BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. METHODS: This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. RESULTS: A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017-1.109 and OR = 2.438, 95%CI 1.023-5.813, respectively). CONCLUSIONS: Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

1st Department of Medicine Hematology 1st Faculty of Medicine Charles University and General Hospital Prague Prague Czech Republic

1st Internal Medicine Department Propaedeutic Hematology Clinical Trial Unit National and Kapodistrian University of Athens Athens Greece

4th Department of Internal Medicine Haematology Faculty of Medicine in Hradec Králové University Hospital and Charles University Prague Hradec Kralove Czech Republic

Centre for Atherothrombosis and Metabolic Disease Hull York Medical School Hull UK

Clinical Centre of Vojvodina Faculty of Medicine University of Novi Sad Novi Sad Serbia

Clinical Hematology Unit Oncology Center Faculty of Medicine Mansoura University Mansoura 35516 Egypt

Consultant Haematologist St James's Hospital Leeds LS9 7TF UK

Consultative Hematology Department with a Day Hospital for Intensive High Dose Chemotherapy National Research Center for Hematology Moscow Russia

Department and Clinic of Hematology Blood Neoplasms and Bone Marrow Transplantation Wroclaw Medical University Pasteura Street 4 50 367 Wrocław Poland

Department Hematooncology and Bone Marrow Transplantation Medical University in Lublin Lublin Poland

Department Internal Medicine Maastricht University Medical Center Maastricht The Netherlands

Department of Biomedicine and Prevention Hematology University Tor Vergata Rome Italy

Department of Haematology Athens Medical Center Psychikon Branch Athens Greece

Department of Hematology and Central Hematology Laboratory Inselspital Bern University Hospital University of Bern Bern Switzerland

Department of Hematology Cancer Center Amsterdam Amsterdam University Medical Centers University of Amsterdam Amsterdam The Netherlands

Department of Hematology Gelderse Vallei Ede Ede The Netherlands

Department of Hematology Haga Teaching Hospital The Hague The Netherlands

Department of Hematology Health Research Institute IIS FJD Fundacion Jimenez Diaz University Hospital Madrid Spain

Department of Hematology Hospital del Mar Barcelona Spain

Department of Hematology Hospital General Universitario Valencia Spain

Department of Hematology Infanta Leonor University Hospital Madrid Spain

Department of Hematology Lymmcare Cancer Center Amsterdam Amsterdam University Medical Centers University of Amsterdam Amsterdam The Netherlands

Department of Hematology Shamir Medical Center Zerifin Israel

Department of Hematology Tel Aviv Sourasky Medical Center and Sackler School of Medicine Tel Aviv University Tel Aviv Israel

Department of Hematology Universitaire Ziekenhuizen Leuven Leuven Belgium

Department of Hematology University Hospital Dubrava Zagreb Croatia

Department of Internal Medicine Albert Schweitzer Hospital Dordrecht The Netherlands

Department of Internal Medicine Hematology and Oncology University Hospital Brno Czechia

Department of Internal Medicine Postgraduate Institute of Medical Education and Research Chandigarh India

Department of Internal Medicine Rijnstate Hospital Arnhem The Netherlands

Department of Medical Genetics and Genomics Faculty of Medicine Masaryk University Brno Czechia

Department of Medical Statistics and Informatics Faculty of Medicine University of Belgrade Belgrade Serbia

Department of Medicine and Surgery Institute of Hematology and Center for Hemato Oncological Research Ospedale S Maria della Misericordia Perugia Italy

Department of Medicine Ottawa Hospital Research Institute University of Ottawa Ottawa ON K1H 8L6 Canada

Department of Medicine Section of Hematology University of Verona Verona Italy

Dipartimento di Diagnostica per Immagini Radioterapia Oncologica ed Ematologia Fondazione Policlinico Universitario Agostino Gemelli IRCCS Rome Italy

Division of Hematology A O U Cittàdella Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences University of Turin Turin Italy

Division of Hematology Fondazione IRCCS Policlinico San Matteo Pavia Italy

Division of Hematology Rabin Medical Center Petah Tikva and the Sackler School of Medicine Tel Aviv University Tel Aviv Israel

Division of Internal Medicine Hematology Unit ASL Vercelli Vercelli Italy

Experimental Hematooncology Department Medical University of Lublin Lublin Poland

Faculty of Medicine University of Belgrade Belgrade Serbia

Federal State Budgetary Educational Institution of Higher Education Academician 1 P Pavlov 1st St Petersburg State Medical University of the Ministry of Healthcare of Russian Federation St Petersburg Russia

Fundación de Investigación del Hospital General Universitario Valencia Spain

FUNDALEU Clinical Research Center Buenos Aires Buenos Aires Argentina

Haematology Department Hospital Universitario de La Princesa Madrid Spain

Hematology and Clinical Immunology Unit Department of Medicine University of Padova Padua Italy

Hematology and Stem Cell Transplant Center Marche Nord Hospital Pesaro Italy

Hematology and Stem Cell Transplantation Unit Ospedale Oncologico A Businco ARNAS G Brotzu Cagliari Italy

Hematology ASST Papa Giovanni XXIII Bergamo Italy

Hematology Center after Prof Yeolyan MH RA Yerevan Armenia

Hematology Clinic ASUFC Udine Italy

Hematology Department and HCT Unit G Papanicolaou Hospital Thessaloniki Greece

Hematology Department Colentina Clinical Hospital Bucharest Romania

Hematology Department from Coltea Clinical Hospital Carol Davila University of Medicine and Pharmacy Bucharest Romania

Hematology Department Hospital Universitario 12de Octubre Madrid Spain

Hematology Department Hospital Universitario Puerta de Hierro Majadahonda Madrid Spain

Hematology Department of Translational and Precision Medicine Sapienza University Rome Italy

Hematology Department Portuguese Institute of Oncology Lisbon Lisbon Portugal

Hematology Department Ramón y Cajal University Hospital Madrid Spain

Hematology Department St John's Cancer Center Lublin Poland

Hematology Department Unit Research Complejo Asistencial Universitario de Burgos Burgos Spain

Hematology Department University Hospital of Salamanca IBSAL Salamanca Spain

Hematology Fondazione IRCCS Istituto Nazionale Tumori Milan Italy

Hematology Section Department of Medical Oncology National Center for Cancer Care and Research Doha Qatar

Hematology Unit and TMO Center AO SS Antonio e Biagio e Cesare Arrigo Alessandria Italy

Hematology Unit AO Cosenza Cosenza Italy

Hematology Unit Azienda Unità Sanitaria Locale IRCCS Reggio Emilia Italy

Hematology Unit Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan Milan Italy

Hematology Unit Nepal Cancer Hospital and Research Center Lalitpur Nepal

Hematology Unit Terrassa Hospital Terrassa Spain

Hospital Clínic de Barcelona Barcelona Spain

Hospital Italiano La Plata La Plata Argentina

Institute of Applied Biosciences Centre for Research and Technology Hellas Thessaloniki Greece

IRCSS Ospedale San Raffaele Milan Italy

Laboratory for Leukemia Diagnostics Department of Medicine 3 University Hospital LMU Munich Munich Germany

Lymphoma Center Clinic for Hematology University Clinical Center of Serbia Belgrade Serbia

S C Ematologia ASST Spedali Civili Brescia Brescia Italy

Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

SC Ematologia AO S Croce e Carle Cuneo Italy

Section of Hematology Department of Medical Sciences University of Modena and Reggio E Modena Italy

Sezione di Ematologia Dipartimento di Scienze Radiologiche ed Ematologiche Università Cattolica del Sacro Cuore Rome Italy

Spanish Society of Haematology and Hemotherapy Madrid Spain

St Anna University Hospital Ferrara Italy

Università Vita Salute San Raffaele and IRCC Ospedale San Raffaele Milan Italy

University Hospital and Research Institute of Marqués de Valdecilla Santander Spain

UOC Ematologia PO Vito Fazzi Lecce Lecce Italy

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Realizing precision medicine in chronic lymphocytic leukemia: Remaining challenges and potential opportunities