Outcomes in Bone Marrow Aplasia.

Aplastic Anemia Idiopathic

Bone marrow aplasia, also known as aplastic anemia (AA) is a potentially fatal bone marrow failure syndrome characterized by a paucity of hematopoietic stem cells (HSCs) and progenitor cells with varying degrees of cytopenia and fatty infiltration of the bone marrow space. Underlying mechanisms include immune-mediated attack, telomere defects, and inherent HSC compartment insufficiency. These events may occur individually or in concert, mostly involving effector T cells Historical treatment has included the use of high-dose chemotherapy and allogeneic stem cell transplantation as well as lymphotoxic immunosuppressive therapy (IST) Thrombopoietin (TPO) regulates platelet production, maturation, and release through binding of c-mpl on megakaryocytes.

Eltrombopag (E-PAG) is an oral synthetic small-molecule, noncompetitive, TPO agonist that initially was approved by the US Food and Drug Administration (FDA) for the treatment of chronic immune thrombocytopenic purpura. Single-agent activity of E-PAG was demonstrated in at least 1 lineage in 40 to 45% of patients with AA that was refractory to IST, leading to its approval by the FDA in this setting (5). Eltrombopag evades cytokines blockade of c-MPL signaling and activates the c-MPL receptor by interacting with the transmembrane receptor domain, resulting in a conformational change without competing with TPO. Regarding AA, it is possible that eltrombopag promotes DNA repair in hematopoietic stem cells and progenitor cells. However, AA may appear to evolve to other hematologic diseases, most notably paroxysmal nocturnal hemoglobinuria and myelodysplastic syndrome, even to acute myeloid leukemia, and about 15% of patients evolve to myelodysplastic syndrome, acute myeloid leukemia or both after immunosuppressive therapy. Therefore, it is unclear but alarming that the use of eltrombopag exacerbates the clone evolution (6). Eltrombopag and cyclosporin was active as front-line treatment of severe aplastic anaemia, with no unexpected safety concerns. This approach might be beneficial where horse-ATG is not available or not tolerated.

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