Frontline Eltrombopag Receives FDA's Breakthrough Therapy Designation for Severe Aplastic Anemia

Eltrombopag (Promacta) has been granted a breakthrough therapy designation by the FDA for use in combination with standard immunosuppressive therapy for the first-line treatment of patients with severe aplastic anemia.

Samit Hirawat

Eltrombopag (Promacta) has been granted a breakthrough therapy designation by the FDA for use in combination with standard immunosuppressive therapy for the first-line treatment of patients with severe aplastic anemia (SAA).

This designation will help expedite the development of the small molecule thrombopoietin receptor agonist in the frontline setting. Eltrombopag has already been approved in the United States for the treatment of patients with SAA who have had an insufficient response to immunosuppressive therapy.

“Promacta is a promising medicine that, if approved for first-line use in severe aplastic anemia, may redefine the standard of care for patients with this rare and serious bone marrow condition,” Samit Hirawat, MD, Head, Novartis Oncology Global Drug Development, the manufacturer of eltrombopag, said in a statement. “We will continue to work closely with the FDA to make Promacta available to patients with SAA who are new to treatment as soon as possible.”

The designation is based on results from research conducted by the National Heart, Lung and Blood Institute of the National Institutes of Health. Investigators found that eltrombopag, administered concurrently with standard immunosuppressive treatment, was associated with a 52% complete response (CR) rate in treatment-naïve patients at 6 months. Overall response rate was 85%.

In results from a prospective single-center phase II trial first presented at the 2015 ASH Annual Meeting, the rate of complete hematologic response was 28% at 3 months and 37% at 6 months, among 92 patients who received eltrombopag in addition to equine antithymocyte globulin (ATG) and cyclosporine. The overall response rate was 81% at 3 months and 86% at 6 months.

Both outcomes exceeded historical response rates with conventional therapy.

In that phase II study, the eltrombopag combination was examined in 3 cohorts of patients with untreated SAA enrolled from July 2012 to October 2015. All patients received standard treatment with ATG and cyclosporine.

The first cohort received eltrombopag starting on day 14 and continuing for 6 months (30 patients). The second cohort received the thrombopoietin inhibitor from day 14 through 3 months to address concerns about potential hepatotoxicity (n = 31). In the third group, eltrombopag was initiated concurrently on day 1 with conventional immunosuppressive therapy and continued for 6 months.

The primary analysis showed CR rates at 3 months of 17% (5/30) in the first cohort, 26% (8/31) in the second cohort, and 44% (11/25 evaluable patients) in the third cohort. Overall, 24 of 92 patients (28%) achieved a CR.

Complete response rates at 6 months were 33% in the first cohort, 26% in the second, and 60% in the third (12 of 20 evaluable patients), resulting in an overall CR rate of 37% across the 3 cohorts.

The highest rates of complete and overall response occurred in the third cohort of patients who received eltrombopag concurrently with ATG and cyclosporine.

The trial resulted in relatively few grade 3/4 eltrombopag-associated adverse events. Two patients developed severe cutaneous reactions and discontinued the drug. About 10% of the total study population developed grade 2/3 transaminase or bilirubin elevations.

The only death during the trial resulted from a thymoma associated with paraneoplastic encephalopathy. Seven patients had clonal evolution.

SAA is a rare blood disorder in which a patient's bone marrow fails to produce enough red blood cells, white blood cells and platelets, leading to symptoms such as fatigue, dyspnea, recurring infections, and abnormal bruising or bleeding. About two-thirds of patients with SAA achieve some degree of hematologic response with conventional immunosuppressive therapy, most often the combination of ATG and cyclosporine. However, response rates have been stable for 3 decades despite ongoing efforts to improve outcomes in the condition.


Townsley DM, Dumitriu B, Scheinberg P, et al. Eltrombopag added to standard immunosuppression for aplastic anemia accelerates count recovery and increases response rates. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract LBA-2.