Safety and Efficacy of Iptacopan in Patients With High-Risk Transplantation-Associated Thrombotic Microangiopathy

Inclusion Criteria: 1. Age ≥12 years at the time of ICF signature. 2. Previous recipient of autologous or allogeneic HSCT. 3. Persistent TA-TMA despite initial management of potential triggers (e.g., CNI/mTOR inhibitor reduction, infection or GVHD treatment), with TMA activity sustained for ≥72 hours post-intervention. 4. TA-TMA diagnosis, confirmed ≤14 days prior to or during screening by either biopsy-proven microthrombi or ≥4 of the following: (1) LDH \> ULN (2) Proteinuria (rUPCR ≥1 mg/mg) (3) Hypertension (age-adjusted) (4) New-onset thrombocytopenia (platelet decrease ≥50%, count ≤50,000/mm³, or transfusion-refractory) (5) New-onset anemia or increased transfusion need (6) Microangiopathy on blood smear (schistocytes ≥1%) or biopsy (7) Elevated terminal complement complex (C5b-9) 5. High-risk TMA features (per 2023 consensus), meeting ≥1 criterion: 1. LDH ≥2× ULN 2. Elevated sC5b-9 3. Proteinuria (rUPCR ≥1 mg/mg) 4. Multi-organ dysfunction syndrome (MODS) 5. Concurrent Grade II-IV acute GVHD 6. Active systemic infection 6. Able to receive oral medication. 7. Failure of first-line therapy (e.g., CNI/mTOR inhibitor adjustment, plasma exchange, rituximab, defibrotide), excluding prior complement inhibitors. 8\. Life expectancy \>8 weeks. 9. Required vaccination against encapsulated bacteria (meningococcal, pneumococcal) per local guidelines, administered ≥2 weeks prior to first dose. If vaccination is delayed, antimicrobial prophylaxis is required. 10\. For subjects unable to receive meningococcal vaccines, antibiotic prophylaxis must be continued throughout treatment and for 8 months post-last dose. 11\. For subjects of reproductive potential: agreement to use effective contraception and, for females, a negative pregnancy test at screening. 12\. Provision of signed informed consent and compliance with study procedures. Exclusion Criteria: 1. Known familial or acquired ADAMTS13 deficiency (activity \<5%). 2. Known Shiga toxin-associated HUS (positive Shiga toxin assay or culture). 3. Positive direct Coombs test with clinically significant immune-mediated hemolysis per investigator. 4. Clinically overt disseminated intravascular coagulation (DIC) according to ISTH criteria. 5. Bone marrow/graft failure. 6. Known HIV infection (confirmed by testing within 6 months prior to screening). 7. Active meningococcal disease. 8. Septic shock requiring vasopressor support within 7 days prior to enrollment. 9. Pregnant or breastfeeding. 10. Any concurrent or prior medical condition unrelated to TA-TMA that, in the opinion of the investigator or sponsor, could increase risk or confound study outcomes (e.g., significant cardiac, pulmonary, renal, endocrine, or hepatic disease). 11. All-cause respiratory failure requiring mechanical ventilation within 72 hours prior to enrollment. 12. Acute/chronic heart failure with left ventricular ejection fraction ≤40%. 13. Prior treatment with iptacopan, eculizumab, or other complement inhibitors within 60 days before first study dose. 14. Use of any investigational agent within 30 days or 5 half-lives (whichever is longer) prior to screening. 15. Recurrent primary malignancy or post-transplant lymphoproliferative disorder (PTLD).