Blood Cancer Journal www.nature.com/bcj CORRESPONDENCE OPEN Long-term follow-up of recovered MPN patients with COVID-19 © The Author(s) 2021 clinical course. We point out that antithrombotic drugs including low Blood Cancer Journal (2021)11:115 ; https://doi.org/ molecular weight heparin (LMWH) and oral anticoagulants were 10.1038/s41408-021-00509-0 prescribed in 54% and 2.5%, respectively, of these 125 patients and that, in spite of this treatment, venous thromboembolism was diagnosed in 7 patients (5.6%) and a stroke in a single case (0.8%). Dear Editor, During the first wave of SARS-CoV-2 infection a European Post-COVID observational study was launched under the auspices of the The blood count values after 6 months from the resolution of the European Leukemia Net (ELN), aiming at gathering information infection are presented in Table S1 as medians and interquartile about the clinical epidemiology of COVID-19 in patients with ranges and do not show substantial alterations. Of note, chest CT- chronic myeloproliferative neoplasms (MPN-COVID study). scan was abnormal in 69% of 19 examined patients and in 10% Thirty-eight hematologic centers from Italy, Spain, Germany, patients the O2 saturation was less than 95%. Among the France, United Kingdom and Poland, participated in the study and laboratory tests, we noted the persistence of increased inflamma- enrolled 180 consecutive patients with WHO-diagnosis of essential tion markers (i.e., CRP ≥ 0.8 mg/dl in 56% of cases; N/L ratio ≥ 3 in thrombocythemia (ET; n = 60), polycythemia vera (PV; n = 58), 48%; D-Dimer ≥500 ng/mL in 18%), as reported in the general prefibrotic-myelofibrosis (pre-PMF; p = 23) and overt primary population after COVID-19 [4]. Cytoreductive therapy was used in myelofibrosis (PMF; n = 39) who developed COVID-19 from February 80% of cases and antithrombotic therapy included antiplatelet 15 to May 31, 2020. During the acute phase of the infection, in- agents in 67.5% of cases and anticoagulants in 17.5%. hospital mortality affected almost 30% of 175 evaluable patients and the most vulnerable MPN subgroup was overt PMF (mortality 48%) [1]. Another result deriving from this cohort concerned the OUTCOMES POST-COVID-19 thrombosis incidence, found significantly elevated in ET, where it Symptoms reached almost 20% vs. 5% in PV and PMF, respectively [2]. A long-term follow-up study of these patients at 6 months post At present, there is no information on the clinical condition of infection revealed ongoing symptoms in a third of the patients MPN patients discharged after COVID-19. Although SARS-CoV-2 (Fig. S1). Among these, fever, cough, and dyspnea were the most infection has a variable clinical severity and mainly manifests itself commonly reported during the acute infection but largely remitted in as a respiratory syndrome, accumulating data revealed damage of the following 6 months. It has been reported that the persistence of hematopoietic system and vascular endothelium. This damage symptoms is more frequent in patients over the age of 60 and in our can persist even after the acute phase of infection [3]. Post COVID- cases, with a median of 70 years of age, it was also associated with 19 related consequences could be more frequent in clonal persistence of inflammatory markers in more than half of them. diseases such as MPN, whose natural history is marked by vascular Overall, these findings suggest a slow recovery after the acute phase complications and inherent risk of clonal evolution into myelofi- of infection as also observed in other series of non-MPN patients [5,6,]. brosis, myelodysplasia (MDS) and acute myeloid leukemia (AML). In this paper, we report the events that occurred in 125 of the 175 Major thromboses and bleedings patients (71%), enrolled in MPN-COVID study, who survived to the Major thrombosis was registered in five patients (4%); in one of them, acute phase of the infection. Participating centers were required to massive fatal intestinal ischemia occurred (Table 1). None of these report in pre-established e-CRFs patient characteristics and outcomes patients experienced thrombosis during COVID-19. The acute collected after at least 6 months after COVID-19 infection recovery. infectious disease of these patients was managed in the ordinary The study was approved by the single center Ethical Committees. wards and, after discharge, antithrombotic therapy with LMWH was only used in a single patient who developed peripheral arterial thrombosis. Of the four patients receiving cytoreductive drugs, three PATIENT CHARACTERISTICS were receiving ruxolitinib for PMF or ET, and the fourth was on Before and at COVID-19 hydroxyurea (HU). It is interesting to know that these events occurred In Table S1, surviving patients examined in the last-follow-up after 5 months after the infection subsided, as it is well illustrated by before COVID-19 (median: 1.4 months; interquartile range [IQR]: the Kaplan Meyer thrombosis-free survival curve of Fig. 1A. 0.8–3.0) presented blood counts and clinical picture consistent A single patient with PMF experienced a recurrence of with the chronic phase of their respective MPN subtypes. gastrointestinal bleeding requiring blood transfusions ~3 months The great majority experienced an infection of moderate severity after discharge. (94.4%) and patients were managed at home (n = 38; 30.4%) or in These findings are difficult to compare with the data reported in regular wards (n = 80; 64%), whereas only seven (5.6%) were in need the general population in the post-infection period. A number of of intensive care unit (ICU) admission. COVID-19 directed therapy studies reported varying incidences of 1–5% of venous thromboem- included antiviral agents (n = 43; 35.8%) and in 28 patients (23.7%) bolism in patients after discharge, depending on the underlying corticosteroids. High C-reactive protein (CRP), neutrophils on disease, comorbidity, and concomitant antithrombotic prophylaxis lymphocytes (N/L) ratio levels and D-Dimer increase marked the [7–9]. Clearly, one factor that may explain some of these differences is Received: 19 May 2021 Revised: 3 June 2021 Accepted: 4 June 2021 Correspondence 2 Table 1. Main characteristics of patients with major outcomes at the 6-month follow-up after COVID-19 recovery. THROMBOSIS (N = 5) Fatal event MPN Age COVID-19 acute phase disposition Cytoreduction Anticoagulation Intestinal ischemia Yes MF 71.7 Regular ward No No Splenic infarction No MF 72.3 Regular ward Ruxolitinib No DVT (legs) + PE No ET 61.5 Regular ward Ruxolitinib No Acute myocardial No PV 80.6 Regular ward Hydroxyurea No infarction Pheripheral arterial No MF 75.4 Regular ward Ruxolitinib Yes thrombosis MALIGNANCY (N = 5) Fatal event MPN Age COVID-19 acute phase disposition Cytoreduction MPN disease duration AML Yes MF 49.3 ICU Hydroxyurea 5.9 years AML No ET 78.3 Regular ward Hydroxyurea 6.0 years AML No Pre- 82.1 Regular ward Hydroxyurea 3.8 years PMF Non-Hodgkin lymphoma No ET 60.0 Regular ward Hydroxyurea 8.6 years Progression of Parotid Yes MF 77.3 Regular ward Ruxolitinib 21.7 years Carcinoma DEATH CAUSES (N = 8) Fatal event MPN Age COVID-19 acute phase disposition Cytoreduction MPN disease duration AML – MF 49.3 ICU Hydroxyurea 5.9 years Progression of solid – MF 77.3 Regular ward Ruxolitinib 21.7 years cancer (parotid) 1234567890();,: Suspected lung cancer – MF 80.9 Regular ward unk 10.9 years Multi Organ Failure – ET 85.7 Regular ward Hydroxyurea 5.8 years Thrombosis – MF 71.7 Regular ward No 10.2 years Heart failure – MF 82.4 Home Unknown 24.7 years Heart failure – Pre- 88.7 Home No 8.8 years PMF Unknown – ET 87.0 Regular ward Unknown 0.8 years A B 84% 82% C D 91% 66% Fig. 1 Major outcomes at 6-months follow-up after COVID-19 recovery. Kaplan–Meier survival estimates from COVID-19 recovery of (A) Thrombosis-free, (B) Malignancy-free, (C) Overall survival and (D) Event-free survival. Blood Cancer Journal (2021)11:115 Correspondence 3 ✉ the observation time after infection. In our cases with MPN, no event Tiziano Barbui 1 , Alessandra Iurlo 2, Arianna Masciulli1, was recorded in the first 5 months but, instead, they occurred later, Alessandra Carobbio 1, Arianna Ghirardi1, Giuseppe Rossi3, during the last period of our observation. Notably, our patients were Claire Harrison4, Alberto Alvarez-Larran5, Elena Maria Elli6, not on LMWH prophylaxis during this time, which could possibly have Jean-Jaques Kiladjian7, Mercedes Gasior Kabat8, reduced these vascular complications [10]. Alberto Marin Sanchez9, Francesca Palandri 10, Marcio Miguel Andrade-Campos11, Alessandro Maria Vannucchi12, Malignancies Gonzalo Carreno-Tarragona 13, Petros Papadopoulos14, Acute myeloid leukemia. AML was diagnosed in 3 patients by Keina Quiroz Cervantes 15, Maria Angeles Foncillas 16, morphology, immunophenotyping, cytogenetics and genetics Maria Laura Fox17, Miguel Sagues Serrano18, Elisa Rumi 19, including next generation sequencing (NGS) (Table S2). Santiago Osorio20, Giulia Benevolo21, Andrea Patriarca 22, Patient #1, with PMF CALR-mutated, upon progression showed Begona Navas Elorza23, Valentin Garcia-Gutierrez24, numerous recurrent karyotype abnormalities, and the presence of Elena Magro Mazo25, Francesca Lunghi26, multiple genetic lesions typically associated with progression in Massimiliano Bonifacio 27, Valerio De Stefano 28, AML was documented. Juan Carlos Hernandez-Boluda 29, Emma Lopez Abadia30, Patient #2, with ET JAK2V617F (variant allele frequency [VAF] Anna Angona31, Blanca Xicoy Cirici32, Marco Ruggeri33, 31%), upon progression to AML showed a karyotype characterized Steffen Koschmieder 34, Marta Anna Sobas35, by the presence of an additional marker, and genetic lesions Beatriz Cuevas 36, Daniele Cattaneo2, Rosa Daffini3, associated with AML evolution were revealed by NGS. Marta Bellini37, Natalia Curto-Garcia4, Marta Garrote5, Patient #3, during chronic phase of pre-PMF, in addition to the Fabrizio Cavalca6, Lina Benajiba7, Beatriz Bellosillo11, MPL mutation (VAF 1%) also showed the presence of high-risk Paola Guglielmelli 12, Oscar Borsani 19, Silvia Betti28, genetic lesions [11]. On progression, a complex karyotype was Silvia Salmoiraghi1,37 and Alessandro Rambaldi 37,38 1 found and the molecular profile documented additional genetic FROM Research Foundation, Papa Giovanni XXIII Hospital, Bergamo, lesions of TP53 (VAF 91%) and RUNX1 (VAF 44%). Italy. 2Hematology Division, Foundation IRCCS Ca’ Granda Ospedale While it is conceivable that the COVID-19 hyperinflammatory Maggiore Policlinico, Milan, Italy. 3Spedali Civili, Brescia, Italy. 4Guy’s state associated with the acute phase of the infection and and St. Thomas’ NHS Foundation Trust, London, UK. 5Hospital Clinic persisting even after recovery could have accelerated disease de Barcelona, Barcelona, Spain. 6Hematology Division and Bone progression in patient #3, the molecular profile of the other two Marrow Transplant Unit. San Gerardo Hospital, ASST Monza, Monza, patients did not suggest such rapid progression to AML. Italy. 7Hospital Saint-Louis, Paris, France. 8Hospital Universitario la Paz, Madrid, Spain. 9Hospital General Universitario de Albacete, Large B-cell Non-Hodgkin lymphoma. Large B-cell non-Hodgkin Albacete, Spain. 10IRCCS Azienda Ospedaliero-Universitaria di lymphoma was diagnosed in a single case; the tumor developed Bologna, Bologna, Italy. 11Hospital del Mar, Barcelona, Spain. 12 predominantly in the brain and patient is currently alive on Center Research and Innovation of Myeloproliferative Neoplasms chemotherapy. (CRIMM), Department of Experimental and Clinical Medicine, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Parotid cancer. The patient had a rapid evolution post-COVID-19, Italy. 13Hospital Universitario 12 de Octubre, Madrid, Spain. 14 whereas it was stable before. The tumor showed an unexpected Hospital Clinico San Carlos, Madrid, Spain. 15Hospital Universitario aggressiveness leading to death of the patient. de Mostoles, Madrid, Spain. 16Hospital Universitario Infanta Leonor, These five malignant events were diagnosed as early as the Madrid, Spain. 17Department of Hematology, Vall d’Hebron Institute second post-COVID-19 month and the probability of their of Oncology (VHIO), Vall d’Hebron Hospital Universitari, Vall d’Hebron occurrence was projected to 20% after 8 months. To our Barcelona Hospital Campus, C/ Natzaret, 115-117, 08035 Barcelona, knowledge, the onset of neoplastic events in the immediate Spain. 18ICO L’Hospitalet-Hospital Moises Broggi, Sant Joan Despì, post-COVID-19 period in patients with MPN has not been reported Barcelona, Spain. 19Department of Molecular Medicine, University of so far. Given the low number of events, we were unable to Pavia, Pavia, Italy. 20H30,ospital Gregorio Maranon, Madrid, Spain. 21 investigate any risk factors. We can speculate that both MPN and AOU Città della Salute e della Scienza di Torino, Torino, Italy. 22AOU COVID-19 share overlapping inflammatory mechanisms that may Maggiore della Carità, Novara, Italy. 23Hospital Moncloa, Madrid, have favored the disease progression of malignant subclones Spain. 24Hospital Ramon y Cajal, IRYCIS, Madrid, Spain. 25Hospital already present in the chronic phase of MPN. Universitario Principe de Asturias, Alcalà de Henares, Madrid, Spain. 26 IRCCS Ospedale San Raffaele, Milano, Italy. 27Ospedale Policlinico Mortality “G.B. Rossi”, Borgo Roma, Verona, Italy. 28Fondazione Policlinico “A. Deaths occurred in eight patients after 9 months and the causes Gemelli” IRCCS, Rome, Italy. 29Hospital Clinico Universitario, INCLIVA, are listed in Table 1. Kaplan–Meier curve indicated that probability Valencia, Spain. 30Hospital General de Elche, Elche (Alicante), of death was 9% (Fig. 1C). Alicante, Spain. 31ICO Girona Hospital Josep Trueta, Girona, Spain. 32 Event-free survival after 9 months, including freedom from Hospital Germans Trias i Pujol, Badalona (Barcelona), Barcelona, thrombosis, malignancies and death, was 66% in the 125 surviving Spain. 33Ospedale San Bortolo, Vicenza, Italy. 34Department of patients, who were followed-up for a median of 6 months post- Hematology, Oncology, Hemostaseology, and Stem Cell COVID-19 recovery (Fig. 1D). Transplantation, Faculty of Medicine, RWTH Aachen University, This multicenter European study, although with a relatively Aachen, Germany. 35Department of Hematology, Blood Neoplasms small number of patients, provides a descriptive analysis of MPN and Bone Marrow Transplantation, Wroclaw Medical University, patients who survived after COVID-19. We here report a diversity Wrocław, Poland. 36Hospital Universitario de Burgos, Burgos, Spain. 37 of complications that further increase mortality and morbidity of ASST Papa Giovanni XXIII, Bergamo, Italy. 38Università degli Studi di MPN patients in the post-COVID-19 period. Indeed, 40% of these Milano, Milano, Italy. ✉email: tbarbui@fondazionefrom.it patients, when followed-up over 6 months after the acute COVID- 19 illness subsided, experienced both fatal and non-fatal events. Our research indicates that the health consequences of COVID- REFERENCES 19 extend far beyond acute infection and suggest larger, multi- 1. Barbui T, Vannucchi AM, Alvarez-Larran A, Iurlo A, Masciulli A, Carobbio A, center analyses to augment and expand our observations. These et al. High mortality rate in COVID-19 patients with myeloproliferative signals should induce careful surveillance in all patients with MPN neoplasms after abrupt withdrawal of ruxolitinib. 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