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Eltrombopag restored hematopoiesis in refractory severe aplastic anemia
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Eltrombopag stimulated stem and progenitor cells and restored tri-lineage hematopoiesis in patients with severe aplastic anemia refractory to immunosuppressive therapy, according to study results.
In addition, results showed robust responders maintained hematopoiesis after discontinuation of eltrombopag (Promacta, GlaxoSmithKline).
The researchers previously demonstrated that eltrombopag appeared efficacious in patients with severe aplastic anemia. Of the 25 patients in the prior analysis, 44% experienced clinically significant hematologic responses.
The current study included safety and efficacy data from an additional 18 patients, as well as long-term follow-up on all 43 patients treated.
The researchers reported a 40% overall response rate at 3 to 4 months. They observed tri- and bi-lineage responses.
Of the 17 patients who remained on eltrombopag as part of an extension study, 14 (82.3%) continued to show improvement. Seven patients experienced a significant increase in neutrophil, red cell and platelet lineages.
Five patients who demonstrated “robust near-normalization of blood counts” discontinued treatment. Discontinuation occurred at a median 28.5 months after study entry (range, 9-37). All five patients maintained stable counts at a median 13 months (range, 1-15) after discontinuation.
Eight patients, including two responders and six non-responders, developed new cytogenetic abnormalities during eltrombopag treatment. Those abnormalities included five incidences of chromosome 7 loss or partial deletion. None of the abnormalities evolved to acute myeloid leukemia, researchers wrote.
“Clonal evolution rates are of concern, although a direct association with eltrombopag is unclear,” the researchers wrote. “Identification of patients with pre-existing clonal hematopoiesis using newer more sensitive techniques or delineation of other factors predisposing patients to clonal progression may prove helpful to guide physicians in referring patients for early allogeneic transplantation versus a trial of eltrombopag, and should be the focus of future clinical trials. Given these concerns, eltrombopag should be used in patients with refractory aplastic anemia with careful attention to potential risks and benefits.”
Disclosure: The researchers report no relevant financial disclosures.
Perspective
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Harry S. Jacob, MD, FRCPath(Hon)
That eltrombopag, albeit a thrombopoietin-mimicking drug, seems also beneficial in stimulating erythropoiesis and leukopoiesis has been explained (perhaps) by the authors in their previous NEJM article (Olnes MJ. N Engl J Med. 2012;367:11-19). The drug stimulates the thrombopoietin receptor c-MPL, a receptor present on hematopoietic stem cells as well as on megakaryocytes. However, it binds the stem cell receptor at a site different from that on platelet precursors. Since approximately 25% of aplastic anemia patients fail immunosuppressive therapy, this report is most welcome.
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