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Giovanetti, M.; Slavov, S. N.; Fonseca, V.; Wilkinson, E.; Tegally, H.; Patané, J. S. L.; Viala, V. L.; San, J. E.; Rodrigues, E. S.; Vieira Santos, E.; Aburjaile, F.; Xavier, J.; Fritsch, H.; Ribeiro Adelino, T. E.; Pereira, F.; Leal, A.; Campos de Melo Iani, F.; de Carvalho Pereira, G.; Vazquez, C.; Mercedes Estigarribia Sanabria, G.; de Oliveira, E. C.; Demarchi, L.; Croda, J.; Dos Santos Bezerra, R.; Oliveira de Lima, L. P.; Martins, A. J.; Dos Santos Barros, C. R.; Marqueze, E. C.; de Souza Todao Bernardino, J.; Moretti, D. B.; Brassaloti, R. A.; de Lello Rocha Campos Cassano, R.; Drummond Sampaio Corrêa Mariani, P.; Kitajima, J. P.; Santos, B.; Proto-Siqueira, R.; Cantarelli, V. V.; Tosta, S.; Brandão Nardy, V.; Reboredo de Oliveira da Silva, L.; Astete Gómez, M. K.; Lima, J. G.; Ribeiro, A. A.; Guimarães, N. R.; Watanabe, L. T.; Barbosa Da Silva, L.; da Silva Ferreira, R.; MP, F. da Penha, Ortega, M. J.; Gómez de la Fuente, A.; Villalba, S.; Torales, J.; Gamarra, M. L.; Aquino, C.; Martínez Figueredo, G. P.; Fava, W. S.; Motta-Castro, A. R. C.; Venturini, J.; do Vale Leone de Oliveira, S. M.; Cavalheiro Maymone Gonçalves, C.; Debur Rossa, M. D. C.; Becker, G. N.; Presibella, M. M.; Marques, N. Q.; Riediger, I. N.; Raboni, S.; Coelho, G. M.; Cataneo, A. H. D.; Zanluca, C.; Dos Santos, C. N. D.; Assato, P. A.; Allan da Silva da Costa, F.; Poleti, M. D.; Chagas Lesbon, J. C.; Mattos, E. C.; Banho, C. A.; Sacchetto, L.; Moraes, M. M.; Tommasini Grotto, R. M.; Souza-Neto, J. A.; Nogueira, M. L.; Fukumasu, H.; Coutinho, L. L.; Calado, R. T.; Neto, R. M.; Bispo de Filippis, A. M.; Venancio da Cunha, R.; Freitas, C.; Leonel Peterka, C. R.; Rangel Fernandes, C. F.; de Araújo, W. N.; do Carmo Said, R. F.; Almiron, M.; Campelo de Albuquerque, E. Melo C. F.; Lourenço, J.; de Oliveira, T.; Holmes, E. C.; Haddad, R.; Sampaio, S. C.; Elias, M. C.; Kashima, S.; de Alcantara, L. C. J.; Covas, D. T..
PubMed; 2022.
Preprint in English | PubMed | ID: ppcovidwho-332259


Brazil has experienced some of the highest numbers of COVID-19 cases and deaths globally and from May 2021 made Latin America a pandemic epicenter. Although SARS-CoV-2 established sustained transmission in Brazil early in the pandemic, important gaps remain in our understanding of virus transmission dynamics at the national scale. Here, we describe the genomic epidemiology of SARS-CoV-2 using near-full genomes sampled from 27 Brazilian states and a bordering country - Paraguay. We show that the early stage of the pandemic in Brazil was characterised by the co-circulation of multiple viral lineages, linked to multiple importations predominantly from Europe, and subsequently characterized by large local transmission clusters. As the epidemic progressed under an absence of effective restriction measures, there was a local emergence and onward international spread of Variants of Concern (VOC) and Variants Under Monitoring (VUM), including Gamma (P.1) and Zeta (P.2). In addition, we provide a preliminary genomic overview of the epidemic in Paraguay, showing evidence of importation from Brazil. These data reinforce the usefulness and need for the implementation of widespread genomic surveillance in South America as a toolkit for pandemic monitoring that provides a means to follow the real-time spread of emerging SARS-CoV-2 variants with possible implications for public health and immunization strategies.

Blood ; 138:2174, 2021.
Article in English | EMBASE | ID: covidwho-1582375


Background: Severe aplastic anemia (SAA) is a rare bone marrow failure disorder associated with significant morbidity and mortality. SAA is characterized by severe pancytopenia and a hypocellular (<25%) bone marrow. The standard of care treatment is hemopoietic stem cell transplant or immunosuppressive therapy (IST) for patients (pts) who are ineligible for transplant. IST usually comprises an antithymocyte globulin (ATG) derived from horse or rabbit, and cyclosporine A (CsA). Although IST can be an effective treatment, individual intolerance, insufficient response, relapse, and clonal evolution remain significant limitations. The lack of global availability of the more effective horse ATG also leaves many pts with limited treatment options and poorer outcomes. In addition, pts with SAA often require transfusions which can be burdensome and negatively impact their quality of life. Eltrombopag (ETB) is indicated for use in pts with SAA who have had an insufficient response to IST (FDA PI, 2014) or are refractory to IST (EMA SmPC, 2015). More recently in the USA, ETB may also be used in combination with IST as first-line (1L) treatment (FDA PI, 2018). Aims: To assess the efficacy and safety of ETB + CsA (without ATG) as 1L therapy in adult pts with SAA. Methods: SOAR (NCT02998645) is a Phase 2, single-arm, multicenter, open-label study. Treatment-naive pts with SAA received ETB + CsA for 6 months;responders continued CsA therapy for an additional 24 months (later reduced to 18 months). The primary efficacy endpoint was overall response rate (ORR) by 6 months. ORR was defined as the proportion of pts with complete response ([CR] = absolute neutrophil count [ANC] ≥1000/μL AND platelet count ≥100,000/μL AND hemoglobin ≥10 g/dL) plus the proportion of pts with partial response ([PR] = any 2 of the following counts: ANC ≥500/μL;platelet count ≥20,000/μL;automated reticulocyte count ≥60,000/μL, but not sufficient for a CR). CR and PR were confirmed by 2 assessments ≥7 days apart;transfusion restrictions were also applied. For the primary endpoint to be considered ‘clinically meaningful’ at least 17/54 pts treated were required to have a response. Other endpoints included ORR by 3 months, ORR at 6 months (ie, confirmed response at the 6-month visit), and transfusion independence, which was defined as transfusion not being required in a period of ≥28 days for platelet transfusions and ≥56 days for red blood cell (RBC) transfusions. Results: Pts (N=54) had a median (interquartile range [IQR]) age of 55.0 (40.0-67.0) years and 63.0% were male. The majority of pts were White (40.7%) or Asian (40.7%). The median (IQR) duration of exposure to ETB and CsA was 5.7 (2.5-5.8) months and 5.7 (2.4-8.1) months, respectively, and the median (IQR) daily ETB dose was 150.0 (100.0-150.0) mg/day. In the full analysis set, the primary endpoint was met, with 25/54 pts having a CR or PR by 6 months (ORR 46.3%;95% confidence interval [CI], 32.6-60.4%). Of the 25 responders, 2 (3.7%) achieved a CR by 6 months. ORR by 3 months was 40.7% (95% CI, 27.6-55.0%;n=22/54), and ORR at 6 months was 37.0% (95% CI, 24.3-51.3%;n=20/54). 70.4% of all pts qualified for ≥1 period of RBC and/or platelet transfusion independence by 6 months, including all 25 (100%) responders and 13/29 (44.8%) non-responders (Fig. 1). 40.7% of all pts (responders: 68.0%;non-responders: 17.2%) qualified for ≥1 period of RBC transfusion independence (corresponding percentages for platelet transfusion independence were the same as for the combined RBC and/or platelet endpoint). Adverse events (AEs) occurred in 52/54 (96.3%) pts;45 (83.3%) pts experienced treatment-related AEs (TAEs), 23 (42.6%) of whom had a grade ≥3 TAE. The most common all-grade AEs were increased blood bilirubin (40.7%), nausea (29.6%), increased alanine aminotransferase (22.2%), and diarrhea (22.2%). Seven (13.0%) pts discontinued treatment due to grade ≥3 AEs. There were 8 on-treatment deaths (aplastic anemia [n=3];COVID-19, hemorrhage, multi-organ dysfunction syndrom , pyrexia, and thrombosis [all n=1]);no deaths were considered treatment-related. Conclusion: Data from the SOAR study indicate that ETB + CsA may be beneficial for pts with SAA ineligible for transplant who cannot access or tolerate ATG. All responders and almost half of non-responders qualified for ≥1 period of transfusion independence by 6 months, suggestive of a decreased transfusion burden. No new safety signals were identified. [Formula presented] Disclosures: Vallejo: Novartis: Honoraria;Sanofi: Honoraria;Pfizer: Honoraria. Finelli: Takeda: Consultancy;Celgene BMS: Consultancy, Research Funding, Speakers Bureau;Novartis: Consultancy, Speakers Bureau. Calado: Agios: Membership on an entity's Board of Directors or advisory committees;AA&MDS International Foundation: Research Funding;Alexion Brasil: Consultancy;Instituto Butantan: Consultancy;Novartis Brasil: Honoraria;Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees. Peffault De Latour: Novartis: Consultancy, Honoraria, Research Funding;Pfizer: Consultancy, Honoraria, Research Funding;Amgen: Research Funding;Alexion: Consultancy, Honoraria, Research Funding;Apellis Pharmaceuticals Inc: Consultancy, Honoraria;Swedish Orphan Biovitrum AB: Consultancy, Honoraria. Kriemler-Krahn: Novartis: Current Employment. Haenig: Novartis: Current Employment. Maier: Novartis: Current Employment. Scheinberg: Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau;Novartis: Consultancy, Honoraria, Speakers Bureau;BioCryst Pharmaceuticals: Consultancy;Roche: Consultancy;Abbvie: Consultancy. OffLabel Disclosure: In the United States, eltrombopag is a thrombopoietin receptor agonist indicated in combination with standard immunosuppressive therapy (ATG + CsA) for the first-line treatment of adult and pediatric patients aged 2 years and older with severe aplastic anemia (SAA). It is also indicated for the treatment of patients with SAA who have had an insufficient response to immunosuppressive therapy. The SOAR trial aims to assess the efficacy and safety of eltrombopag + CsA (without ATG) as first-line therapy in adult patients with SAA.

Blood ; 138:4972, 2021.
Article in English | EMBASE | ID: covidwho-1582237


COVID-19 is an infectious disease caused by the virus SARS-CoV-2, which was first described at the end of 2019. Since then, it has affected a growing portion of the world's population because of its high transmissibility. Most patients are asymptomatic or present with mild symptoms, but approximately 5-10% of cases can develop more serious manifestations, such as severe acute respiratory syndrome, acute kidney injury, shock, myocardial injury and even death. These features seem to occur more commonly in patients with essential hypertension, diabetes mellitus, obesity and chronic pulmonary disease. However, there are few studies that clarify the natural history of the disease and its broad clinical spectrum owing to the fact that it is a new entity. Since individuals with malignancies tend to present some degree of immunological deficiency and are more prone to opportunistic infections, especially those being treated with immunosuppressive drugs, it is possible that this group has a higher incidence of COVID-19. The current recommendations of oncology specialists advise to postpone treatments and to use less toxic drugs when possible. However, we still do not know how much these measures will affect in cancer mortality. Also, the incidence of COVID-19 in this population remains undetermined. We do not know if infectious symptoms are a good parameter to motivate these therapeutic changes or if there is benefit to test asymptomatic patients. In this context, this research submitted 100 patients with hematological malignancies or solid tumors on chemotherapy at the Ribeirão Preto Medical School of the University of São Paulo's Hospital, asymptomatic for COVID-19, to RT PCR to determine the SARS-CoV-2 infection incidence in this population. Only two patients were diagnosed with COVID-19. Both had gastrointestinal cancer. One of them developed symptoms, but none presented severe manifestations. Both had their treatment postponed initially and reinitiated after the appropriate period of isolation. Hence, we believe that it's reasonable not to test every asymptomatic patient when the resource for that is scarce, prioritizing those at greater risk of infection and those more prone to severe outcomes as long as the appropriate preventive measures are being taken. Disclosures: Calado: Team Telomere, Inc.: Membership on an entity's Board of Directors or advisory committees;Agios: Membership on an entity's Board of Directors or advisory committees;Instituto Butantan: Consultancy;Alexion Brasil: Consultancy;AA&MDS International Foundation: Research Funding;Novartis Brasil: Honoraria.