SOHO State of the Art Updates and Next Questions | Infections in Chronic Lymphocytic Leukemia Patients: Risks and Management.

Although chronic lymphocytic leukemia (CLL) is a malignancy characterized by accumulation of tumor cells in the blood, bone marrow, lymph nodes and secondary lymphoid tissues, the hallmark of the disease and the major cause of death for patients with CLL is actually immune dysfunction and associated infections. Despite improvement in treatment based on combination chemoimmunotherapy and targeted treatment with BTK and BCL-2 inhibitors leading to longer overall survival for patients with CLL, the mortality due to infections have not improved over the last 4 decades. Thus, infections are now the main cause of death for patients with CLL, posing threats to the patient whether during the premalignant state of monoclonal B lymphocytosis (MBL), during the watch & wait phase for treatment naïve patients, or upon treatment in terms of chemoimmunotherapy or targeted treatment. To test whether the natural history of immune dysfunction and infections in CLL can be changed, we have developed the machine learning based algorithm CLL-TIM.org to identify these patients. The CLL-TIM algorithm is currently being used for selection of patients for the clinical trial PreVent-ACaLL (NCT03868722), testing whether short-term treatment with the BTK inhibitor acalabrutinib and the BCL-2 inhibitor venetoclax can improve immune function and decrease the risk of infections for this high-risk patient population. We here review the background for and management of infectious risks in CLL.

Readmissions, post-discharge mortality and sustained recovery among patients admitted to hospital with COVID-19.

BACKGROUND: Many interventional in-patient COVID-19 trials assess primary outcomes through day 28 post-randomization. Since a proportion of patients experience protracted disease or relapse, such follow-up period may not fully capture the course of the disease, even when randomization occurs a few days after hospitalization. METHODS: Among adults hospitalized with COVID-19 in Eastern Denmark from March 18, 2020 - January 12, 2021 we assessed: all-cause mortality, recovery and sustained recovery 90 days after admission, and readmission and all-cause mortality 90 days after discharge. Recovery was defined as hospital discharge and sustained recovery as recovery and alive without readmissions for 14 consecutive days. RESULTS: Among 3,386 patients included in the study 2,796 (82.6%) reached recovery and 2,600 (77.0%) achieved sustained recovery. Of those discharged from hospital, 556 (19.9%) were readmitted, and 289 (10.3%) died. Overall, the median time to recovery was 6 days (Interquartile range (IQR), 3-10), and 19 days (IQR, 11-33) among patients in intensive care in the first two days of admission. CONCLUSIONS: Post-discharge readmission and mortality rates were substantial. Therefore, sustained recovery should be favored to recovery outcomes in clinical COVID-19 trials. A 28-day follow-up period may be too short the critically ill.

Chest x-ray imaging score is associated with severity of COVID-19 pneumonia: the MBrixia score.

Spatial resolution in existing chest x-ray (CXR)-based scoring systems for coronavirus disease 2019 (COVID-19) pneumonia is low, and should be increased for better representation of anatomy, and severity of lung involvement. An existing CXR-based system, the Brixia score, was modified to increase the spatial resolution, creating the MBrixia score. The MBrixia score is the sum, of a rule-based quantification of CXR severity on a scale of 0 to 3 in 12 anatomical zones in the lungs. The MBrixia score was applied to CXR images from COVID-19 patients at a single tertiary hospital in the period May 4th-June 5th, 2020. The relationship between MBrixia score, and level of respiratory support at the time of performed CXR imaging was investigated. 37 hospitalized COVID-19 patients with 290 CXRs were identified, 22 (59.5%) were admitted to the intensive care unit and 10 (27%) died during follow-up. In a Poisson regression using all 290 MBrixia scored CXRs, a higher MBrixia score was associated with a higher level of respiratory support at the time of performed CXR. The MBrixia score could potentially be valuable as a quantitative surrogate measurement of COVID-19 pneumonia severity, and future studies should investigate the score's validity and capabilities of predicting clinical outcomes.

Personalized survival probabilities for SARS-CoV-2 positive patients by explainable machine learning.

Interpretable risk assessment of SARS-CoV-2 positive patients can aid clinicians to implement precision medicine. Here we trained a machine learning model to predict mortality within 12 weeks of a first positive SARS-CoV-2 test. By leveraging data on 33,938 confirmed SARS-CoV-2 cases in eastern Denmark, we considered 2723 variables extracted from electronic health records (EHR) including demographics, diagnoses, medications, laboratory test results and vital parameters. A discrete-time framework for survival modelling enabled us to predict personalized survival curves and explain individual risk factors. Performance on the test set was measured with a weighted concordance index of 0.95 and an area under the curve for precision-recall of 0.71. Age, sex, number of medications, previous hospitalizations and lymphocyte counts were identified as top mortality risk factors. Our explainable survival model developed on EHR data also revealed temporal dynamics of the 22 selected risk factors. Upon further validation, this model may allow direct reporting of personalized survival probabilities in routine care.

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

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 significantly, 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 test.

COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus.

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79-7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.