Acquired aplastic anemia is an immune-mediated bone marrow failure in most cases. Its treatment is based on immunosuppressive strategies, whether via allogeneic bone marrow transplantation (BMT), providing immunosuppression (through high dose chemotherapy) plus healthy hematopoietic progenitor cells; or with lymphotoxic drugs, such as ATG and cyclosporine.
Whereas BMT yields excellent results, with survival rates as high as 70-90%, immunosuppressive therapy (IST) fails to improve hematologic counts in up to one-third of cases, even when potent drugs are added to standard horse ATG plus cyclosporine. It is not clear whether refractoriness represents failure of IST to completely ablate auto-reactive immune cells (one third of patients who fail horse ATG still respond to alternative IST), or a stem cell depletion in the absence of active immune attack. The latter hypothesis has been supported by recent eltrombopag studies.
Eltrombopag is a synthetic drug that mimics thrombopoietin (TPO) effect, a hematopoietic growth factor that was initially believed to act stimulating megakariocytes to produce platelets. However, hematopoietic stem and progenitor cells, the targets of immune attack in aplastic anemia, also express TPO receptor (called c-mpl), and can be stimulated by eltrombopag, rendering this drug a potential therapy in case of stem cell depletion in refractory aplastic anemia.
Eltrombopag was used for 43 aplastic anemia patients who were refractory to IST at National Institutes of Health (NIH), improving blood counts in 40% of patients; seven patients eventually showed trilineage responses. An increase in bone marrow cellularity was seen in several responders. Six patients who achieved trilineage responses had eltrombopag withdrawn and all maintained stable blood counts and normal marrow cellularity after a median of 24 months off drug.
Considering these results, eltrombopag is currently being incorporated to standard IST as first-line treatment in several clinical trials in an attempt to improve and accelerate responses. This may prevent both short-term complications of aplastic anemia, such as infections and bleeding, and clonal evolution (progression to MDS or AML), since robust hematologic response is associated with decreased risk of evolution. However, in the study conducted at NIH 19% of patients developed new cytogenetic abnormalities, quite similar to the observed in other studies in refractory patients, but a theoretical concern that growth factors like eltrombopag could cause destabilization of the genome leading to emergence of clonal evolution still remains and warrant further elucidation in ongoing clinical trials with IST-naïve patients.
In conclusion, eltrombopag is a promising drug in the treatment of aplastic anemia. The US Food and Drug Agency has recently approved eltrombopag for aplastic anemia patients refractory to IST but its role in first-line therapy still remains to be established.