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Patients with CLL have a lower risk of death from COVID-19 in the Omicron era

(cid:1) In the of the Omicron variant of COVID-19, lower fatality rates CLL are seen milder disease Patients with CLL who have hospital contact and test positive for SARS-CoV-2 should still be considered for preemptive therapy. Previous studies have shown that patients with chronic lymphocytic leukemia (CLL) and coronavirus disease 2019 (COVID-19) have high mortality rates. Infection with the Omicron variant has been described as a milder disease course in the general population. However, the outcome for immunocompromised patients has not previously been reported. In a cohort of patients with CLL tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at hospital test sites in the time periods before and after dominance of the Omicron variant, rates of hospitalizations and intensive care unit admissions declined signi ﬁ cantly, whereas 30-day mortality remained as high as 23% in the period with dominance of the Omicron sublineage BA.2 variant. However, for a larger population-based cohort of patients with CLL (including the hospital cohort), 30-day mortality was 2%. Thus, patients with CLL with close hospital contacts and, in particular, those > 70 years of age with 1 or more comorbidities should be considered for closer monitoring and preemptive antiviral therapy upon a positive SARS-CoV-2


Introduction
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (Omicron) variant of coronavirus disease 2019 (COVID-19) is reported to give milder disease in the general population; outcomes for immunocompromised patients have not been reported. Here, hospital-and population-based data on outcome for patients with chronic lymphocytic leukemia (CLL) upon infection with the Omicron variant of SARS-CoV-2 warrant close monitoring and preemptive therapy upon a positive SARS-CoV-2 test for patients with CLL and frequent hospital contacts; other patients with CLL can expect a mild course of COVID-19.
Patients with CLL have increased morbidity and mortality following infection with SARS-CoV-2, leading to COVID-19. 1,2 The immune dysfunction inherent to CLL itself and CLL treatment, whether targeted or chemoimmunotherapy based, is considered the likely cause of increased susceptibility to severe COVID-19. 3 During the first and second pandemic waves, most CLL patients with COVID-19 developed severe disease, and the 30-day mortality was 31% to 50% for those admitted, although one study indicates improved survival for patients with CLL upon COVID-19 later in the pandemic. 1,2,4 Further, patients with CLL demonstrated impaired vaccination response in terms of ability to produce neutralizing anti-SARS-CoV-2 antibodies, even though the T-cell response was also impaired for part of the populations. [5][6][7][8] Data on outcome upon infection with SARS-CoV-2 Omicron variant is warranted for immunocompromised patients in general and for patients with CLL in particular. 9 The first Danish Omicron case was detected on 25 November 2021. The variant became dominant in Denmark by 17 December 2021, enabling high levels of breakthrough infections among vaccinated individuals. 10 In Denmark, all patients diagnosed with a hematological malignancy were offered third and fourth booster vaccination against SARS-CoV-2 in August 2021 and January 2022, respectively. At the same time, a single dose of anti-SARS-CoV-2 monoclonal antibody (mAb) was recommended for immunocompromised patients testing positive for SARS-CoV-2 with sotrovimab being the most widely used mAb in Denmark, while the standard of care for immunocompromised patients admitted with moderate to severe COVID-19 was dexamethasone, low molecular weight heparin, and remdesivir. 11,12 Remdesivir was widely used for hematological patients regardless of disease severity since approval mid-2020. 13,14 Sotrovimab retained its neutralizing activities against the Omicron BA.1 sublineage, but recently, in vitro studies have shown reduced activity against the BA.2 sublineage. 15,16 Methods Insights into potential variation in clinical outcome for immunocompromised patients upon infection with the Omicron variant is limited. Here, we investigated the rate of hospitalization, .024     . P values were calculated using log-rank test for differences across the 4 subgroups.
the EHR system for Eastern Denmark (EHR cohort). Two reinfections were identified with positive PCR tests .1 year apart. Additionally, we identified 640 patients within the Danish CLL registry with a positive SARS-CoV-2 PCR test outside the EHR system (population cohort). No reinfections in terms of patients with positive PCR tests .12 weeks apart were identified within this cohort (patients within the EHR cohort were excluded from the population cohort). Stratified by period, 59, 40, 32, and 22 patients in the EHR cohort were first PCR positive in time periods 1 to 4, respectively. In the population cohort, 24, 66, 73, and 477 patients were first PCR positive in periods 1 to 4, respectively. There were no significant differences in baseline characteristics between the 4 periods, but patients in the EHR cohort were significantly older compared with patients in the population cohort (P 5 .0052), even though the patients in the EHR cohort were also diagnosed with CLL significantly more recently (Table 1; P 5 .024). At least 43 of 109 (39%) and 190 of 640 (30%) patients in the EHR and population cohort, respectively, had received CLL therapy prior to testing positive for SARS-CoV-2 (P5.054. For the EHR cohort, the rate of hospitalizations for patients with CLL testing positive for SARS-CoV-2 was significantly higher (.75%) during the second period compared with periods 3 (Omicron emergence) and 4 (Omicron dominance), where preemptive mAb were administered during hospital admissions for patients with CLL upon a positive SARS-CoV-2 PCR test ( Figure 1A; P , .014). During period 3 and 4, mAb were administered at outpatient visits, which likely explains the lower 30-day admission rates (56% to 60% vs 83%). ICU admission rates were highest prior to emergence of Omicron (12% to 12.5% vs 0% to 3%, Figure 1B), which may reflect impact of a third and fourth booster vaccine, improved care for patients with COVID-19, and differences in severity between SARS-CoV-2 variants. 11,12,20 The ICU admission rates were lower than previously reported in international cohorts of COVID-19 in CLL (26% to 37% for hospitalized patients). 1,2 This could be due to the full implementation of early treatment with mAb, almost universal treatment with remdesivir for hospitalized patients without renal failure, and high vaccination rates and administration of up to 30 L/min oxygen outside the ICU in Denmark.
For the EHR cohort, 30-day OS was above 75% in all 4 periods (77% to 91%, Figure 1C). Despite representing a cohort with close hospital connection (EHR cohort), these survival rates are slightly better than the previously reported OS rates for COVID-19 in CLL during the first part of the pandemic (64% to 73%), although one study reported a higher OS rate of 89% for CLL patients testing positive for SARS-CoV-2 after 1 May 2020. 1 Figure 1D). When combining the 2 cohorts, 30-day OS rates gradually improved from periods 1 to 4 (88.0%, 89.6%, 93.3%, and 98.2%, respectively), with a significantly higher OS in the O BA.2 period compared with periods 1 to 3 (P # .0077; pairwise log-rank, Figure 1E).
Limitations apply to this study; the size of the EHR patient population was limited, and patients with CLL testing positive for SARS-CoV-2 outside EHR test sites were only included in the population cohort. Thus, the improved outcome in the population cohort may reflect less severe CLL, less severe COVID-19, and/or less comorbidity.
Based on epidemiological data from South Africa, 21 the incidence of SARS-CoV-2 seems decoupled from the incidences of hospitalization and death upon emergence of the Omicron variant, while previous vaccination seems to protect less against infection with the Omicron variant of SARS-CoV-2. 22 This study indicate that Omicron sublineage BA.2 pose a similar risk of fatal COVID-19 only for patients with impaired immune function due to CLL and a close hospital contact either due to CLL or COVID-19, 3,18 with an estimated 30-day OS rate of 77%. It should be emphasized that patients in the population cohort may also have been hospitalized, but no data on this were accessible. The overall population of patients with CLL seems to have a much milder course of COVID-19 during the era of the Omicron variant, especially during BA.2 dominance, with a 30-day fatality rate ,2%. Thus, patients .70 with CLL and 1 or more comorbidities and hospital contact due to CLL or COVID-19 should be considered for closer monitoring and preemptive antiviral therapy upon a positive SARS-CoV-2 test.