Eltrombopag & Cyclosporine in Children With Sever Aplastic Anemia

Aplastic anemia is a rare disorder characterized by pancytopenia and a hypo cellular bone marrow.but,It is very serious disease causing morbidity and mortality.

Aplastic anemia can be treated effectively with haematopoietic stem cell transplantation and immunosuppressive drug regimens but haematopoietic stem cell transplantation has limitations due to its cost and many patient are unsuitable. Immunosuppressive drug has a significant number of patients have persistent cytopenias. Currently, the treatment of these patients is regular transfusion, which are expensive, inconvenient, and associated with serious side effects related to iron overload and transfusion.

Eltrombopag is an oral thrombopoietin mimetic that selectively binds at the transmembrane and juxtamembrane domains of the thrombopoietin receptor, at sites distinct from the binding site of thrombopoietin therefore it does not compete for binding with the native molecule. It promoting thrombopoiesis and release of platelets from mature megakaryocytes. Also, promote other hematopoietic stem cell as well as in thrombopoiesis .

Aplastic anemia is a rare disorder characterized by pancytopenia and a hypo cellular bone marrow.This causes a deficiency of all three blood cell types (pancytopenia): red blood cells (anemia), white blood cells (leukopenia), and platelets (thrombocytopenia) . The clinical consequences are anemia, usually with a requirement for frequent red blood cell transfusions, life-threatening bleeding from thrombocytopenia, and infection because of neutropenia. Bacterial and fungal infections are most common and are a significant cause of morbidity and mortality.

The incidence of acquired Aplastic anemia in Europe and North America is around two per million children per year . The incidence is 2-3 times higher in East Asia. There is no significant difference in incidence between males and females .

The pathogenesis of Aplastic anemia is complex and involves an abnormal hematopoietic microenvironment, hematopoietic stem cell/progenitor cell deficiencies and immunity disorders. The etiological basis for marrow failure includes primary defects in or damage to the stem cell or the marrow microenvironment. The distinction between acquired and inherited disease may present a clinical challenge, Congenital or inherited causes of Aplastic anemia are responsible for at least 25% of children with this condition and for perhaps up to 10% of adults. Acquired causes of Aplastic anemia form (80%) of cases, include Idiopathic (\> 80 %), Post-infectious 15% (particularly after hepatitis 9%, Epstein-Barr virus , human immune deficiency virus, parvovirus, and mycobacteria, Drug-induced and toxins (4%).

Definitive and potentially curative therapy with haematopoietic stem cell transplantation However, only a minority (30 %) of patients have a suitable donor. Immunosuppressive therapy with horse or rabbit antithymocyte globulin plus cyclosporine is the most commonly used alternative treatment in about two thirds of cases. Response is associated with a favorable long-term outlook. 30 -40% of patients are refractory to immunosuppressive therapy and remain pancytopenic after therapy. Even patients that respond to immunosuppressive therapies with an improvement in their life-threatening neutropenia sometimes have persistent thrombocytopenia .

Aplastic anemia can be treated effectively with haematopoietic stem cell transplantation and immunosuppressive drug regimens but haematopoietic stem cell transplantation has limitations due to its cost and many patient are unsuitable. Immunosuppressive drug has a significant number of patients have persistent cytopenias. Currently, the treatment of these patients is regular transfusion, which are expensive, inconvenient, and associated with serious side effects related to iron overload and transfusion.

Thrombopoietin is a glycoprotein class 1 hematopoietic cytokine, produced primarily in the liver. It is a critical regulator of hematopoiesis. It acts through the thrombopoietin receptor which is expressed on hematopoietic stem and progenitor cells. Action results in a number of signal transduction events that prevent apoptosis, improve cell viability, promote growth, and possibly increase differentiation.

Eltrombopag is an oral thrombopoietin mimetic that selectively binds at the transmembrane and juxtamembrane domains of the thrombopoietin receptor, at sites distinct from the binding site of thrombopoietin therefore it does not compete for binding with the native molecule. It promoting thrombopoiesis and release of platelets from mature megakaryocytes. Also, promote other hematopoietic stem cell as well as in thrombopoiesis .Eltrombopag became the first oral platelet growth factor to receive Food and Drug Administration approval in 2008. This initial indication was for adult patients with chronic immune thrombocytopenic purpura. In 24 August 2015, this indication was extended to children age 1 to 17 with the same condition. In addition, it has been recently shown to be efficacious in the setting of aplastic anemia with trilineage responses in some patients and many achieving transfusion independence. It has license by the European Medicines Agency for this indication in August 2015. In 2017, the National Institutes of Health made Eltrombopag a standard of care in Aplastic anemia

Eligibility Criteria:
Inclusion Criteria:

Current diagnosis of sever Aplastic anemia

* Diagnosis of sever Aplastic anemia is established if Bone marrow cellularity \<25% or and at least two of the following criteria are met:- (i) absolute neutrophil count less than 0.5 × 109/L, (ii) platelet count less than 20 × 109/L, and (iii) reticulocyte count less than 20 × 109/L
* No, evidence of viral or drug suppression of the marrow, dysplasia, or underproduction anemias secondary to B12, folate, iron or other reversible causes.
* Age equal to 1 years old to 18 years old
* Written informed consent signed by a parent or legal guardian prior to initiation of any study specific procedure.
* Hematopoietic stem cell transplantation is not available or suitable as a treatment option or has been refused by the patient.
* Bone marrow aspirate and biopsy at any time during the 4 weeks prior to first dose of eltrombopag

Exclusion Criteria:

Prior and/or active medical history of:-

* Fanconi anemia (via chromosomal breakage test or growth arrest by flow cytometry). Other known underlying congenital/inherited marrow failure syndromes.
* Symptomatic Paroxysmal Nocturnal Hemoglobinuria
* Other known or suspected underlying primary immunodeficiency
* Any malignancy
* Active infection not responding to appropriate therapy
* Any out of range lab values Creatinine \>2.5 mg/dL× the upper limit of normal, Total bilirubin \>1.5 × the upper limit of normal mg/dL ,Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>2.5 × the upper limit of normal
* Hypersensitivity to eltrombopag or its components
* Moribund status or concurrent hepatic, renal, cardiac, neurologic, pulmonary, infectious, or metabolic disease of such severity that it would preclude the patient's ability to tolerate protocol therapy, or that death within 7-10 days is likely.