Eltrombopag Has Potential in Aplastic Anemia

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By Crystal Phend, Senior Staff Writer, MedPage Today

Published: July 06, 2012

Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Action Points

• Eltrombopag, a thrombopoietin mimetic, improved at least one cell line in 11 of 25 patients with refractory aplastic anemia.
• Note that nine patients were able to stop platelet transfusions, and late improvement in one or two more cell lineages was observed in some patients who continued the drug after the initial trial period.

Aplastic anemia refractory to other treatments may respond to the thrombopoietin mimetic eltrombopag (Promacta), an early-phase clinical trial showed.
The oral drug yielded a clinically significant response at 12 weeks in platelet, red cell, or neutrophil lineages in 11 of 25 patients (44%) for whom standard immunosuppression did not work, reported Cynthia E. Dunbar, MD, of the National Heart, Lung and Blood Institute in Bethesda, Md.
Blood counts rose enough for nine of the patients to go off platelet transfusions, they reported in the July 5 issue of the New England Journal of Medicine.
Aplastic anemia is thought to be an autoimmune attack on the bone marrow, but about one-third of patients don't respond to immunosuppression and have persistent, severe cytopenia and profoundly low levels of the hematopoietic stem cells and progenitor cells that give rise to mature blood cells.
Thus far, attempts to stimulate those stem cells and progenitor cells with erythropoietin and granulocyte colony-stimulating factor haven't worked for aplastic anemia.
Eltrombopag binds to the receptor for the principle regulator of platelet production in a different way than thrombopoietin. This might make the drug able to activate abnormal receptors that some animal studies suggested might play a role in aplastic anemia, explained Donald Metcalf, MD, of the Institute of Medical Research in Parkville, Australia, in an accompanying editorial.
"If confirmed, the implication of these intriguing [trial] results is that in many patients with aplastic anemia, the hematopoietic stem cells and their progenitor-cell progeny may have acquired defective MPL receptors that are unresponsive to thrombopoietin but remain able to be activated by eltrombopag," he wrote.
The phase II trial included 25 patients with immunosuppression-refractory aplastic anemia who received eltrombopag at a dose of 50 mg, ramped up to the maximum 150 mg daily in all but one patient, for a total of 12 weeks.
For the primary endpoint of a response in at least one blood cell lineage (four patients had more than one):

• Nine patients had a platelet response, defined as an increase of 20,000 cells/mm³ or more above baseline or independence from platelet transfusions for at least 8 weeks if previously transfusion-dependent.
• Two patients had a red cell response, with an increase in hemoglobin by 1.5 g/dL or more over pretreatment levels below 9 g/dL without transfusion of packed red cells or a reduction by at least 4 units transfused for 8 consecutive weeks.
• Four patients had a neutrophil response, an absolute increase of more than 500 per mm³.

Of the 11 total patients who had a response, most stopped getting transfusions by 12 weeks but two met only the neutrophil response criteria.
Eight maintained a response without relapse for a median of 10 months. The seven who stayed on the drug beyond 12 weeks (median 16 months) in an extension study continued to see clinically significant improvements in their blood counts.
One patient added a response in another lineage of blood cells during the longer term use; six eventually had a response in all three lineages.
Predictors of response were the top quartile of baseline immature platelet count (P=0.03) and higher mean reticulocyte count at baseline (P=0.01).
With regard to averse events, hospitalization occurred for the following reasons:

• Abdominal pain and orthostatic hypotension in a patient with diabetic gastroparesis
• Severe rash at the initiation of cephalosporin treatment
• Severe gingival bleeding
• Episodes of fever with neutropenia with some linked to culture-confirmed infection

While studies have raised concern about bone marrow fibrosis with chronic stimulation of the MPL receptor that eltrombopag targets, none of the patients showed an increase in fibrosis or reticulin on bone marrow–biopsy specimens obtained at 12 weeks or thereafter for patients who stayed on the drug.
Two patients without a response developed clonal evolution to myelodysplasia or leukemia, which is also considered a possible risk of MPL stimulation.
"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," Dunbar's group concluded. "In our opinion, treatment should be limited to clinical trials."
The drug is already approved for treatment of chronic immune thrombocytopenic purpura.
"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," the researchers suggested.

The study was funded by the National Heart, Lung and Blood Institute.
GlaxoSmithKline supplied the drug for the trial directly.
Dunbar reported a cooperative agreement with the company for partial support of a new trial of eltrombopag paid to her institution.
Metcalf reported employment with the Carden Fellowship Cancer Council of Victoria; grants from the Cancer Council of Victoria, National Health Institutes, Australian National Health and Medical Research Council, and the now defunct AMRAD Corp.; and multiple patents with royalties to himself and his institution.

Primary source: New England Journal of Medicine
Source reference:
Olnes MJ, et al "Eltrombopag and improved hematopoiesis in refractory aplastic anemia" N Engl J Med 2012; 367: 11-19.
Additional source: New England Journal of Medicine
Source reference:
Metcalf D "A promising new treatment for refractory aplastic anemia" N Engl J Med 2012; 367: 74-75.

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Crystal Phend
Staff Writer
Crystal Phend joined MedPage Today in 2006 after roaming conference halls for publications including The Medical Post, Oncology Times, Doctor’s Guide, and the journal IDrugs. When not covering medical meetings, she writes from Silicon Valley, just south of the San Francisco fog.