COVID-19 severity in patients with chronic lymphocytic leukemia treated with venetoclax: a single-center observational cohort study

COVID-19 severity in patients with chronic lymphocytic leukemia treated with venetoclax: a single-center observational cohort study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article COVID-19 severity in patients with chronic lymphocytic leukemia treated with venetoclax: a single-center observational cohort study Sophie Thau, Christian Bjørn Poulsen, Christian Brieghel, Morten Kranker Larsen, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3750075/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Apr, 2024 Read the published version in Annals of Hematology → Version 1 posted 7 You are reading this latest preprint version Abstract Patients with chronic lymphocytic leukemia (CLL) are at high risk of developing severe COVID-19. The present study was undertaken to elucidate COVID-19 related morbidity and mortality in CLL patients treated with venetoclax. We present a single-center study of 108 patients with small lymphocytic lymphoma or CLL treated with venetoclax. Primary outcome was 30-day COVID-19 mortality. Secondary outcomes included COVID-19 severity and hospitalization rate. Forty-eight (44%) patients had PCR-verified SARS-COV-2 between March 2020 and January 2023. Thirty-six patients (75%) presented with asymptomatic/mild COVID-19 and 12 (25%) with severe/critical disease. The hospitalization rate was 46% with a 30-day mortality rate of only 4% and severe comorbidities as the primary cause of death. There was no significant difference in mortality when compared to venetoclax-naïve CLL patients (n = 90) from our single-center cohort with proven COVID-19. COVID-19 severity and mortality were similar before and during the Omicron era. High CIRS-scores (P < 0.02) and thrombocytopenia (P < 0.01) were more frequent in patients with severe/critical disease. In real-world data, most venetoclax treated patients presented with mild COVID-19. Hospitalization and mortality rates were low compared to data of general CLL populations. Our data indicate that venetoclax was a safe treatment option for CLL patients during the pandemic. CLL (chronic lymphocytic leukemia) Small lymphocytic lymphoma Venetoclax COVID-19 Figures Figure 1 Figure 2 Introduction Chronic lymphocytic leukemia (CLL) patients diagnosed with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are at high risk of hospitalization and death [ 1 ]. Risk factors for severe coronavirus disease 2019 (COVID-19) infections including hypogammaglobulinemia, B and T-cell defects, CD4 + lymphopenia, neutropenia, innate immune dysfunction, treatment with anti-CD20 targeting agents, and age-related medical conditions are often present in CLL patients [ 2 ]. Early studies of COVID-19 and CLL have indicated high mortality rates at approximately 30% among hospitalized patients [ 1 , 3 ]. The majority of COVID-19 positive CLL patients required hospitalization, especially in the beginning of the pandemic [ 3 – 5 ]. The rates for intensive care unit (ICU) admission and intensive treatments with oxygen supplements and mechanical ventilation were also excessive compared to patients without a hematological disease ​ [ 6 ]. High age, poor performance status, anemia and thrombocytopenia were among risk factors for developing severe COVID-19 [ 7 ]. Over the past decade, treatment of CLL has shifted from chemoimmunotherapy to targeted therapy [ 8 ]. Targeting B cell lymphoma 2 (BCL-2) with venetoclax in combination with anti-CD20 antibodies has improved clinical outcomes in patients with CLL both in treatment naïve patients and in the relapsed/refractory setting [ 9 , 10 ]. A fixed-duration venetoclax in combination with obinutuzumab is a recommended first-line treatment for patients with CLL and small lymphocytic lymphoma (SLL)​, and venetoclax in combination with rituximab is a recommended second-line treatment [ 9 – 11 ]. Venetoclax has demonstrated an overall acceptable toxicity profile in patients with CLL. However, among the most common grade 3/4 adverse events are neutropenia, febrile neutropenia, pneumonia, and sepsis [ 12 ]. There are few available data on COVID-19 in patients receiving venetoclax-based treatments. A study has suggested that venetoclax blocks the interaction between the SARS-CoV-2 spike (S) glycoprotein and the angiotensin-converting enzyme 2 receptor through spike protein degradation [ 13 ]. Venetoclax may therefore exhibit protective mechanisms against COVID-19 by inhibiting viral nucleic acid sequences to enter the host cell. In agreement with these observations, a recent study reported only two (7%) hospitalizations and/or deaths after contracting COVID-19 among 27 CLL patients receiving venetoclax, and no events were recorded in patients receiving nirmatrelvir plus ritonavir [ 14 ]. Other studies have proposed that treatment with venetoclax is correlated with higher immunogenicity and seroconversion rates after COVID-19 booster vaccines compared to ibrutinib [ 15 ] ​ . Here we present real-world data of the frequency, severity and mortality of COVID-19 in an observational single-center study of CLL and SLL patients consecutively treated with venetoclax during the COVID-19 pandemic. Our data were collected during both the pre- and post-vaccine era as well as the pre-Omicron and Omicron wave. Methods Patients Patients diagnosed with CLL or SLL and treated with venetoclax were included in an observational single-institution study. Patients were identified in the electronic patient health record platform (EPIC). Venetoclax treatment was initiated between April 2017 and December 2022. Patients were treated with standard ramp up and steady state dose of venetoclax. Dose level and duration of treatment varied depending on tolerability and efficacy. SARS-CoV-2 testing COVID-19 was defined as a positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) test. Local guidelines at our institution included testing of all hematological patients upon admission or out-patient visits, and mass screening twice a week during surges. A high frequency of positive SARS-CoV-2 samples were whole genome sequenced and the information on SARS-CoV-2 including sublineage was retrieved from the Danish national microbiology database ( https://www.covid19genomics.dk/nextstrain ) [ 16 ]. We used a cut-off point corresponding to January 2022 to compare patients with COVID-19 before and during the Omicron era. The Omicron subvariants were dominating in Denmark since January 2022, including the most frequent variant B.1.1.529​ [ 4 ]. Prior to this, Delta B.1.617.2 (original Delta variant) and Delta AY.4.2 (Delta plus variant) were the dominating variants. The Danish COVID-19 Genome Consortium (DCGC) provided data on the SARS-CoV-2 subvariants. Clinical data collection Data were collected from electronic patient records between August 2022 and January 2023. Baseline characteristics and clinical outcomes were recorded including severity and mortality of COVID-19 infections. The primary outcome of the study was 30-day COVID-19 mortality rate, defined by death within 30 days from positive PCR test. Secondary outcomes included COVID-19 severity, hospitalization rate, admission rate to ICU, 90-day COVID-19 mortality, and treatments of COVID-19. Survival data were also recorded in our venetoclax-naïve patients with CLL/SLL and a positive SARS-CoV-2 PCR test. Secondary infections were recorded and defined as clinically (e.g., clinical examination, laboratory test results or imaging) or microbiologically proven infections occurring within a 2-month period after a positive PCR test. Statistics All data were registered in a local secured research database (REDCap). Statistical analyses were performed in R software (version 4.2.3). Clinical variables were summarized using descriptive statistics. Categorical variables are presented as numbers and percentages and continuous variables as median and ranges or interquartile ranges (IQR). Categorical variables were analyzed by Fisher’s exact test. 30-day COVID-19 mortality rate was estimated as the proportion alive 30 days after verified SARS-CoV-2 infection. The hospitalization rate was measured as the proportion of patients with hospitalization of minimum 24-hours duration within 30-days from a positive PCR test. ICU admission rate was calculated as the proportion of patients admitted to an ICU within one month of verified infection. Overall survival (OS) in venetoclax-treated and venetoclax-naïve patients with CLL/SLL and proven COVID-19.was measured from the date of verified infection until death or censoring 90 days after SARS-CoV-2 infection, whichever came first. Time-to-event analyses were performed using Kaplan-Meier plots and log-rank test was used for the comparison of survival in different groups. The level of statistical significance was defined as P < 0.05. Results Patient characteristics We identified 112 patients with CLL or SLL treated with venetoclax. Four patients with COVID-19 infection prior to initiation of venetoclax were excluded. Of the remaining 108 patients, 48 (44%) patients had a positive SARS-CoV-2 PCR test after initiation of venetoclax treatment. Flowchart of clinical subgroups in the study cohort is provided in Fig. 1 . We identified the SARS-CoV-2 variant in 27/48 (56%) patients, with 6 cases of B.1.617.2 (Delta-variant) and 21 cases of B.1.1.529 (Omicron-variant). The distribution of SARS-CoV-2 variants was in accordance with our cut-off point with a case of B.1.617.2 (Delta-variant) detected in 2022 as the only exception. Most patients (98%) had received the recommended number of vaccines in Denmark with 92% being vaccinated with ≥ 4 doses. Sufficient vaccine antibody response measured with enzyme-linked immunosorbent assay (ELISA) was observed in 15/32 (47%). Baseline clinical characteristics of the total cohort and for patients with and without COVID-19 are shown in Table 1 . In the total cohort (n = 108), median (range) age was 71 years (47–89) and 77 (71%) were males. No significant differences in frequencies of baseline features were found between patients with and without COVID-19 with only a trend toward lower steady state dose of venetoclax in the cohort with COVID-19 (P = 0.05). The most frequent causes of dose reduction were toxicity including gastrointestinal symptoms and neutropenia. Median (range) lines of therapy prior to venetoclax were 1 (0–6). The treatment regimens were combined venetoclax and CD20-antibodies including rituximab or obinutuzumab (n = 95), venetoclax and BTKi including ibrutinib or acalabrutinib (n = 11), or venetoclax monotherapy (n = 9). Four patients received a rituximab-obinutuzumab-venetoclax combination, two patients received an obinutuzumab-ibrutinib-venetoclax combination, and one patient received an obinutuzumab-acalabrutinib-venetoclax combination. The median (IQR) duration of venetoclax treatment was 13 months (12–24). COVID-19 infection was detected during ongoing venetoclax treatment in 29/48 (60%) and after discontinuation of venetoclax in 19/48 (40%). Median (IQR) time between initiation of venetoclax and a positive SARS-CoV-2 PCR test was 19 months (8–26). Table 1 Clinical characteristics at initiation of venetoclax treatment Variables Cohort with COVID-19 (n = 48) Cohort without COVID-19 (n = 60) Total cohort (n = 108) Age ≥70 years 26 (54%) 38 (63%) 64 (59%) Gender male 31 (65%) 46 (77%) 77 (71%) Binet stage C 21 (44%) 32 (53%) 53 (49%) Genetics: Del(11q) 13 (27%) 17 (28%) 30 (28%) TP53 disruption 8 (26%) 18 (42%) 26 (35%) Missing 34 (31%) IGHV unmutated 26 (66%) 37 (74%) 63 (71%) Missing 19 (18%) CLL treatments: ≥ 1 prior lines of therapy 28 (58%) 42 (70%) 70 (65%) Treated with venetoclax + CD20 antibody 41 (85%) 50 (83%) 91 (84%) Treated with venetoclax + BTK inhibitor 7 (15%) 4 (7%) 11 (10%) Treated with venetoclax monotherapy 2 (4%) 7 (12%) 9 (8%) Reduced venetoclax steady state (< 400 mg) 17 (35%) 13 (22%) 30 (28%) Blood analyses: Hemoglobin ≤ 10 g/dL 7 (15%) 10 (17%) 17 (16%) Missing 2 (2%) Thrombocytes ≤ 100x10 9 /L 8 (17%) 11 (18%) 19 (18%) Missing 2 (2%) IgG ≤ 6 g/L 24 (57%) 26 (45%) 50 (50%) Missing 8 (7%) Supportive G-CSF 21 (44%) 25 (42%) 46 (43%) Comorbidity: CIRS score ≥ 6 24 (50%) 36 (60%) 60 (56%) History of diabetes 5 (10%) 11 (19%) 16 (15%) History of pulmonary disease 13 (27%) 17 (28%) 30 (28%) Active smoker 9 (19%) 9 (15%) 18 (17%) History of cardiovascular disease 18 (38%) 26 (43%) 44 (41%) History of kidney disease 5 (10%) 10 (17%) 15 (14%) BMI ≥ 25 33 (69%) 38 (63%) 71 (66%) COVID-19 severity and mortality Most patients presented with mild symptoms or asymptomatic COVID-19 disease (75%) and the hospitalization rate at 30 days was 46%. No significant differences in severity were detected between patients with COVID-19 during and after the pre-Omicron era (Table 2 ). Three patients (6%) experienced reactivation of the same SARS-CoV-2 origin within 2 months after a negative PCR test. Two patients experienced reactivation with the B.1.1.539-variant (Omicron type) and one patient had reactivation with the B.1.617-variant (Delta type) with all 3 cases of reactivation being symptomatic. Distribution of clinical characteristics at initiation of venetoclax between patients with asymptomatic/mild disease and patients with severe/critical disease is shown in Table 3 . Only thrombocytopenia and high CIRS-score were found with a significantly higher frequency in patients with severe/critical disease. Treatments of the COVID-19 infection are shown in Table 4 . The antiviral treatment was given according to Danish national guidelines. Patients with ongoing venetoclax treatment more frequently received treatments with antiviral antibodies (24/29 (83%) and 10/19 (53%), respectively; P = 0.04), other antiviral drugs (13/29 (45%) and 2/19 (11%), respectively; P = 0.02), and antibiotics (15/29 (52%) and 6/19 (32%), respectively; P < 0.01). Table 2 COVID-19 outcomes according to SARS-CoV-2 variants Outcome COVID-19 pre-Omicron (n = 12) COVID-19 Omicron-era (n = 36) COVID-19 total cohort (n = 48) Asymptomatic or mild COVID-19 disease 9 (75%) 27 (75%) 36 (75%) Severe or critical COVID-19 disease 3 (25%) 9 (25%) 12 (25%) Hospitalization 6 (50%) 16 (44%) 22 (46%) Pulmonary infiltrates on X-ray 5 (42%) 8 (22%) 13 (27%) SpO2 < 90% 1 (8%) 7 (19%) 8 (17%) ICU admission 0 0 0 Table 3 Distribution of baseline clinical features at initiation of venetoclax in patients with asymptomatic/mild and severe/critical COVID-19 Variables Asymptomatic/mild disease (n = 36) Severe/critical disease (n = 12) P value Age ≥ 70 years 19 (53%) 7 (58%) 1 Gender male 22 (61%) 9 (75%) 0.50 Binet stage C 13 (36%) 8 (67%) 0.09 TP53 disruption 6 (17%) 1 (8%) 0.66 Missing 13 (36%) 4 (33%) IGHV unmutated 19 (53%) 7 (58%) 1 Missing 5 (14%) 4 (33%) Hemoglobin ≤ 10 g/dL 6 (17%) 1 (8%) 1 Missing 1 (3%) 1 (8%) Thrombocytes ≤ 100x10 9 /L 6 (17%) 4 (33%) < 0.01 Missing 1 (3%) 1 (8%) IgG ≤ 6 g/L 22 (69%) 7 (70%) 1 Missing 4 (11%) 2 (17%) CIRS-score ≥ 6 14 (39%) 10 (83%) < 0.02 Diabetes 4 (11%) 1 (8%) 1 Pulmonary disease 7 (19%) 6 (50%) 0.08 Cardiovascular disease 13 (36%) 5 (42%) 0.74 BMI ≥ 25 25 (69%) 8 (66%) 1 Table 4 COVID-19 treatments Treatment COVID-19 cohort (n = 48) Dexamethasone 10 (21%) Anticoagulants 11 (23%) Antiviral antibodies (sotrovimab, tixagevimab/cilgavimab, casirivimab/imdevimab) 34 (71%) Other antivirals (remdesivir, nirmatrelvir/ritonavir) 15 (31%) Treated with oxygen supplements 10 (21%) Antibiotics 21 (44%) No treatments 12 (25%) Only two patients died within 30 days of a positive SARS-CoV-2 PCR test. Both deaths were regarded as non-related to COVID-19 infection. In one case the primary cause of death was given as pulmonary cancer and in the other case as Richter’s transformation. No additional deaths were observed 90 days after a positive SARS-CoV-2 PCR test. The 30-day mortality rates in the venetoclax-treated and venetoclax-naïve cohorts were 2/48 (4%) and 9/90 (10%), respectively (P = 0.32). The 90-day OS of the two cohorts is shown in Fig. 2 . Treatments in the venetoclax-naïve group consisted of combined chemoimmunotherapy and anti-CD20, other targeted treatments including BTKi, or watch-and-wait. The frequency of patients with advanced disease was higher in the venetoclax-treated cohort with a total of 21/48 (44%) presenting with Binet stage C while the frequency was 19/90 (21%) in the venetoclax-naïve cohort. The overall frequency of deaths in our single-center CLL/SLL cohort of patients without proven COVID-19 infection was 1% in the corresponding period. Secondary infections In the cohort of patients treated with venetoclax (n = 48), secondary infections were observed in 17 (35%) patients while 21 (44%) of the patients were treated with antibiotics. The infections were either verified clinically (e.g., clinical examination or pulmonary infiltrates on imaging) or by microbiological detection of pathogens. Most cases were pneumonias, upper respiratory or urinary tract infections. A pseudomembranous colitis was observed in one case. No systemic mycoses or other severe fungal infections were detected. The most common pathogen was Haemophilus influenzae (3 cases). All cases of secondary infections including microbiological pathogens are detailed in Table 5 . Table 5 Secondary infections after COVID-19 (within 2 months from positive PCR test) Focus of infection Detected pathogen Clinical signs of infection Pneumonia Influenza A virus Pulmonary infiltrates (X-ray), symptoms of pneumonia Pneumonia None Pulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels Pneumonia None Pulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels Pneumonia None Pulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels Pneumonia None Symptoms of pneumonia, increasing CRP levels Upper respiratory infection / otitis media Haemophilus influenzae Symptoms of upper respiratory infections and otitis media, increasing CRP levels Urinary tract infection Escherichia coli Symptoms of urinary tract infection Pneumonia Haemophilus influenzae Pulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels Gastroenteritis Rotavirus Symptoms of gastroenteritis, increasing CRP levels Pneumonia None Pulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels Pneumonia Haemophilus influenzae Pulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels Urinary tract infection Citrobacter freundii, Morganella morganii Symptoms of urinary tract infection, increasing CRP levels Pneumonia Respiratory syncytial virus Pulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels Pneumonia Streptococcus pneumoniae, Moraxella catarrhalis Symptoms of pneumonia, increasing CRP Urinary tract infection and pseudomembranous colitis Proteus mirabilis (urine), Clostridium difficile (faeces) Symptoms of urinary tract infection and pseudomembranous colitis, increasing CRP Pneumonia None Symptoms of pneumonia, increasing CRP Pneumonia None Pulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels Discussion 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. Declarations Ethical approval: The study was approved by the regional Data Protection Agency (ID: EMN-2022-11065). Consent to participate: Informed consent was provided by patients alive at follow-up. Conflict of interests: CB has received honoria from Octapharma and AstraZeneca. The remaining authors have nothing to disclose. Funding: This work was funded by Region Zealand, DK (ID: EMN-2022-00760). Author Contribution S.T. collected data, interpreted analyses and wrote the first draft of the manuscript; C.B.P. and L.M.P. designed the study, collected data and interpreted analyses; C.B. collected data and interpreted analyses; M.K.L. performed statistical analyses; L.W. interpreted analyses; X.C.N. collected data and interpreted analyses. All authors contributed to the editing of the manuscript. All authors read and approved the final manuscript. Acknowledgement: We thank the Danish COVID-19 Genome Consortium (DCGC) for providing data on the SARS-CoV-2 subvariants in our patients. Data availability: Data were collected and managed using the REDCap electronic data capture tool hosted at Ascension. Data are available from the corresponding author upon reasonable request. The individual level data collected during the study are not publicly available due to protection of participants privacy and ethical restrictions. 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Eur J Haematol 106(1):72–81. https://doi.org/10.1111/ejh.13519 Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF et al (2016) Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 374(4):311–322. https://doi.org/10.1056/nejmoa1513257 Ruiz-Camps I, Aguilar-Company J (2021) Risk of infection associated with targeted therapies for solid organ and hematological malignancies Ther. Adv Infec Dis 8:2049936121989548. https://doi.org/10.1177/2049936121989548 Ghosh S, Bhattacherjee D, Satpati P, Bhabak KP (2022) Venetoclax: a promising repurposed drug against SARS-CoV-2 main protease. J Biomol Struc Dyn 40(22):12088–12099. https://doi.org/10.1080/07391102.2021.1967786 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 18 Apr, 2024 Read the published version in Annals of Hematology → Version 1 posted Editorial decision: Revision requested 05 Mar, 2024 Reviews received at journal 09 Jan, 2024 Reviewers agreed at journal 27 Dec, 2023 Reviewers invited by journal 27 Dec, 2023 Submission checks completed at journal 26 Dec, 2023 Editor assigned by journal 26 Dec, 2023 First submitted to journal 13 Dec, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3750075","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":263765422,"identity":"f7aecaf8-d2e3-4143-90a5-8ea6163f8015","order_by":0,"name":"Sophie Thau","email":"","orcid":"","institution":"Zealand University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Sophie","middleName":"","lastName":"Thau","suffix":""},{"id":263765430,"identity":"9ce67fa7-7196-412c-a4aa-dc1655b706da","order_by":1,"name":"Christian Bjørn Poulsen","email":"","orcid":"","institution":"Zealand University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"Bjørn","lastName":"Poulsen","suffix":""},{"id":263765431,"identity":"67594e84-c83f-4146-a96a-3fb9434138e5","order_by":2,"name":"Christian Brieghel","email":"","orcid":"","institution":"Zealand University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Brieghel","suffix":""},{"id":263765432,"identity":"bab18d7a-4e51-4261-8dee-525299b17547","order_by":3,"name":"Morten Kranker Larsen","email":"","orcid":"","institution":"Zealand University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Morten","middleName":"Kranker","lastName":"Larsen","suffix":""},{"id":263765434,"identity":"8075f589-64a2-4b0a-9517-ba35e5f79bc5","order_by":4,"name":"Lothar Wiese","email":"","orcid":"","institution":"Zealand University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lothar","middleName":"","lastName":"Wiese","suffix":""},{"id":263765436,"identity":"c1e66940-2c7d-47c9-8b69-e979cf839659","order_by":5,"name":"Xiaohui Chen Nielsen","email":"","orcid":"","institution":"Zealand University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaohui","middleName":"Chen","lastName":"Nielsen","suffix":""},{"id":263765438,"identity":"ed176e33-12ef-400f-b3a5-cf79ec85d852","order_by":6,"name":"Lars Møller Pedersen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYBACPhDxAYjZQAwJBgYZPjDNloBTC0gl4wwkLTxsxGhh5kESIEKL2Nljj2332Nj1sfce/mBRY8PDxn724A2GsjTcWqTz0o1znqUlt/GcS5OQOJbGw8aTl2zBcC4Hj5YcM+mcA4eT2SRyzBgk2A4DHZZjJsHYVoFfi8WB/yAtxh8k/v3nYeN/Q4QWhgMH7IBaDCQk2w7wgKwDasHnsLw0yZ4DyQlsPGfMJCT7koFa3hhbJJzD7X1+6dxjEj8O2NnLt/cYf5b4ZifHz59jeONDWTJOLcCIAJOJDUCCWQImmIBHA0yLPYhg/IBX5SgYBaNgFIxUAABSM0QLXQZqsQAAAABJRU5ErkJggg==","orcid":"","institution":"Zealand University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Lars","middleName":"Møller","lastName":"Pedersen","suffix":""}],"badges":[],"createdAt":"2023-12-13 19:59:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3750075/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3750075/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00277-024-05738-4","type":"published","date":"2024-04-18T22:54:35+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49078018,"identity":"44b13b38-5328-4322-a66b-9fbd6e946598","added_by":"auto","created_at":"2024-01-02 19:14:03","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23900,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart with stratification of the study cohort\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3750075/v1/877613441e7553843ee7b673.png"},{"id":49078017,"identity":"33a9fe16-e1ff-49c2-b8c9-142c92255b58","added_by":"auto","created_at":"2024-01-02 19:14:03","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":31784,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier plots of survival probability in the cohort of CLL patients with confirmed COVID-19 in patients treated with venetoclax (n=48) and venetoclax-naïve patients (n=90)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3750075/v1/92a7a47b2403a9078f186630.png"},{"id":55691647,"identity":"67c39a10-a2ee-4127-bc56-e42b4a5bfe46","added_by":"auto","created_at":"2024-05-01 23:27:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":701253,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3750075/v1/46a442f5-73a1-4cd9-88c2-f9f004bafb2a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"COVID-19 severity in patients with chronic lymphocytic leukemia treated with venetoclax: a single-center observational cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChronic lymphocytic leukemia (CLL) patients diagnosed with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) are at high risk of hospitalization and death [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Risk factors for severe coronavirus disease 2019 (COVID-19) infections including hypogammaglobulinemia, B and T-cell defects, CD4\u0026thinsp;+\u0026thinsp;lymphopenia, neutropenia, innate immune dysfunction, treatment with anti-CD20 targeting agents, and age-related medical conditions are often present in CLL patients [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Early studies of COVID-19 and CLL have indicated high mortality rates at approximately 30% among hospitalized patients [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The majority of COVID-19 positive CLL patients required hospitalization, especially in the beginning of the pandemic [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The rates for intensive care unit (ICU) admission and intensive treatments with oxygen supplements and mechanical ventilation were also excessive compared to patients without a hematological disease\u003csup\u003e​\u003c/sup\u003e [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. High age, poor performance status, anemia and thrombocytopenia were among risk factors for developing severe COVID-19 [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOver the past decade, treatment of CLL has shifted from chemoimmunotherapy to targeted therapy [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Targeting B cell lymphoma 2 (BCL-2) with venetoclax in combination with anti-CD20 antibodies has improved clinical outcomes in patients with CLL both in treatment na\u0026iuml;ve patients and in the relapsed/refractory setting [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A fixed-duration venetoclax in combination with obinutuzumab is a recommended first-line treatment for patients with CLL and small lymphocytic lymphoma (SLL)​, and venetoclax in combination with rituximab is a recommended second-line treatment [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Venetoclax has demonstrated an overall acceptable toxicity profile in patients with CLL. However, among the most common grade 3/4 adverse events are neutropenia, febrile neutropenia, pneumonia, and sepsis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. There are few available data on COVID-19 in patients receiving venetoclax-based treatments. A study has suggested that venetoclax blocks the interaction between the SARS-CoV-2 spike (S) glycoprotein and the angiotensin-converting enzyme 2 receptor through spike protein degradation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Venetoclax may therefore exhibit protective mechanisms against COVID-19 by inhibiting viral nucleic acid sequences to enter the host cell. In agreement with these observations, a recent study reported only two (7%) hospitalizations and/or deaths after contracting COVID-19 among 27 CLL patients receiving venetoclax, and no events were recorded in patients receiving nirmatrelvir plus ritonavir [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Other studies have proposed that treatment with venetoclax is correlated with higher immunogenicity and seroconversion rates after COVID-19 booster vaccines compared to ibrutinib [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003csup\u003e​\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHere we present real-world data of the frequency, severity and mortality of COVID-19 in an observational single-center study of CLL and SLL patients consecutively treated with venetoclax during the COVID-19 pandemic. Our data were collected during both the pre- and post-vaccine era as well as the pre-Omicron and Omicron wave.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003ePatients diagnosed with CLL or SLL and treated with venetoclax were included in an observational single-institution study. Patients were identified in the electronic patient health record platform (EPIC). Venetoclax treatment was initiated between April 2017 and December 2022. Patients were treated with standard ramp up and steady state dose of venetoclax. Dose level and duration of treatment varied depending on tolerability and efficacy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSARS-CoV-2 testing\u003c/h2\u003e \u003cp\u003eCOVID-19 was defined as a positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) test. Local guidelines at our institution included testing of all hematological patients upon admission or out-patient visits, and mass screening twice a week during surges. A high frequency of positive SARS-CoV-2 samples were whole genome sequenced and the information on SARS-CoV-2 including sublineage was retrieved from the Danish national microbiology database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.covid19genomics.dk/nextstrain\u003c/span\u003e\u003cspan address=\"https://www.covid19genomics.dk/nextstrain\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. We used a cut-off point corresponding to January 2022 to compare patients with COVID-19 before and during the Omicron era. The Omicron subvariants were dominating in Denmark since January 2022, including the most frequent variant B.1.1.529​ [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Prior to this, Delta B.1.617.2 (original Delta variant) and Delta AY.4.2 (Delta plus variant) were the dominating variants. The Danish COVID-19 Genome Consortium (DCGC) provided data on the SARS-CoV-2 subvariants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eClinical data collection\u003c/h2\u003e \u003cp\u003eData were collected from electronic patient records between August 2022 and January 2023. Baseline characteristics and clinical outcomes were recorded including severity and mortality of COVID-19 infections. The primary outcome of the study was 30-day COVID-19 mortality rate, defined by death within 30 days from positive PCR test. Secondary outcomes included COVID-19 severity, hospitalization rate, admission rate to ICU, 90-day COVID-19 mortality, and treatments of COVID-19. Survival data were also recorded in our venetoclax-na\u0026iuml;ve patients with CLL/SLL and a positive SARS-CoV-2 PCR test. Secondary infections were recorded and defined as clinically (e.g., clinical examination, laboratory test results or imaging) or microbiologically proven infections occurring within a 2-month period after a positive PCR test.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistics\u003c/h2\u003e \u003cp\u003eAll data were registered in a local secured research database (REDCap). Statistical analyses were performed in R software (version 4.2.3). Clinical variables were summarized using descriptive statistics. Categorical variables are presented as numbers and percentages and continuous variables as median and ranges or interquartile ranges (IQR). Categorical variables were analyzed by Fisher\u0026rsquo;s exact test. 30-day COVID-19 mortality rate was estimated as the proportion alive 30 days after verified SARS-CoV-2 infection. The hospitalization rate was measured as the proportion of patients with hospitalization of minimum 24-hours duration within 30-days from a positive PCR test. ICU admission rate was calculated as the proportion of patients admitted to an ICU within one month of verified infection. Overall survival (OS) in venetoclax-treated and venetoclax-na\u0026iuml;ve patients with CLL/SLL and proven COVID-19.was measured from the date of verified infection until death or censoring 90 days after SARS-CoV-2 infection, whichever came first. Time-to-event analyses were performed using Kaplan-Meier plots and log-rank test was used for the comparison of survival in different groups. The level of statistical significance was defined as P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePatient characteristics\u003c/h2\u003e \u003cp\u003eWe identified 112 patients with CLL or SLL treated with venetoclax. Four patients with COVID-19 infection prior to initiation of venetoclax were excluded. Of the remaining 108 patients, 48 (44%) patients had a positive SARS-CoV-2 PCR test after initiation of venetoclax treatment. Flowchart of clinical subgroups in the study cohort is provided in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. We identified the SARS-CoV-2 variant in 27/48 (56%) patients, with 6 cases of B.1.617.2 (Delta-variant) and 21 cases of B.1.1.529 (Omicron-variant). The distribution of SARS-CoV-2 variants was in accordance with our cut-off point with a case of B.1.617.2 (Delta-variant) detected in 2022 as the only exception. Most patients (98%) had received the recommended number of vaccines in Denmark with 92% being vaccinated with \u0026ge;\u0026thinsp;4 doses. Sufficient vaccine antibody response measured with enzyme-linked immunosorbent assay (ELISA) was observed in 15/32 (47%).\u003c/p\u003e \u003cp\u003eBaseline clinical characteristics of the total cohort and for patients with and without COVID-19 are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. In the total cohort (n\u0026thinsp;=\u0026thinsp;108), median (range) age was 71 years (47\u0026ndash;89) and 77 (71%) were males. No significant differences in frequencies of baseline features were found between patients with and without COVID-19 with only a trend toward lower steady state dose of venetoclax in the cohort with COVID-19 (P\u0026thinsp;=\u0026thinsp;0.05). The most frequent causes of dose reduction were toxicity including gastrointestinal symptoms and neutropenia. Median (range) lines of therapy prior to venetoclax were 1 (0\u0026ndash;6). The treatment regimens were combined venetoclax and CD20-antibodies including rituximab or obinutuzumab (n\u0026thinsp;=\u0026thinsp;95), venetoclax and BTKi including ibrutinib or acalabrutinib (n\u0026thinsp;=\u0026thinsp;11), or venetoclax monotherapy (n\u0026thinsp;=\u0026thinsp;9). Four patients received a rituximab-obinutuzumab-venetoclax combination, two patients received an obinutuzumab-ibrutinib-venetoclax combination, and one patient received an obinutuzumab-acalabrutinib-venetoclax combination. The median (IQR) duration of venetoclax treatment was 13 months (12\u0026ndash;24). COVID-19 infection was detected during ongoing venetoclax treatment in 29/48 (60%) and after discontinuation of venetoclax in 19/48 (40%). Median (IQR) time between initiation of venetoclax and a positive SARS-CoV-2 PCR test was 19 months (8\u0026ndash;26).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics at initiation of venetoclax treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCohort with COVID-19 (n\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCohort without COVID-19 (n\u0026thinsp;=\u0026thinsp;60)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTotal cohort (n\u0026thinsp;=\u0026thinsp;108)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge \u0026ge;70 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (54%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e64 (59%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31 (65%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46 (77%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e77 (71%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBinet stage C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53 (49%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGenetics:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDel(11q)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (28%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTP53\u003c/em\u003e disruption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (26%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26 (35%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e34 (31%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIGHV unmutated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37 (74%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63 (71%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (18%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCLL treatments:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e 1 prior lines of therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42 (70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70 (65%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreated with venetoclax\u0026thinsp;+\u0026thinsp;CD20 antibody\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (85%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50 (83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e91 (84%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreated with venetoclax\u0026thinsp;+\u0026thinsp;BTK inhibitor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11 (10%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreated with venetoclax monotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (12%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e9 (8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReduced venetoclax steady state (\u0026lt;\u0026thinsp;400 mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (28%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood analyses:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin\u0026thinsp;\u0026le;\u0026thinsp;10 g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (16%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytes\u0026thinsp;\u0026le;\u0026thinsp;100x10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (18%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (18%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (2%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgG\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026le;\u003c/span\u003e\u0026thinsp;6 g/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (57%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (45%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e50 (50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (7%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSupportive G-CSF\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e46 (43%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComorbidity:\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIRS score\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36 (60%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e60 (56%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of diabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16 (15%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of pulmonary disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (27%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17 (28%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e30 (28%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eActive smoker\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e18 (17%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of cardiovascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26 (43%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e44 (41%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of kidney disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (10%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (14%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38 (63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e71 (66%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eCOVID-19 severity and mortality\u003c/h2\u003e \u003cp\u003eMost patients presented with mild symptoms or asymptomatic COVID-19 disease (75%) and the hospitalization rate at 30 days was 46%. No significant differences in severity were detected between patients with COVID-19 during and after the pre-Omicron era (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Three patients (6%) experienced reactivation of the same SARS-CoV-2 origin within 2 months after a negative PCR test. Two patients experienced reactivation with the B.1.1.539-variant (Omicron type) and one patient had reactivation with the B.1.617-variant (Delta type) with all 3 cases of reactivation being symptomatic. Distribution of clinical characteristics at initiation of venetoclax between patients with asymptomatic/mild disease and patients with severe/critical disease is shown in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Only thrombocytopenia and high CIRS-score were found with a significantly higher frequency in patients with severe/critical disease. Treatments of the COVID-19 infection are shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The antiviral treatment was given according to Danish national guidelines. Patients with ongoing venetoclax treatment more frequently received treatments with antiviral antibodies (24/29 (83%) and 10/19 (53%), respectively; P\u0026thinsp;=\u0026thinsp;0.04), other antiviral drugs (13/29 (45%) and 2/19 (11%), respectively; P\u0026thinsp;=\u0026thinsp;0.02), and antibiotics (15/29 (52%) and 6/19 (32%), respectively; P\u0026thinsp;\u0026lt;\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCOVID-19 outcomes according to SARS-CoV-2 variants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCOVID-19 pre-Omicron (n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCOVID-19 Omicron-era (n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCOVID-19 total cohort (n\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAsymptomatic or mild COVID-19 disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36 (75%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSevere or critical COVID-19 disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16 (44%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e22 (46%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary infiltrates on X-ray\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e13 (27%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSpO2\u0026thinsp;\u0026lt;\u0026thinsp;90%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8 (17%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICU admission\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDistribution of baseline clinical features at initiation of venetoclax in patients with asymptomatic/mild and severe/critical COVID-19\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAsymptomatic/mild disease\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;36)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere/critical disease\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;12)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u0026thinsp;\u0026ge;\u0026thinsp;70 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender male\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (61%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBinet stage C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTP53\u003c/em\u003e disruption\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIGHV unmutated\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (53%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (58%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin\u0026thinsp;\u0026le;\u0026thinsp;10 g/dL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytes\u0026thinsp;\u0026le;\u0026thinsp;100x10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4 (33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.01\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIgG\u0026thinsp;\u0026le;\u0026thinsp;6 g/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7 (70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMissing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCIRS-score\u0026thinsp;\u0026ge;\u0026thinsp;6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (39%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.02\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (11%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePulmonary disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (19%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.08\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiovascular disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.74\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI\u0026thinsp;\u0026ge;\u0026thinsp;25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8 (66%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCOVID-19 treatments\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreatment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCOVID-19 cohort (n\u0026thinsp;=\u0026thinsp;48)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDexamethasone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (21%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnticoagulants\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (23%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntiviral antibodies (sotrovimab, tixagevimab/cilgavimab, casirivimab/imdevimab)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34 (71%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther antivirals (remdesivir, nirmatrelvir/ritonavir)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (31%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreated with oxygen supplements\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (21%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntibiotics\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (44%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo treatments\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eOnly two patients died within 30 days of a positive SARS-CoV-2 PCR test. Both deaths were regarded as non-related to COVID-19 infection. In one case the primary cause of death was given as pulmonary cancer and in the other case as Richter\u0026rsquo;s transformation. No additional deaths were observed 90 days after a positive SARS-CoV-2 PCR test. The 30-day mortality rates in the venetoclax-treated and venetoclax-na\u0026iuml;ve cohorts were 2/48 (4%) and 9/90 (10%), respectively (P\u0026thinsp;=\u0026thinsp;0.32). The 90-day OS of the two cohorts is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Treatments in the venetoclax-na\u0026iuml;ve group consisted of combined chemoimmunotherapy and anti-CD20, other targeted treatments including BTKi, or watch-and-wait. The frequency of patients with advanced disease was higher in the venetoclax-treated cohort with a total of 21/48 (44%) presenting with Binet stage C while the frequency was 19/90 (21%) in the venetoclax-na\u0026iuml;ve cohort. The overall frequency of deaths in our single-center CLL/SLL cohort of patients without proven COVID-19 infection was 1% in the corresponding period.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eSecondary infections\u003c/h2\u003e \u003cp\u003eIn the cohort of patients treated with venetoclax (n\u0026thinsp;=\u0026thinsp;48), secondary infections were observed in 17 (35%) patients while 21 (44%) of the patients were treated with antibiotics. The infections were either verified clinically (e.g., clinical examination or pulmonary infiltrates on imaging) or by microbiological detection of pathogens. Most cases were pneumonias, upper respiratory or urinary tract infections. A pseudomembranous colitis was observed in one case. No systemic mycoses or other severe fungal infections were detected. The most common pathogen was \u003cem\u003eHaemophilus influenzae\u003c/em\u003e (3 cases). All cases of secondary infections including microbiological pathogens are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSecondary infections after COVID-19 (within 2 months from positive PCR test)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFocus of infection\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDetected pathogen\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClinical signs of infection\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eInfluenza A virus\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePulmonary infiltrates (X-ray), symptoms of pneumonia\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSymptoms of pneumonia, increasing CRP levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUpper respiratory infection / otitis media\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eHaemophilus influenzae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSymptoms of upper respiratory infections and otitis media, increasing CRP levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary tract infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eEscherichia coli\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSymptoms of urinary tract infection\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eHaemophilus influenzae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastroenteritis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRotavirus\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSymptoms of gastroenteritis, increasing CRP levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eHaemophilus influenzae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary tract infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eCitrobacter freundii, Morganella morganii\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSymptoms of urinary tract infection, increasing CRP levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRespiratory syncytial virus\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eStreptococcus pneumoniae, Moraxella catarrhalis\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSymptoms of pneumonia, increasing CRP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUrinary tract infection and pseudomembranous colitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eProteus mirabilis (urine), Clostridium difficile (faeces)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSymptoms of urinary tract infection and pseudomembranous colitis, increasing CRP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSymptoms of pneumonia, increasing CRP\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePulmonary infiltrates (X-ray), symptoms of pneumonia, increasing CRP levels, decreasing SpO2-levels\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe 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\u003csup\u003e​\u003c/sup\u003e and the average positive rate during the entire pandemic was estimated to be 5.03% (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://ourworldindata.org/coronavirus/country/denmark)\u003c/span\u003e\u003cspan address=\"https://ourworldindata.org/coronavirus/country/denmark)\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.​ 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 \u003cem\u003eTP53\u003c/em\u003e 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 \u0026gt;\u0026thinsp;40% of patients treated with venetoclax but humoral responses to vaccines were significantly higher in treatment-na\u0026iuml;ve CLL patients [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. The incidence of COVID-19 in our cohort was 44%, in accordance with the general Danish population between March 2020 and March 2023 (54%) (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.sst.dk/da/corona/Status-og-materiale/Coronatal\u003c/span\u003e\u003cspan address=\"https://www.sst.dk/da/corona/Status-og-materiale/Coronatal\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). 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\u0026ndash;22% [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003csup\u003e​\u003c/sup\u003e. 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.\u003c/p\u003e \u003cp\u003eThe 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-na\u0026iuml;ve cohorts. However, higher mortality rates of 19\u0026ndash;33% among CLL patients have been reported in other studies [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. 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 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. 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%) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. 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 \u003cem\u003eTP53\u003c/em\u003e disruption status. This comparison, therefore, points towards a generally mild course of COVID-19 infections among patients treated with venetoclax.\u003c/p\u003e \u003cp\u003eIn 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\u0026ndash;4 infection rates at estimated 20% in patients during treatment, most frequently pneumonia, sepsis or febrile neutropenia [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Furthermore, cytopenia including neutropenia are one of the most common grade 3\u0026ndash;4 adverse events related to venetoclax [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. 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.\u003c/p\u003e \u003cp\u003e \u003cem\u003eIn vitro\u003c/em\u003e studies investigated the ability of venetoclax to bind and degrade the spike protein in SARS-CoV-2 [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. 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\u0026rsquo; 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\u0026rsquo; entry into the host cell. Venetoclax may therefore express some properties with a protective effect against severe COVID-19 disease.\u003c/p\u003e \u003cp\u003eThe 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-na\u0026iuml;ve 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.\u003c/p\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eEthical approval:\u003c/strong\u003e \u003cp\u003eThe study was approved by the regional Data Protection Agency (ID: EMN-2022-11065).\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate:\u003c/strong\u003e \u003cp\u003eInformed consent was provided by patients alive at follow-up.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eConflict of interests:\u003c/h2\u003e \u003cp\u003eCB has received honoria from Octapharma and AstraZeneca. The remaining authors have nothing to disclose.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding:\u003c/h2\u003e \u003cp\u003eThis work was funded by Region Zealand, DK (ID: EMN-2022-00760).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eS.T. collected data, interpreted analyses and wrote the first draft of the manuscript; C.B.P. and L.M.P. designed the study, collected data and interpreted analyses; C.B. collected data and interpreted analyses; M.K.L. performed statistical analyses; L.W. interpreted analyses; X.C.N. collected data and interpreted analyses. All authors contributed to the editing of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement:\u003c/h2\u003e \u003cp\u003eWe thank the Danish COVID-19 Genome Consortium (DCGC) for providing data on the SARS-CoV-2 subvariants in our patients.\u003c/p\u003e\u003ch2\u003eData availability:\u003c/h2\u003e \u003cp\u003eData were collected and managed using the REDCap electronic data capture tool hosted at Ascension. Data are available from the corresponding author upon reasonable request. The individual level data collected during the study are not publicly available due to protection of participants privacy and ethical restrictions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eScarf\u0026ograve; L, Chatzikonstantinou T, Rigolin GM, Quaresmini G, Motta M, Vitale C 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 et al (2020) Leukemia 34(9): 2354\u0026ndash;2363. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1038/s41375-020-0959-x\u003c/span\u003e\u003cspan address=\"10.1038/s41375-020-0959-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRossi D, Shadman M, Condoluci A, Brown JR, Byrd JC, Gaidano G et al (2020) How we manage patients with chronic lymphocytic leukemia during the SARS-CoV-2 pandemic Hemasphere 4(4): e432. https://doi.org/10.1097%2FHS9.0000000000000432\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMato AR, Roeker LE, Lamanna N, Allan JN, Leslie L, Pagel JM et al (2020) Outcomes of COVID-19 in patients with CLL: a multicenter international experience Blood. 136(10):1134\u0026ndash;1143. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1182/blood.2020006965\u003c/span\u003e\u003cspan address=\"10.1182/blood.2020006965\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNiemann CU, da Cunha-Bang C, Helleberg M, Ostrowski SR, Brieghel C (2022) Patients with CLL have a lower risk of death from COVID-19 in the Omicron era Blood. 140(5):445\u0026ndash;450. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1182/blood.2022016147\u003c/span\u003e\u003cspan address=\"10.1182/blood.2022016147\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBronstein Y, Levi S, Herishanu Y (2023) Improved outcomes in patients with chronic lymphocytic leukaemia infected during the omicron BA.5 subvariant surge. 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J Biomol Struc Dyn 40(22):12088\u0026ndash;12099. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1080/07391102.2021.1967786\u003c/span\u003e\u003cspan address=\"10.1080/07391102.2021.1967786\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"CLL (chronic lymphocytic leukemia), Small lymphocytic lymphoma, Venetoclax, COVID-19","lastPublishedDoi":"10.21203/rs.3.rs-3750075/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3750075/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePatients with chronic lymphocytic leukemia (CLL) are at high risk of developing severe COVID-19. The present study was undertaken to elucidate COVID-19 related morbidity and mortality in CLL patients treated with venetoclax. We present a single-center study of 108 patients with small lymphocytic lymphoma or CLL treated with venetoclax. Primary outcome was 30-day COVID-19 mortality. Secondary outcomes included COVID-19 severity and hospitalization rate. Forty-eight (44%) patients had PCR-verified SARS-COV-2 between March 2020 and January 2023. Thirty-six patients (75%) presented with asymptomatic/mild COVID-19 and 12 (25%) with severe/critical disease. The hospitalization rate was 46% with a 30-day mortality rate of only 4% and severe comorbidities as the primary cause of death. There was no significant difference in mortality when compared to venetoclax-na\u0026iuml;ve CLL patients (n\u0026thinsp;=\u0026thinsp;90) from our single-center cohort with proven COVID-19. COVID-19 severity and mortality were similar before and during the Omicron era. High CIRS-scores (P\u0026thinsp;\u0026lt;\u0026thinsp;0.02) and thrombocytopenia (P\u0026thinsp;\u0026lt;\u0026thinsp;0.01) were more frequent in patients with severe/critical disease. In real-world data, most venetoclax treated patients presented with mild COVID-19. Hospitalization and mortality rates were low compared to data of general CLL populations. Our data indicate that venetoclax was a safe treatment option for CLL patients during the pandemic.\u003c/p\u003e","manuscriptTitle":"COVID-19 severity in patients with chronic lymphocytic leukemia treated with venetoclax: a single-center observational cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-02 19:13:59","doi":"10.21203/rs.3.rs-3750075/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-03-05T14:30:31+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-09T10:25:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"2c5cc528-ab15-4434-b043-6f4f977e99f2","date":"2023-12-27T17:03:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-12-27T05:18:33+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-12-26T14:42:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-12-26T14:42:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"Annals of Hematology","date":"2023-12-13T19:46:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"annals-of-hematology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"aohe","sideBox":"Learn more about [Annals of Hematology](http://link.springer.com/journal/277)","snPcode":"277","submissionUrl":"https://submission.nature.com/new-submission/277/3","title":"Annals of Hematology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"09fa9b7c-579b-4002-bf49-be10218185e2","owner":[],"postedDate":"January 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-05-01T22:54:35+00:00","versionOfRecord":{"articleIdentity":"rs-3750075","link":"https://doi.org/10.1007/s00277-024-05738-4","journal":{"identity":"annals-of-hematology","isVorOnly":false,"title":"Annals of Hematology"},"publishedOn":"2024-04-18 22:54:35","publishedOnDateReadable":"April 18th, 2024"},"versionCreatedAt":"2024-01-02 19:13:59","video":"","vorDoi":"10.1007/s00277-024-05738-4","vorDoiUrl":"https://doi.org/10.1007/s00277-024-05738-4","workflowStages":[]},"version":"v1","identity":"rs-3750075","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3750075","identity":"rs-3750075","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}