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EBMT 2020 Annual Meeting - Haematological therapies at the crossroads of the COVID-19 pandemic

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Special Session - Tuesday 1 September, 16:00-17:00H, Auditorium 1

One of our final sessions this year will look at the direct role that haematological therapies and treatments are having on the successful management of COVID-19, including endothelial dysfunction in COVID-19 and its management, mesenchymal stromal cells, convalescent donor plasma and monoclonal antibodies.

The session will be opened by Professor Jose M. Moraleda, Head of the Hematology and Cell Therapy Department at University Hospital Virgen de la Arrixaca and based at the University of Murcia, Spain. He will explain how endothelial cells (ECs) play a key role in the pathogenesis of ARDS and multi-organ failure in COVID-19.

“Infection with SARS-CoV-2 through ACE-2 receptors provokes endotheliitis, perivascular inflammation, and activation of the kallikrein-bradykinin pathway and complement system which in turn induces vascular leakage, recruitment of neutrophils and immune activated cells, oxidative stress and cytokine release,” says Professor Moraleda.

This pathological loop leads to further endothelial damage and subendothelial exposure, with secretion of Von Willebrand factor, P-selectin, and activation of platelets and coagulation pathway, leading to thrombosis, disseminated intravascular coagulation, ischemia, multiorgan failure and death. EC dysfunction and overexpression of leukocyte adhesion molecules and heparinase promote the leakage of fluids and activated leukocytes to the alveolar space, lymphocytopenia and an uncontrolled immune response that contribute to ARDS in COVID-19.

This hypothesis has been substantiated by pathological findings showing diffuse alveolar damage, severe endothelial damage associated with intracellular SARS-CoV-2 virus, disruption of the EC membrane barrier, and thrombosis in small and large vessels in multiple organs. Professor Moraleda concludes: “These findings provide scientific support for therapeutic approaches targeting ECs modifying dysfunction and endothelial protection. Treatment strategies with dipiridamol or eculizumab have been proposed. Defibrotide, a mixture of polydeoxyribonucleotides with pleiotropic properties, including anti-thrombotic, profibrinolytic, anti-inflammatory and protective effects on endothelial cells, has also been proposed and randomised clinical trials are underway.”

The second talk will be given by Dr Felipe Prosper of the University of Navarra, Spain, whose presentation will focus on the identification of effective treatments in severe cases of COVID-19 requiring mechanical ventilation and the rationale and the potential of mesenchymal stromal cells (MSC) to treat severe patients.

“The basis for this form of therapy is two-fold,” says Dr Prosper. “First the well described role of hyperinflammation in the development of ARDS in patients with COVID-19 infection, and also the well described role of MSC as an anti-inflammatory treatment.”

He will provide some information about this rationale and will describe the results of his team’s recent study, in which 13 adult COVID-19 patients under invasive mechanical ventilation who had received previous antiviral and/or anti-inflammatory treatments (including steroids, lopinavir/ritonavir, hydroxychloroquine and/or tocilizumab, among others) were treated with allogeneic AT-MSC (Adipose Derived-Mesenchymal Stem Cells).

Ten patients received two doses, with the second dose administered between 2-6 days after the first one. Two patients received a single dose and another patient received 3 doses. Dr Prosper will discuss the outcomes for these patients, 70% of whom showed clinical improvement.

Congress President Professor Rafael Duarte of Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain, will give a presentation on the use of convalescent donor plasma (CP), an inexpensive and easily accessible potential treatment for COVID-19, which has been used in other viral pandemics for more than a century. However, evidence from controlled clinical trials is lacking.

Professor Duarte explains: “We have conducted a multi-center, randomised clinical trial (ConPlas-19) to assess the efficacy and safety of CP used to prevent progression to severe disease or death in patients hospitalised for COVID-19. There are only two prior randomised controlled trials in this field, both halted prematurely, and both have recently reported negative results on the potential benefit of convalescent plasma in patients with advanced forms of COVID-19, including critically-ill patients in ICU.”

“Unlike these trials, ConPlas-19 excluded patients requiring high-flow oxygen devices or mechanical ventilation and targeted a population relatively early after a median of only eight days from symptoms onset. With 81 patients randomised, we found no patients progressing to mechanical ventilation or death among the 38 patients assigned to receive plasma (0%) versus 6 out of 43 patients (14%) progressing in the control arm. Undoubtedly, premature closure with a lower than expected number of patients and events limits our ability to draw definitive general conclusions from this study. Nevertheless, for the first time in a randomised controlled design, our study suggests that convalescent plasma could be superior to standard of care in avoiding progression to mechanical ventilation or death in hospitalised patients with earlier less-severe forms of COVID-19.”

Professor Duarte concludes: “Our data support studying convalescent plasma earlier in the course of the disease in less-severe cases, rather than in critically-ill patients in ICU. We believe that these findings will contribute to clarify the current contentious debate on the use and approval of convalescent plasma in COVID-19.”

Finally, Christian Chabannon of the Institut Paoli-Calmettes in Marseille, and Professor of Medicine in Cell Biology at Aix Marseille Université (AMU), France, will then discuss monoclonal antibodies and other forms of immunotherapy.

“SARS-CoV-2, the virus responsible for COVID-19 does not only affect the respiratory tract, but also many other organs and tissues, including the haematopoietic system. Thus, COVID-19 is s systemic disease and not exclusively a respiratory infection,” explains Professor Chabannon, who is also Chair of the EBMT Cellular Therapy and Immunobiology Working Party.

He will discuss that an interesting aspect of COVID-19 is the exacerbated immune response that significantly contributes to the lethality of the most severe forms of the disease. Since the phenomenon mimics several aspects of the cytokine release syndrome (CRS) seen after therapy with immune effector cells such as CAR T-cells or after haplo-identical transplantation, some agents used to treat CRS were proposed for patients with COVID-19.

During this presentation, Professor Chabannon will review available data that evaluate the use of Anti-IL6/IL6-R or anti- IL1/IL1-R in COVID-19 patients. He will also review other innovative approaches in development that target other aspects of the immune and inflammatory cascades, or that target the interaction of the SARS-CoV-2 virus with its receptor.

He says: “I will conclude with a review of coagulation disorders in patients infected with SARS-CoV-2, and potential strategies to mitigate their consequences. Although the COVID-19 pandemic has rapidly generated a huge amount of data from basic, translational and clinical studies, drawing robust conclusions in terms of clinical utility remains hazardous.”