Treatment of refractory or relapsed acquired aplastic anemia: review of established and experimental approaches

Abstract

In a substantial number of patients with aplastic anemia (AA), immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and cyclosporine A (CSA) leads to long-lasting remissions and is thus regarded as standard therapy. However, no consensus exists on how to treat refractory or relapsed AA, especially when no related stem cell donor is available. For selected patients, matched unrelated donor stem cell transplant (MUDSCT) is an option. In addition, umbilical cord blood and haploidentical donors have been considered as an alternative source of stem cells. Patients without a suitable donor may benefit from a second cycle of ATG and CSA. Alternatives are alemtuzumab and high dose cyclophosphamide, both of which induce remission in more than 50% of patients with relapsed AA. Further experimental drugs are androgens, hematopoietic growth factors (interleukins IL-3, IL-6, and IL-11 and stem cell factor [SCF]), and the tumor necrosis factor (TNF)-targeting agent etanercept. Clinical trials with these agents are ongoing and will explore long-term outcomes and potential beneficial effects of drug combinations.

Etanercept-Associated Transient Bone Marrow Aplasia: A Review of the Literature and Pathogenetic Mechanisms

“…On one hand, TNFα (and interferon γ) are overexpressed in the BM of patients with acquired aplastic anemia and can be involved in BM stem cell apoptosis and suppression of erythropoiesis [19, 20]. Thus, treatment with TNFα antagonists can be a useful approach to the treatment of refractory aplastic anemia [21–23]. On the other hand, under different conditions, TNFα interacting with other cytokines directly enhances the clonal growth of BM progenitors and suppresses hematopoietic stem cell apoptosis [17, 24].…”

Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries

“…Androgens appeared effective in some patients 19 . Growth factors, introduced in the 1980s, were tested in SAA but with limited activity 86,87 …”

Activity of eltrombopag in severe aplastic anemia

“…Unfortunately, efforts to stimulate this primitive compartment with growth factors, such as erythropoietin, granulocyte colonystimulating factor (G-CSF), stem cell factor, and interleukins among others, have been to no avail. [23][24][25] Approximately 10 years ago, agonists of the thrombopoietin (Tpo) receptor, which stimulated megakaryocytes to produce platelets, were approved for immune thrombocytopenia. These agents led to platelet count recovery in the majority of refractory cases of immune thrombocytopenia.…”