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Tacrolimus and Danazol Combination As a Second-Line Therapeutic Strategy for Steroid-Resistant or Relapsed Immune Thrombocytopenia: A Prospective, Randomized, Multicenter, Open-Label Study

Program: ASH Poster Walks
Session: ASH Poster Walk on Hemostasis and Thrombosis hosted by Blood VTH (For In-person Participants)
Saturday, December 9, 2023, 4:00 PM-5:00 PM

Xiaohui Zhang, MD

Peking University People's Hospital, Beijing, China

Abstract Text:

Introduction: Immune thrombocytopenia (ITP) is an important health concern as a severe autoimmune bleeding disorder characterized by low platelet counts and an increased risk of bleeding. Traditionally, the first-line treatment for ITP involves glucocorticoids. However, a substantial number of patients develop resistance or relapse within the first year of treatment, presenting a formidable challenge for medical practitioners. The consequences of prolonged glucocorticoid therapy, such as severe adverse effects, further necessitate the exploration of alternative, more effective, and safer treatments. In recent years, tacrolimus, a potent calcineurin inhibitor, has emerged as a potential candidate for managing ITP. It has shown promising efficacy against anti-platelet antibody-mediated thrombocytopenia, thus expanding the therapeutic options for resistant or relapsed ITP patients. Our previous work (BJH 2022) also highlighted the potential of tacrolimus in suppressing the activation of NLRP3 inflammasomes and the apoptosis of MSCs-C+ cells both in vivo and in vitro. This research formed a solid foundation for further investigation into the roles of tacrolimus in ITP. Building on this background, our current research focuses on evaluating the effectiveness and safety of combining tacrolimus and danazol as a second-line therapy for patients with steroid-resistant or relapsed ITP. This study was designed to provide a comprehensive understanding of this therapeutic combination, which could pave the way for optimized treatment regimens for ITP, ultimately improving patient outcomes and quality of life.

Methods: This phase 2, randomized, open-label trial involved adult ITP patients demonstrating drug resistance or relapse from seven tertiary medical centers across China. Participants were randomly assigned to receive a 12-week treatment of either tacrolimus (initial dose 0.03 mg/kg/d, maintaining a blood concentration between 3-5 ng/mL) combined with danazol (200 mg bid) or monotherapy with danazol (200 mg bid). The primary endpoint entailed a 6-month sustained response, denoted by maintaining platelet counts > 50×10^9/L without additional ITP-modifying therapies at the 6-month follow-up. Secondary endpoints comprised an initial response, response duration, bleeding scores, and adverse events. This trial is registered with ClinicalTrials (NCT05471050).

Results: The study enrolled 90 steroid-resistant or relapsed ITP patients, with 43 assigned to the tacrolimus plus danazol group and 47 to the danazol monotherapy group. The participants in the combination group had a median age of 48 years (range: 30-53), and in the monotherapy group, it was 40 years (range: 28-51). Both groups had a marginally higher proportion of female participants. The median primary ITP duration was two months for both groups. Baseline bleeding scores and bleeding or platelet transfusion instances at enrollment were similar across groups. The results showed a promising improvement in the patient response. The tacrolimus plus danazol group showed a significantly higher 6-month sustained response rate (53%, n=23) than the danazol group (30%, n=14) (odds ratio: 2.17, 95% CI: 1.16-6.13, p=0.032). While there was no significant difference in the response times across the groups, the combination group attained a significantly higher peak platelet count (90 ×10^9/L) than the monotherapy group (70 ×10^9/L) (p=0.031). This suggests that the addition of tacrolimus to the therapy can significantly boost the platelet count, potentially improving the clinical outcomes for the patients. Response durations were comparable in both groups, indicating that the addition of tacrolimus did not negatively impact the duration of response. Last, treatment was well-tolerated with no grade 3 or 4 events or treatment-related deaths reported in both groups.

Conclusions: The tacrolimus and danazol combination emerges as a promising second-line treatment for steroid-resistant or relapsed ITP. This regimen demonstrated a higher 6-month sustained response rate and peak platelet count compared to danazol monotherapy, substantiating its potential role as a novel treatment strategy for adult ITP patients.

Disclosures: No relevant conflicts of interest to declare.

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