According to results from a multicenter, prospective study presented at the 22nd Congress of the European Hematology Association, the combination of all-trans retinoid acid (ATRA) and danazol may improve sustained response in non-splenectomized patients with corticosteroid-resistant and/or relapsed immune thrombocytopenia (ITP).
“Despite decades of research, the treatment of severe, corticosteroid-resistant or relapsed disease remains a great challenge,” the study authors, led by Fei-Er Feng, from the Peking University Institute of Hematology in Beijing, China, noted.
The steroid danazol has a hematopoietic stimulatory and immunomodulatory effect, the authors noted, and the agent has recently been shown to reverse abnormal telomere function in patients with thrombocytopenia. Previous research suggested that ATRA has an immunomodulatory effect on hematopoiesis and could be a potential treatment for ITP.
In this study, the authors hypothesized that the combination of ATRA and danazol would work synergistically to target both increased platelet destruction and insufficient platelet production associated with ITP.
The investigators enrolled adult patients between 2012 and 2016 from four medical centers in Beijing and one center in Shandong, China. Patients were included if they had a platelet count of <30×109/L, had not achieved a sustained response (>4 weeks) to treatment with full-dose corticosteroids, or had relapsed during steroid-tapering or after its discontinuation. Patients with secondary ITP (e.g., patients with HIV, hepatitis C virus, H. pylori infection, or systemic lupus erythematosus) were excluded.
Ninety-three patients were randomized to receive danazol 400 mg twice-daily (n=48) or danazol 400 mg twice-daily plus ATRA 10 mg twice-daily (n=45).
Treatment with ATRA plus danazol more than doubled the proportion of patients who responded to therapy: 92.5 percent in the combination group and 42.5 percent in the danazol-alone group (92.5% and 42.5%). Only 58.3 percent and 11.1 percent of patients who received danazol monotherapy achieved any response and CR, respectively.
After 1 year of follow-up, 71.6 percent of patients in the combination group achieved sustained partial or complete response (CR; primary endpoint), compared with 47.2 percent of patients in the danazol group (p<0.001).
Among responding patients, those who received both danazol and ATRA appeared to achieve a treatment response more rapidly, and these responses were deeper, compared with the danazol monotherapy group:
- median time to treatment response: 30.5 days vs. 49 days (p value not provided)
- peak platelet count: 155×109/L vs. 69×109/L (p value not provided)
The authors also found that, in multivariate analyses, both initial response at day 28, and median duration of ITP were potentially associated with a sustained response.
There were no treatment-related deaths, but one patient receiving danazol monotherapy died from an intracranial hemorrhage 4 weeks after study enrollment.
“Our findings demonstrate that the combination of ATRA and danazol is safe and effective in achieving a rapid and long-lasting response,” the authors concluded, “making it a potential promising therapeutic option for patients with non-splenectomized corticosteroid-resistant/relapsed ITP.”
These results are limited by the small patient population and, because patients were enrolled mainly from centers in Beijing, the results might not be generalizable. Also, the trial was unblinded, which could potentially introduce bias.
The authors report no relevant conflicts of interest.
Feng F, Wang M, Feng R, et al. The combination of oral all-trans retinoic acid and danazol vs. danazol as second-line treatment in adult immune thrombocytopenia: a multicenter, randomized, open-label trial. Abstract #S431. Presented at the 22nd Congress of the European Hematology Association, June 24, 2017; Madrid, Spain.