable course in venetoclax treated patients and a very low mortality mostly related to accompanying comorbidities.
In vitro studies investigated the ability of venetoclax to bind and degrade the spike protein in SARS-CoV-2 [14, 21]. The pharmacological properties and the abilities to interact with the spike protein of SARS-CoV-2 were investigated. Venetoclax was able to degrade the expression of the spike protein and blocking the virus’ interaction with the ACE-2 receptor. These findings indicate that blocking the interaction between the spike protein and the ACE-2 receptor potentially prevent the virus’ entry into the host cell. Venetoclax may therefore express some properties with a protective effect against severe COVID-19 disease.
The present study has some limitations, including a small sample size, missing data on some SARS-COV-2 variants and partly missing data on antibody levels. The size of the cohort did not allow more extended analyses with most data being descriptively presented. Furthermore, our comparison with a heterogeneous venetoclax-naïve CLL cohort must be taken with some caution. However, our data clearly suggest that CLL patients who are treated with venetoclax generally present with manageable COVID-19 and a low mortality rate. Compared with data of general CLL populations, venetoclax-treated patients in our cohort had a mild course of COVID-19 and suggest that venetoclax is a safe treatment option for CLL patients with adequately treated COVID-19.