key: cord-0692064-ikw9kzek
authors: Niemann, C. U.; da Cunha-Bang, C.; Helleberg, M.; Ostrowski, S. R.; Brieghel, C.
title: Patients with CLL have similar high risk of death upon the omicron variant of COVID-19 as previously during the pandemic.
date: 2022-03-02
journal: nan
DOI: 10.1101/2022.03.01.22271685
sha: 38df115ca560e28c1b3de7d135505c64bbb9a291
doc_id: 692064
cord_uid: ikw9kzek

Previous studies have shown that patients with chronic lymphocytic leukemia (CLL) and coronavirus disease 2019 (COVID-19) have high mortality rates. The omicron variant has been reported to give milder disease in the general population, but outcomes of infections with the omicron variant among immunocompromised patients have not previously been reported. In a population-based cohort we assessed rates of hospitalizations, ICU-admissions, and 30-day all-cause mortality among all patients with CLL from Eastern Denmark testing positive for severe adult respiratory syndrome coronavirus 2 (SARS-CoV-2) in time periods before and after dominance of the omicron variant. Rates of hospitalizations and ICU-admissions declined significantly, whereas 30-day mortality remained as high as 23% in the period with dominance of the omicron sublineage BA.2 variant. Thus, patients with CLL in general and in particular those above 70 years of age with one or more comorbidities should be considered for closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test.

Patients with chronic lymphocytic leukemia (CLL) have increased morbidity and mortality following infection with severe adult respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to coronavirus disease 2019 (COVID-19). 1, 2 The immune dysfunction inherent to CLL itself and CLL treatment whether targeted or chemoimmunotherapy based, 3 is considered the likely cause of increased susceptibility to severe COVID-19. During the first and second pandemic wave, most CLL patients with COVID-19 developed severe disease and 30-day mortality was 31-50% for those admitted. 1, 2 Further, patients with CLL demonstrated impaired vaccination response in terms of ability to produce neutralizing anti-SARS-CoV-2 antibodies, while the T-cell response remained intact for more patients. [4] [5] [6] [7] Data on outcome upon infection with SARS-CoV-2 B.1.1.529 (omicron) variant is warranted for immunocompromised patients in general and for patients with CLL in particular. 8 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 (mAbs) was recommended for immunocompromised patients testing positive for SARS-CoV-2, while the standard of care for immunocompromised patients admitted with moderate to severe COVID-19 was dexamethasone, heparin and remdesivir. 10, 11 Remdesivir was widely used for hematological patients regardless of disease severity since approval mid-2020. 12, 13 The mAbs sotrovimab retain its neutralizing activities against the omicron BA.1 sublineage, but very recently, in vitro studies have shown reduced activity against the BA.2 sublineage. 14 15 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, admission to intensive care unit (ICU) and mortality following infection with SARS-CoV-2 among patients with CLL in a Danish population-based cohort from March 2020 through January 2022. As perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in 16 We included all patients registered with a CLL diagnosis (DC91.1) and a positive PCR for SARS-CoV-2 within the EHR. Patients with multiple positive PCR tests within 12 weeks were considered as having one infection. Baseline characteristics were stratified by time-period of first positive SARS-CoV-2 PCR test (Table 1) . Primary outcomes were time to hospital admission, time to ICU admission and 30-day mortality. We followed patients from date of first positive PCR until event, death or date of last follow-up (22 nd Feb 2022). The study was approved by the Ethics Committee and Data Protection Agency.

Until 28 th January 2022, 151 patients with CLL were registered with 153 first positive PCR test for SARS-CoV-2 in the EHR system for Eastern Denmark, two patients with positive PCR tests more than a year apart were counted as two separate infections. There were no significant differences in baseline characteristics between the four periods (Table 1) , at least 85 (56%) patients had received CLL therapy prior to testing positive for SARS-CoV-2. The rate of hospitalizations for patients with CLL testing positive for SARS-CoV-2 was highest (above 75%) during the second period, where preemptive mAbs were administered during hospital admissions for patients with CLL upon a positive SARS-CoV-2 PCR test ( Figure 1A ). During period 3 (omicron emergence) and period 4 (omicron dominance), mAbs were administered on an outpatient basis, which may in part explain the lower 30-day admission rates (56-60% vs 83%). ICU admission rates were highest prior to emergence of omicron (12-12.5% vs 0-3%, Figure 1B) , which may reflect impact of a third COVID-19 vaccine and improved care for patients with COVID-19 as well as differences in severity between SARS-CoV-2 variants. 10, 11 The ICU admission rates in general 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 mAbs, almost universal treatment with remdesivir for hospitalized patients without renal failure and high vaccination rates.

Overall survival (OS) within 30 days after a positive PCR test for SARS-CoV-2 were above 75% for this immunocompromised population in all four time periods (77-91%). The estimated 30-day OS rate was lowest in period 4 when the omicron BA.2 sublineage was dominant, which may not be All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted March 2, 2022. ; https://doi.org/10.1101/2022.03.01.22271685 doi: medRxiv preprint susceptible to Sotrovimab pre-emptive treatment. 15 These survival rates are slightly better than the previously reported OS rates for COVID-19 in CLL during the first part of the pandemic (64-73%); although one study reported a higher OS rate of 89% for CLL patients testing positive for SARS-CoV-2 after 1 st May 2020. 1, 2 The estimated 30-day OS rate for period 3 seemed to indicate improved OS for CLL patients contracting COVID-19 after the emergence of the omicron variant. However, following patients for up to 90 days, the estimated OS rate decreased towards 75% for the first three Limitations apply to this study; the size of the patient population was limited, patients with CLL testing positive for SARS-CoV-2 at test sites not reported within the EHR may represent less severe CLL, thus causing overrepresentation of patients with more aggressive CLL in this study.

Based on epidemiological data from South Africa, 17 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 not to protect against infection with the omicron variant of SARS-CoV-2. This study indicate that omicron sublineage BA.2 pose a similar risk of fatal COVID-19 for patients with impaired immune function due to CLL and/or treatment, 3, 18 with an estimated 30-day OS rate of 77%, as prior variants. Thus, patients above 70 with CLL and one or more comorbidities should be considered for closer monitoring and pre-emptive antiviral therapy upon a positive SARS-CoV-2 test.

All rights reserved. No reuse allowed without permission. perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in The copyright holder for this this version posted March 2, 2022. ; https://doi.org/10.1101/2022.03.01.22271685 doi: medRxiv preprint

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