COVID-19 in adult acute myeloid leukemia patients: a long-term follow-up study from the European Hematology Association survey (EPICOVIDEHA)

Francesco Marchesi,1* Jon Salmanton-García,2,3* Ziad Emarah,4 Klára Piukovics,5 Marcio Nucci,6 Alberto López-García,7 Zdeněk Ráčil,8 Francesca Farina,9 Marina Popova,10 Sofia Zompi,11 Ernesta Audisio,11 Marie-Pierre Ledoux,12 Luisa Verga,13,14 Barbora Weinbergerová,15 Tomas Szotkovski,16 Maria Gomes Da Silva,17 Nicola Fracchiolla,18 Nick De Jonge,19 Graham Collins,20 Monia Marchetti21 Gabriele Magliano22 Carolina García-Vidal23 Monika M. Biernat24 Jaap Van Doesum,25 Marina Machado,26 Fatih Demirkan,27 Murtadha Al-Khabori,28 Pavel Žák,29 Benjamín Víšek,29 Igor Stoma,30 Gustavo-Adolfo Méndez,31 Johan Maertens,32 Nina Khanna,33 Ildefonso Espigado,34 Giulia Dragonetti,35 Luana Fianchi,35 Maria Ilaria Del Principe,36 Alba Cabirta,37,38 Irati Ormazabal- Vélez,39 Ozren Jaksic,40 Caterina Buquicchio,41 Valentina Bonuomo,42 Josip Batinić,43,44,45 Ali S. Omrani,46 Sylvain Lamure,47 Olimpia Finizio,48 Noemí Fernández,49 Iker Falces-Romero,50 Ola Blennow,51 Rui Bergantim,52 Natasha Ali,53 Sein Win,54 Jens Van Praet,55 Maria Chiara Tisi,56 Ayten Shirinova,57 Martin Schönlein,58 Juergen Prattes,59 Monica Piedimonte,60 Verena Petzer,61 Milan Navrátil,62 Austin Kulasekararaj,63 Pavel Jindra,64 Jiří Sramek,65,66 Andreas Glenthøj,67 Rita Fazzi,68 Cristina De Ramón-Sánchez,69,70 Chiara Cattaneo,71 Maria Calbacho,72 Nathan C. Bahr,73 Shaimaa El-Ashwah,4 Raul Cordoba,7 Michaela Hanakova,8 Giovanni Paolo Maria Zambrotta,13 Giovanni Zambrotta,14 Mariarita Sciumè,18 Stephen Booth,20 Raquel Nunes Rodrigues,17 Maria Vittoria Sacchi,21 Nicole García-Poutón,23 Juan-Alberto Martín-González,74 Sofya Khostelidi,75 Stefanie Gräfe,76,2,3 Laman Rahimli,2,3 Emanuele Ammatuna,25 Alessandro Busca,11 Paolo Corradini,77 Martin Hoenigl,78,79,80 Nikolai Klimko,75 Philipp Koehler,2,3 Antonio Pagliuca,81 Francesco Passamonti,82 Oliver A. Cornely2,3,83,84# and Livio Pagano35,85# 1Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy; 2University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany; 3University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), Cologne, Germany; 4Oncology Center, Mansoura University, Mansoura, Egypt; 5Department of Internal Medicine, South Division Faculty of Medicine University of Szeged, Szeged, Hungary; 6Department of Internal Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; 7Fundacion Jimenez Diaz University Hospital, Health Research Institute IIS-FJD, Madrid, Spain; 8Institute of Hematology and Blood Transfusion, Prague, Czech Republic; 9IRCCS Ospedale San Raffaele, Milan, Italy; 10RM Gorbacheva Research Institute, Pavlov University, St. Petersburg, Russia; 11Stem Cell Transplant Center, AOU Citta' della Salute e della Scienza, Turin, Italy; 12Institut de Cancérologie Strasbourg Europe (ICANS), Strasbourg, France; 13Azienda Ospedaliera San Gerardo - Monza, Monza, Italy; 14Università Milano- Bicocca, Milan, Italy; 15Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic; 16University Hospital Olomouc, Olomouc, Czech Republic; 17Portuguese Institute of Oncology, Lisbon, Portugal; 18Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; 19Amsterdam UMC, location VUmc, Amsterdam, the Netherlands; 20Oxford University Hospitals, Oxford, UK; 21Azienda Ospedaliera Nazionale “SS. Antonio e Biagio e Cesare Arrigo”, Alessandria, Italy; 22ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; 23Department of Infectious Diseases, Hospital Clinic de Barcelona, University of Barcelona, IDIBAPS, Barcelona, Spain; 24Department of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland; 25University Medical Center Groningen, Groningen, the Netherlands; 26Clinical Microbiology and Infectious Diseases Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain; 27Division of Hematology, Dokuz Eylul University, Izmir, Turkey; 28Sultan Qaboos University Hospital, Muscat, Oman; 29University Hospital Hradec Králové, Hradec Králové, Czech Republic; 30Gomel State Medical University, Gomel, Belarus; 31Hospital Escuela de Agudos Dr. Ramón Madariaga, Posadas, Argentina; 32Department of Microbiology, Immunology, and Transplantation, KULeuven and Department of Hematology, UZ Leuven, Leuven, Belgium; 33Division of Infectious Diseases and Hospital Epidemiology, and Department of Clinical Research, University and University Hospital of Basel, Basel, Switzerland; 34Department of Hematology, University Hospital Virgen Macarena - University Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC), Universidad de Sevilla, Seville, Spain; 35Hematology Unit, Fondazione Policlinico Universitario Agostino Gemelli - IRCCS, Rome, Italy; 36Hematology Unit, Department of Biomedicine and Prevention, Tor Vergata University of Rome, Italy; 37Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain; 38Department of Hematology, Vall d’Hebron Hospital Universitari, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain; 39Complejo Hospitalario de Navarra, Iruña- Pamplona, Spain; 40University Hospital Dubrava, Zagreb, Croatia; 41Ematologia con Trapianto, Ospedale Dimiccoli Barletta, Barletta, Italy; 42Department of Medicine, Section of Hematology, University of Verona, Verona, Italy; 43Croatian Cooperative Group for Hematological Diseases (CROHEM), Zagreb, Croatia; 44Faculty of Medicine University of Zagreb, Zagreb, Croatia; 45University Hospital Centre Zagreb, Zagreb, Croatia; 46Hamad Medical Corporation, Division of Infectious Diseases, Doha, Qatar; 47Département d’Hématologie Clinique, CHU de Montpellier, UMRCNRS 5535, Universite de Montpellier, Montpellier, France; 48UOC Hematology, AORN Cardarelli, Naples, Italy; 49Hospital Universitario Marqués de Valdecilla, Santander, Spain; 50La Paz University Hospital, Madrid, Spain; 51Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden; 52Centro Hospitalar e Universitário São João, Porto, Portugal; 53Aga Khan University Hospital, Karachi, Pakistan; COVID-19 in adult acute myeloid leukemia patients: a long-term follow-up study from the European Hematology Association survey (EPICOVIDEHA) Haematologica | 108 January 2023 22 ARTICLE - Acute Myeloid Leukemia Correspondence: J. SALMANTON-GARCÍA [email protected] Received: February 11, 2022. Accepted: May 5, 2022. Prepublished: May 12, 2022. https://doi.org/10.3324/haematol.2022.280847 ©2023 Ferrata Storti Foundation Published under a CC BY-NC license 54Department of Clinical Hematology, Yangon General Hospital, University of Medicine, Yangon, Myanmar; 55Department of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge-Oostende AV, Brugge, Belgium; 56Ospedale San Bortolo, Vicenza, Italy; 57Azerbaijan Scientific Research Hematology and Transfusiology Institute, Baku, Azerbaijan; 58Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 59Medical University of Graz, Department for Infectious Diseases, Graz, Austria; 60AOU Sant'Andrea, Rome, Italy; 61Department of Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; 62Head of the ICU and Transplant Unit, Department of Hematooncology, University Hospital of Ostrava, Ostrava-Poruba, Czech Republic; 63King's College Hospital, London, UK; 64University Hospital Pilsen, Pilsen, Czech Republic; 65Department of Hematology and Oncology, University Hospital Pilsen, Pilsen, Czech Republic; 66Department of Histology and Embryology, Faculty of Medicine, Pilsen, Czech Republic; 67Department of Hematology, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark; 68AOUP - Azienda Ospedaliera Università Pisana - Cisanello, Pisa, Italy; 69Hematology Department, Hospital Universitario de Salamanca, Salamanca, Spain; 70IBSAL, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain; 71Hematology Unit, ASST-Spedali Civili, Brescia, Italy; 72Hospital Universitario 12 de Octubre, Madrid, Spain; 73University of Kansas Medical Center, Kansas City, USA; 74Hospital Univesitario Virgen del Rocío, Seville, Spain; 75North-Western State Medical University named after Iliá Ilich Méchnikov, Saint-Petersburg, Russia; 76Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany; 77University of Milan and Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 78Clinical and Translational Fungal- Working Group, University of California San Diego, La Jolla, CA, USA; 79Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, San Diego, CA, USA; 80Division of Infectious Diseases, Department of Internal Medicine, Medical University of Graz, Graz, Austria; 81Department of Haematological Medicine, Kings College Hospital NHS Foundation Trust, London, UK; 82Department of Medicine and Surgery, University of Insubria and ASST Sette Laghi, Ospedale di Circolo of Varese, Varese, Italy; 83German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany; 84University of Cologne, Faculty of Medicine and University Hospital Cologne, Clinical Trials Centre Cologne (ZKS Köln), Cologne, Germany and 85Hematology Unit, Università Cattolica del Sacro Cuore, Rome, Italy *FM and JSG contributed equally as co-first authors. #OAC and LP contributed equally as co-senior authors. Patients with acute myeloid leukemia (AML) are at high risk of dying from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our multicenter study included 388 adult AML patients diagnosed with COVID-19 between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the preceding 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died; death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%), whereas in 3.9% of cases the reason was unknown. Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with better survival when AML treatment could be delayed (80%; P<0.001). Overall survival in patients with a diagnosis of COVID-19 between January 2020 and August 2020 was significantly lower than that in patients diagnosed between September 2020 and February 2021 and between March 2021 and September 2021 (39.8% vs. 60% vs. 61.9%, respectively; P=0.006). COVID-19 in AML patients was associated with a high mortality rate and modifications of therapeutic algorithms. The best approach to improve survival was to delay AML treatment, whenever possible. Introduction Acute myeloid leukemia (AML) is an aggressive hematologic malignancy often requiring immediate chemotherapy because of a high risk of early disease-related lifethreatening complications including death.1 AML patients are severely immunocompromised, and infections are frequently associated with both the disease-related weakened immunity and the aggressive chemotherapeutic regimen.2 Although viral infections are less relevant than bacterial and fungal infections, respiratory viruses may also affect AML patients, particularly during seasonal epidemics.3 Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with a severe clinical presentation in AML patients. Most of the studies performed in the pre-vaccine era reported mortality rates higher than 40%.4-8 The literature regarding COVID-19 in AML patients is limited to small cohorts,9-10 case reports and case series,10-14 expert opinions and consensus,13,15 or series reporting both patients with AML and acute lymphoblastic leukemia.16-17 Specific data on large cohorts of patients with long-term follow-up are, therefore, still lacking. To the best of our knowledge, there are still no evidence-based algorithms guiding clinicians to choose the best therapeutic approach and timing, par- Abstract Haematologica | 108 January 2023 23 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. ticularly in patients with a simultaneous diagnosis of AML and COVID-19. Thus, in order to establish the best therapeutic approach, we aimed to describe clinical features and long-term follow-up of a large cohort of AML patients with COVID-19 registered in the EPICOVIDEHA registry, with a particular focus on patients with a concomitant diagnosis of AML and COVID-19. Methods Study design, patients, and procedures This was an observational multicenter study of AML patients who developed COVID-19 between February 2020 and October 2021, with data from EPICOVIDEHA (registered with www.clinicaltrials.gov; ID NCT04733729), an international open web-based registry for hematologic malignancies and COVID-19 patients initiated in February 2020 by members of the Infections in Hematology Scientific Working Group of the European Hematology Association (EHA). EPICOVIDEHA was approved by the local ethics committee of the Fondazione Policlinico Universitario Agostino Gemelli - IRCCS, Università Cattolica del Sacro Cuore of Rome, Italy (ID 3226). All consecutive AML patients diagnosed with COVID-19 were captured and registered in this web-based registry. The respective local ethics committee of each participating institution provided approval as appropriate. The methodology of EPICOVIDEHA has been described elsewhere.18 The electronic case report form is accessible online at www.clinicalsurveys.net (EFS Summer 2021, TIVIAN GmbH, Cologne, Germany).19 Each patient was reviewed and validated by infectious diseases and hematology experts. Inclusion criteria were: (i) active AML within the 5 years preceding the diagnosis of COVID- 19; (ii) age ≥18 years old; and (iii) a laboratory-based diagnosis of COVID-19. Patients’ conditions before COVID-19 (i.e., age, sex, AML status at COVID-19 diagnosis, comorbidities), AML clinical management, COVID-19 diagnosis and management, and outcome were also recorded. Information regarding AML treatment modifications (i.e., delay or discontinuation) due to COVID-19, and the contribution of the diagnosis of COVID-19 to AML relapse or status at the last day of follow-up was also collected. Status of the hematologic malignancy at the onset of COVID-19 and last follow-up was defined as active (onset, stable disease, refractory/resistant) or controlled (complete response) based on reports from the respective participating institution. COVID-19 severity was graded according to international standards as previously described.4,20,21 Patients were divided in three groups according to period of diagnosis: (i) January to August 2020 (first global wave of the pandemic); (ii) September 2020 to February 2021 (diagnosed in the 2020-2021 New Year holiday period); and (iii) March to September 2021 (diagnosed after SARS-CoV-2 vaccines became available). Patients with incomplete data about COVID-19 diagnosis, AML treatment phase/disease status and date of last follow-up were excluded from the final analysis. Study objectives The primary objective of this study was to evaluate the epidemiology and outcome of AML patients with COVID- 19. Secondary objectives were to estimate the prevalence of disease severity, to describe the overall case-fatality rate, and to stratify patients according to their treatment phase (induction, consolidation, maintenance, palliative, reinduction), chemotherapeutic program modification due to COVID-19 (treatment discontinuation, delay or continuation), and timing of COVID-19 diagnosis. Sample size and statistical analysis Categorical variables were described using frequencies and percentages, whereas continuous variables were expressed as median, interquartile range (IQR) and absolute range. A Cox regression hazard model was designed and run with variables considered to play a role in the mortality of AML patients with COVID-19, as previously described.4 A multivariable Cox regression model was calculated with the Wald backward method, and only those variables with P≤0.1 were displayed. Mortality was analyzed using Kaplan- Meier survival plots. A log-rank test was used to compare the survival probability of the patients included in the different models. A P-value ≤0.05 was considered statistically significant. SPSS v27.0 was employed for statistical analyses (SPSS, IBM Corp., Chicago, IL, USA). Results Between February 2020 and October 2021, 556 consecutive adult AML patients with confirmed SARS-CoV-2 infection were reported in the EPICOVIDEHA registry from 132 centers and 20 countries around the world. Out of these patients, 168 (30.2%) were excluded from this analysis because of missing data. In 25 cases (6.4%), a diagnosis of acute promyelocytic leukemia (APL) was reported. The demographic and clinical characteristics of the remaining 388 patients are shown in Table 1. Their median age was 59 years (IQR, 45-70) and there was a slight male predominance (52.6%). Most patients had at least one underlying comorbidity, with chronic heart disease (e.g., hypertension, obstructive arteriopathy, atrial fibrillation) being the most frequent, whereas 175 patients (45.1%) had comorbidities. At the time of the COVID-19 diagnosis, 196 patients (50.5%) had controlled AML, and 192 (49.5 %) had active disease, including 79 (20.4%) patients at the onset of their leukemia. Only 110 patients (28.3%) were not on Haematologica | 108 January 2023 24 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. active treatment; of these 110 patients, only four were on best supportive care, 18 were at the disease onset, whereas the remaining cases were in complete remission or in off-treatment follow-up. Overall, 237 patients (64.6%) had received intensive chemotherapy and transplantation, which were the most common strategies immediately before COVID-19. The chemotherapeutic program was modified because of COVID-19 in 174 (44.8%) patients; in 106 (60.9%) it was discontinued permanently, whereas in the remaining 68 (39.1%) it was delayed and resumed at a median of 1 month (IQR, 1-2) after the diagnosis of COVID- 19, once a negative SARS-CoV-2 swab had been documented. At COVID-19 onset, 71 (18.3%) and 53 (13.7%) patients had neutrophil and lymphocyte counts below 0.5x109/L and 0.2x109/L, respectively. Two hundred and twenty patients (56.7%) had pulmonary symptoms at the onset of COVID-19, mainly cough and dyspnea, 82 (21.1%) exhibited only extra-pulmonary symptoms and 86 (22.2%) were asymptomatic and diagnosed with COVID-19 after screening. As shown in Table 1, COVID-19 severity was criti- N % Sex Female 184 47.4 Male 204 52.6 Age, years Median (IQR) Range 59 (45-70) 18-89 Comorbidities 213 54.9 AML status at COVID-19 diagnosis Controlled disease 196 50.5 Complete remission 196 50.5 Active disease 192 49.5 Onset 79 20.4 Refractory/resistant 113 29.2 Last/ongoing treatment strategy before COVID-19 Treatment 367 94.6 Conventional chemotherapy 250 64.4 Last month 172 44.3 Last 3 months 46 11.9 >3 months 32 8.2 HSCT 72 18.6 Last month 8 2.1 Last 3 months 11 2.8 >3 months 53 13.7 Best supportive care 45 11.6 Last month 27 7.0 Last 3 months 9 2.3 >3 months 4 1.0 Not stated 5 1.3 No treatment 21 5.4 COVID-19 infection Critical infection 82 21.1 Severe infection 160 41.2 Mild infection 69 17.9 Asymptomatic 77 19.8 COVID-19 diagnosis Swab 376 96.9 BAL+swab 5 1.3 Serology 4 1.0 BAL 3 0.8 Table 1. Demographic and clinical features of 388 patients with acute myeloid leukemia at the time of COVID-19 diagnosis. COVID-19: coronavirus disease 2019; IQR: interquartile range; AML: acute myeloid leukemia; HSCT: hematopoietic stem cell transplantation; BAL: bronchoalveolar lavage; IQR: interquartile range; ICU: intensive care unit; MV: mechanical ventilation; HM: hematologic malignancy. N % Symptoms at COVID-19 onset Pulmonary 144 37.1 Screening 86 22.2 Extrapulmonary 82 21.1 Pulmonary + extrapulmonary 76 19.6 Neutrophils, x 109/L ≤0.5 71 18.3 0.501-0.999 38 9.8 ≥1 203 52.3 Lymphocytes, x 109/L ≤0.2 0.201-0.499 ≥0.5 53 56 211 13.7 14.4 54.4 Stay during COVID-19 Admitted to hospital 293 75.5 Duration of stay in hospital, days Median (IQR) Range 17 (8-30) 1-210 Admitted to ICU 82 21.1 Duration of ICU stay, days Median (IQR) Range 10 (5-20) 1-111 Invasive MV 63 16.2 Non-invasive MV 19 4.9 At home 117 30.2 Outcome Alive 208 53.6 Observation time, days Median (IQR) Range 325 (117-386) 3-639 Dead 180 46.4 Observation time, days Median (IQR) Range 20 (8-58) 0-528 Reason for death COVID-19 78 43.3 COVID-19 + HM 48 26.7 HM 47 26.1 Unknown reasons 7 3.9 Haematologica | 108 January 2023 25 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. cal in 82 patients (21.1%), severe in 160 (41.2%), mild in 69 (17.9%), and asymptomatic in the remaining cases (19.8%). Overall, 293 patients (75.5%) were hospitalized during their SARS-CoV-2 infection for a median of 17 days (IQR, 8-30). Eighty-two patients (21.1%) were admitted to an intensive care unit for a median stay of 10 days (IQR, 5-20), 63 (76.8%) of whom required invasive mechanical ventilation. After a median follow-up of 325 days (IQR, 3-639), 180 patients (46.4%) had died. The reported primary reason for death was COVID-19 in 78 (43.3%) patients, AML in 47 (26.1%), a combination of both in 48 (26.7%) and unknown in seven patients (3.9%) (Table 1, Figure 1). The mortality rate of patients with ongoing or recent (<1 month before COVID-19 diagnosis) AML treatment, like those treated 1 to 3 months prior to their COVID-19 diagnosis, was significantly higher than that of patients receiving treatment until 3 months or earlier before the diagnosis COVID-19 (P<0.001) (Figure 2). When considering AML patients whose last chemotherapy was administered within the month before the COVID-19 diagnosis, a higher mortality rate was observed in 68 (80.9%) patients who discontinued treatment, regardless of the treatment phase (Figure 3). Of note, patients who discontinued treatment were not different in terms of median age, but more often had at least one comorbidity and had a slightly but not statistically significant worse clinical presentation of COVID-19. A significantly lower overall mortality rate was observed in patients in whom chemotherapy was delayed (overall mortality rate: 18.4%, 9/49), as opposed to that of patients whose treatment was not delayed (37.5%, 9/24) (P<0.001), with the only exception of the re-induction subgroup of patients (Figures 3 and 4). The overall mortality rate of patients in induction (67.1%, n=51) or re-induction (77.7%, n=28) was higher than that of patients receiving consolidation (20%, n=10) during the last month prior to COVID-19 (P<0.001). Interestingly, we did not find any statistically significant difference in terms of survival between patients in complete remission (off-treatment) and those in complete remission but under consolidation treatment (mortality rate: 20.2% vs. 24.1%; P=0.677). In the univariable analysis, several factors were associated with an increased mortality (Table 2): older age, previous comorbidities (i.e., chronic heart disease or renal impairment), active malignancy, critical COVID-19, or permanent AML treatment discontinuation. Contrariwise, hav- Figure 1. Flow-chart of registered patients with acute myeloid leukemia. For five patients, it is not known when they received their treatment. Numbers for the reasons of death may be super-additive. AML: acute myeloid leukemia; COVID-19: coronavirus disease 2019; EPICOVIDEHA; COVID-19 study of the European Hematology Association. Haematologica | 108 January 2023 26 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. Figure 2. Survival probability by timing of last received treatment. AML: acute myeloid leukemia; COVID-19: coronavirus disease 2019; tx: treatment. ing a neutrophil or lymphocyte count above 0.5x109/L and 0.2x109/L, respectively, AML treatment >3 months before COVID-19 diagnosis and AML treatment delay were associated with a reduced mortality. In the multivariable model, active disease (hazard ratio [HR]=4.197, 95% confidence interval [95% CI]: 2.196-8.020; P<0.001), older age (HR=1.016, 95% CI: 1.004-1.028; P=0.012), and treatment discontinuation (HR=4.417, 95% CI: 2.306-8.460; P<0.001) were associated with a higher mortality, as opposed to treatment delay, which was found to be protective (HR=0.367, 95% CI: 0.151-0.891; P=0.027). After a time-dependent analysis, it was observed that overall survival in patients diagnosed Figure 3. Treatment modification in patients with acute myeloid leukemia whose last treatment was ongoing less than 1 month before COVID-19. In one patient the last treatment strategy was unknown. *In one patient with induction as last chemotherapy strategy, information on treatment continuation after COVID-19 is missing. **In one patient with no treatment delay, the last chemotherapy strategy is unknown. Patients who underwent allogeneic or autologous hematopoietic stem cell transplantation were included in “Reinduction” in this figure. AML: acute myeloid leukemia; COVID-19: coronavirus disease 2019. Haematologica | 108 January 2023 27 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. with COVID-19 between January 2020 and August 2020 was significantly lower than that of patients who were diagnosed between September 2020 and February 2021 and between March 2021 and September 2021 (39.8% vs. 60% vs. 61.9%, respectively; P=0.006) (Online Supplementary Figure S2). Table 3 presents the demographic and clinical features of the 79 patients with a simultaneous diagnosis of AML and COVID-19. In 18 patients (22.8%), COVID-19 was diagnosed before the start of induction, resulting in a treatment delay. Overall survival was higher among patients whose treatment was delayed (80%) than among those whose treatment was not delayed and not discontinued (64%) or was discontinued (6%) (P<0.001) (Table 3, Online Supplementary Figure S1). Finally, a separate sub-analysis was carried out focusing on AML patients receiving consolidation treatment (Online Supplementary Figure S3), relapsed/refractory patients being given re-induction (Online Supplementary Figure S4) and patients in complete remission (Online Supplementary Figure S5), confirming the better clinical outcome in patients in whom treatment was delayed. Discussion There is a gap of knowledge regarding COVID-19 in AML patients, as the current evidence is restricted to small cohorts of patients, case reports/series, or expert opinions.9- 17 This gap has made it difficult to establish the best strategy to manage AML patients during the pandemic.22,23 Taken together, the current evidence suggests that AML patients often present with a severe clinical form of COVID-19, frequently with respiratory distress and a very high mortality rate, between 40 and 50% higher than that in the pre-vaccine era. Here we present, to the best of our knowledge, the largest survey of AML patients with COVID- 19, with 388 patients reported from 132 institutions, with a special focus on their long-term follow-up. The data presented in our manuscript confirm that AML patients frequently have a severe clinical presentation of COVID-19, mainly with respiratory symptoms, and a high rate of intensive care unit admission, even among those with lowrisk AML (i.e., acute promyelocytic leukemia). Neutrophil and lymphocyte counts were not found to be significantly associated with mortality in our multivariable model. The potential role of neutropenia as a risk factor for death in AML is of particular relevance considering that impairment of neutrophil function is a typical feature of this malignancy. There are many studies addressing neutropenia as a potential risk factor in COVID-19, but only four of them were able to support its role as a factor affecting survival.24-27 In particular, a recent study from the Memorial Sloan Kettering Cancer Center (New York, NY, USA) showed that neutropenia between 7 days immediately prior to and up to 28 days after SARS-CoV-2 diagnosis was associated Figure 4. Survival probability by modification of initial chemotherapeutic program due to COVID-19 diagnosis. COVID-19: coronavirus disease 2019; Tx: therapeutic program for acute myeloid leukemia. Haematologica | 108 January 2023 28 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. with an increased odds of death.27 In our study, severe neutropenia was found to be significantly associated with the risk of death in univariable analysis, but the association was lost in the multivariable model, suggesting that severe neutropenia may not be associated with death in AML patients developing COVID-19. In our study, we tried to establish the best therapeutic strategy for AML patients with COVID-19. So far, the best therapeutic option for these patients and timing for treatment initiation have been based only on expert opinions and consensus,22,23 given the lack of evidence-based algorithms to guide clinicians. This is particularly relevant for treatment-naïve AML patients with a concomitant symptomatic SARS-CoV-2 infection. The general recommenda- Overall mortality Univariable Multivariable 95% CI 95% CI P value HR Lower limit Upper limit P value HR Lower limit Upper limit Sex Female - - - - - - - - Male 0.403 1.135 0.844 1.526 - - - - Age <0.001 1.029 1.019 1.040 0.012 1.016 1.004 1.028 Comorbidities 0.001 1.699 1.251 2.308 0.437 0.831 0.520 1.326 AML status Controlled disease - - - - - - - - Active disease <0.001 4.353 3.111 6.092 <0.001 4.197 2.196 8.020 COVID-19 infection Asymptomatic - - - - - - - - Mild infection 0.370 0.770 0.435 1.363 0.566 0.804 0.382 1.694 Severe infection 0.454 1.187 0.758 1.857 0.812 1.073 0.600 1.920 Critical infection <0.001 3.624 2.306 5.696 0.249 1.417 0.783 2.565 Neutrophils, x 109/L ≤0.5 - - - - - - - - 0.501-0.999 0.017 0.529 0.314 0.891 0.359 0.761 0.424 1.365 ≥1 <0.001 0.426 0.299 0.608 0.473 1.198 0.732 1.961 Lymphocytes, x 109/L ≤0.2 - - - - - - - - 0.201-0.499 0.982 1.006 0.624 1.620 0.309 0.702 0.355 1.389 ≥0.5 0.009 0.581 0.388 0.872 0.144 0.661 0.379 1.152 Last chemotherapy/HSCT In the last month - - - - - - - - In the last 3 months 0.464 0.863 0.583 1.279 0.903 1.038 0.568 1.897 Chemotherapy ended > 3 months before COVID-19 <0.001 0.368 0.235 0.577 0.225 2.204 0.614 7.909 Not stated 0.291 0.346 0.048 2.479 0.566 1.916 0.208 17.667 Not applicable 0.955 1.018 0.548 1.892 0.819 0.891 0.333 2.386 AML treatment delay Tx NOT delayed and NOT discontinued - - - - - - - - Tx delayed but NOT discontinued 0.013 0.361 0.161 0.808 0.027 0.367 0.151 0.891 Tx discontinued <0.001 4.271 2.372 7.690 <0.001 4.417 2.306 8.460 Relapse after COVID-19 No - - - - - - - - Yes, due to COVID-19 0.350 0.712 0.350 1.451 - - - - Yes, NOT due to COVID-19 0.796 0.928 0.527 1.636 - - - - Unknown 0.182 1.746 0.770 3.958 - - - - 95% CI: 95% confidence interval; HR: hazard ratio;; COVID-19, coronavirus disease 2019; AML: acute myeloid leukemia; Tx: therapeutic program for AML. Table 2. Overall mortality predictors of death in patients with acute myeloid leukemia and COVID-19. Haematologica | 108 January 2023 29 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. Overall (N=79) No treatment before COVID-19 (N=18) Induction treatment before start of COVID-19 (N=61) N % N % N % Sex Female 35 44.3 10 55.6 25 41.0 Male 44 55.7 8 44.4 36 59.0 Age, years Median (IQR) Range 65 (50-76) 18-88 66 (55-72) 18-88 65 (50-76) 19-86 Comorbidities 48 60.8 11 61.1 37 60.7 COVID-19 infection Critical infection 23 29.1 3 16.7 20 32.8 Severe infection 36 45.6 8 44.4 28 45.9 Mild infection 10 12.7 4 22.2 6 9.8 Asymptomatic 10 12.7 3 16.7 7 11.5 COVID-19 diagnosis Swab 76 96.2 18 100 58 95.1 BAL+swab 2 2.5 0 0 2 3.3 Serology 1 1.3 0 0 1 1.6 Symptoms at COVID-19 onset Pulmonary 39 49.4 9 50.0 30 49.2 Extrapulmonary 14 17.7 4 22.2 10 16.4 Pulmonary + extrapulmonary 13 16.5 2 11.1 11 18.0 Screening 13 16.5 3 16.7 10 16.4 Neutrophils, x109/L° ≤0.5 24 30.4 4 22.2 20 32.8 0.501-0.999 10 12.7 2 11.1 8 13.1 ≥1 34 43.0 9 50.0 25 41.0 Lymphocytes, x109/L° ≤0.2 11 13.9 1 5.6 10 16.4 0.201-0.499 11 13.9 2 11.1 9 14.8 ≥0.5 50 63.3 13 72.2 37 60.7 Stay during COVID-19 Admitted to hospital 73 92.4 15 83.3 58 95.1 Duration of stay in hospital, days Median (IQR) Range 20 (9-32) 2-106 14 (4-24) 2-86 22 (9-36) 3-106 Admitted to ICU 23 29.1 3 16.7 20 32.8 Duration of ICU stay, days Median (IQR) Range 7 (4-12) 1-32 5 (2-10) 2-10 7 (4-12) 1-32 Invasive mechanical ventilation 18 22.8 1 5.6 17 27.9 Non-invasive mechanical ventilation 4 5.1 0 0.0 4 6.6 At home 10 12.7 4 22.2 6 9.8 Outcome Alive 26 32.9 8 44.4 18 29.5 Observation time, days Median (IQR) Range 266.5 (85-386) 11-613 266.5 (122-353) 44-613 277.5 (75-408) 11-601 Continued on following page. Table 3. Demographic and clinical features of 79 patients with acute myeloid leukemia at the onset of their malignancy at COVID- 19 diagnosis. Haematologica | 108 January 2023 30 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al.