1154706 research-article20232023 TAH0010.1177/20406207231154706Therapeutic Advances in HematologyM Marchetti, J Salmanton-García Therapeutic Advances in Hematology Original Research Outcomes of SARS-CoV-2 infection in Ther Adv Hematol 2023, Vol. 14: 1–15 Ph-neg chronic myeloproliferative DOI: 10.1177/ https://doi.org/10.1177/20406207231154706 https://doi.org/10.1177/20406207231154706 20406207231154706 neoplasms: results from the EPICOVIDEHA © The Author(s), 2023. Article reuse guidelines: sagepub.com/journals- registry permissions Correspondence to: Jon Salmanton-García Monia Marchetti*, Jon Salmanton-García* , Shaimaa El-Ashwah, Luisa Verga, Department I of Internal Federico Itri, Zdeněk Ráčil, Julio Dávila-Valls, Sonia Martín-Pérez, Jaap Van Doesum, Medicine, Excellence Center for Medical Francesco Passamonti, Ghaith Abu-Zeinah, Francesca Farina, Alberto López-García, Mycology (ECMM), Faculty Giulia Dragonetti, Chiara Cattaneo, Maria Gomes Da Silva, Yavuz M. Bilgin, Pavel Žák, of Medicine and University Hospital Cologne, Verena Petzer, Andreas Glenthøj, Ildefonso Espigado, Caterina Buquicchio, University of Cologne, Valentina Bonuomo, Lucia Prezioso, Stef Meers, Rafael Duarte, Rui Bergantim, Cologne, Germany. Ozren Jaksic, Natasha Čolović, Ola Blennow, Martin Cernan, Martin Schönlein, Cologne Excellence Cluster on Cellular Stress Michail Samarkos, Maria Enza Mitra, Gabriele Magliano, Johan Maertens, Responses in Aging- Marie-Pierre Ledoux, Moraima Jiménez, Fatih Demirkan, Graham P. Collins , Associated Diseases (CECAD), Faculty of Alba Cabirta, Stefanie K. Gräfe, Anna Nordlander, Dominik Wolf, Elena Arellano, Medicine and University Raul Cordoba, Michaela Hanakova, Giovanni Paolo Maria Zambrotta, Raquel Nunes Hospital Cologne, University of Cologne, Rodrigues, Giulia Limberti, Francesco Marchesi, Oliver A. Cornely and Livio Pagano Cologne, Germany jon.salmanton-garcia@ uk-koeln.de Abstract Monia Marchetti Giulia Limberti Background: Patients with Philadelphia-negative chronic myeloproliferative neoplasms Azienda Ospedaliera (MPN) typically incur high rates of infections and both drugs and comorbidities may modulate Nazionale SS. Antonio e Biagio e Cesare Arrigo, infection risk. Alessandria, Italy Objectives: The present study aims to assess the effect of immunosuppressive agents on Shaimaa El-Ashwah Oncology Center, clinical outcomes of MPN patients affected by the coronavirus disease 2019 (COVID-19). Mansoura University, Mansoura, Egypt Design: This is an observational study. Luisa Verga Methods: We specifically searched and analyzed MPN patients collected by EPICOVIDEHA Giovanni Paolo Maria online registry, which includes individuals with hematological malignancies diagnosed with Zambrotta Azienda Ospedaliera San COVID-19 since February 2020. Gerardo–Monza, Monza, Italy; Università Milano- Results: Overall, 398 patients with MPN were observed for a median of 76 days [interquartile Bicocca, Milan, Italy range (IQR): 19–197] after detection of SARS-CoV2 infection. Median age was 69 years (IQR: Federico Itri San Luigi Gonzaga 58–77) and 183 individuals (46%) had myelofibrosis (MF). Overall, 121 patients (30%) of the Hospital–Orbassano, whole cohort received immunosuppressive therapies including steroids, immunomodulatory Orbassano, Italy drugs, or JAK inhibitors. Hospitalization and consecutive admission to intensive care unit Zdeněk Ráčil Michaela Hanakova was required in 216 (54%) and 53 patients (13%), respectively. Risk factors for hospital Institute of Hematology and Blood Transfusion, admission were identified by multivariable logistic regression and include exposure to Prague, Czech Republic immunosuppressive therapies [odds ratio (OR): 2.186; 95% confidence interval (CI): 1.357– Julio Dávila-Valls Sonia Martín-Pérez 3.519], age ⩾70 years, and comorbidities. The fatality rate was 22% overall and the risk of Hospital Nuestra Señora death was independently increased by age ⩾70 years [hazard ratio (HR): 2.191; 95% CI: 1.363– de Sonsoles, Ávila, Spain 3.521], previous comorbidities, and exposure to immunosuppressive therapies before the Jaap Van Doesum University Medical Center infection (HR: 2.143; 95% CI: 1.363–3.521). Groningen, Groningen, The Netherlands Conclusion: COVID-19 infection led to a particularly dismal outcome in MPN patients receiving Francesco Passamonti immunosuppressive agents or reporting multiple comorbidities. Therefore, specific preventive University Insubria, Varese, Italy strategies need to be tailored for such individuals. journals.sagepub.com/home/tah 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Hematology Volume 14 Ghaith Abu-Zeinah Plain language summary Division of Hematology and Oncology, Weill Cornell EPICOVIDEHA registry reports inferior outcomes of COVID-19 in patients with Philadelphia- Medicine, New York, NY, USA negative chronic myeloproliferative neoplasms receiving immunosuppressive therapies. Francesca Farina IRCCS Ospedale San Patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) incur Raffaele, Milan, Italy high rates of infections during the course of their disease. Alberto López-García Health Research Institute The present study was aimed at assessing which patient characteristics predicted a worse IIS-FJD, Fundación outcome of SARS-COV-2 infection in individuals with MPN. Jimenez Diaz University Hospital, Madrid, Spain To pursue this objective, the researchers analyzed the data collected by EPICOVIDEHA, an Giulia Dragonetti Hematology Unit, international online registry, which includes individuals with hematological malignancies Fondazione Policlinico diagnosed with COVID-19 since February 2020. Universitario Agostino Gemelli–IRCCS, Rome, The database provided clinical data of 398 patients with MPN incurring COVID-19: Italy Chiara Cattaneo • Patients were mostly elderly (median age was 69 years); Hematology Unit, ASST- Spedali Civili, Brescia, Italy • Forty-six percent of them were affected by myelofibrosis, which is the most severe MPN; Maria Gomes Da Silva • M  oreover, 32% were receiving immunosuppressive therapies (JAK inhibitors, such as Raquel Nunes Rodrigues Portuguese Institute of ruxolitinib, steroids, or immunomodulatory IMID drugs, such as thalidomide) before Oncology, Lisbon, Portugal COVID-19. Yavuz M. Bilgin Department of Internal Hospitalization was required in 54% of the patients, and the risk of being hospitalized for Medicine, ADRZ, Goes, The Netherlands severe COVID-19 was independently predicted by Pavel Žák University Hospital Hradec • Older age; Králové, Hradec Králové, • Comorbidities; Czech Republic • Exposure to immunosuppressive therapies. Verena Petzer Dominik Wolf Department of Hematology Overall, 22% of MPN patients deceased soon after COVID-19 and the risk of death was and Oncology, Medical independently increased over twofold by University of Innsbruck, Innsbruck, Austria • Older age; Andreas Glenthøj Department of • Comorbidities; Hematology, • Exposure to immunosuppressive therapies before the infection. Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark In conclusion, COVID-19 infection led to a particularly dismal outcome in MPN patients Ildefonso Espigado Department of receiving immunosuppressive agents, including JAK inhibitors, or reporting multiple Hematology, University comorbidities. Therefore, specific preventive strategies need to be tailored for such individuals. Hospital Virgen Macarena–University Hospital Virgen del Rocío, Instituto de Biomedicina Keywords: COVID-19, essential thrombocytemia, hydroxyurea, myelofibrosis, Philadelphia- de Sevilla (IBIS/CSIC) and Departamento de negative chronic myeloproliferative neoplasms, polycythemia vera, ruxolitinib, SARS-CoV-2 Medicina, Universidad de Sevilla, Seville, Spain Received: 17 August 2022; revised manuscript accepted: 17 January 2023. Caterina Buquicchio Ematologia con Trapianto, Ospedale Dimiccoli Introduction hematological malignancies (HM) were reported Barletta, Barletta, Italy Valentina Bonuomo Coronavirus disease 2019 (COVID-19) is a pub- to incur twofold higher mortality compared with Section of Hematology, lic health emergency of international concern the general population.3,4 Department of Medicine, University of Verona, since February 2020. It is caused by severe acute Verona, Italy respiratory syndrome coronavirus-2 (SARS- Philadelphia-negative chronic myeloproliferative Lucia Prezioso CoV-2), a rapidly spreading novel coronavirus neoplasms (MPN) represent one-third of mye- Hematology and Bone Marrow Unit, Hospital which principally causes pneumonia and respira- loid malignancies and, due to its indolent course, University of Parma, tory failure, alongside damage to several organs prevalence is high (50 per 100,000 inhabitants).5 Parma, Italy by inflammatory and pro-thrombotic path- MPN is characterized by thrombocytosis, leu- Stef Meers AZ KLINA, Brasschaat, ways.1,2 Age and comorbidity were reported to kocytosis, and erythrocytosis, but they may also Belgium independently predict the fatality rate (FR) in present with or develop cytopenias, that associ- COVID-19, and individuals affected by baseline ate with adverse clinical outcomes. Arterial and 2 journals.sagepub.com/home/tah M Marchetti, J Salmanton-García et al. venous thromboses are the most common Cases could be registered according to the follow- Rafael Duarte Hospital Universitario complications of MPNs, due to intrinsic abnor- ing inclusion criteria: (1) age equal to or greater Puerta de Hierro, malities of endothelial cells as well as altered than 18 years, (2) history of active HM at any Majadahonda, Spain platelet and leukocyte function, which may be stage within the last 5 years before COVID-19, Rui Bergantim Centro Hospitalar e exacerbated by infections. Of significance, the and (3) report of SARS-CoV-2 positive test Universitário São João, risk of viral infections is threefold higher in MPN documented by real-time reverse transcriptase Porto, Portugal Ozren Jaksic compared with matched controls.6,7 Based on the polymerase chain reaction (RT-PCR) diagnostic University Hospital above clinical features, MPN patients with panels. Dubrava, Zagreb, Croatia COVID-19 are expected to have an increased risk Natasha Čolović University Clinical Center for severe outcomes. Qualitative demographic and clinical data were Serbia, Medical Faculty described by frequencies and percentages, while University Belgrade, Belgrade, Serbia The present study aimed to assess clinical out- medians and interquartile ranges (IQR) were Ola Blennow comes of COVID-19 in patients with MPN. used to summarize quantitative variables. Chi- Anna Nordlander More specifically, we aimed at testing the impact square test, Fisher’s exact test, and Mann– Department of Infectious Diseases, Karolinska of previous therapies for MPN onto SARS-CoV-2 Whitney’s U test were used for comparisons, as University Hospital, infection outcomes and to identify the more frail appropriate. Logistic and Cox multivariable Stockholm, Sweden subgroups potentially requiring intensified pre- regressions allowed to identify predictors of the Martin Cernan University Hospital ventive measures (e.g. application of preventive outcomes. Olomouc, Olomouc, Czech monoclonal antibodies). Republic Martin Schönlein SPSS software has been employed for the descrip- Department of Oncology, tive and inferential statistical analyses (SPSS, ver- Hematology and Bone Marrow Transplantation Methods sion 25.0, Chicago, IL, USA). with Section of In February 2020, an international cooperative Pneumology, University Medical Center Hamburg- registry, named EPICOVIDEHA, was initiated The reporting of this study conforms to the Eppendorf, Hamburg, by the Scientific Working Group Infection in STROBE statement (www.equator-network.org/ Germany Hematology of the European Hematology reporting-guidelines/strobe/). Michail Samarkos Laikon Hospital, Association (EHA).8 EPICOVIDEHA is a multi- Athens, Greece center, noninterventional, observational study Maria Enza Mitra approved by the local Institutional Review Board Results UO Ematologia, AOUP P. Giaccone, Palermo, Italy and Ethics Committee of the Fondazione Overall, 398 MPN patients with COVID-19 Gabriele Magliano Policlinico Universitario Agostino Gemelli– were registered in EPICOVIDEHA from ASST Grande Ospedale IRCCS, Università Cattolica del Sacro Cuore of February 2020 to March 2022 (Table 1): 113 Metropolitano Niguarda, Milan, Italy Rome, Italy (Study ID: 3226). The correspond- individuals (28.4%) with essential thrombo- Johan Maertens ing local ethics committee of each participating cythemia (ET), 183 (46.0%) with myelofibrosis KU Leuven, Leuven, Belgium institution may approve additionally the (MF), and 102 (25.6%) with polycythemia vera Marie-Pierre Ledoux EPICOVIDEHA study when applicable. (PV). Thirty individuals were newly diagnosed ICANS, Strasbourg, France EPICOVIDEHA is registered at http://www.clin MPN concomitantly or within 1 month from Moraima Jiménez icaltrials.gov, with the identifier NCT 04733729. diagnosis of SARS-CoV-2 infection. Overall, Alba Cabirta Department of 148 patients (37.2%) had received hydroxyurea Hematology, Vall d’Hebron Researchers from different countries were invited as the most recent treatment before COVID- Hospital Universitari, Experimental Hematology, to retrospectively review all episodes of COVID- 19, while 111 patients (27.9%) had received Vall d’Hebron Institute 19 disease occurring in patients with blood can- JAK inhibitors. More specifically, 92 MF of Oncology (VHIO), Vall d’Hebron Barcelona cers identified at their institutions from February patients (50.3%) and 17 PV patients (16.7%) Hospital Campus, 2020 onward. The EPICOVIDEHA electronic were receiving JAK inhibitors, while 10 patients Barcelona, Spain case report form is available at www.clinicalsur- were receiving other therapies with an immuno- Departament de Medicina, Universitat Autònoma de veys.net (EFS Summer 2021, TIVIAN GmbH, suppressive potential, namely immunomodu- Barcelona, Bellaterra, Cologne, Germany). lating agents (IMID), such as thalidomide or Spain Fatih Demirkan lenalidomide, or steroids. Overall, 121 patients Division of Hematology, The anonymized electronic clinical report form is (who did had not underwent transplantation) Dokuz Eylul University, Izmir, Turkey the single access for each participating institution received therapies with an immunosuppressive Graham P. Collins and is structured in different thematic pages, as potential: this corresponds to 30.4% of the NIHR Oxford Biomedical follows: (1) identification, (2) demographics, (3) overall cohort and 55.2% of the MF subgroup. Research Centre, Churchill Hospital, underlying diseases, (4) HM, (5) COVID-19, Moreover, 8.3% of the overall cohort (33 Oxford, UK and (6) outcome. patients) were refractory or resistant to ongoing journals.sagepub.com/home/tah 3 Therapeutic Advances in Hematology Volume 14 Stefanie K. Gräfe Table 1. Baseline characteristics and outcomes according to the underlying malignancy. Universitätsklinikum Hamburg-Eppendorf, All MPN Essential Myelofibrosis Polycythemia Hamburg, Germany n = 398 thrombocythemia n = 183 vera Department I of Internal n = 113 n = 102 Medicine, Excellence Center for Medical n % n % n % n % Mycology (ECMM), Faculty of Medicine and University Hospital Cologne, Sex (male) 232 58.3 54 47.8 109 59.6 69 67.6 University of Cologne, Cologne, Germany Age (median, IQR) 69 58–77 67 51–78 69 61–75 68 59–77 Cologne Excellence Cluster on Cellular Stress <50 years old 52 13.1 27 23.9 16 8.7 9 8.8 Responses in Aging- Associated Diseases 51–69 years old 158 39.7 31 27.4 81 44.3 46 45.1 (CECAD), Faculty of Medicine and University 188 47.2 55 48.7 86 47.0 47 46.1 Hospital Cologne, >70 years old University of Cologne, Cologne, Germany Comorbidities Elena Arellano Department of No comorbidities 155 38.9 49 43.4 59 32.2 47 46.1 Hematology, University Hospital Virgen Macarena, 1 comorbidity 130 32.7 37 32.7 62 33.9 31 30.4 Seville, Spain Raul Cordoba 2 comorbidities 73 18.3 21 18.6 36 19.7 16 15.7 Health Research Institute IIS-FJD, Fundacion ⩾3 comorbidities 40 10.1 6 5.3 26 14.2 8 7.8 Jimenez Diaz University Hospital, Madrid, Spain Cardiovascular comorbidities 144 36.2 40 35.4 66 36.1 38 37.3 Francesco Marchesi Hematology and Stem Cell Diabetes mellitus 59 14.8 13 11.5 35 19.1 11 10.8 Transplant Unit, IRCCS Regina Elena National Smoking history 41 10.3 7 6.2 25 13.7 9 8.8 Cancer Institute, Rome, Italy Disease status at COVID-19 onset Oliver A. Cornely Department I of Internal Newly diagnosed 30 7.5 6 5.3 19 10.4 5 4.9 Medicine, Excellence Center for Medical Refractory 33 8.3 2 1.8 25 13.7 6 5.9 Mycology (ECMM), Faculty of Medicine and University Hospital Cologne, Ongoing treatment – Drug therapies University of Cologne, Cologne, Germany Hydroxyurea 148 37.2 66 58.4 32 17.5 50 49.0 Chair Translational Research, Cologne JAK inhibitors 111 27.9 2 1.8 92 50.3 17 16.7 Excellence Cluster on Cellular Stress Responses Immunosuppressive therapy 121 30.4 2 1.8 101 55.2 18 17.6 in Aging-Associated Diseases (CECAD), Faculty COVID-19 vaccination status of Medicine and University Hospital Cologne, At least one dose 80 20.1 21 18.6 41 22.4 18 17.6 University of Cologne, Cologne, Germany COVID-19 severity Clinical Trials Centre Cologne (ZKS Köln), Asymptomatic 66 16.6 25 22.1 23 12.6 18 17.6 Faculty of Medicine and University Hospital Pulmonary symptoms 212 53.3 62 54.9 97 53.0 53 52.0 Cologne, University of Cologne, Cologne, Severe/Critical 239 60.1 59 52.2 125 68.3 55 53.9 Germany Center for Molecular Hospital stay and management during COVID-19 Medicine Cologne (CMMC), Faculty of Medicine Hospital admission 216 54.3 49 43.4 114 62.3 53 52.0 and University Hospital Cologne, University of Cologne, Cologne, Intensive care unit 53 13.3 8 7.1 32 17.5 13 12.7 Germany Invasive ventilation 29 7.3 5 4.4 16 8.7 8 7.8 German Centre for Infection Research (DZIF), Partner Site COVID-19 outcome Bonn-Cologne, Cologne, Germany Fatality rate 89 22.4 15 13.3 57 31.1 17 16.7 COVID-19, coronavirus disease 2019; IQR, interquartile range; n, number of patients; MPN, chronic myeloproliferative neoplasms. 4 journals.sagepub.com/home/tah M Marchetti, J Salmanton-García et al. therapies: the rate was lower in ET (1.8%), predictor of the risk of hospital admission for Livio Pagano Hematology Unit, while it was higher in MF (13.7%). Overall, MPN patients with COVID-19 [odds ratio Fondazione Policlinico seven patients (1.7%) had received allogeneic (OR): 2.186; 95% confidence interval (CI): Universitario Agostino Gemelli–IRCCS, Rome, hematopoietic stem cell transplant (HSCT): 1.357–3.519] and so was age >70 years (OR: Italy three of them were transplanted more than 6 2.636; 95% CI: 1.683–4.129). However, prior Hematology Unit, Università Cattolica del months before COVID-19. exposure to ruxolitinib was not by itself an inde- Sacro Cuore, Rome, Italy pendent predictor of hospital admission. *MM and JS-G are shared Males were 58.3% of the whole cohort and junior authors. median age at infection was 69 years (IQR: 58– Overall, 53 out of 216 hospitalized patients were 77, range: 22–97). Moreover, in 61.1% of the admitted to intensive care unit (ICU) (24.5%) patients, at least one comorbidity was reported, and mechanical ventilation was required for 29 while in 10.1%, three or more comorbidities were patients (13.4%). The rate of admission to ICU listed in the medical history checking seven ever was significantly higher in MF compared with the major comorbidities, namely chronic cardiovas- other MPN subtypes: 17.5% of the overall MF cular and pulmonary diseases, renal failure, dia- patients required ICU support versus 7.1% of betes, liver diseases, obesity, and concurrent patients with ET patients. Median length of the neoplasms. In particular, 144 patients (36.2%) ICU stay was 10 days (IQR: 5–18). suffered from cardiovascular diseases (e.g. atrial fibrillation, arterial hypertension, obstructive MPN patients were followed for a median of 76 arteriopathy), 52 from chronic pulmonary disease days (IQR: 19–197) and the reported mortality (13.1%), 59 from diabetes (14.9%), 21 from liver rate was 22.4%, which declined gradually over disease (5.3%), 27 from obesity (6.8%), 18 from the time of the COVID-19 pandemic. During the renal impairment (e.g. serum creatinine above 2 first half of the year 2020, it was 38.9% (49 out of mg/dl) (4.5%). Smoking history was reported in 126 patents), declining to 17.6% (27 out of 153) 41 patients (10.3%). during the second half of 2020 subsequently fur- ther dropping down to 10.9% from 2021 on Overall, 76 (19.1%) individuals had received at (p < 0.001) (Figures 1 and 2). Death occurred least two prior vaccination doses before COVID- after a median of 14 days (IQR: 8–49) upon diag- 19 and 37 (9.3%) had received three doses. nosis of infection and was principally attributable Messenger ribonucleic acid (mRNA) vaccines to COVID-19 in 68 patients (76.4%) and con- were administered to 70 (17.6%) patients. tributable by COVID-19 in 10 (11.2%). In a small portion of patients (16.6%), asympto- Multivariable Cox regression analysis revealed matic SARS-CoV-2 infection was documented, that age >70 years was an independent predictor while cough or dyspnea was reported by most of of mortality [hazard ratio (HR): 2.191; 95% CI: the individuals (53.3%). Both extrapulmonary 1.363–3.521], as well as comorbidity burden and pulmonary symptoms were observed in 66 (Table 3). Mortality varied among MPN diseases individuals (21.9%) and exclusively extrapulmo- from 13.3% in patients with ET to 31.1% in those nary symptoms in 65 (23.4%). with MF. Exposure to immunosuppressive agents before SARS-CoV-2 infection was an independ- Overall, 216 patients (54.3%) were admitted to ent predictor of death (HR: 2.143; 95% CI: hospital and the median duration of hospital stay 1.369–3.354) (Table 3), as was the exposure to was 14 days (IQR: 6–22, range: 1–90). ruxolitinib (HR: 2.161; 95% CI: 1.381–3.354). A Univariable logistic regression identified MPN- sub-analysis of 155 MF patients receiving active related and unrelated clinical factors signifi- pharmacologic treatment for their disease before cantly related to the chance of hospitalization COVID-19 suggested that those exposed to (Table 2). Among MPN-related factors, MF immunosuppressive therapies might have an infe- and exposure to immunosuppressive therapies rior survival compared with those receiving any were the most important variables, while among other type of treatment (p = 0.059). MPN-unrelated factors, age >70 years, cardi- opathy, and number of comorbidities appeared Multivariable Cox regression analysis of mor- to be linked to hospitalization. In multivariable tality reported similar results after including regression analysis, exposure to immunosup- time from MPN diagnosis and COVID-19 pressive agents remained an independent infection wave (Table 4). Similarly, exposure journals.sagepub.com/home/tah 5 Therapeutic Advances in Hematology Volume 14 Table 2. Logistic regression analysis of hospital admission. Univariate analysis Multivariate analysis p value OR 95% CI 95% CI p value OR 95% CI 95% CI lower upper lower upper limit limit limit limit Age <70 years old – – – – – – – – ⩾70 years old <0.001 3.091 2.046 4.67 <0.001 2.636 1.683 4.129 Immunosuppressive therapies Cytoreductive drug therapy – – – –  Immunosuppressive <0.001 2.134 1.363 3.34 0.001 2.186 1.357 3.519 cytoreductive drug therapy  No cytoreductive or 0.321 1.370 0.735 2.554 0.222 1.519 0.776 2.971 immunosuppressive drug therapy Malignancy Essential thrombocythemia – – – – – – – – Myelofibrosis 0.002 2.158 1.339 3.478 0.147 1.564 0.854 2.864 Polycythemia vera 0.208 1.413 0.825 2.419 0.231 1.427 0.798 2.553 Comorbidities No comorbidities – – – – – – – – 1 comorbidity <0.001 2.603 1.612 4.205 0.005 2.060 1.241 3.418 2 comorbidities <0.001 3.124 1.746 5.591 0.016 2.146 1.156 3.982 3 or more comorbidities <0.001 4.290 1.994 9.228 0.009 2.932 1.313 6.548 Cardiopathy <0.001 2.233 1.460 3.416 – – – – CI, confidence interval; OR, odds ratio. to immunosuppressive drugs independently the underlying substrates for the above clinical predicted a higher hospitalization rate irrespec- manifestations.6,7,9–13 MPN phenotypes largely tive of the infection wave and time from MPN vary upon age at disease presentation, and thera- diagnosis (Table 5). pies for MPN may specifically modulate the risk of thrombosis, infections, and secondary neo- plasms.14 Moreover, registry-based propensity- Discussion adjusted studies and two meta-analyses registered MPN is a heterogeneous family of diseases par- an increased risk of infections, mostly viral, in ticularly prone to thrombosis and bleeding, but patients treated with the JAK2/2 inhibitor ruxoli- also to infections and secondary neoplasms due to tinib.15–17 We, therefore, aimed to assess whether dysregulated innate and adaptive immunity. the exposure to ‘immunosuppressive’ therapies, Spleen neoangiogenesis and chronic inflamma- namely JAK inhibitors, IMIDs, or steroids, might tion driven by MPN-specific mutations (e.g. aggravate the clinical course of COVID-19 in JAK2 V617F) are hypothesized to be MPN patients. As a consequence, we performed 6 journals.sagepub.com/home/tah M Marchetti, J Salmanton-García et al. 45% 1 40% 35% 30% 25% 20% 2 3 15% 4 10% 5 5% 0% Year 2020 Year 2020 Year 2021 Year 2021 Year 2022 Quarter 1-2 Quarter 3-4 Quarter 1-2 Quarter 3-4 Quarter 1 Figure 1. COVID-19 mortality rate in different time periods. The bars report percent mortality of MPN patients with COVID-19 infection in consecutive quarters from first 2020 quarter to first 2022 quarter. Figure 2. Survival curves after SARS-CoV-2 infection according to the period. The line shows the survival after COVID-19 in the first wave, while orange, yellow, and green lines show subsequent waves. The rectangle reports p values for pairwise comparisons. a specific query to the EPICOVIDEHA registry, As of 31 March 2022, overall, 398 MPN patients which had previously reported very high admis- were reported by the EPICOVIDEHA survey: sion rates to hospital (73.1%) and to ICU (18.1%) 46.0% of the patients suffered from MF, 30.4% and mortality (31.2%) in the 3801 patients sur- were on immunosuppressive therapies (JAK veyed during the year 2020.8,18 inhibitors, steroids, or IMIDs), 47.2% were above journals.sagepub.com/home/tah 7 Therapeutic Advances in Hematology Volume 14 Table 3. Cox regression analysis of fatality rate. Univariable analysis Multivariable analysis p value HR 95% CI 95% CI p value HR 95% CI 95% CI lower upper lower upper limit limit limit limit Age <70 years old – – – – – – – – ⩾70 years old <0.001 2.877 1.837 4.504 0.001 2.191 1.363 3.521 Immunosuppressive therapies Cytoreductive drug therapy – – – –  Immunosuppressive drug <0.001 2.156 1.389 3.345 <0.001 2.143 1.369 3.354 therapy  No cytoreductive or 0.891 1.052 0.509 2.177 0.944 0.974 0.466 2.037 immunosuppressive drug therapy Malignancy Essential thrombocythemia – – – – – – – – Myelofibrosis <0.001 2.644 1.496 4.673 0.073 1.888 0.944 3.779 Polycythemia vera 0.463 1.297 0.647 2.598 0.312 1.443 0.709 2.937 Comorbidities No comorbidities – – – – – – – – 1 comorbidity 0.003 2.485 1.353 4.564 0.033 1.967 1.056 3.663 2 comorbidities <0.001 3.176 1.667 6.049 0.009 2.441 1.247 4.780 3 or more comorbidities <0.001 8.000 4.154 15.408 <0.001 5.487 2.765 10.889 Cardiopathy <0.001 2.468 1.625 3.750 – – – – CI, confidence interval; HR, hazard ratio. 70 years of age, and 10.1% suffered from at least exposure to ruxolitinib was an independent pre- three comorbidities. Out of the overall MPN dictor of mortality (HR: 2.161; 95% CI: cohort, 54.3% were admitted to hospital, 13.3% 1.381–3.379). were admitted to ICU, and 22.4% deceased. The outcomes of infection varied according to the JAK inhibitors have been reported to ameliorate underlying disease, MF being associated with the systemic inflammation driven by SARS-CoV-2 and highest rates of hospitalization.19 COVID-19 out- have even been proposed as potential therapeutic comes were worsened by previous exposure to principles also for patients without MPN.20 immunosuppressive therapies before infection However, based on the broad immunosuppressive onset. Exposure to immunosuppressive agents potential of JAK inhibitors (in particular, of ruxoli- independently increased the risk of both hospi- tinib), longer exposure to ruxolitinib limits T-cell talization (OR: 2.186; 95% CI: 1.357–3.519) and and humoral responses to BNT162b2 (Pfizer/ mortality (HR: 2.143; 95% CI: 1.369–3.354) and BioNTech®) and mRNA-1273 (Moderna®) 8 journals.sagepub.com/home/tah M Marchetti, J Salmanton-García et al. Table 4. Cox regression analysis of fatality rate including the pandemic wave and disease duration. Univariable analysis Multivariable analysis p value HR 95% CI 95% CI p value HR 95% CI 95% CI lower upper lower upper limit limit limit limit Age <70 years old – – – – – – – – ⩾70 years old <0.001 2.877 1.837 4.504 <0.001 2.285 1.408 3.708 Immunosuppressive therapies Cytoreductive drug therapy – – – – Immunosuppressive drug therapy <0.001 2.16 1.389 3.345 <0.001 2.19 1.394 3.443  No cytoreductive or 0.891 1.05 0.509 2.177 0.594 0.82 0.387 1.721 immunosuppressive drug therapy Malignancy Essential thrombocythemia – – – – – – – – Myelofibrosis <0.001 2.644 1.496 4.673 0.034 2.151 1.061 4.363 Polycythemia vera 0.463 1.297 0.647 2.598 0.216 1.572 0.767 3.220 Months from malignancy (diagnosis) 0.564 0.999 0.996 1.002 – – – – to COVID-19 Comorbiditiesa No comorbidities – – – – – – – – 1 comorbidity 0.003 2.485 1.353 4.564 0.052 1.873 0.994 3.528 2 comorbidities <0.001 3.176 1.667 6.049 0.039 2.078 1.039 4.157 3 or more comorbidities <0.001 8.000 4.154 15.408 <0.001 4.723 2.338 9.540 Pandemic wave 2020 Q1–Q2 – – – – – – – – 2020 Q3–Q4 0.004 0.492 0.305 0.793 0.031 0.584 0.359 0.951 2021 Q1–Q2 0.097 0.421 0.152 1.170 0.119 0.440 0.157 1.234 2021 Q3–Q4 0.047 0.390 0.154 0.989 0.099 0.450 0.174 1.162 2022 Q1 0.083 0.400 0.142 1.128 0.049 0.349 0.122 0.995 CI, confidence interval; COVID-19, coronavirus disease 2019; HR, hazard ratio. aSingle comorbidities with statistically significant predictive value uniquely at univariate analysis included chronic cardiopathy (HR: 0.468; 95% CI: 1.625–3.750), chronic pulmonary disease (HR: 2.346; 95% CI: 1.438–3.829), diabetes mellitus (HR: 2.793; 95% CI: 1.758–4.438), liver disease (HR: 2.527; 95% CI: 1.217–5.247), and renal impairment (HR: 4.112; 95% CI: 2.178–7.763). journals.sagepub.com/home/tah 9 Therapeutic Advances in Hematology Volume 14 Table 5. Logistic regression analysis of hospital admission including the pandemic wave and disease duration. Univariate analysis Multivariate analysis p value OR 95% CI 95% CI upper p value OR 95% CI 95% CI lower limit limit lower limit upper limit Age <70 years old – – – – – – – – ⩾70 years old <0.001 3.091 2.046 4.670 <0.001 2.894 1.782 4.700 Immunosuppressive therapies  Cytoreductive drug – – – – therapy  Immunosuppressive <0.001 2.134 1.363 3.34 <0.001 2.428 1.458 4.043 drug therapy  No cytoreductive or 0.321 1.37 0.735 2.554 0.672 1.175 0.557 2.48 immunosuppressive drug therapy Malignancy  Essential – – – – – – – – thrombocythemia Myelofibrosis 0.002 2.158 1.339 3.478 0.089 1.770 0.918 3.415 Polycythemia vera 0.208 1.413 0.825 2.419 0.213 1.498 0.793 2.832 Months from malignancy 0.845 1.000 0.997 1.003 (diagnosis) to COVID-19 Comorbiditiesa No comorbidities – – – – – – – – 1 comorbidity <0.001 2.603 1.612 4.205 0.010 2.047 1.183 3.539 2 comorbidities <0.001 3.124 1.746 5.591 0.124 1.679 0.867 3.251  3 or more <0.001 4.290 1.994 9.228 0.026 2.652 1.121 6.273 comorbidities Pandemic wave 2020 Q1–Q2 – – – – – – – – 2020 Q3–Q4 <0.001 0.241 0.142 0.408 <0.001 0.266 0.151 0.469 2021 Q1–Q2 0.117 0.476 0.188 1.203 0.127 0.460 0.170 1.247 2021 Q3–Q4 <0.001 0.143 0.068 0.302 <0.001 0.131 0.058 0.298 2022 Q1 <0.001 0.161 0.079 0.328 <0.001 0.119 0.054 0.264 CI, confidence interval; COVID-19, coronavirus disease 2019; OR, odds ratio; HR, hazard ratio. aStatistically significant comorbidities only at univariate analysis: chronic cardiopathy (OR: 2.23; 95% CI: 1.460–3.416), chronic pulmonary disease (OR: 2.301; 95% CI: 1.218–4.347), diabetes mellitus (OR: 3.158; 95% CI: 1.671–5.968). 10 journals.sagepub.com/home/tah M Marchetti, J Salmanton-García et al. SARS-CoV-2 vaccines.21–29 Moreover, ruxolitinib COVID-19 infection could not be accurately discontinuation has recently reported to be asso- tracked by the study, which may hamper a defi- ciated with worse outcome in SARS-CoV-2- nite analysis of the causes of death. Finally, abrupt infected MPN patients.19 At this first analysis of interruption of, rather than prior exposure to, the EPICOVIDEHA MPN cohort, we could not JAK inhibitors might explain the higher FR in ascertain whether worse outcomes were most hospitalized patients; however, this information attributable to interruption of immunosuppres- was not required in the former data collection sive therapies; however, we planned to better form and is currently not available. address these issues in subsequent enquiries. For the above reasons, future data collection will The COVID-19 vaccination campaign has led to be focused on drug–outcome relationships in a a reduction in hospitalization rate and mortality, fully vaccinated population and will explore but risks are still high in patients with blood can- COVID-19 outcome in patients treated with JAK cers. Further primary preventive strategies for inhibitors, considering disease severity and ther- frail patients include administration of fourth vac- apy discontinuation among the covariates. cination dose and long-life monoclonal agents, such as tixagevibam plus cilgavimab.29–31 While immune response to vaccination is still being Conclusion ascertained in patients with HM and may vary In conclusion, the present study confirmed dis- according to the prevalent viral variant, long-life mal outcomes in the older MPN patients and in monoclonal agents in European Union are cur- those with higher comorbidity burden, (i.e. car- rently being restricted to patients undergoing cell diovascular or pulmonary disease or diabetes). In therapy.31–33 This study enrolled many patients addition, to the best of our knowledge, this study involved by the first SARS-CoV-2 waves and thus is the first reporting that exposure to immuno- a very low percentage of patients had received at suppressive agents before SARS-CoV-2 infection least one vaccine dose. The present report also independently increased hospitalization rates suggests to devote intensified preventive meas- and risk of death. Specific preventive strategies ures to patients with MPN receiving immunosup- need, thus, to be tailored for these individuals at pressive agents. risk, including application of potentially protec- tive preventive antibody cocktails as well as There are limitations of our study that must be mindful tapering strategies in MPN patients pre- acknowledged. First, MF patients are likely to be treated with JAK inhibitors. Finally, therapeutic slightly overrepresented in our series, but we decisions in the future should also consider the could not attribute this skewness to the higher abovementioned risk factors. severity of COVID-19 in MF patients. Second, as we included patients from different countries and Declarations centers, and diagnosed in different waves of the pandemic, a certain heterogeneity in our data is to Ethics approval and consent to participate be expected. In addition, only a small number of Institutional Review Board and Ethics Committee patients in this series were vaccinated: this is due of Fondazione Policlinico Universitario A. to the fact that most data were collected during Gemelli – IRCCS – Università Cattolica del Sacro early waves, where vaccinations were not broadly Cuore, Rome, Italy (Study ID: 3226). available. Furthermore, SARS-CoV-2 vaccina- tion was reported to be effective in patients with Consent for publication MPN; therefore, a few breakthrough infections All the authors agreed for publication of the man- are expected to occur. Another limitation of the uscript in its present form. study relates to data on outcome and survival, Patient consent was managed according to local which must be interpreted carefully, since from approval. the limited data forms, we could not ascertain any covariate that was correlated with JAK-inhibitor therapy and that might explain the inferior out- Author contributions come. In particular, receiving immunosuppres- Monia Marchetti: Conceptualization; Investi­ sive drugs may be related to advanced disease gation; Methodology; Writing – original draft; stage. Moreover, thromboembolic events after Writing – review & editing. journals.sagepub.com/home/tah 11 Therapeutic Advances in Hematology Volume 14 Jon Salmanton-García: Conceptualization; Lucia Prezioso: Resources; Writing – review & Data curation; Formal analysis; Investigation; editing. Methodology; Project administration; Resources; Stef Meers: Resources; Writing – review & Software; Supervision; Validation; Visualization; editing. Writing – review & editing. Rafael Duarte: Resources; Writing – review & Shaimaa El-Ashwah: Resources; Writing – editing. review & editing. Luisa Verga: Resources; Writing – review & Rui Bergantim: Resources; Writing – review & editing. editing. Federico Itri: Resources; Writing – review & Ozren Jaksic: Resources; Writing – review & editing. editing. Zdeněk Ráčil: Resources; Writing – review & Natasha Čolović: Resources; Writing – review & editing. editing. Julio Dávila-Valls: Resources; Writing – review Ola Blennow: Resources; Writing – review & & editing. editing. Sonia Martín-Pérez: Resources; Writing – Martin Cernan: Resources; Writing – review & review & editing. editing. Jaap Van Doesum: Resources; Writing – review Martin Schönlein: Resources; Writing – review & editing. & editing. Francesco Passamonti: Resources. Michail Samarkos: Resources; Writing – review Ghaith Abu-Zeinah: Resources; Writing – & editing. review & editing. Maria Enza Mitra: Resources; Writing – review Francesca Farina: Resources; Writing – review & editing. & editing. Gabriele Magliano: Resources; Writing – review Alberto López-García: Resources; Writing – & editing. review & editing. Johan Maertens: Resources; Writing – review & Giulia Dragonetti: Resources; Writing – review editing. & editing. Marie-Pierre Ledoux: Resources; Writing – Chiara Cattaneo: Resources; Writing – review review & editing. & editing. Moraima Jiménez: Resources; Writing – review Maria Gomes Da Silva: Resources; Writing – & editing. review & editing. Fatih Demirkan: Resources; Writing – review & Yavuz M. Bilgin: Resources; Writing – review & editing. editing. Pavel Žák: Resources; Writing – review & Graham P. Collins: Resources; Writing – review editing. & editing. Verena Petzer: Resources; Writing – review & Alba Cabirta: Resources; Writing – review & editing. editing. Andreas Glenthøj: Resources; Writing – review Stefanie K. Gräfe: Resources; Writing – review & editing. & editing. Ildefonso Espigado: Resources; Writing – Anna Nordlander: Resources; Writing – review review & editing. & editing. Caterina Buquicchio: Resources; Writing – Dominik Wolf: Resources; Writing – review & review & editing. editing. Valentina Bonuomo: Resources; Writing – Elena Arellano: Resources; Writing – review & review & editing. editing. 12 journals.sagepub.com/home/tah M Marchetti, J Salmanton-García et al. Raul Cordoba: Resources; Writing – review & Competing interests editing. The author declared the following potential con- flicts of interest with respect to the research, Michaela Hanakova: Resources; Writing – authorship, and/or publication of this article: JSG review & editing. reports speaker honoraria from Gilead and Pfizer, Giovanni Paolo Maria Zambrotta: Resources; outside of the submitted work. DW received Writing – review & editing. speakers honorary and research funding from Raquel Nunes Rodrigues: Resources; Writing Novartis, AOP Pharma, Incyte, Bexxalta, BMS/ – review & editing. Celgene, outside of the submitted work. MM received consultancy fees from Gilead, outside of Giulia Limberti: Resources; Writing – review & the submitted work. OAC reports grants or con- editing. tracts from Amplyx, Basilea, BMBF, Cidara, Francesco Marchesi: Resources; Supervision; DZIF, EU-DG RTD (101037867), F2G, Gilead, Validation; Writing – review & editing. Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees Oliver A. Cornely: Funding acquisition; from Abbvie, Amplyx, Biocon, Biosys, Cidara, Resources; Supervision; Writing – review & Da Volterra, Gilead, Matinas, MedPace, editing. Menarini, Molecular Partners, MSG-ERC, Livio Pagano: Funding acquisition; Resources; Noxxon, Octapharma, Pardes, PSI, Scynexis, Supervision; Writing – review & editing. Seres; Honoraria for lectures from Abbott, Al-Jazeera Pharmaceuticals, Astellas, Grupo Acknowledgements Biotoscana/United Medical/Knight, Hikma, Toni Valkovič, Christian Bjørn Poulsen, Klára MedScape, MedUpdate, Merck/MSD, Mylan, Piukovics, Monica Piedimonte, Irati Ormazabal- Pfizer; Payment for expert testimony from Cidara; Vélez, Hans-Beier Ommen, Joseph Meletiadis, Participation on a Data Safety Monitoring Board Maria Stamouli, Marina Machado, Austin or Advisory Board from Actelion, Allecra, Cidara, Kulasekararaj, Carolina Garcia-Vidal, Nicola Entasis, IQVIA, Janssen, MedPace, Paratek, PSI, Fracchiolla, María Fernández-Galán, Noemí Pulmocide, Shionogi; A patent at the German Fernández, Rita Fazi, Alessandro Busca, Marcio Patent and Trade Mark Office (DE 10 2021 113 Nucci, Milan Navrátil, Carolina Miranda-Castillo, 007.7), outside of the submitted work. No rele- Nick De Jonge, Michelina Dargenio, Annarosa vant conflicts of interest are reported by all the Cuccaro, Barbora Weinbergerová, Jens Van Praet, other authors. Zlate Stojanoski, Uluhan Sili, Guldane Cengiz Seval, Ikhwan Rinaldi, László Imre Pinczés, Jan Availability of data and materials Novák, Jorge Loureiro-Amigo, Lisset Lorenzo De For data sharing, please contact the correspond- La Peña, Tobias Lahmer, Jorge Labrador, Nina ing author. Khanna, María-Josefa Jiménez-Lorenzo, Anna Guidetti, Tomás-José González-López, Iker ORCID iDs Falces-Romero, Maria Ilaria Del Principe, Cristina Jon Salmanton-García https://orcid.org/0000- De Ramón, François Danion, Nicola Coppola, 0002-6766-8297 Maria Calbacho, Nathan Bahr, Natasha Ali, Graham P. Collins https://orcid.org/0000- Osman Ilhan, Ramón García-Sanz, Josep Maria 0002-8803-4234 Ribera-Santasusana, Agostino Tafuri, Nicole García-Poutón, Sofia Zompi, Mariarita Sciumè. Funding References The authors disclosed receipt of the following 1. 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