Simona Pagliuca, MD | Aplastic Anemia and MDS International Foundation

Simona Pagliuca, MD

Impact of Eltrombopag treatment in combination with immunosuppression on immune derangements of aplastic anemia: (translational) research from the randomized EBMT race study
Original Research Center: 
The Health Establishment Hospital Saint-Louis – Lariboisiere
Pubmed Author Name: 
Pagliuca S

Aplastic anaemia, is a rare disease in which the bone marrow and the hematopoietic stem cells that reside there are damaged. This causes a deficiency of all three blood cell types (pancytopenia): red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia). If untreated, this disease has a high risk of death. Research of last decades characterize aplastic anemia as an immune disorder in which aberrant immune effector are directed against hematopoietic stem cells. That is the reason why main treatment approaches of this disease concern allogeneic hematopoietic stem cell transplantation and immunosuppressive therapy based on two drugs: "cyclosporine" and "anti-thymoglobuline". Unfortunately not all patients are eligible to transplantation and standard therapies have a risk of recurrence of this disease.

In 2014 the experimental study named RACE has been approved to try to improve the results of standard therapy, by association with an other drug, called "eltrombopag". Researchers want to answer a simple question: Which is the best treatment for patients with a diagnosis of aplastic anemia? cyclosporine and anti-thymoglobuline or cyclosporine, anti-thymoglobuline + eltrombopag? So patients accepting to participate to this study will be assigned by chance to one of the two groups and treated accordingly.

However this study is not merely “clinic”: it includes also a research laboratory part concerning a biological intention: to study the immune defect existing in patients with aplastic anemia and to define the biological response after each treatment. Our work is centred on this part of the study. We will perform the prefixed objectives by analysing blood and marrow samples of patients participating to the study and giving their consensus to the research. We will expect that the normal immunological background seeing in a healthy subject could be entirely devastated in an aplastic anemia patient, and that the peculiar immunological profile of those patients could predict the response to the treatment. We are also confident that both standard immunosuppressive treatment and experimental eltrombopag-associated treatment could regulate the immunological dysfunction in different ways. In this context experimental treatment is expected to give a more promising immune-modulation, restoring damaged hematopoietic stem cells in a shorter laps.

First Year Report: 

Aplastic anaemia is a rare disease characterized by the damage of the bone marrow and of the hematopoietic stem cells that reside there. This damage causes a deficiency of all three blood cell lineages (pancytopenia): red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia). If untreated, this disease has a high risk of severe complications and even death. The destruction of hematopoietic stem cells in aplastic anemia is caused by some aberration of immune system. Possibilities of treatments are limited to two options: allogeneic hematopoietic stem cell transplantation (for a young patient with a suitable donor) or immunosuppressive treatment for patients not eligible to transplant. Standard immunosuppression exploits two main agents: cyclosporine A and anti-thymoglobuline.

In 2014 the experimental trial named RACE has been started in Europe trying to improve the results of standard immunosuppression, combining the standard platform of two-drug immunosuppression (cyclosporine and anti-thymoglobuline) with a third non-immunosuppressive agent, called "eltrombopag". So patients accepting to participate to this study are assigned by chance to one of two groups of treatment: standard therapy: cyclosporine and anti-thymoglobuline  or experimental therapy: cyclosporine, anti-thymoglobuline + eltrombopag.

Our research concerns the biological part arising from this clinical trial: we are trying to characterize the immunological aberration in patients with aplastic anemia and possible differences on immunological response arising from these the two different treatments. For this purpose we exploit several laboratory techniques, including cell surface analysis, DNA analysis and measure of inflammatory products.

With the first samples of patients enrolled in the RACE study, we performed the first part of our proposal, which included analysis of cell surface with techniques of standard and deep flow cytometry. At the moment, preliminary data are available, since initial experiments  mostly served to establish the experimental model on samples from the limited number of patients initially enrolled in the study. Now that the experimental design has been validated, we assume that data will be collected more quickly, and that by the end of clinical study, in 2019, final results will be available. Our study promise to provide pivotal information in the field of bone marrow failure research, because the comparison between samples collected from the two arms represents an unique opportunity to investigate the possible effect of eltrombopag (an agent which is classically considered non-immunosuppressive) on the immune derangements underlying aplastic anemia. Hopefully, our data will lead to the understanding of the deep mechanism of action of an agent that, based on the clinical data available from a study from NIH, promises to change the standard of care for patients suffering from aplastic anemia.