Oral iptacopan demonstrates efficacy as salvage therapy for high-risk transplant-associated thrombotic microangiopathy: First real-world experience

Abstract Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT), historically associated with a mortality rate as high as 80%. Recent advances in complement inhibition have demonstrated promising therapeutic potential, as evidenced by eculizumab (Jodele S, et al. Blood 2024). However, limitations in the clinical use of eculizumab arise from its substantial infection risk, unstable plasma levels, and the lack of an oral administration option. Activated complement factor B product is significantly elevated in the early period of TA-TMA, thereby supporting the predominant pathogenic role of the alternative pathway. Iptacopan, an oral small-molecule complement factor B inhibitor, can efficiently block the formation of C3 convertase, inhibit C5 convertase, decrease the membrane attack complex formation, and reduce damage to the endothelial system. Thus, iptacopan has the potential role to block the core pathological process of TA-TMA. Here, we present the multicenter study to identify the efficacy and safety of iptacopan as salvage therapy for high-risk TA-TMA in real-world setting.Method: In this retrospective, real world study, a total of 26 high-risk TA-TMA patients from 7 Chinese institutions receiving iptacopan therapy between July 2024 and May 2025 were included. TA-TMA diagnosis and treatment response were assessed according to Jodele et al. High-risk disease was defined by ≥ 1 of the following: concomitant infection, peak LDH ≥ 2 ULN, aGVHD, end-organ dysfunction, rUPCR ≥ 1 mg/mg, and sC5b-9 plasma levels ≥ 250 ng/mL. All patients received prophylactic antimicrobial therapy that includes coverage for Neisseria meningitidis.Results: Among the 26 patients [16 male, median age (40, IQR 24-53) years], 22 patients underwent myeloablative conditioning (MAC) and 4 received reduced intensity conditioning regimen, respectively. Twenty-four patients received calcineurin inhibitors (CNI) based GVHD prophylaxis regimen. TA-TMA was diagnosed with a median time of 86 days (IQR 29-214) after transplantation. 12, 5, and 5 patients, respectively, showed intestinal, renal, and central nervous system involvement. At the time of diagnosis, 21 patients had concomitant infection. Elevated urinary protein excretion (rUPCR ≥1 mg/mg) and elevated sC5b-9 level were present in 10 and 13 patients, respectively. The treatment before iptacopan included calcineurin inhibitor withdrawal (n=18), plasma exchange (n=7), defibrotide administration (n=4), anti-CD20 therapy (n=11), and anti-C5 therapy (n=9). However, only 1 patient had achieved complete response (CR) but experienced subsequent TMA flare. The median interval from TA-TMA diagnosis to the initiation of iptacopan treatment was 14 (IQR 2-55) days, which was employed as a median of third line (range: 1-5) therapy. The median duration of iptacopan treatment was 33 (IQR 17-98) days. Following iptacopan therapy, we observed an overall response rate (ORR) of 76.9%. Ten (38.5%) patients achieved CR and ten (38.5%) achieved partial response (PR). The ORR to second-line and ≥ third-line therapies were 100% (8/8) and 69% (11/16), respectively (P=0.13). Iptacopan resulted in marked reduction of lactate dehydrogenase from baseline at 1 month (median 553 IU/L vs 339 IU/L, p=0.0013). Among CR patients, 9 of 10 (90%) achieved LDH normalization after a median of 52 (IQR 14-90) days, and all showed schistocyte clearance after a median of 26 (IQR 8-51) days. Patients achieved independence from red blood cell transfusion at a median of 33 days (IQR 17-80) and from platelet transfusion at 14 (IQR 10-48) days. The most frequent adverse events were infectious complications (n=8) and 4 patients died of infection. No relapse of underlying diseases was observed after iptacopan. At the last follow-up (range 7-247 days), the 6-month overall survival rate after TMA diagnosis was 64.4% (95%CI 44.7%-92.7%), with 75% of responders (15/20) remaining alive.Conclusion: The oral complement inhibitor iptacopan demonstrated significant clinical efficacy as salvage therapy in high-risk TA-TMA patients, particularly when administered as second-line therapy, with infections being the most common adverse events. These findings support further prospective evaluation of iptacopan as a targeted therapy for TA-TMA.Keywords: Iptacopan; Hematopoietic stem cell transplantation; Transplant-associated thrombotic microangiopathy