ARTICLE - Acute Myeloid Leukemia 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 Correspondence: J. SALMANTON-GARCÍA Alberto López-García,7 Zdeněk Ráčil,8 Francesca Farina,9 Marina Popova,10 Sofia Zompi,11 Ernesta jon.salmanton-garcia@uk-koeln.de 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 Received: February 11, 2022. Marchetti21 Gabriele Magliano22 Carolina García-Vidal23 Monika M. Biernat24 Jaap Van Doesum,25 Accepted: May 5, 2022. Prepublished: May 12, 2022. 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 https://doi.org/10.3324/haematol.2022.280847 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. ©2023 Ferrata Storti Foundation Omrani,46 Sylvain Lamure,47 Olimpia Finizio,48 Noemí Fernández,49 Iker Falces-Romero,50 Ola Published under a CC BY-NC license 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# 1 Hematology 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; 36 Hematology 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; 42 Department 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; 46 Hamad Medical Corporation, Division of Infectious Diseases, Doha, Qatar; 47Département d’Hématologie Clinique, CHU de Montpellier, UMR- CNRS 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; Haematologica | 108 January 2023 22 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. 54 Department 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; 75 North-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; 82 Department 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. Abstract 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. Coronavirus disease 2019 (COVID-19), caused by severe Introduction acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Acute myeloid leukemia (AML) is an aggressive hemato- is associated with a severe clinical presentation in AML pa- logic malignancy often requiring immediate chemotherapy tients. Most of the studies performed in the pre-vaccine because of a high risk of early disease-related life- era reported mortality rates higher than 40%.4-8 The litera- threatening complications including death.1 AML patients ture regarding COVID-19 in AML patients is limited to small are severely immunocompromised, and infections are fre- cohorts,9-10 case reports and case series,10-14 expert opinions quently associated with both the disease-related and consensus,13,15 or series reporting both patients with weakened immunity and the aggressive chemotherapeutic AML and acute lymphoblastic leukemia.16-17 Specific data regimen.2 Although viral infections are less relevant than on large cohorts of patients with long-term follow-up are, bacterial and fungal infections, respiratory viruses may therefore, still lacking. To the best of our knowledge, there also affect AML patients, particularly during seasonal epi- are still no evidence-based algorithms guiding clinicians demics.3 to choose the best therapeutic approach and timing, par- 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 period); and (iii) March to September 2021 (diagnosed after and COVID-19. SARS-CoV-2 vaccines became available). Patients with in- Thus, in order to establish the best therapeutic approach, complete data about COVID-19 diagnosis, AML treatment we aimed to describe clinical features and long-term fol- phase/disease status and date of last follow-up were ex- low-up of a large cohort of AML patients with COVID-19 cluded from the final analysis. registered in the EPICOVIDEHA registry, with a particular focus on patients with a concomitant diagnosis of AML and Study objectives COVID-19. 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 Methods rate, and to stratify patients according to their treatment Study design, patients, and procedures phase (induction, consolidation, maintenance, palliative, This was an observational multicenter study of AML pa- reinduction), chemotherapeutic program modification due tients who developed COVID-19 between February 2020 to COVID-19 (treatment discontinuation, delay or continu- and October 2021, with data from EPICOVIDEHA (registered ation), and timing of COVID-19 diagnosis. with www.clinicaltrials.gov; ID NCT04733729), an inter- national open web-based registry for hematologic malig- Sample size and statistical analysis nancies and COVID-19 patients initiated in February 2020 Categorical variables were described using frequencies by members of the Infections in Hematology Scientific and percentages, whereas continuous variables were ex- Working Group of the European Hematology Association pressed as median, interquartile range (IQR) and absolute (EHA). EPICOVIDEHA was approved by the local ethics range. A Cox regression hazard model was designed and committee of the Fondazione Policlinico Universitario run with variables considered to play a role in the mortality Agostino Gemelli - IRCCS, Università Cattolica del Sacro of AML patients with COVID-19, as previously described.4 A Cuore of Rome, Italy (ID 3226). All consecutive AML pa- multivariable Cox regression model was calculated with tients diagnosed with COVID-19 were captured and regis- the Wald backward method, and only those variables with tered in this web-based registry. The respective local P≤0.1 were displayed. Mortality was analyzed using Kaplan- ethics committee of each participating institution provided Meier survival plots. A log-rank test was used to compare approval as appropriate. The methodology of EPICOVIDEHA the survival probability of the patients included in the dif- has been described elsewhere.18 The electronic case report ferent models. A P-value ≤0.05 was considered statistically form is accessible online at www.clinicalsurveys.net (EFS significant. SPSS v27.0 was employed for statistical ana- Summer 2021, TIVIAN GmbH, Cologne, Germany).19 Each lyses (SPSS, IBM Corp., Chicago, IL, USA). 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 diag- Results nosis of COVID-19. Patients’ conditions before COVID-19 Between February 2020 and October 2021, 556 consecu- (i.e., age, sex, AML status at COVID-19 diagnosis, comor- tive adult AML patients with confirmed SARS-CoV-2 infec- bidities), AML clinical management, COVID-19 diagnosis tion were reported in the EPICOVIDEHA registry from 132 and management, and outcome were also recorded. In- centers and 20 countries around the world. Out of these formation regarding AML treatment modifications (i.e., patients, 168 (30.2%) were excluded from this analysis be- delay or discontinuation) due to COVID-19, and the con- cause of missing data. In 25 cases (6.4%), a diagnosis of tribution of the diagnosis of COVID-19 to AML relapse or acute promyelocytic leukemia (APL) was reported. status at the last day of follow-up was also collected. The demographic and clinical characteristics of the re- Status of the hematologic malignancy at the onset of maining 388 patients are shown in Table 1. Their median COVID-19 and last follow-up was defined as active (onset, age was 59 years (IQR, 45-70) and there was a slight male stable disease, refractory/resistant) or controlled (com- predominance (52.6%). Most patients had at least one plete response) based on reports from the respective par- underlying comorbidity, with chronic heart disease (e.g., ticipating institution. COVID-19 severity was graded hypertension, obstructive arteriopathy, atrial fibrillation) according to international standards as previously de- being the most frequent, whereas 175 patients (45.1%) had scribed.4,20,21 Patients were divided in three groups accord- comorbidities. At the time of the COVID-19 diagnosis, 196 ing to period of diagnosis: (i) January to August 2020 (first patients (50.5%) had controlled AML, and 192 (49.5 %) had global wave of the pandemic); (ii) September 2020 to Feb- active disease, including 79 (20.4%) patients at the onset ruary 2021 (diagnosed in the 2020-2021 New Year holiday 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 median of 1 month (IQR, 1-2) after the diagnosis of COVID- best supportive care, 18 were at the disease onset, 19, once a negative SARS-CoV-2 swab had been docu- whereas the remaining cases were in complete remission mented. At COVID-19 onset, 71 (18.3%) and 53 (13.7%) or in off-treatment follow-up. Overall, 237 patients (64.6%) patients had neutrophil and lymphocyte counts below had received intensive chemotherapy and transplantation, 0.5x109/L and 0.2x109/L, respectively. Two hundred and which were the most common strategies immediately be- twenty patients (56.7%) had pulmonary symptoms at the fore COVID-19. The chemotherapeutic program was mod- onset of COVID-19, mainly cough and dyspnea, 82 (21.1%) ified because of COVID-19 in 174 (44.8%) patients; in 106 exhibited only extra-pulmonary symptoms and 86 (22.2%) (60.9%) it was discontinued permanently, whereas in the were asymptomatic and diagnosed with COVID-19 after remaining 68 (39.1%) it was delayed and resumed at a screening. As shown in Table 1, COVID-19 severity was criti- Table 1. Demographic and clinical features of 388 patients with acute myeloid leukemia at the time of COVID-19 diagnosis. N % N % Sex Symptoms at COVID-19 onset Female 184 47.4 Pulmonary 144 37.1 Male 204 52.6 Screening 86 22.2 Age, years Extrapulmonary 82 21.1 Median (IQR) 59 (45-70) Pulmonary + extrapulmonary 76 19.6 Range 18-89 Neutrophils, x 109/L Comorbidities 213 54.9 ≤0.5 71 18.3 0.501-0.999 38 9.8 AML status at COVID-19 dia- ≥1 203 52.3 gnosis Lymphocytes, x 109/L Controlled disease 196 50.5 ≤0.2 53 13.7 Complete remission 196 50.5 0.201-0.499 56 14.4 Active disease 192 49.5 ≥0.5 211 54.4 Onset 79 20.4 Stay during COVID-19 Refractory/resistant 113 29.2 Admitted to hospital 293 75.5 Last/ongoing treatment stra- Duration of stay in hospital, tegy before COVID-19 days Treatment 367 94.6 Median (IQR) 17 (8-30) Conventional chemotherapy 250 64.4 Range 1-210 Last month 172 44.3 Admitted to ICU 82 21.1 Last 3 months 46 11.9 Duration of ICU stay, >3 months 32 8.2 days HSCT 72 18.6 Median (IQR) 10 (5-20) Last month 8 2.1 Range 1-111 Last 3 months 11 2.8 Invasive MV 63 16.2 >3 months 53 13.7 Best supportive care 45 11.6 Non-invasive MV 19 4.9 Last month 27 7.0 At home 117 30.2 Last 3 months 9 2.3 Outcome >3 months 4 1.0 Alive 208 53.6 Not stated 5 1.3 Observation time, days No treatment 21 5.4 Median (IQR) 325 (117-386) COVID-19 infection Range 3-639 Critical infection 82 21.1 Dead 180 46.4 Severe infection 160 41.2 Observation time, days Mild infection 69 17.9 Median (IQR) 20 (8-58) Asymptomatic 77 19.8 Range 0-528 COVID-19 diagnosis Reason for death Swab 376 96.9 COVID-19 78 43.3 BAL+swab 5 1.3 COVID-19 + HM 48 26.7 Serology 4 1.0 HM 47 26.1 BAL 3 0.8 Unknown reasons 7 3.9 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. Haematologica | 108 January 2023 25 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. 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. cal in 82 patients (21.1%), severe in 160 (41.2%), mild in 69 note, patients who discontinued treatment were not dif- (17.9%), and asymptomatic in the remaining cases (19.8%). ferent in terms of median age, but more often had at least Overall, 293 patients (75.5%) were hospitalized during their one comorbidity and had a slightly but not statistically sig- SARS-CoV-2 infection for a median of 17 days (IQR, 8-30). nificant worse clinical presentation of COVID-19. A signifi- Eighty-two patients (21.1%) were admitted to an intensive cantly lower overall mortality rate was observed in patients care unit for a median stay of 10 days (IQR, 5-20), 63 in whom chemotherapy was delayed (overall mortality rate: (76.8%) of whom required invasive mechanical ventilation. 18.4%, 9/49), as opposed to that of patients whose treat- After a median follow-up of 325 days (IQR, 3-639), 180 pa- ment was not delayed (37.5%, 9/24) (P<0.001), with the only tients (46.4%) had died. The reported primary reason for exception of the re-induction subgroup of patients (Figures death was COVID-19 in 78 (43.3%) patients, AML in 47 3 and 4). The overall mortality rate of patients in induction (26.1%), a combination of both in 48 (26.7%) and unknown (67.1%, n=51) or re-induction (77.7%, n=28) was higher than in seven patients (3.9%) (Table 1, Figure 1). The mortality that of patients receiving consolidation (20%, n=10) during rate of patients with ongoing or recent (<1 month before the last month prior to COVID-19 (P<0.001). Interestingly, COVID-19 diagnosis) AML treatment, like those treated 1 to we did not find any statistically significant difference in 3 months prior to their COVID-19 diagnosis, was signifi- terms of survival between patients in complete remission cantly higher than that of patients receiving treatment until (off-treatment) and those in complete remission but under 3 months or earlier before the diagnosis COVID-19 consolidation treatment (mortality rate: 20.2% vs. 24.1%; (P<0.001) (Figure 2). When considering AML patients whose P=0.677). In the univariable analysis, several factors were last chemotherapy was administered within the month be- associated with an increased mortality (Table 2): older age, fore the COVID-19 diagnosis, a higher mortality rate was previous comorbidities (i.e., chronic heart disease or renal observed in 68 (80.9%) patients who discontinued treat- impairment), active malignancy, critical COVID-19, or per- ment, regardless of the treatment phase (Figure 3). Of manent AML treatment discontinuation. Contrariwise, hav- Haematologica | 108 January 2023 26 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. ing a neutrophil or lymphocyte count above 0.5x109/L and 95% CI: 1.004-1.028; P=0.012), and treatment discontinu- 0.2x109/L, respectively, AML treatment >3 months before ation (HR=4.417, 95% CI: 2.306-8.460; P<0.001) were associ- COVID-19 diagnosis and AML treatment delay were associ- ated with a higher mortality, as opposed to treatment ated with a reduced mortality. In the multivariable model, delay, which was found to be protective (HR=0.367, 95% CI: active disease (hazard ratio [HR]=4.197, 95% confidence in- 0.151-0.891; P=0.027). After a time-dependent analysis, it terval [95% CI]: 2.196-8.020; P<0.001), older age (HR=1.016, was observed that overall survival in patients diagnosed Figure 2. Survival probability by timing of last received treatment. AML: acute myeloid leukemia; COVID-19: coronavirus disease 2019; tx: treatment. 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. 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. with COVID-19 between January 2020 and August 2020 horts of patients, case reports/series, or expert opinions.9- was significantly lower than that of patients who were di- 17 This gap has made it difficult to establish the best strat- agnosed between September 2020 and February 2021 and egy to manage AML patients during the pandemic.22,23 between March 2021 and September 2021 (39.8% vs. 60% Taken together, the current evidence suggests that AML vs. 61.9%, respectively; P=0.006) (Online Supplementary patients often present with a severe clinical form of Figure S2). COVID-19, frequently with respiratory distress and a very Table 3 presents the demographic and clinical features of high mortality rate, between 40 and 50% higher than that the 79 patients with a simultaneous diagnosis of AML and in the pre-vaccine era. Here we present, to the best of our COVID-19. In 18 patients (22.8%), COVID-19 was diagnosed knowledge, the largest survey of AML patients with COVID- before the start of induction, resulting in a treatment delay. 19, with 388 patients reported from 132 institutions, with Overall survival was higher among patients whose treat- a special focus on their long-term follow-up. The data ment was delayed (80%) than among those whose treat- presented in our manuscript confirm that AML patients ment was not delayed and not discontinued (64%) or was frequently have a severe clinical presentation of COVID-19, discontinued (6%) (P<0.001) (Table 3, Online Supplementary mainly with respiratory symptoms, and a high rate of in- Figure S1). Finally, a separate sub-analysis was carried out tensive care unit admission, even among those with low- focusing on AML patients receiving consolidation treat- risk AML (i.e., acute promyelocytic leukemia). ment (Online Supplementary Figure S3), relapsed/refrac- Neutrophil and lymphocyte counts were not found to be tory patients being given re-induction (Online significantly associated with mortality in our multivariable Supplementary Figure S4) and patients in complete re- model. The potential role of neutropenia as a risk factor mission (Online Supplementary Figure S5), confirming the for death in AML is of particular relevance considering that better clinical outcome in patients in whom treatment was impairment of neutrophil function is a typical feature of delayed. this malignancy. There are many studies addressing neu- tropenia 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 Discussion Sloan Kettering Cancer Center (New York, NY, USA) showed There is a gap of knowledge regarding COVID-19 in AML pa- that neutropenia between 7 days immediately prior to and tients, as the current evidence is restricted to small co- up to 28 days after SARS-CoV-2 diagnosis was associated Haematologica | 108 January 2023 28 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. Table 2. Overall mortality predictors of death in patients with acute myeloid leukemia and COVID-19. Overall Univariable Multivariable mortality 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 <0.001 0.368 0.235 0.577 0.225 2.204 0.614 7.909 COVID-19 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 0.013 0.361 0.161 0.808 0.027 0.367 0.151 0.891 discontinued 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 0.796 0.928 0.527 1.636 - - - - COVID-19 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. with an increased odds of death.27 In our study, severe strategy for AML patients with COVID-19. So far, the best neutropenia was found to be significantly associated with therapeutic option for these patients and timing for treat- the risk of death in univariable analysis, but the association ment initiation have been based only on expert opinions was lost in the multivariable model, suggesting that severe and consensus,22,23 given the lack of evidence-based algo- neutropenia may not be associated with death in AML pa- rithms to guide clinicians. This is particularly relevant for tients developing COVID-19. treatment-naïve AML patients with a concomitant symp- In our study, we tried to establish the best therapeutic tomatic SARS-CoV-2 infection. The general recommenda- Haematologica | 108 January 2023 29 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. Table 3. Demographic and clinical features of 79 patients with acute myeloid leukemia at the onset of their malignancy at COVID- 19 diagnosis. No treatment before Induction treatment Overall COVID-19 before start of COVID-19 (N=79) (N=18) (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) 65 (50-76) 66 (55-72) 65 (50-76) Range 18-88 18-88 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) 20 (9-32) 14 (4-24) 22 (9-36) Range 2-106 2-86 3-106 Admitted to ICU 23 29.1 3 16.7 20 32.8 Duration of ICU stay, days Median (IQR) 7 (4-12) 5 (2-10) 7 (4-12) Range 1-32 2-10 1-32 Invasive mechanical ventilation 18 22.8 1 5.6 17 27.9 Non-invasive mechanical 4 5.1 0 0.0 4 6.6 ventilation 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) 266.5 (85-386) 266.5 (122-353) 277.5 (75-408) Range 11-613 44-613 11-601 Continued on following page. Haematologica | 108 January 2023 30 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. Dead 53 67.1 10 55.6 43 70.5 Observation time, days Median (IQR) 19 (6.5-57) 14 (5-48) 21 (7-63) Range 0-528 0-528 0-331 Reason for death° COVID-19 20 37.7 3 30.0 17 39.5 COVID-19 + hematologic 16 30.2 4 40.0 12 27.9 malignancy Hematologic malignancy 17 32.1 3 30.0 14 32.6 °Data can be super additive. COVID-19: coronavirus disease 2019; IQR: interquartile range; BAL: bronchoalveolar lavage; ICU: intensive care unit. tion for these patients has been to postpone all treatments of the local physician, and consequently less reliable when not requiring urgent initiation, including a limitation of used in a risk factor assessment. Conversely, the overall cytoreductive therapies if needed.22 Although the current mortality rate is not influenced by subjective interpre- dogma of considering AML a medical urgency is changing, tations and it is, therefore, more reliable for our study aim, as suggested by some recent studies,28 prompt treatment even when the potential role of other confounding factors, initiation is often recommended in routine practice, es- e.g., primarily leukemia progression, is taken into account. pecially in patients with de novo or relapsed/refractory dis- We observed an increased mortality rate associated with ease. Our data suggest that delayed treatment is the best age and active malignancy, in agreement with previously therapeutic option for AML patients with COVID-19, as published data.4,9 In addition, comorbidities and sex did not shown by a lower death rate when treatment was post- have an impact on mortality rate, unlike in other studies,9,17 poned. A Spanish group made a similar finding:9 in their co- but consistent with the previously published study from hort of 108 patients, a lower mortality rate was observed the EPICOVIDEHA registry.4 in patients in whom chemotherapy was delayed as com- Finally, we performed a time-dependent analysis, showing pared to the rate in those with or without treatment modi- that the overall survival rate of patients diagnosed with fication. However, their results were observed only in the COVID-19 from January to August 2020 was significantly univariable analysis. Our multivariable model confirmed lower than that of patients diagnosed more recently, con- that a delay in a chemotherapeutic program was associ- firming an improvement in the clinical outcome of AML pa- ated with a reduced death rate, having a significant pro- tients throughout the different waves of the pandemic. tective role (HR=0.367; P=0.027). Interestingly, even when These observations could be explained by a combination focusing on patients with new-onset AML and COVID-19, of factors, including improved management of the disease we found a better overall survival in those patients in and detection of a larger number of asymptomatic/mild whom a delay in AML induction was possible. The negative cases by screening programs. Although the current data on impact of AML treatment discontinuation on the observed the SARS-CoV-2 pandemic show a progressive decrease of death rate in our multivariable analysis can be explained hospitalization and deaths in the overall population, pa- by the death of patients in whom the program was discon- tients with a hematologic malignancy remain a particularly tinued. Contrary to other reports showing an increased high-risk population. mortality rate for patients treated with intensive chemo- Our study has some limitations. First, those intrinsically therapy,6,14,16 we did not detect significant differences be- linked to the initial project design. We did not request tween patients given different treatment schedules, any details regarding the therapeutic approaches to including those based on demethylating agents. However, COVID-19, as these were extremely heterogeneous and these data should be interpreted with caution, considering treatment recommendations changed quickly. Data on that these patients may have been older or less fit when viral strains were only infrequently available and about their disease developed. one third of patients were excluded from the final analy- The overall mortality rate in our study was 46.4%, a value sis because of missing information. In addition, only a comparable to that in other publications.9,10 We found that very few cases from our cohort (n=7) were documented COVID-19 was the primary or a main reason for death in as breakthrough infections in fully vaccinated patients, most cases (70%), although we deliberately decided to which did not allow us to draw conclusion on vaccine ef- focus our study on overall mortality rather than on attribu- fectiveness. Interestingly, this aspect was partially ad- table mortality. Even though attributable mortality might dressed by our previous preliminary data on vaccinated seem more appropriate for evaluating the impact of an in- patients with a hematologic malignancy, which showed fection in patients with a hematologic malignancy, it can a mild decrease in mortality of vaccinated AML patients.29 also be more easily influenced by the subjective judgment Finally, it is not possible to exclude a potential selection Haematologica | 108 January 2023 31 ARTICLE - COVID-19 in adult AML patients F. Marchesi et al. bias in patients, since AML patients who were able to Acknowledgments delay treatment could have had less aggressive disease, The authors thank all contributors for their great contribu- whereas those who permanently discontinued the treat- tion to and support of the project during a pandemic situ- ment might have had serious COVID-19 complications, ation and to Susann Blossfeld and Sebastian Rahn for their becoming unfit for further therapy. administrative and technical assistance. In conclusion, our study shows that COVID-19 in AML pa- tients poses a serious challenge, as it adds a layer of com- Funding plication which can lead to modified therapeutic EPICOVIDEHA has received funds from Optics COMMITTM algorithms. The mortality rate in this group of patients was (COVID-19 Unmet Medical Needs and Associated Research very high, even taking into consideration the significant re- Extension) COVID-19 RFP program by Gilead Science, USA duction over the course of the pandemic. According to our (Project 2020-8223). The funder of the study had no role findings, the best approach to improve the survival of AML in the study design, data analysis, interpretation, or writing patients with COVID-19 seems to be to delay treatment for of the report. All authors had full access to the data and the hematologic malignancy, whenever possible. had final responsibility for the decision to submit for pub- lication. Disclosures No conflicts of interest to disclose. Data-sharing statement Data will be available from the corresponding author upon Contributions reasonable request. LP was the principal investigator. FM, JSG and LP con- tributed to the study design, study supervision, and data in- Collaborative Group terpretation and wrote the paper. AB, PC, MH, NK, PK, AP, EPICOVIDEHA working group: Toni Valković, Alexandra Serris, FP, AOC and LP conceived the idea of the study. LP, JSG and Michail Samarkos, Lucia Prezioso, Christian Bjørn Poulsen, FM did the statistical plan and analysis and interpreted the Jan Novák, Joseph Meletiadis, Panagiotis Tsirigotis, Anasta- data. All the authors recruited participants and collected sia Antoniadou, Jorge Labrador, Chi Shan Kho, Federico Itri, and interpreted data. All authors contributed to writing and Tomás-José González-López, Michelina Dargenio, Elena reviewing the manuscript. 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