Incidence and Management of COVID-19 Infections in Vaccinated Patients with CLL
Authors: Ujjani Chaitra S , Gooley Ted , Siddiqi Tanya , Stephens Deborah M. , Broome Catherine , Spurgeon Stephen E , Lai Catherine , Winter Allison , Pongas Georgios , Greninger Alex , Hill Joshua A. , O'Brien Susan M. , Davids Matthew S , Rogers Kerry A , Danilov Alexey , Quezada Genesis , Zhu Haiying , Sperling Amy , Sorensen Tyler , Launchbury Kelsey , Wierda William G. , Shadman Mazyar , Thompson Philip A. 
Published: December 2023

Introduction:
Due to impaired immune function and medical comorbidities, CLL patients (pts) are at risk for significant mortality with COVID-19. Given our concern for this vulnerable population, we formed a national collaboration to evaluate the efficacy of SARS-CoV-2 vaccines (NCT04852822). We previously reported decreased seroconversion rates amongst pts receiving B-cell directed therapy and characterized the T-cell responses (Ujjani et al, Blood Advances, 2022). Here we present data regarding the incidence and management of COVID-19 in this vaccinated population.
Methods:
In this prospective observational study, adults with CLL/SLL were eligible if no known prior history of SARS-CoV-2 infection. Pts enrolled into 2 cohorts: 1) at time of initial 2-dose mRNA vaccine or 1-dose adenoviral vector vaccine, 2) at the time of the subsequently authorized booster vaccine. Pts in the initial vaccination cohort were permitted to enroll in the booster cohort. Patient reported infections, subsequent boosters, and therapeutic interventions were collected at 6, 12, 18, 24 months.
Results:
There were 243 pts enrolled in the initial vaccine cohort from 03/21-09/21 and 129 in the booster cohort from 08/21-02/22; 73 pts from initial cohort enrolled into the booster cohort. Patient characteristics are in Table 1. Eight pts (3.3%) reported COVID-19 in the initial cohort within 1 year of receiving the initial vaccine or prior to receipt of a booster (06/21-12/21). In the booster cohort, 32 pts (25%) reported at least 1 COVID-19 infection; first infections reported 10/21-12/22. Infections occurred a median of 135 days (93-247) after the initial vaccine and 132 days (range 19-312) after the booster. Second infections were noted in 1 patient (0.4%) in the initial cohort and 6 in the booster cohort (5%).
The incidence of COVID-19 was comparable amongst men and women in the initial cohort (4%, 2%) and booster cohort (25%, 24%) as well as those who received mRNA-1273 and BNT162b2 vaccines (2%, 4%) and (24%, 26%). There were no infections in the 6 pts who received Ad26.COV2.S in the initial cohort nor 4 in booster cohort. Infections by treatment in initial cohort: 1% of treatment-native, 4% BTKi, 7% CD20 mAb + venetoclax, 9% BTKi + venetoclax. Infections in booster cohort: 24% of treatment-native, 28% BTKi, 33% CD20 mAb + venetoclax, 20% CD20 mAb + BTKi, 25% BTKi + venetoclax, 67% BTKi + venetoclax + CD20 mAb.
Treatment for COVID-19 was administered to 75% of infected pts in initial cohort; 63% in booster cohort. Therapies are listed in Table 2. Hospitalization rates amongst infected pts in the initial and booster cohorts were 38% (3/8) and 13% (4/32). Two pts required ICU stay in the initial cohort; 1 was intubated; whereas only 1 patient in the booster cohort required ICU but was not intubated. The median length of hospital stay was 8 days (range 5-30) for the initial cohort; 3 days (range 1-9) for the booster cohort. Three pts died of COVID-19 in the initial cohort; there were no deaths in the booster cohort.
Twenty percent of pts received tixagevimab/cilgavimab for COVID-19 prophylaxis in the initial cohort; 37% in booster cohort. All infections (8/8) occurred in the initial cohort prior to the receipt of tixagevimab/cilgavimab or in those who did not receive prophylaxis; 84% (27/32) in the booster cohort. Most pts developed COVID-19 after first booster (75%); 19% after second booster, 6% after third booster.
Several clinical features were evaluated as potential risk factors for infection: age, anti-S level, treatment, gender, vaccine brand. By univariate logistic regression models, none were found to be statistically predictive of infection. However, increasing values of anti-S levels were associated with a numerically decreased probability of infection in both cohorts: initial cohort OR 0.71 (95% CI 0.49-1.03), booster cohort OR 0.91 (95% CI 0.83-1.00).
Conclusion
In one of the largest and longest prospective evaluations of vaccinated pts with CLL, we noted the incidence of COVID-19 to rise from 3.3% in the initial cohort to 25% in the booster cohort, likely due to the emergence of new variants and reduction in social distancing practices. Shorter hospital stays and improved mortality reflect dominance of variants that cause less severe illness, use of anti-viral therapy, and improved measures in supporting critically ill pts, despite suboptimal utilization of prophylaxis. Higher levels of anti-S trended with lower rates of infection.