Outcomes for patients with hematologic malignancy infected with COVID-19 have not been aggregated. The objective of this study was to perform a systematic review and meta-analysis to estimate the risk of death and other important outcomes for these patients. We searched Pubmed and EMBASE up to August 20, 2020, to identify reports of patients with hematologic malignancy and COVID-19. The primary outcome was a pooled mortality estimate, considering all patients and only hospitalized patients. Secondary outcomes included risk of ICU admission and ventilation in hospitalized patients. Subgroup analyses included mortality stratified by age, treatment status, and malignancy subtype. Pooled prevalence, risk ratios (RR), and 95% confidence intervals (CI) were calculated using a random-effects model. 34 adult and 5 pediatric studies (3377 patients) from Asia, Europe, and North America were included (14/34 adult studies included only hospitalized patients). The risk of death amongst adult patients was 34% (95% CI 28-39, N=3240) in this sample of predominantly hospitalized patients. Patients aged >60 years had a significantly higher risk of death than patients <60 years (RR 1.82, 95% CI 1.45-2.27, N=1169). The risk of death in pediatric patients was 4% (95% CI 1-9, N=102). The RR of death comparing patients with recent systemic anti-cancer therapy to no treatment was 1.17 (95% CI 0.83-1.64; N=736). Adult patients with hematologic malignancy and COVID-19, especially hospitalized patients, have a high risk of dying. Patients >60 years have significantly higher mortality, and pediatric patients appear to be relatively spared. Recent cancer treatment does not appear to significantly increase the risk of death.

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.

Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to Coronavirus disease 2019 (COVID-19) due to age, disease, and treatment-related immunosuppression. We aimed to assess risk factors of outcome and elucidate the impact of CLL-directed treatments on the course of COVID-19. We conducted a retrospective, international study, collectively including 941 patients with CLL and confirmed COVID-19. Data from the beginning of the pandemic until March 16, 2021, were collected from 91 centers. The risk factors of case fatality rate (CFR), disease severity, and overall survival (OS) were investigated. OS analysis was restricted to patients with severe COVID-19 (definition: hospitalization with need of oxygen or admission into an intensive care unit). CFR in patients with severe COVID-19 was 38.4%. OS was inferior for patients in all treatment categories compared to untreated (p < 0.001). Untreated patients had a lower risk of death (HR = 0.54, 95% CI:0.41–0.72). The risk of death was higher for older patients and those suffering from cardiac failure (HR = 1.03, 95% CI:1.02–1.04; HR = 1.79, 95% CI:1.04–3.07, respectively). Age, CLL-directed treatment, and cardiac failure were significant risk factors of OS. Untreated patients had a better chance of survival than those on treatment or recently treated.

The somatic hypermutation (SHM) status of the clonotypic immunoglobulin heavy variable (IGHV) gene is a critical biomarker for assessing the prognosis of patients with chronic lymphocytic leukemia (CLL). Importantly, independent studies have documented that IGHV SHM status is also a predictor of responses to therapy, including both chemoimmunotherapy (CIT) and novel, targeted agents. Moreover, immunogenetic analysis in CLL has revealed that different patients may express (quasi)identical, stereotyped B cell receptor immunoglobulin (BcR IG) and are classified into subsets based on this common feature. Patients in certain stereotyped subsets display consistent biology, clinical presentation, and outcome that are distinct from other patients, even with concordant IGHV gene SHM status. All of the above highlights the relevance of immunogenetic analysis in CLL, which is considered a cornerstone for accurate risk stratification and clinical decision making. Recommendations for robust immunogenetic analysis exist thanks to dedicated efforts by ERIC, the European Research Initiative on CLL, covering all test phases, from the pre-analytical and analytical to the post-analytical, pertaining to the analysis, interpretation, and reporting of the findings. That said, these recommendations apply to Sanger sequencing, which is increasingly being superseded by next generation sequencing (NGS), further underscoring the need for an update. Here, we present an overview of the clinical utility of immunogenetics in CLL and update our analytical recommendations with the aim to assist in the refined management of patients with CLL.

Coronavirus disease 2019 (COVID-19) has markedly impacted on the management of patients with chronic lymphocytic leukemia (CLL) and their outcome in the last year. The cumulative incidence of COVID-19 in patients with CLL in 1 year was approximately 3% in the recent Italian CAMPUS CLL survey; large retrospective studies have documented a higher mortality in patients with CLL hospitalized for severe COVID-19 compared with the general population. Controversial results for CLL-directed treatment have been reported, with some studies suggesting a potential benefit for BTK inhibitors. Reducing the number of hospital visits, delaying treatment whenever possible, and using oral therapy have become the mainstay of management in these patients. Available results with severe acute respiratory syndrome coronavirus 2 vaccines indicate an immune serological response in 40% of patients only, with a detrimental effect of recent therapy with or without anti-CD20 therapy, older age, and hypogammaglobulinemia. Further studies are needed to determine the best strategies in patients with CLL regarding (i) management of concomitant COVID-19, (ii) identification of patients in whom CLL therapy can be safely postponed, (iii) CLL treatment algorithms, and (iv) optimal severe acute respiratory syndrome coronavirus 2 vaccination strategies.

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