Background: Primary immune thrombocytopenia (ITP) is an autoimmune bleeding disorder. Eltrombopag is a preferred second-line treatment of ITP, but many patients still have no response or relapse due to unknown reasons. Our preclinical data indicate that rhein, the active metabolite of diacerein, can enhance megakaryocyte sensitivity to thrombopoietin receptor agonists, and promote megakaryocyte polyploidization and platelet formation in ITP. Thus, a prospective randomized controlled trial was conducted to compare the efficacy and safety of eltrombopag plus diacerein versus eltrombopag alone in adult ITP. Here we report the interim analysis of this study.

Methods: This multicenter, open-label, randomized, phase 2 trial screened eltrombopag-inefficient or relapsed ITP patients from five tertiary medical hospitals in China. Eligible participants were randomly assigned into the combination arm (eltrombopag orally at an initial dose of 75 mg daily for 14 days, plus diacerein orally at an initial dose of 50 mg bid for 14 days) or the monotherapy arm (eltrombopag orally at an initial dose of 75 mg daily for 14 days) by masked statisticians. To maintain participants’ platelet counts at a safe range, individualized dosages were allowed to be adjusted by physicians according to the protocol. The primary outcome was initial response at day 15. Complete response was defined as a platelet count at or above 100×109/L and an absence of bleeding. Partial response was defined as a platelet count at or above 30×109/L but less than 100×109/L and at least a doubling of the baseline platelet count and an absence of bleeding. No response was defined as a platelet count of less than 30×109 cells per L, or less than two-times increase from baseline platelet count, or bleeding. Key secondary enpoints included response at day 28, time to response (TTR), duration of response, bleeding scores, health-related quality of life assessment and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04917679).

Results: From September 2020 to December 2021, 90 patients were screened for eligibility, of whom 24 were ineligible, 66 were randomly assigned to receive either eltrombopag plus diacerein (n=32) or eltrombopag alone (n=34). Four patients did not receive allocated intervention and they were excluded from the analysis. Baseline characteristics were balanced between the two arms. The total population (female accounted for 51.6%) had a mean age of 42.6 years and a mean platelet count of 8.6 ×109/L. At day 15, a significantly higher proportion of participants in the eltrombopag plus diacerein arm (13 [43.3%] of 30) than in the eltrombopag monotherapy arm (5 [15.6%] of 32) had an initial response (p=0.0247). At day 28, the response rate in the combination arm was higher than that in the eltrombopag arm even though it did not reach statistical significance (10 [33.3%] of 30 vs 4 [12.5%] of 32, p=0.0699). There was no significant difference in median TTR between the two arms (p>0.05). During the follow-up period, the duration of response was longer in the eltrombopag plus diacerein arm than in the eltrombopag arm by the Kaplan Meier analysis (Hazard ratio 0.57, 95% CI 0.34-0.96, p=0.0178). Eltrombopag plus diacerein exhibited lower bleeding scores and better health-related quality of life scores than eltrombopag. Incidence of AEs was similar between the two arms. Most of AEs were mild and resolved spontaneously after treatment was completed. The incidence of gastrointestinal reactions in the combination arm was slightly higher, but no significant difference was observed. There were no grade 4 or 5 AEs. No treatment-related deaths occurred.

Conclusions: In conclusion, our findings suggest that the addition of diacerein as a sensitizer to eltrombopag has improved initial response than eltrombopag alone for eltrombopag-inefficient or relapsed ITP patients. This oral combination therapy warrants further exploration.

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No relevant conflicts of interest to declare.

It includes information or discussion of off-label drug use of diacerein.

Author notes

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Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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