key: cord-0875201-29zci40v authors: Barbui, Tiziano; Iurlo, Alessandra; Masciulli, Arianna; Carobbio, Alessandra; Ghirardi, Arianna; Carioli, Greta; Sobas, Marta Anna; Elli, Elena Maria; Rumi, Elisa; De Stefano, Valerio; Lunghi, Francesca; Marchetti, Monia; Daffini, Rosa; Gasior Kabat, Mercedes; Cuevas, Beatriz; Fox, Maria Laura; Andrade-Campos, Marcio Miguel; Palandri, Francesca; Guglielmelli, Paola; Benevolo, Giulia; Harrison, Claire; Foncillas, Maria Angeles; Bonifacio, Massimiliano; Alvarez-Larran, Alberto; Kiladjian, Jean-Jacques; Bolaños Calderón, Estefanía; Patriarca, Andrea; Quiroz Cervantes, Keina; Griessammer, Martin; Garcia-Gutierrez, Valentin; Marin Sanchez, Alberto; Magro Mazo, Elena; Ruggeri, Marco; Hernandez-Boluda, Juan Carlos; Osorio, Santiago; Carreno-Tarragona, Gonzalo; Sagues Serrano, Miguel; Kusec, Rajko; Navas Elorza, Begona; Angona, Anna; Xicoy Cirici, Blanca; Lopez Abadia, Emma; Koschmieder, Steffen; Cattaneo, Daniele; Bucelli, Cristina; Cichocka, Edyta; Masternak Kulikowska de Nałęcz, Anna; Cavalca, Fabrizio; Borsani, Oscar; Betti, Silvia; Benajiba, Lina; Bellini, Marta; Curto-Garcia, Natalia; Rambaldi, Alessandro; Vannucchi, Alessandro Maria title: Second versus first wave of COVID-19 in patients with MPN date: 2022-01-21 journal: Leukemia DOI: 10.1038/s41375-022-01507-2 sha: 1f1fa51909867727bbd2b9a63b9d419d9936c2d3 doc_id: 875201 cord_uid: 29zci40v nan illustrates the distribution probability of incidence and density of COVID-19 cases by Kernel method [5] for to the two pandemic periods. During the first wave, a peak was documented from April to May followed by a decline during the summer season, whereas the second wave peaked in November/ December 2020 and did not completely decline until June 2021. The shape of the incidence curve was substantially similar, while the density function of deaths was less pronounced in the second wave. In comparison with the first, patients in the second wave were younger, had with less comorbidities and presented with moderate COVID-19 infection (Table 1) . They were less symptomatic, most were treated at home, intensive respiratory support being required in a limited number of cases, and an elevation of blood inflammatory markers (C-Reactive Protein and Neutrophil to Lymphocyte Ratio) was found in a lower proportion of cases. In regard to COVID-19 and MPN directed therapy, steroids were more frequently prescribed than in the first wave (p = 0.007); conversely, ruxolitinib was discontinued in fewer MF hospitalized patients. Therefore, all of these clinical and laboratory data were consistent with a less severe COVID-19 infection. Survival during the first vs. second wave (69% vs. 91%) at 60 days after COVID-19 diagnosis, was statistically different (p < 0.001) (Fig. 1A) . Among 26 deaths registered during the second wave, 4 (15%) occurred at home, 19 (73%) on the regular word and 3 (12%) in the ICU, and occurred in MF (n = 17, 65%), ET (n = 5, 19%) and PV (n = 4, 15%) (p < 0.001). In a multivariate Cox regression model fitted on the whole cohort and adjusted for the wave to which patients belonged (Fig. 1B) , significant independent risk factors for death were age over 70 years (HR = 5.22, 95% CI 1.80-15.14, p = 0.002), male sex (HR = 1.88, 95% CI 1.13-3.13, p = 0.016), severity of COVID-19 defined by the need for respiratory support (HR = 4.45, 95% CI 1.85-10.70, p = 0.001), and ruxolitinib discontinuation (HR = 2.98, 95% CI 1.29-6.89, p = 0.011). Conversely, continuation of ruxolitinib was not a significant predictor (HR = 1.21, p = 0.566). Compared to the first wave, mortality in patients aged 60-70 was reduced from 35 to 2%. By contrast, deaths in patients over 70 years of age were recorded in 36% and 21% in the first and second wave, respectively. These patients, compared with those <70 years (Supplementary Table 1S) , had more comorbidities, prior history of thrombosis, were more frequently hospitalized and in need of respiratory support. In these patients, deaths occurred in 59%, 23% and 18% of MF, ET and PV, respectively. Therefore, the benefit on survival was documented in patients younger than 70 years and more fit, with a limited degree of inflammation. At 60 days from COVID-19 diagnosis, only 5 incident cases of thrombosis were registered out of 304 patients (1.6%) during the second wave, significantly lower than in the first wave (14 thrombosis on 175 patients, 8.0%), although an antithrombotic treatment was prescribed less frequently (Table 1) . Such findings mirror the less severe clinical presentation noticed in the present case series. However, almost all events (n = 4/5) were venous and we confirmed in multivariate model that most of these events occurred in patients with ET (SHR = 4.4, 95% CI 1.8-10.7, p = 0.001). As in the first wave, we did not find a significant difference in venous thrombosis between cases treated with prophylactic doses of heparin compared to controls. Two-hundred twenty-three patients survived after the acute phase of the second wave of COVID-19 and were followed up for a median of 141 days (IQR: 94-173). Two of them died, 4 were diagnosed with deep vein thrombosis of the legs with or without pulmonary embolism and one with arterial cerebral thrombosis, and 4 developed bleeding, accounting together for an event-free survival (EFS) of 93.82%, a figure significantly different from the first wave (EFS: 65.70%, p = 0.0312). COMMENT This is the largest analysis of MPN patients who contracted COVID-19 in the 12 months subsequent to the first wave of the coronavirus pandemic, which was characterized by conditions of exceptional lethality. Patients of the second wave presented, compared to those of the first, with a less severe disease, including a lower degree of inflammation, leading to hospitalization in a Correspondence smaller percentage of cases. Overall, the mortality rate was significantly lower, likely due to early COVID-19 diagnosis, facilitated by the greater availability of swabs than in the first wave, more efficient management of infected patients, better prepared health systems and preferential protection of older and higher-risk MPN vulnerable subjects. However, patients over 70 years still presented with an excess of mortality, particularly when associated with comorbidities and an MF phenotype. Unfortunately, no data are available so far in our series to support a role of vaccinations. The high thrombosis rate in patients with ET was confirmed, suggesting that in this MPN phenotype regimens of antithrombotic prophylaxis in addition to heparin should be explored. Also in the second wave, but to a lesser extent than in the first, the health consequences of COVID-19 protracted far beyond acute infection, suggesting careful and permanent surveillance of patients with MPN who have survived the acute phase of SARS-CoV-2 virus infection. Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, C/ Natzaret Department of Experimental and Clinical Medicine 20 Hospital Clinic de Barcelona 25 Oncology, Hemostaseology and Palliative Care 32 Hospital Universitario 12 de Octubre, Madrid, Spain. 33 ICO L'Hospitalet-Hospital Moises Broggi Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study Cellular and humoral immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine in patients with hematologic malignancies. Blood Adv. 2021 Outcomes of patients with hematologic malignancies and COVID-19: a report from the ASH Research Collaborative Data Hub High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal of ruxolitinib Density estimation The study was supported by a research grant by the COVID "3 × 1 project", BREMBO S.p. A., Bergamo, Italy (TB) and by AIRC 5 × 1000 call "Metastatic disease: the key unmet need in oncology" to MYNERVA project, #21267 (MYeloid NEoplasms Research Venture AIRC). A detailed description of the MYNERVA project is available at https://progettomynerva.it (AMV, PG). The study was also supported by HARMONY PLUS, which is funded through the Innovative Medicines Initiative (IMI), Europe's largest public-private initiative aiming to speed up the development of better and safer medicines for patients. The HARMONY Alliance has received funding from IMI 2 Joint Undertaking and is listed under grant agreement No. 945406. This Joint Undertaking receives support from the European Union's Horizon 2020 Research and Innovation Programme and the European Federation of Pharmaceutical Industries and Associations (EFPIA). IMI supports collaborative research projects and builds networks of industrial and academic experts in order to boost pharmaceutical innovation in Europe. TB conceived and designed the study, supervised the analysis and wrote the paper. AMV, VDS, AR revised the study and contributed to manuscript writing. AM directed the project. AC planned and performed statistical analyses. AG, GC contributed to dataset preparation. AI, MAS, EME, ER The authors declare no competing interests. Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41375-022-01507-2.Correspondence and requests for materials should be addressed to Tiziano Barbui. Reprints and permission information is available at http://www.nature.com/ reprintsPublisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.