الفهرس 
ACKNOWLEDGEMENTOnly 14 pages are availabe for public view
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Abstract
Severe aplastic anemia is a life-threatening disorder, characterized by failure of the bone marrow which is manifested by pancytopenia and hypocellularity of bone marrow. The pathogenesis of AA is multifactorial and it involves an abnormal hematopoietic microenvironment, hematopoietic stem cell/progenitor cell deficiencies, immunity disorder, and mutation in genes controlling hematopoiesis. Any of these factors causes primary defects in or damage to the stem cell or the marrow microenvironment. There is a clinical challenge to distinguish between acquired and inherited disease. Inherited causes of aplastic anemia are responsible for at least 20- 25% of children with this condition. Acquired causes of aplastic anemia form 80% of cases and include Idiopathic (> 80%), Post-infectious 15%, and Drug-induced and toxins (4%). All patients should be screened to rule out hypoplastic myelodyslasia /leukemia, congenital marrow failure, infections, and Paroxysmal Nocturnal Haemoglobinuria. Immunosuppressive therapy is a well-established alternative treatment for patients with SAA when human leukocyte antigen-matched familial donors are unavailable. This is usually through co-administration of anti-thymocyte globulin and CsA. However, relapse, treatment failure and clonal evolution remain concerns. E-PAG is a thrombopoietin receptor agonist that has proven effective in adults with AA when combined with IST. E-PAG is well-tolerated, and produces improved response rates, recovery of blood cell counts, and restoration of trilineage haematopoiesis, even after drug discontinuation. Recently E-PAG in combination with IST is approved by FDA for children aged ≥2 years as front-line treatment for SAA. The purpose of this study was to compare the efficacy and safety of immunosuppressive monotherapy with CsA with that of combined E-PAGand CsA treatment in children with SAA. This was a prospective clinical trial with a patient sample of 20 children diagnosed with SAA. One of the groups was treated with CsA monotherapy. The other group was treated with combined E-PAG + CsA. All patients were evaluated for hematological response, complete response, and partial response at 3, 6, and 12 months. We also measured overall response rates, overall survival rates, and treatment safety. The overall response rate for the E-PAG patients was 40% after three months of therapy. At six months, this had increased to 80%, and the percentage of patients showing a complete response (40%) was significantly higher than in the CsA group (p = 0.006). After a year of regular treatment, the complete response rate for the E-PAG regimen had increased to 60% and the overall response rate to 90%, compared to a rate of 20% in the CsA group (p = 0.01). The survival rate at 12 months was 100% in the E-PAG group compared to 80% in the CsA cohort. At 24 months, the survival rate in the E-PAG group was 90%, with relapse reported in one patient. In order to evaluate the safety and tolerability of E-PAG, the present study showed that the main adverse effect of E-PAG was slight to moderately elevated bilirubin level which was temporary and controllable, accounting for about 30% (3/10) of patients. The second common side effect was transient transaminemia, which subsided after dose reduction and was recorded in one patient (10%) in our study. In summary, CsA + E-PAG as first-line treatment for SAA reached an OR rate of 80% after 6 months with a decreased need for transfusion. Our findings suggest that E-PAG is safe and effective in children with SAA. It also has good compliance and controllable side effects. The combination of E-PAG with IST may help patients to earn the time for allogenic HSCT or may allow the omittance of HSCT altogether. Combined cyclosporine + eltrombopag was found to be an effective, well- tolerated, and safe alternative treatment for pediatric severe aplastic anemia. The small size of our cohorts limits the power to detect differences in outcomes. Large randomized trials are warranted the validation efficacy and dosing of E-PAG in different age groups and various degrees of disease severity. Randomized trials are now needed to evaluate the long-term response rate and toxicities of Eltrombopag-containing IST regimens compared to either MSD or alternative donor allogeneic HSCT as first line treatment for pediatric AA patients. Because E-PAG is a thrombopoietic growth factor, there is a potentially increased risk of malignant clonal evolution. So the factors that may affect the therapeutic efficacy of E-PAG and the mechanism of clonal evolution induced by E-PAG were not determined. Further studies are needed to address these issues. More studies are needed to establish protocols in pediatrics for the use of Eltrombopag. Effort should be done to support the availability of E-PAG in Assiut University Children Hospital for the treatment of severe aplastic anemia