1133 - COVID-19 infection in chronic lymphocytic leukemia (CLL) patients treated with venetoclax: a Danish single-center experience

Introduction:
Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have shown to be at high risk of developing severe COVID-19 disease and studies have reported COVID-19 mortality rates at approximately 30% (Chatzikonstantinou et al., 2021; Niemann et al., 2022; Glenthøj et al, 2021). Many CLL patients present with dysfunction of the innate and adaptive immune system and are frequently treated with immunosuppressants. Venetoclax blocks the interaction between the ACE2 receptor and the SARS-CoV-2 spike (S) glycoprotein in vitro (Chen et. al, 2022) and may have a protective role against COVID-19 in CLL patients. However, the American Society of Hematology recommended that venetoclax treatment should be avoided during the COVID-19 pandemic due to a high number of clinical visits and lab testing. We performed an observational single-center study of CLL patients treated with venetoclax in a real-world setting during the COVID-19 pandemic. The primary aim was to elucidate morbidity and mortality of COVID-19 infections. The extensive Danish testing strategy and the access to nationwide registries made it possible to present a large collection of COVID-19 data among CLL patients treated with venetoclax.

Methods:
The cohort consisted of 108 patients with CLL/SLL treated with venetoclax at the Department of Hematology, Zealand University Hospital, Denmark. Patients were treated with venetoclax according to national guidelines including a five week ramp up schedule and a steady state dose of 400 mg. Venetoclax was used in combinations with anti-CD20 (84.3%), BTK inhibitors (10.2%) or as monotherapy (8.3%). The Danish mass testing strategy identified positive SARS-COV-2 real-time reverse transcription-PCR (qRT-PCR) tests in 48 (44%) of the cohort. We collected data from patients with COVID-19 prior to and during the Danish Omicron era (cut off point January 2022). Our primary outcome was 30-day COVID-19 mortality. Secondary outcomes were COVID-19 severity (according to Wu & McGoogan’s criteria), hospitalization rate and treatment with antiviral drugs. All clinical data was collected from electronic records and from the Danish Pathology Data Registry. The study was approved by the regional Data Protection Agency (ID: EMN-2022-11057 and EMN-2022-11065).

Results:
Mean age was 71 years and 71% were male. Median (range) lines of therapy prior to venetoclax were 1 (0-6). Median (range) length of venetoclax treatment was 13 months (1-36). The majority of patients (92%) had received more than four COVID-19 vaccines. Most patients presented with asymptomatic/mild COVID-19 (75%) and only two deaths (4%) were registered within 30 days from positive SARS-COV-2 PCR test (Table 1). The causes of death were Richter transformation in a patient with mild COVID-19 and both pulmonary cancer and COVID-19 in a patient with critical COVID-19. The hospitalization rate was 46% with no ICU admissions (Table 1.). Thrombocytopenia prior to venetoclax treatment (P < 0.01) and high CIRS scores (P < 0.02) were identified as risk factors for developing severe COVID-19 disease. In five patients (10%), a reactivation of the same SARS-COV-2 origin was detected within 2 months after a negative PCR test. COVID-19 treatment characteristics are outlined in Table 2. COVID-19 severity, morbidity and mortality were similar before and in the Omicron era. Patients with COVID-19 during active treatment with venetoclax received more intensive treatment with antiviral antibodies (P=0.03), anticoagulants (P=0.03), Piperacillin/Tazobactam (P < 0.01) and antiviral drugs (P=0.02) compared to patients with COVID-19 after the end of venetoclax treatment.

Conclusions:
Our results suggest that CLL/SLL patients treated with venetoclax generally present with mild COVID-19 and low mortality rates compared to data from studies of general CLL populations. COVID-19 morbidity and mortality are highly associated with other comorbidities. The results point to venetoclax having a potential protective effect against severe COVID-19.