The hallmark of severe aplastic anemia is an autoimmune attack against the bone marrow, resulting in a paucity of hematopoietic stem and progenitor cells.1
We administered eltrombopag, a synthetic small-molecule thrombopoietin agonist, in patients with refractory aplastic anemia to determine whether pharmacologic stimulation of the c-MPL receptor can improve hematopoiesis. We observed clinically significant responses in platelet, erythroid, and neutrophil lineages in 11 of 25 patients at 12 weeks, with normalization of bone marrow cellularity and trilineage hematopoiesis in patients with a response who continued to receive eltrombopag. These findings, which suggest that eltrombopag stimulates hematopoiesis at the level of primitive hematopoietic cells, are consistent with the results of previous laboratory studies.7–10
Previous studies of cytokines in aplastic anemia have not shown a benefit, probably because hematopoietic stem and progenitor cells do not have receptors for erythropoietin or G-CSF.21
Thrombopoietin levels are significantly elevated in patients with aplastic anemia, in contrast to thrombopoietin levels in patients with immune thrombocytopenic purpura, which are at the high end of the normal range.20
Eltrombopag does not compete with thrombopoietin for binding to c-MPL, since it binds in the membrane-spanning region outside the ligand-binding pocket of c-MPL, and it activates signaling through JAK-STAT (Janus-associated kinase–signal transducers and activators of transcription) and MAPK (mitogen-activated protein kinase) pathways.22
Eltrombopag may stimulate hematopoiesis by non-competitive activation of c-MPL, despite elevated thrombopoietin levels, and it may activate signaling in a way that is distinct from that of thrombopoietin.
All 25 patients in our study who received eltrombopag were dependent on platelet transfusions at enrollment. In 9 patients, treatment with eltrombopag eliminated the need for platelet transfusions. The increases in platelet counts in these patients occurred over several months, whereas the response to eltrombopag in patients with immune thrombocytopenic purpura is more rapid, with an increase in platelet counts within 2 weeks after the start of treatment.23
The kinetics of the delayed response in aplastic anemia may reflect inherently slow cycling of hematopoietic stem and progenitor cells, as compared with the more rapid effects of the drug on maturing megakaryocytes. Patients in our study who did not have a response at 12 weeks might have had a response to more prolonged use of eltrombopag, given that the patients with a response at 12 weeks who participated in the extension study had additional lineage responses and markedly improved counts with continued treatment. The only patient or laboratory characteristics that predicted a response in this small cohort were less profoundly depressed baseline reticulocyte and immature platelet counts, which may reflect residual stem cells that can respond to eltrombopag. Response to initial immunosuppression also correlated with the baseline reticulocyte count in a previous study.24
It is possible that c-MPL stimulation enhances clonal evolution to myelodysplasia or leukemia. Clonal evolution occurs in 10 to 15% of patients with aplastic anemia overall, and the incidence of disease progression is highest in patients without a response and in those with short telomeres.15,25,26
Some studies have shown an association of prolonged G-CSF treatment with clonal evolution to monosomy 7 and the myelodysplastic syndrome, but this is more frequent in patients with severe, refractory aplastic anemia than in patients who have a good response to immunosuppression, and patients with refractory disease more often receive long-term treatment with G-CSF.27
In our cohort, monosomy 7 was detected at the conclusion of the study in two patients without a response, one of whom had extremely short telomeres. Patients with a response continued to receive the drug and were monitored by means of serial bone marrow biopsies and cytogenetic analysis; these patients did not have progression to myelodysplasia or clonal hematopoiesis. Given the uncertainty about this risk, it would be prudent to monitor patients with aplastic anemia who receive eltrombopag by performing serial bone marrow biopsies and cytogenetic analysis; in our opinion, treatment should be limited to clinical trials.
As with other autoimmune disorders such as multiple sclerosis and Crohn’s disease, recovery in aplastic anemia may be limited not only by ongoing immune attack but also by profound depletion of tissue stem cells.28
Hematopoietic stem and progenitor cells have inherent expansion capabilities, but they may require exogenous stimulation to regenerate adequate hematopoiesis. Data are lacking on whether the addition of eltrombopag to up-front immunosuppressive therapy can preserve hematopoietic stem cells and progenitor cells and improve the rate and quality of responses in aplastic anemia. Expansion of hematopoietic stem cells and progenitor cells with eltrombopag might also benefit patients undergoing prolonged chemotherapy or speed recovery of hematopoiesis after umbilical-cord blood transplantation.