Outcomes of SARS-CoV-2 infection in Ph-neg chronic myeloproliferative neoplasms: results from the EPICOVIDEHA registry

https://doi.org/10.1177/20406207231154706 https://doi.org/10.1177/20406207231154706 Ther Adv Hematol 2023, Vol. 14: 1–15 DOI: 10.1177/ 20406207231154706 © The Author(s), 2023. Article reuse guidelines: sagepub.com/journalspermissions 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 Outcomes of SARS-CoV-2 infection in Ph-neg chronic myeloproliferative neoplasms: results from the EPICOVIDEHA registry Monia Marchetti*, Jon Salmanton-García*, Shaimaa El-Ashwah, Luisa Verga, Federico Itri, Zdeneˇk Rácˇil, Julio Dávila-Valls, Sonia Martín-Pérez, Jaap Van Doesum, Francesco Passamonti, Ghaith Abu-Zeinah, Francesca Farina, Alberto López-García, Giulia Dragonetti, Chiara Cattaneo, Maria Gomes Da Silva, Yavuz M. Bilgin, Pavel Žák, Verena Petzer, Andreas Glenthøj, Ildefonso Espigado, Caterina Buquicchio, Valentina Bonuomo, Lucia Prezioso, Stef Meers, Rafael Duarte, Rui Bergantim, Ozren Jaksic, Natasha C ˇolovic´, Ola Blennow, Martin Cernan, Martin Schönlein, Michail Samarkos, Maria Enza Mitra, Gabriele Magliano, Johan Maertens, Marie-Pierre Ledoux, Moraima Jiménez, Fatih Demirkan, Graham P. Collins , Alba Cabirta, Stefanie K. Gräfe, Anna Nordlander, Dominik Wolf, Elena Arellano, Raul Cordoba, Michaela Hanakova, Giovanni Paolo Maria Zambrotta, Raquel Nunes Rodrigues, Giulia Limberti, Francesco Marchesi, Oliver A. Cornely and Livio Pagano Abstract Background: Patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) typically incur high rates of infections and both drugs and comorbidities may modulate infection risk. Objectives: The present study aims to assess the effect of immunosuppressive agents on clinical outcomes of MPN patients affected by the coronavirus disease 2019 (COVID-19). Design: This is an observational study. Methods: We specifically searched and analyzed MPN patients collected by EPICOVIDEHA online registry, which includes individuals with hematological malignancies diagnosed with COVID-19 since February 2020. Results: Overall, 398 patients with MPN were observed for a median of 76 days [interquartile range (IQR): 19–197] after detection of SARS-CoV2 infection. Median age was 69 years (IQR: 58–77) and 183 individuals (46%) had myelofibrosis (MF). Overall, 121 patients (30%) of the whole cohort received immunosuppressive therapies including steroids, immunomodulatory drugs, or JAK inhibitors. Hospitalization and consecutive admission to intensive care unit was required in 216 (54%) and 53 patients (13%), respectively. Risk factors for hospital admission were identified by multivariable logistic regression and include exposure to immunosuppressive therapies [odds ratio (OR): 2.186; 95% confidence interval (CI): 1.357– 3.519], age ⩾70 years, and comorbidities. The fatality rate was 22% overall and the risk of death was independently increased by age ⩾70 years [hazard ratio (HR): 2.191; 95% CI: 1.363– 3.521], previous comorbidities, and exposure to immunosuppressive therapies before the infection (HR: 2.143; 95% CI: 1.363–3.521). Conclusion: COVID-19 infection led to a particularly dismal outcome in MPN patients receiving immunosuppressive agents or reporting multiple comorbidities. Therefore, specific preventive strategies need to be tailored for such individuals. Correspondence to: Jon Salmanton-García Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. Cologne Excellence Cluster on Cellular Stress Responses in Aging- Associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany jon.salmanton-garcia@ uk-koeln.de Monia Marchetti Giulia Limberti Azienda Ospedaliera Nazionale SS. Antonio e Biagio e Cesare Arrigo, Alessandria, Italy Shaimaa El-Ashwah Oncology Center, Mansoura University, Mansoura, Egypt Luisa Verga Giovanni Paolo Maria Zambrotta Azienda Ospedaliera San Gerardo–Monza, Monza, Italy; Università Milano- Bicocca, Milan, Italy Federico Itri San Luigi Gonzaga Hospital–Orbassano, Orbassano, Italy Zdeneˇk Rácˇil Michaela Hanakova Institute of Hematology and Blood Transfusion, Prague, Czech Republic Julio Dávila-Valls Sonia Martín-Pérez Hospital Nuestra Señora de Sonsoles, Ávila, Spain Jaap Van Doesum University Medical Center Groningen, Groningen, The Netherlands Francesco Passamonti University Insubria, Varese, Italy 1154706TAH0010.1177/20406207231154706Therapeutic Advances in HematologyM Marchetti, J Salmanton-García research-article20232023 Original Research Volume 14 2 journals.sagepub.com/home/tah TherapeuTic advances in hematology Plain language summary EPICOVIDEHA registry reports inferior outcomes of COVID-19 in patients with Philadelphianegative chronic myeloproliferative neoplasms receiving immunosuppressive therapies. Patients with Philadelphia-negative chronic myeloproliferative neoplasms (MPN) incur high rates of infections during the course of their disease. The present study was aimed at assessing which patient characteristics predicted a worse outcome of SARS-COV-2 infection in individuals with MPN. To pursue this objective, the researchers analyzed the data collected by EPICOVIDEHA, an international online registry, which includes individuals with hematological malignancies diagnosed with COVID-19 since February 2020. The database provided clinical data of 398 patients with MPN incurring COVID-19: • Patients were mostly elderly (median age was 69 years); • Forty-six percent of them were affected by myelofibrosis, which is the most severe MPN; • Moreover, 32% were receiving immunosuppressive therapies (JAK inhibitors, such as ruxolitinib, steroids, or immunomodulatory IMID drugs, such as thalidomide) before COVID-19. Hospitalization was required in 54% of the patients, and the risk of being hospitalized for severe COVID-19 was independently predicted by • Older age; • Comorbidities; • Exposure to immunosuppressive therapies. Overall, 22% of MPN patients deceased soon after COVID-19 and the risk of death was independently increased over twofold by • Older age; • Comorbidities; • Exposure to immunosuppressive therapies before the infection. In conclusion, COVID-19 infection led to a particularly dismal outcome in MPN patients receiving immunosuppressive agents, including JAK inhibitors, or reporting multiple comorbidities. Therefore, specific preventive strategies need to be tailored for such individuals. Keywords: COVID-19, essential thrombocytemia, hydroxyurea, myelofibrosis, Philadelphianegative chronic myeloproliferative neoplasms, polycythemia vera, ruxolitinib, SARS-CoV-2 Received: 17 August 2022; revised manuscript accepted: 17 January 2023. Ghaith Abu-Zeinah Division of Hematology and Oncology, Weill Cornell Medicine, New York, NY, USA Francesca Farina IRCCS Ospedale San Raffaele, Milan, Italy Alberto López-García Health Research Institute IIS-FJD, Fundación Jimenez Diaz University Hospital, Madrid, Spain Giulia Dragonetti Hematology Unit, Fondazione Policlinico Universitario Agostino Gemelli–IRCCS, Rome, Italy Chiara Cattaneo Hematology Unit, ASST- Spedali Civili, Brescia, Italy Maria Gomes Da Silva Raquel Nunes Rodrigues Portuguese Institute of Oncology, Lisbon, Portugal Yavuz M. Bilgin Department of Internal Medicine, ADRZ, Goes, The Netherlands Pavel Žák University Hospital Hradec Králové, Hradec Králové, Czech Republic Verena Petzer Dominik Wolf Department of Hematology and Oncology, Medical University of Innsbruck, Innsbruck, Austria Andreas Glenthøj Department of Hematology, Copenhagen University Hospital–Rigshospitalet, Copenhagen, Denmark Ildefonso Espigado Department of Hematology, University Hospital Virgen Macarena–University Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS/CSIC) and Departamento de Medicina, Universidad de Sevilla, Seville, Spain Caterina Buquicchio Ematologia con Trapianto, Ospedale Dimiccoli Barletta, Barletta, Italy Valentina Bonuomo Section of Hematology, Department of Medicine, University of Verona, Verona, Italy Lucia Prezioso Hematology and Bone Marrow Unit, Hospital University of Parma, Parma, Italy Stef Meers AZ KLINA, Brasschaat, Belgium Introduction Coronavirus disease 2019 (COVID-19) is a public health emergency of international concern since February 2020. It is caused by severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2), a rapidly spreading novel coronavirus which principally causes pneumonia and respiratory failure, alongside damage to several organs by inflammatory and pro-thrombotic pathways.1,2 Age and comorbidity were reported to independently predict the fatality rate (FR) in COVID-19, and individuals affected by baseline hematological malignancies (HM) were reported to incur twofold higher mortality compared with the general population.3,4 Philadelphia-negative chronic myeloproliferative neoplasms (MPN) represent one-third of myeloid malignancies and, due to its indolent course, prevalence is high (50 per 100,000 inhabitants).5 MPN is characterized by thrombocytosis, leukocytosis, and erythrocytosis, but they may also present with or develop cytopenias, that associate with adverse clinical outcomes. Arterial and M Marchetti, J Salmanton-García et al. journals.sagepub.com/home/tah 3 venous thromboses are the most common complications of MPNs, due to intrinsic abnormalities of endothelial cells as well as altered platelet and leukocyte function, which may be exacerbated by infections. Of significance, the risk of viral infections is threefold higher in MPN compared with matched controls.6,7 Based on the above clinical features, MPN patients with COVID-19 are expected to have an increased risk for severe outcomes. The present study aimed to assess clinical outcomes of COVID-19 in patients with MPN. More specifically, we aimed at testing the impact of previous therapies for MPN onto SARS-CoV-2 infection outcomes and to identify the more frail subgroups potentially requiring intensified preventive measures (e.g. application of preventive monoclonal antibodies). Methods In February 2020, an international cooperative registry, named EPICOVIDEHA, was initiated by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA).8 EPICOVIDEHA is a multicenter, noninterventional, observational study approved by the local Institutional Review Board and Ethics Committee of the Fondazione Policlinico Universitario Agostino Gemelli– IRCCS, Università Cattolica del Sacro Cuore of Rome, Italy (Study ID: 3226). The corresponding local ethics committee of each participating institution may approve additionally the EPICOVIDEHA study when applicable. EPICOVIDEHA is registered at http://www.clin icaltrials.gov, with the identifier NCT 04733729. Researchers from different countries were invited to retrospectively review all episodes of COVID- 19 disease occurring in patients with blood cancers identified at their institutions from February 2020 onward. The EPICOVIDEHA electronic case report form is available at www.clinicalsurveys.net (EFS Summer 2021, TIVIAN GmbH, Cologne, Germany). The anonymized electronic clinical report form is the single access for each participating institution and is structured in different thematic pages, as follows: (1) identification, (2) demographics, (3) underlying diseases, (4) HM, (5) COVID-19, and (6) outcome. Cases could be registered according to the following inclusion criteria: (1) age equal to or greater than 18 years, (2) history of active HM at any stage within the last 5 years before COVID-19, and (3) report of SARS-CoV-2 positive test documented by real-time reverse transcriptase polymerase chain reaction (RT-PCR) diagnostic panels. Qualitative demographic and clinical data were described by frequencies and percentages, while medians and interquartile ranges (IQR) were used to summarize quantitative variables. Chisquare test, Fisher’s exact test, and Mann– Whitney’s U test were used for comparisons, as appropriate. Logistic and Cox multivariable regressions allowed to identify predictors of the outcomes. SPSS software has been employed for the descriptive and inferential statistical analyses (SPSS, version 25.0, Chicago, IL, USA). The reporting of this study conforms to the STROBE statement (www.equator-network.org/ reporting-guidelines/strobe/). Results Overall, 398 MPN patients with COVID-19 were registered in EPICOVIDEHA from February 2020 to March 2022 (Table 1): 113 individuals (28.4%) with essential thrombocythemia (ET), 183 (46.0%) with myelofibrosis (MF), and 102 (25.6%) with polycythemia vera (PV). Thirty individuals were newly diagnosed MPN concomitantly or within 1 month from diagnosis of SARS-CoV-2 infection. Overall, 148 patients (37.2%) had received hydroxyurea as the most recent treatment before COVID- 19, while 111 patients (27.9%) had received JAK inhibitors. More specifically, 92 MF patients (50.3%) and 17 PV patients (16.7%) were receiving JAK inhibitors, while 10 patients were receiving other therapies with an immunosuppressive potential, namely immunomodulating agents (IMID), such as thalidomide or lenalidomide, or steroids. Overall, 121 patients (who did had not underwent transplantation) received therapies with an immunosuppressive potential: this corresponds to 30.4% of the overall cohort and 55.2% of the MF subgroup. Moreover, 8.3% of the overall cohort (33 patients) were refractory or resistant to ongoing Rafael Duarte Hospital Universitario Puerta de Hierro, Majadahonda, Spain Rui Bergantim Centro Hospitalar e Universitário São João, Porto, Portugal Ozren Jaksic University Hospital Dubrava, Zagreb, Croatia Natasha C ˇolovic´ University Clinical Center Serbia, Medical Faculty University Belgrade, Belgrade, Serbia Ola Blennow Anna Nordlander Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden Martin Cernan University Hospital Olomouc, Olomouc, Czech Republic Martin Schönlein Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg- Eppendorf, Hamburg, Germany Michail Samarkos Laikon Hospital, Athens, Greece Maria Enza Mitra UO Ematologia, AOUP P. Giaccone, Palermo, Italy Gabriele Magliano ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy Johan Maertens KU Leuven, Leuven, Belgium Marie-Pierre Ledoux ICANS, Strasbourg, France Moraima Jiménez Alba Cabirta Department of Hematology, Vall d’Hebron Hospital Universitari, Experimental Hematology, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain Departament de Medicina, Universitat Autònoma de Barcelona, Bellaterra, Spain Fatih Demirkan Division of Hematology, Dokuz Eylul University, Izmir, Turkey Graham P. Collins NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK Volume 14 4 journals.sagepub.com/home/tah TherapeuTic advances in hematology Table 1. Baseline characteristics and outcomes according to the underlying malignancy. All MPN n = 398 Essential thrombocythemia n = 113 Myelofibrosis n = 183 Polycythemia vera n = 102 n%n%n%n% Sex (male) 232 58.3 54 47.8 109 59.6 69 67.6 Age (median, IQR) 69 58–77 67 51–78 69 61–75 68 59–77 <50 years old 52 13.1 27 23.9 16 8.7 9 8.8 51–69 years old 158 39.7 31 27.4 81 44.3 46 45.1 >70 years old 188 47.2 55 48.7 86 47.0 47 46.1 Comorbidities No comorbidities 155 38.9 49 43.4 59 32.2 47 46.1 1 comorbidity 130 32.7 37 32.7 62 33.9 31 30.4 2 comorbidities 73 18.3 21 18.6 36 19.7 16 15.7 ⩾3 comorbidities 40 10.1 6 5.3 26 14.2 8 7.8 Cardiovascular comorbidities 144 36.2 40 35.4 66 36.1 38 37.3 Diabetes mellitus 59 14.8 13 11.5 35 19.1 11 10.8 Smoking history 41 10.3 7 6.2 25 13.7 9 8.8 Disease status at COVID-19 onset Newly diagnosed 30 7.5 6 5.3 19 10.4 5 4.9 Refractory 33 8.3 2 1.8 25 13.7 6 5.9 Ongoing treatment – Drug therapies Hydroxyurea 148 37.2 66 58.4 32 17.5 50 49.0 JAK inhibitors 111 27.9 2 1.8 92 50.3 17 16.7 Immunosuppressive therapy 121 30.4 2 1.8 101 55.2 18 17.6 COVID-19 vaccination status At least one dose 80 20.1 21 18.6 41 22.4 18 17.6 COVID-19 severity Asymptomatic 66 16.6 25 22.1 23 12.6 18 17.6 Pulmonary symptoms 212 53.3 62 54.9 97 53.0 53 52.0 Severe/Critical 239 60.1 59 52.2 125 68.3 55 53.9 Hospital stay and management during COVID-19 Hospital admission 216 54.3 49 43.4 114 62.3 53 52.0 Intensive care unit 53 13.3 8 7.1 32 17.5 13 12.7 Invasive ventilation 29 7.3 5 4.4 16 8.7 8 7.8 COVID-19 outcome 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. Stefanie K. Gräfe Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Cologne Excellence Cluster on Cellular Stress Responses in Aging- Associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Elena Arellano Department of Hematology, University Hospital Virgen Macarena, Seville, Spain Raul Cordoba Health Research Institute IIS-FJD, Fundacion Jimenez Diaz University Hospital, Madrid, Spain Francesco Marchesi Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy Oliver A. Cornely Department I of Internal Medicine, Excellence Center for Medical Mycology (ECMM), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Chair Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Clinical Trials Centre Cologne (ZKS Köln), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany M Marchetti, J Salmanton-García et al. journals.sagepub.com/home/tah 5 therapies: the rate was lower in ET (1.8%), while it was higher in MF (13.7%). Overall, seven patients (1.7%) had received allogeneic hematopoietic stem cell transplant (HSCT): three of them were transplanted more than 6 months before COVID-19. Males were 58.3% of the whole cohort and median age at infection was 69 years (IQR: 58– 77, range: 22–97). Moreover, in 61.1% of the patients, at least one comorbidity was reported, while in 10.1%, three or more comorbidities were listed in the medical history checking seven ever major comorbidities, namely chronic cardiovascular and pulmonary diseases, renal failure, diabetes, liver diseases, obesity, and concurrent neoplasms. In particular, 144 patients (36.2%) suffered from cardiovascular diseases (e.g. atrial fibrillation, arterial hypertension, obstructive arteriopathy), 52 from chronic pulmonary disease (13.1%), 59 from diabetes (14.9%), 21 from liver disease (5.3%), 27 from obesity (6.8%), 18 from renal impairment (e.g. serum creatinine above 2 mg/dl) (4.5%). Smoking history was reported in 41 patients (10.3%). Overall, 76 (19.1%) individuals had received at least two prior vaccination doses before COVID- 19 and 37 (9.3%) had received three doses. Messenger ribonucleic acid (mRNA) vaccines were administered to 70 (17.6%) patients. In a small portion of patients (16.6%), asymptomatic SARS-CoV-2 infection was documented, while cough or dyspnea was reported by most of the individuals (53.3%). Both extrapulmonary and pulmonary symptoms were observed in 66 individuals (21.9%) and exclusively extrapulmonary symptoms in 65 (23.4%). Overall, 216 patients (54.3%) were admitted to hospital and the median duration of hospital stay was 14 days (IQR: 6–22, range: 1–90). Univariable logistic regression identified MPN- related and unrelated clinical factors significantly related to the chance of hospitalization (Table 2). Among MPN-related factors, MF and exposure to immunosuppressive therapies were the most important variables, while among MPN-unrelated factors, age >70 years, cardiopathy, and number of comorbidities appeared to be linked to hospitalization. In multivariable regression analysis, exposure to immunosuppressive agents remained an independent predictor of the risk of hospital admission for MPN patients with COVID-19 [odds ratio (OR): 2.186; 95% confidence interval (CI): 1.357–3.519] and so was age >70 years (OR: 2.636; 95% CI: 1.683–4.129). However, prior exposure to ruxolitinib was not by itself an independent predictor of hospital admission. Overall, 53 out of 216 hospitalized patients were admitted to intensive care unit (ICU) (24.5%) and mechanical ventilation was required for 29 patients (13.4%). The rate of admission to ICU was significantly higher in MF compared with the other MPN subtypes: 17.5% of the overall MF patients required ICU support versus 7.1% of patients with ET patients. Median length of the ICU stay was 10 days (IQR: 5–18). MPN patients were followed for a median of 76 days (IQR: 19–197) and the reported mortality rate was 22.4%, which declined gradually over the time of the COVID-19 pandemic. During the first half of the year 2020, it was 38.9% (49 out of 126 patents), declining to 17.6% (27 out of 153) during the second half of 2020 subsequently further dropping down to 10.9% from 2021 on (p < 0.001) (Figures 1 and 2). Death occurred after a median of 14 days (IQR: 8–49) upon diagnosis of infection and was principally attributable to COVID-19 in 68 patients (76.4%) and contributable by COVID-19 in 10 (11.2%). Multivariable Cox regression analysis revealed that age >70 years was an independent predictor of mortality [hazard ratio (HR): 2.191; 95% CI: 1.363–3.521], as well as comorbidity burden (Table 3). Mortality varied among MPN diseases from 13.3% in patients with ET to 31.1% in those with MF. Exposure to immunosuppressive agents before SARS-CoV-2 infection was an independent predictor of death (HR: 2.143; 95% CI: 1.369–3.354) (Table 3), as was the exposure to ruxolitinib (HR: 2.161; 95% CI: 1.381–3.354). A sub-analysis of 155 MF patients receiving active pharmacologic treatment for their disease before COVID-19 suggested that those exposed to immunosuppressive therapies might have an inferior survival compared with those receiving any other type of treatment (p = 0.059). Multivariable Cox regression analysis of mortality reported similar results after including time from MPN diagnosis and COVID-19 infection wave (Table 4). Similarly, exposure Livio Pagano Hematology Unit, Fondazione Policlinico Universitario Agostino Gemelli–IRCCS, Rome, Italy Hematology Unit, Università Cattolica del Sacro Cuore, Rome, Italy *MM and JS-G are shared junior authors. Volume 14 6 journals.sagepub.com/home/tah TherapeuTic advances in hematology to immunosuppressive drugs independently predicted a higher hospitalization rate irrespective of the infection wave and time from MPN diagnosis (Table 5). Discussion MPN is a heterogeneous family of diseases particularly prone to thrombosis and bleeding, but also to infections and secondary neoplasms due to dysregulated innate and adaptive immunity. Spleen neoangiogenesis and chronic inflammation driven by MPN-specific mutations (e.g. JAK2 V617F) are hypothesized to be the underlying substrates for the above clinical manifestations.6,7,9–13 MPN phenotypes largely vary upon age at disease presentation, and therapies for MPN may specifically modulate the risk of thrombosis, infections, and secondary neoplasms.14 Moreover, registry-based propensityadjusted studies and two meta-analyses registered an increased risk of infections, mostly viral, in patients treated with the JAK2/2 inhibitor ruxolitinib.15–17 We, therefore, aimed to assess whether the exposure to ‘immunosuppressive’ therapies, namely JAK inhibitors, IMIDs, or steroids, might aggravate the clinical course of COVID-19 in MPN patients. As a consequence, we performed Table 2. Logistic regression analysis of hospital admission. Univariate analysis Multivariate analysis p value OR 95% CI lower limit 95% CI upper limit p value OR 95% CI lower limit 95% CI upper 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 cytoreductive drug therapy <0.001 2.134 1.363 3.34 0.001 2.186 1.357 3.519 No cytoreductive or immunosuppressive drug therapy 0.321 1.370 0.735 2.554 0.222 1.519 0.776 2.971 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. M Marchetti, J Salmanton-García et al. journals.sagepub.com/home/tah 7 1 23 4 5 Year 2020 Quarter 1-2 Year 2020 Quarter 3-4 Year 2021 Quarter 1-2 Year 2021 Quarter 3-4 Year 2022 Quarter 1 0% 5% 10% 15% 20% 25% 30% 35% 40% 45% 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, which had previously reported very high admission rates to hospital (73.1%) and to ICU (18.1%) and mortality (31.2%) in the 3801 patients surveyed during the year 2020.8,18 As of 31 March 2022, overall, 398 MPN patients were reported by the EPICOVIDEHA survey: 46.0% of the patients suffered from MF, 30.4% were on immunosuppressive therapies (JAK inhibitors, steroids, or IMIDs), 47.2% were above Volume 14 8 journals.sagepub.com/home/tah TherapeuTic advances in hematology 70 years of age, and 10.1% suffered from at least three comorbidities. Out of the overall MPN cohort, 54.3% were admitted to hospital, 13.3% were admitted to ICU, and 22.4% deceased. The outcomes of infection varied according to the underlying disease, MF being associated with the highest rates of hospitalization.19 COVID-19 outcomes were worsened by previous exposure to immunosuppressive therapies before infection onset. Exposure to immunosuppressive agents independently increased the risk of both hospitalization (OR: 2.186; 95% CI: 1.357–3.519) and mortality (HR: 2.143; 95% CI: 1.369–3.354) and exposure to ruxolitinib was an independent predictor of mortality (HR: 2.161; 95% CI: 1.381–3.379). JAK inhibitors have been reported to ameliorate systemic inflammation driven by SARS-CoV-2 and have even been proposed as potential therapeutic principles also for patients without MPN.20 However, based on the broad immunosuppressive potential of JAK inhibitors (in particular, of ruxolitinib), longer exposure to ruxolitinib limits T-cell and humoral responses to BNT162b2 (Pfizer/ BioNTech®) and mRNA-1273 (Moderna®) Table 3. Cox regression analysis of fatality rate. Univariable analysis Multivariable analysis p value HR 95% CI lower limit 95% CI upper limit p value HR 95% CI lower limit 95% CI upper 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 therapy <0.001 2.156 1.389 3.345 <0.001 2.143 1.369 3.354 No cytoreductive or immunosuppressive drug therapy 0.891 1.052 0.509 2.177 0.944 0.974 0.466 2.037 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. M Marchetti, J Salmanton-García et al. journals.sagepub.com/home/tah 9 Table 4. Cox regression analysis of fatality rate including the pandemic wave and disease duration. Univariable analysis Multivariable analysis p value HR 95% CI lower limit 95% CI upper limit p value HR 95% CI lower limit 95% CI upper 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 immunosuppressive drug therapy 0.891 1.05 0.509 2.177 0.594 0.82 0.387 1.721 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) to COVID-19 0.564 0.999 0.996 1.002 – – – – 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).