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
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
20
An oral thrombopoietin receptor agonist
Facility of medicine
Asyut, Egypt
changes in Platelet count (at Baseline, 26 Weeks and up to 52 week)
increase of platelet count from baseline by 20,000/microliter or more (in the absence of platelet transfusion), or independence from platelet transfusions for a minimum of 8 weeks in patients who were previously transfusion-dependent.
Time frame: 52 week
Changes in hemoglobin count (at Baseline, 26 Weeks and up to 52 week)
measuring the following: Increase from baseline by 1.5 gram g/dL or more when the baseline hemoglobin level is \<8.5 g/dL and no red blood cell (RBC) transfusion at baseline. A decrease of at least four units in RBC transfusions in the post-treatment 8-week period compared to the pre-treatment 8-week period..
Time frame: 52 week
changes in absolute Neutrophil count (at Baseline, 26 Weeks and up to 52 week)
measuring the increase in the absolute neutrophil count of more than 500 per cubic millimeter
Time frame: 52 week
complete response (CR) - 12 month
CR defined as all three parameters meet the following criteria : Hb ≥100 g/l, platelet count ≥100 × 109/L, and ANC ≥1 × 109/L. Additionally, patients had to be transfusion and growth factor independent
Time frame: 52 weeks
Partial response (PR) - 12 month
PR was defined as blood count no longer meeting Camitta criteria for severs aplastic anemia in case of sever aplastic anemia (SAA): Absolute neutrophil count (ANC) \>500/μL Platelet count \>20 000/μL Reticulocyte count \>20 000/μL
Time frame: 52 weeks
The hematological responses
Duration of hematologic response Time from the date of the start of response to the date of relapse defined as again meeting criteria for severe or moderate aplastic anemia Duration of platelet and blood transfusion independence Transfusion independency is defined when blood and platelet transfusions are not required in a consecutive 8-week period. Transfusion dependency will be defined as at least 2 units of red blood cells or five units of random platelets or equivalent apheresis per month for a period of 8 weeks. The duration of platelet and blood transfusion independence will be evaluated separately.
Time frame: up to to 52 week
The toxicity
Number of participants with adverse events Measure toxicity, using CTCAE associated with assessment of eltrombopag use, dose, and tolerability in patients with sever to very severe aplastic anemia
Time frame: Up to 30 days after last dose of study treatment
complete response (CR)- 6 month
CR defined as all three parameters meet the following criteria : Hb ≥100 g/l, platelet count ≥100 × 109/L, and ANC ≥1 × 109/L. Additionally, patients had to be transfusion and growth factor independent
Time frame: 26 week
Partial response (PR) - 6 month
PR was defined as blood count no longer meeting Camitta criteria for severs aplastic anemia in case of SAA. Absolute neutrophil count (ANC) \>500/μL Platelet count \>20 000/μL Reticulocyte count \>20 000/μL
Time frame: 26 week
Overall hematologic response (CR + PR) rate - 6 month
Overall hematologic response = patients with complete response + patients with partial response . Partial response is defined as blood count no longer meeting Camitta criteria for severs aplastic anemia in case of SAA ANC \>500/μL Platelet count \>20 000/μL Reticulocyte count \>20 000/μL Complete response is defined as all three parameters meet the following criteria: ANC \> 1 000/μL Platelet count \>100 000/μL Hemoglobin \>10 g/L
Time frame: 26 week
Overall hematologic response (CR + PR) rate - 12 month
Overall hematologic response = patients with complete response + patients with partial response. Partial response is defined as blood count no longer meeting Camitta criteria for severs aplastic anemia in case of SAA ANC \>500/μL Platelet count \>20 000/μL Reticulocyte count \>20 000/μL Complete response is defined as all three parameters meet the following criteria: ANC \> 1 000/μL Platelet count \>100 000/μL Hemoglobin \>10 g/L
Time frame: 52 week
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