A prospecitive, multicenter study of chidamide in adult patients with refractory primary immune thrombocytopenia

Abstract Background: Primary immune thrombocytopenia (ITP) is an acquired autoimmune bleeding disorder. Our preclinical data revealed that chidamide, a histone deacetylase inhibitor (HDACi), can reduce macrophage phagocytosis of antibody-coated platelets, promote the production of natural Foxp3+ Tregs, and enhance CTLA4 expression by modulating histone H3K27 acetylation. We herein evaluated the efficacy and safety of chidamide administered in two different dosage regimens in adult patients with refractory ITP. Methods: This prospective, multicenter, open-label, randonmized clinical trial screened refractory ITP patients from five tertiary medical centers in China. Eligible participants (at least 18 years old, had ITP for more than 6 months, did not respond or relapsed after previous first-line treatment, and lack of response to rituximab, TPO agents, or splenectomy) were randomly assigned in a 1:1 ratio to receive chidamide at a dosage of either 2.5 mg or 5 mg twice per week. The primary endpoint was the overall response rate at week 12. No additional interventions specific to primary immune thrombocytopenia was permitted, except for a stable dose of corticosteroids, TPO-RAs, or danazol before randomization. If an initial response was achieved by week 12, the allocated treatment could be continued. Patients in the 2.5 mg group were allowed to increase their dose to 5 mg if platelet counts were less than 30×109/L or less than doubled from baseline by week 12, based on the investigators' advice and the patients' decision. Patients who did not respond to chidamide at 5 mg for 12 weeks would stop the allocated treatment and were continuously followed up. The secondary endpoints included a 6-month sustained response, time to response (TTR), duration of response, bleeding scores, health-related quality of life assessments and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT03838354). Results: Between June 1, 2021, and September 1, 2023, 80 individuals were screened for eligibility, of whom 19 were ineligible and excluded, 61 were randomly assigned to either the 2.5 mg group (n=31) or the 5 mg group (n=30) for intention-to-treat analysis (Figure 1). Three patients did not complete the allocated treatment due to the need for other interventions (two vs. one), one patient was lost to follow-up (none vs. one). All participants were Asian, with 65.6% females and having a median age of 44 (IQR 27-60) years. The baseline median platelet count was 10×109/L (IQR 6-16) in the 2.5 mg groups versus 12.5×109/L (IQR 7.8-20) in the 5 mg group. The median number of previous therapies was 5 (IQR 4-6) in the 2.5 mg group and 5 (IQR 4-6) in the 5 mg group. Concomitant therapy was adnimistered to 16 (51.6%) of 31 patients in the 2.5 mg group versus 18 (60%) of 30 patients in the 5 mg group. By week 12, a significantly higher proportion of participants in the 5 mg group achieved an overall response than in the 2.5 mg group (13 [43.3%] of 30 vs 5 [16.1%] of 31, p=0.0262). Among the eigtht patients who transitioned from the 2.5 mg to the 5 mg doseage, four (50%) achieved an overall response. The 6-month sustained response rate was significantly higher in the 5 mg group than in the 2.5 mg group (33.3% vs 3.2%, p=0.0026). No significant difference was observed in the median TTR between the two arms (p>0.05). Additionally, responders in the 5 mg group experienced a longer median duration of response, lasting 48 (IQR 25-52) weeks, compared to 8 (IQR 6-34) weeks in the 2.5 mg group (p=0.0180). Patients in the 5 mg group exhibited reduced bleeding scores and improved health-related quality of life compared to baseline. The two most frequently observed treatment-emergent AEs were fatigue and elevated liver enzymes in the 5 mg group, and fatigue and respiratory infection in the 2.5 mg group. There were no grade 4 or 5 AEs. No treatment-related deaths occurred. Conclusions: Chidamide was well tolerated, with the recommended dosage of 5 mg twice per week yielding higher overall response rates and longer duration of response than the 2.5mg dosage, offering an effective therapeutic option for patients with refractory ITP.