N-Acetylcysteine as Therapy for Transplantation- Associated Thrombotic Microangiopathy

Overview

This multicenter, prospective, single-arm clinical trial aims to evaluate the efficacy and safety of N-acetylcysteine (NAC) for treating Transplantation-Associated Thrombotic Microangiopathy (TA-TMA), a severe complication of hematopoietic stem cell transplantation characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury, with an incidence of 4%-30%. Current treatments, including plasma exchange (response rate \<10%) and costly complement inhibitors like Eculizumab (71% response) which are not widely accessible, are inadequate. Inspired by NAC's success in treating the related condition thrombotic thrombocytopenic purpura (TTP) and supported by bioinformatic analyses of patient data revealing enhanced oxidative stress pathways and identifying NAC as a potential targeted therapy, our prior study demonstrated that NAC prophylaxis significantly reduces TA-TMA incidence and improves survival. Building on this promising foundation, this study will enroll patients meeting TA-TMA diagnostic criteria for NAC treatment, assessing its potential as a safe, effective, and affordable therapeutic option.

Background: Transplantation-associated thrombotic microangiopathy (TA-TMA) is a severe complication of hematopoietic stem cell transplantation, characterized by microangiopathic hemolytic anemia, thrombocytopenia, elevated lactate dehydrogenase, elevated serum creatinine, schistocytes on peripheral blood smear, and microvascular thrombosis. Its pathogenesis is associated with complement system activation leading to endothelial injury. The incidence of TA-TMA ranges from 4% to 30%. Current treatments, including withdrawal of calcineurin inhibitors, switching to other immunosuppressants, and plasma exchange (which has a response rate below 10%), are unsatisfactory. Complement-targeted therapies like the C5 monoclonal antibody Eculizumab and the lectin pathway inhibitor Narsoplimab show promise with response rates of 71% and 61%, respectively. However, their high cost and limited availability (e.g., some are not accessible in China) restrict widespread use. There is a clear lack of prospective clinical trials for TA-TMA treatment. Thrombotic thrombocytopenic purpura (TTP) shares similar clinical features with TA-TMA. In 2016, N-acetylcysteine (NAC) combined with plasma exchange achieved complete remission in three refractory TTP patients. NAC, a safe, economical, and readily available antioxidant, is approved for acetaminophen toxicity and COPD. It inhibits platelet adhesion to von Willebrand factor (VWF) by reducing disulfide bonds in VWF, thereby decreasing the size of soluble high molecular weight VWF multimers, as validated in animal TTP models. This success in TTP suggests a potential therapeutic direction for TA-TMA. Analysis of RNA sequencing data from TA-TMA patients in the GEO database revealed enhanced oxidative stress-related gene expression. Furthermore, whole-genome sequencing of a TA-TMA patient's blood and analysis via the IPA database identified NAC as a potential effective treatment. A subsequent prospective trial demonstrated that NAC prophylaxis significantly reduced TA-TMA incidence, delayed its onset, and improved event-free survival in transplant patients. However, no clinical trial has yet investigated NAC for the treatment of established TA-TMA. Compared to expensive complement inhibitors, NAC represents a safe, accessible, and affordable drug with the potential to offer effective and feasible therapy for TA-TMA patients. Objective: To evaluate the efficacy and safety of N-acetylcysteine in patients with diagnosed TA-TMA. Study Design: This is a multicenter, prospective, single-arm clinical study. Methods: Patients who meet the TA-TMA diagnostic criteria will be screened based on predefined inclusion and exclusion criteria. Enrolled patients will receive N-acetylcysteine treatment. The primary endpoints will be the assessment of treatment efficacy (including response rates) and safety (monitoring of adverse events).