Severe COVID-19 Infection in Patients with Chronic Lymphocytic Leukemia or Indolent B-Cell Non-Hodgkin Lymphoma Who Received Pre-Exposure Prophylaxis with Tixagevimab and Cilgavimab in Italy: Preliminary Results of the Observational Study By the Gimema Working Party on Chronic Lymphoproliferative Disorders and By the Fondazione Italiana Linfomi

Patients with chronic lymphocytic leukemia (CLL) or indolent B-cell non-Hodgkin lymphoma (iB-NHL) are at risk of developing severe COVID-19 infection, with a high mortality rate in the pre-vaccination era (18%-30%). These patients respond poorly to vaccination, especially those receiving anti-CD20 monoclonal antibodies, Bruton tyrosine kinase inhibitors (BTKi) or the BCL2 inhibitor venetoclax. Pre-exposure prophylaxis (PrEP) with the neutralizing antibodies tixagevimab and cilgavimab drastically reduced the incidence of symptomatic COVID-19 infection in subjects with a higher chance of an inadequate response to vaccination against SARS-CoV-2. Therefore, we designed this observational study with the primary objective to describe the incidence of severe COVID-19 infection (COVID-19-related hospitalization or COVID-19 related death) in patients with CLL or iB-NHL (follicular lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma) who received PrEP with tixagevimab and cilgavimab (NCT05803395). Each patient had a minimum follow-up of 6 months from the first PrEP dose.

Overall, 513 patients (CLL n=343, iB-NHL n= 170) aged ≥ 18 years who received the study drug as per label between March and October 2022 were included in the present study. Ninety-nine% of patients received PrEP with tixagevimab and cilgavimab at a dosage of 300 mg as per approved indications in Italy. Key baseline characteristics were: median age 72 years (range 33-94), Male/Female 62%/38%, ECOG performance status ≤ 2 96%, one or more comorbidities 69%, advanced stage (Ann Arbor 3-4, Binet B-C) 62%. Forty-one% of the patients had received more than one previous line of therapy, 73% were on anti CLL/NHL treatment at the time of PrEP administration and 25% of them had received previous treatment with anti-CD20 monoclonal antibodies. Ninety-eight% of the patients had received previous anti COVID-19 vaccination and 26% of the cases had a previous COVID infection.

At 6 months from PrEP, 159/513 patients (31%) had a COVID-19 infection and 39% of these patients received an anti-viral treatment with nirmatrelvir/ritonavir or remdesivir. The 6-month rate of severe infections was 3.5% (18/513, 12 CLL, 6 B-iNHL). The median time between PrEP and severe infection was 3.35 months, (IQR 1.85, 4.68). Overall, 50% of the patients with severe infection required oxygen therapy, with intensive care hospitalization in 22% of the cases and a COVID-related death in 22% (n=4). At 6 months, the overall COVID-19 related mortality rate among all patients who had an infection was 2.5%. Patients with severe infection were older as compared with patients with mild infection (75 vs 71 years p=0.014). A diagnosis of B-iNHL or CLL, the presence of comorbidities, previous or ongoing treatment, previous COVID-19 vaccination or previous COVID-19 infection had no impact on the risk of severe COVID. Noteworthy, 17/18 cases of severe COVID infection occurred in a period (August 2022-January 2023) in which the Omicron sub-variants BA.5 and BQ.1 were prevalent in Italy.

In conclusion, in this population of CLL and iB-NHL at high risk for poor response to vaccination, the modern management strategy that included PrEP with tixagevimab and cilgavimab and treatment with antiviral drugs resulted in low rates of severe COVID infection and death.

Funding: the study was supported by an unconditional grant from AstraZeneca S.p.A.