Updated Outcome from Biomarker MSC-C5b-9-Guided All-Trans Retinoic Acid Treatment for Resistant/Recurrent ITP: A Multicenter, Randomized, Open-Label, Phase 3 Clinical Trial

Introduction:

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia due to increased platelet destruction and decreased platelet production mediated by the loss of immune tolerance. Steroids, as first-line treatments, don’t provide long-term relief. Our previous clinical trials firstly confirmed the efficacy and safety of all-trans retinoic acid (ATRA) in the treatment of ITP and revealed that MSC-C5b-9 may be a stratification marker for evaluating the efficacy of ATRA (Lancet Haematol,2021; Blood,2022). This research aimed to develop a new treatment approach for resistant/recurrent ITP on the basis of the marker MSC-C5b-9.

Method:

We conducted a multicenter, randomized clinical trial to evaluate the efficacy and safety of ATRA combined with eltrombopag based on MSC-C5b-9 for the treatment of steroid-resistant/recurrent ITP. Following enrollment, patients were assigned randomly in a 1:1 ratio to either the eltrombopag group or the eltrombopag + ATRA group, contingent upon negative or positive results of MSC-C5b-9, respectively. The initial dose of eltrombopag was 50 mg daily, with dose adjustments based on platelet levels. For patients assigned to the ATRA group, ATRA was administered at a dose of 10 mg twice daily. Peripheral blood cell counts, bleeding, health-related quality of life and adverse events (AEs) are regularly monitored. The primary endpoint was a sustained response (SR) at 18 months after randomization, and the secondary endpoints included complete response (CR), response, relapse, early response (ER), initial response (IR) and AEs. All the statistical tests were two-sided, and we considered p values < 0.05 to be statistically significant. We performed all the statistical analyses with SPSS Statistics 27. The study has been registered at clinicaltrials.gov. NCT05438875.

Results

Patients were enrolled from 2022 to 2023. During this period, 96 patients were enrolled, including 29 MSC-C5b-9-positive patients. On the day of enrollment, patients were randomly assigned at a 1:1 ratio and treated with eltrombopag combined with ATRA (n=48) or eltrombopag (n=48) monotherapy. The median ages were 39.5 and 38 years, and the median durations from diagnosis were 30.5 and 15 months in the ATRA and control groups, respectively. The median baseline platelet count was 13.0 × 10⁹/L in the ATRA group and 18.0 × 10⁹/L in the control group.

Among all the patients, SR was achieved in 64.5% of patients in the ATRA group compared with 33.3% of patients in the control group (p=0.015) at 18 months after enrollment. Among the MSC-C5b-9-negative patients, SR was achieved in 72% of patients in the ATRA group, whereas it was achieved in 23.8% of patients in the control group (p=0.003) at 18 months after enrollment. There was no significant difference in the complete response rate or response rate between the two groups (p>0.05). Notably, among the MSC-C5b-9-negative patients, the ATRA group had a significantly higher CR rate and better treatment efficacy compared with the control group (p=0.008, p=0.038). Further analysis revealed that patients who were negative for MSC-C5b-9 achieved a higher CR rate (p=0.017), and there was still a difference in the CR rate in the ATRA group (p=0.002). Stratified analysis of MSCs-C5b-9 revealed that, in the overall and ATRA groups, the efficacy of treatment in the MSC-C5b-9-negative patients was greater than that in the MSC-C5b-9-positive patients (p=0.013, p=0.006). During the follow-up period, the recurrence rate in the control group was greater (p=0.037), and the difference was more significant within MSC-C5b-9-negative patients (p=0.004). We further analyzed the time to relapse (duration of efficacy) and found that, compared with the control group, the ATRA group had a longer duration to relapse among the MSC-C5b-9-negative patients (p=0.024, p=0.004). Compared with baseline, both groups showed improvements in bleeding scores and health-related quality of life at 18 months.

The severity of the AEs was grade 1-2. There was no significant difference in AEs between the groups (p>0.05).

Conclusions:

ATRA treatment of steroid-resistant/recurrent ITP can improve the response rate, bleeding rate and health-related quality of life and prolong the duration of treatment efficacy. Our study confirmed that MSC-C5b-9 is a biomarker for steroid-resistant/recurrent ITP and can be used to guide patient treatment.