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Multicenter Study
. 2022 Aug 26;15(1):116.
doi: 10.1186/s13045-022-01333-0.

Thrombotic and bleeding complications in patients with chronic lymphocytic leukemia and severe COVID-19: a study of ERIC, the European Research Initiative on CLL

Darko Antic  1   2 , Natasa Milic  3 , Thomas Chatzikonstantinou  4   5 , Lydia Scarfò  6 , Vladimir Otasevic  7 , Nina Rajovic  3 , David Allsup  8 , Alejandro Alonso Cabrero  9 , Martin Andres  10 , Monica Baile Gonzales  11 , Antonella Capasso  12 , Rosa Collado  13   14 , Raul Cordoba  15 , Carolina Cuéllar-García  16 , Juan Gonzalo Correa  17 , Lorenzo De Paoli  18 , Maria Rosaria De Paolis  19 , Giovanni Del Poeta  20 , Maria Dimou  21 , Michael Doubek  22   23 , Maria Efstathopoulou  24 , Shaimaa El-Ashwah  25 , Alicia Enrico  26 , Blanca Espinet  27 , Lucia Farina  28 , Angela Ferrari  29 , Myriam Foglietta  30 , Alberto Lopez-Garcia  15 , José A García-Marco  31 , Rocío García-Serra  13   14 , Massimo Gentile  32 , Eva Gimeno  27 , Maria Gomes da Silva  33 , Odit Gutwein  34   35 , Yervand K Hakobyan  36 , Yair Herishanu  37 , José Ángel Hernández-Rivas  38 , Tobias Herold  39 , Gilad Itchaki  40 , Ozren Jaksic  41 , Ann Janssens  42 , Olga B Kalashnikova  43 , Elżbieta Kalicińska  44 , Arnon P Kater  45 , Sabina Kersting  46 , Maya Koren-Michowitz  34   35 , Jorge Labrador  47 , Deepesh Lad  48 , Luca Laurenti  49   50 , Alberto Fresa  49   50 , Mark-David Levin  51 , Carlota Mayor Bastida  9   52 , Lara Malerba  53 , Roberto Marasca  54 , Monia Marchetti  55 , Juan Marquet  56 , Biljana Mihaljevic  7   57 , Ivana Milosevic  58 , Fatima Mirás  59 , Marta Morawska  60   61 , Marina Motta  62 , Talha Munir  63 , Roberta Murru  64 , Raquel Nunes  33 , Jacopo Olivieri  65 , Miguel Arturo Pavlovsky  66 , Inga Piskunova  67 , Viola Maria Popov  68 , Francesca Maria Quaglia  69 , Giulia Quaresmini  70 , Gianluigi Reda  71 , Gian Matteo Rigolin  72 , Amit Shrestha  73 , Martin Šimkovič  74 , Svetlana Smirnova  67 , Martin Špaček  75 , Paolo Sportoletti  76 , Oana Stanca  77 , Niki Stavroyianni  4 , Doreen Te Raa  78 , Kristina Tomic  7 , Sanne Tonino  79 , Livio Trentin  80 , Ellen Van Der Spek  81 , Michel van Gelder  82 , Marzia Varettoni  83 , Andrea Visentin  80 , Candida Vitale  84 , Vojin Vukovic  7 , Ewa Wasik-Szczepanek  85 , Tomasz Wróbel  44 , Lucrecia Yáñez San Segundo  86 , Mohamed Yassin  87 , Marta Coscia  84 , Alessandro Rambaldi  70 , Emili Montserrat  17 , Robin Foà  88 , Antonio Cuneo  72 , Marc Carrier  89 , Paolo Ghia #  6 , Kostas Stamatopoulos #  5
Affiliations
Multicenter Study

Thrombotic and bleeding complications in patients with chronic lymphocytic leukemia and severe COVID-19: a study of ERIC, the European Research Initiative on CLL

Darko Antic et al. J Hematol Oncol. .

Abstract

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.

Keywords: Age; Anticoagulation therapy; Bleeding; CLL; COVID-19; D-dimer; LMWH; Thromboprophylaxis; Thrombosis.

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Conflict of interest statement

L.S. received advisory boards fees from AbbVie and Janssen; educational activity AstraZeneca. DA received funding to attend symposia from Gilead and Bayer. MA received advisory boards fees from AbbVie, AstraZeneca, Janssen-Cilag; travel support from AbbVie and Novartis. RC received speaker fees from Roche, Janssen, AbbVie, AstraZeneca, Celgene, BMS, Kite, and Takeda; advisory board fees from Janssen, AbbVie, Celgene, BMS, Kite, Takeda, Incyte, Kyowa-Kirin, and ADCT; travel and accommodation expenses from Roche, Janssen, AbbVie, Celgene, BMS, Kite, Takeda, and Pfizer; research grant from Pfizer. MC received honoraria from AbbVie, Gilead, Janssen, and AstraZeneca. LS received advisory boards fees from AbbVie, BeiGene and Janssen; educational activity AstraZeneca. BE received consulting or advisory boards fees from Janssen, Roche, Novartis, AbbVie, Gilead, Celgene, ArQule, AstraZeneca, Oxford Biomedica (UK), and BeiGene; speaker / speaker’s bureau fees from Janssen, Gilead, Roche, AbbVie, Novartis, Celgene, Adaptive Biotechnologies, BioGene, and AstraZeneca; research support / research funding from Janssen, Gilead, Roche, AbbVie, BeiGene, and AstraZeneca; travel, accommodations, expenses from Janssen, Roche, Novartis, AbbVie, Gilead, and Celgene. MF received honoraria from Abbvie, Janssen, Gilead. JAG-M received honoraria for advisory board and speaker´s bureau from Mundipharma, Glaxo, AbbVie, Roche, Gilead, AstraZeneca, and Janssen; research support from Hoffman-La Roche, AbbVie, and Janssen. RG-S received educational grants from AbbVie, Janssen, and Novartis. EG received travel grants, honoraria as a consultant and/or speaker bureau for Janssen-Cilag, Roche, and AbbVie. MGDS received honoraria for consultancy/advisory boards with Roche, Janssen Cilag, Gilead, AbbVie, and BMS; research Grant from Gilead, and AstraZeneca. YH received honoraria from AbbVie, Janssen, AstraZeneca, Roche and Medison, outside the submitted work. JAH received honoraria and advisory boards fees from Janssen, AbbVie, AstraZeneca, Roche, Beigene, Gilead, and BMS-Celgene. OJ received honoraria from AbbVie, Janssen, and Roche. AK received honoraria from Janssen, BMS, Astra Zeneca, Roche/Genentech; research money from Janssen, BMS, AstraZeneca, and Roche/Genentech. SK received Travel grant from Celgene; research funding from Janssen, Roche/Genentech, and AbbVie. LL received honoraria for advisory board and lecturing from Janssen, Gilead, AbbVie, Roche, and AstraZeneca. M-DL received advisory board and travel expenses from AbbVie, Janssen, Takeda, and Roche. AG received speaker’s bureau fees from Roche, Janssen, AbbVie, Celgene, Fresenius, Novonordisk; advisory board participation fees from Janssen, and AbbVie; travel and accommodation expenses from Roche, Janssen, and AbbVie. MoMa received speaker bureau fees from Amgen, honoraria as a consultant from Gilead. JM received honoraria and travel grants from AbbVie, Janssen, Roche, Gilead, and Takeda. JAHR received honoraria and advisory boards fees from Janssen, Abbvie, AstraZeneca, Roche, Beigene, Lilly, Gilead, and BMS-Celgene. MD received honoraria from AbbVie, Janssen, Astra-Zeneca, and Novartis. FRM received research funding from Gilead; advisory board participation fees from AbbVie, Gilead, Janssen, AstraZeneca, Takeda, and Roche; speakers bureau fees from Gilead, Janssen, and AbbVie. TM received honoraria from AbbVie, Janssen, AstraZeneca, Gilead, Roche, and Alexion; advisory board participation fees from AbbVie, AstraZeneca, Janssen, Alexion, Morphosys, and Sunesis. RM received honoraria from Janssen, AbbVie, and AstraZeneca. MAP received advisory board participation fees from Janssen, AbbVie, Astra Zeneca, and Merck; speaker’s bureau fees from Janssen, AbbVie, AstraZeneca, Varifarma, and Merck. FMQ received advisory board participation fees from Astrazeneca, and Janssen; speakers bureau fees from AstraZeneca, and Janssen; consultant (but no fees) for Sandoz; travel accommodation from Amgen and Gentili. GR received consultancy fees and honoraria from Abbvie, AstraZeneca, and Janssen. MaMo received consultancy fees from Gilead srl. GMR received honoraria from AbbVie, Gilead, and Janssen; received research funding from Gilead. MS received consultancy fees, advisory board participation fees, travel grants, honoraria from Janssen, Gilead, Roche, AstraZeneca, AbbVie. MS received honoraria from AbbVie, AstraZeneca, Gilead, Janssen, and Roche. PS received funding from Gilead; advisory board participation fees from AbbVie and Janssen; honorarium AbbVie, Janssen, and AstraZeneca. SEA received speaker fees from Janssen, and Takeda. LT received advisory board participation fees from Janssen, Roche, AbbVie, Gilead, Takeda; research funding from Janssen, Roche, Takeda, and Gilead. EVDS received teaching activities fees from Amgen; speaker fees from Janssen. MV received advisory board participation fees from Janssen, Roche, Astra Zeneca, Beigene; speaker fees from Abbvie. AJ received consultancy fees from AstraZeneca, Janssen, Novartis, and Sanofi; advisory board participation fees from Astra Zeneca, Janssen, Sobi, Novartis, Sandoz, MSD, and Incyte, Beigene; speaker fees from Astra Zeneca, Janssen, Sobi, Incyte, Novartis, Abbvie, Amgen, Takeda, and Beigene. AE received honoraria and advisory boards fees from Janssen, Abbvie, Novartis, Biosidus and BMS-Celgene. AV received speaker’s bureau fees from Italfarmaco and Gilead; advisory board participation fees from Janssen and Takeda. CV received honoraria from Janssen. IM received speaker Fees from Janssen, Roche, Abbvie, Sandoz. FM received fees from Janssen, and Gilead. TW received research funding from Roche; honoraria for advisory board, and research funding from Janssen; honoraria, advisory board participation fees, and travel grant from AbbVie; speaker’s bureau fees from Gilead. TC, AK, GK, AAC, DA, MB, MBG, AC, SC, J-GC, CC-G, LDP, MRDP, GDP, CD, MD, DD, ME, MKM, LF, AF, MoF, MG, OG, YKH, TH, II, GI, OBK, EK, JLG, DL, EL, LM, RM, MaMa, MaMot, RN, JO, LO, MP, IP, VMP, GQ, RR, JGC, SS, GS, AS, OS, NS, TT, DTR, ST, MVG, EWS, MY, AR have no conflict of interest to disclose.

Figures

Fig. 1
Fig. 1
Flow chart of study participants
Fig. 2
Fig. 2
Receiver operating characteristic curve for D-dimer in distinguishing CLL patients with COVID-19, with and without thrombosis
See this image and copyright information in PMC

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