Safety and Efficacy of Eculizumab in High-risk TA-TMA

High-risk, complement-mediated, untreated transplant-associated thrombotic microangiopathy (hrTA-TMA) carries a very poor prognosis due to multiple organ dysfunction syndrome (MODS). The complement C5 inhibitor eculizumab has shown promising efficacy in children with hrTA-TMA, but has not been prospectively studied in adult allogeneic hematopoietic stem cell transplantation (HSCT) recipients. The investigators plan to conduct the first multicenter prospective study in adults to evaluate eculizumab as an early targeted intervention for hrTA-TMA. The investigators hypothesize that eculizumab will more than double the survival rate of hrTA-TMA in adult HSCT recipients compared with untreated hrTA-TMA patients from our previous study, who will serve as historical controls. Inclusion criteria are a confirmed diagnosis of TA-TMA with at least one of the following hrTA-TMA features: random urine protein-to-creatinine ratio (rUPCR) ≥2 mg/mg, multiple organ dysfunction syndrome (MODS), or elevated plasma IL-10 (≥2× upper limit of normal). The primary endpoint is survival at 6 months after diagnosis of hrTA-TMA. Secondary endpoints are the cumulative incidence of MODS at 6 months after diagnosis of hrTA-TMA, and 1-year post-transplant survival. The eculizumab regimen consists of an intensive loading dose, an induction dose, and a maintenance dose, with a total treatment duration of up to 24 weeks. This study aims to investigate the safety and efficacy of eculizumab in the treatment of high-risk TA-TMA.

Dosing Regimen

Weight-based induction therapy:

Eculizumab 10-<40 kg: 600 mg

* 40 kg: 900 mg

Dosing frequency:

Loading phase (first 5 doses) First 5 doses: 1 dose every 48 hours × 2 doses, then 1 dose every 72 hours × 3 doses Induction phase (subsequent 4 doses) Subsequent 4 doses: once weekly for 4 weeks Maintenance phase Once every 2 weeks, continued up to 24 weeks

Dose adjustment principles:

Based on eculizumab trough concentration (target ≥100 μg/mL), CH50 level (<10% of the lower limit of normal), and sC5b-9 target: <244 ng/mL

Monitoring frequency:

Loading phase: daily monitoring Induction and maintenance phases: monitoring prior to each dose

• Eculizumab (Drug): Dosing Regimen Weight-based induction therapy: Eculizumab 10-<40 kg: 600 mg * 40 kg: 900 mg Dosing frequency: Loading phase (first 5 doses) First 5 doses: 1 dose every 48 hours × 2 doses, then 1 dose every 72 hours × 3 doses Induction phase (subsequent 4 doses) Subsequent 4 doses: once weekly for 4 weeks Maintenance phase Once every 2 weeks, continued up to 24 weeks Dose adjustment principles: Based on eculizumab trough concentration (target ≥100 μg/mL), CH50 level (<10% of the lower limit of normal), and sC5b-9 target: <244 ng/mL Monitoring frequency: Loading phase: daily monitoring Induction and maintenance phases: monitoring prior to each dose

Primary outcomes

• 6-month overall survival rate after diagnosis of TA-TMA [6 months after diagnosis of TA-TMA]: This endpoint is defined as the proportion of patients who survive for 6 months (180 days) from the date of TA-TMA diagnosis among all enrolled patients with confirmed TA-TMA in the study population.

Secondary outcomes

• Complete TMA response (cTMA-R) [26-week treatment period]: Within the 26-week treatment period, the subject must meet all of the following criteria: 1) platelet count improvement of ≥50% from baseline; 2) urine protein-to-creatinine ratio (UPCR) reduction of ≥50% from baseline; 3) lactate dehydrogenase (LDH) returning to the normal range and no schistocytes on peripheral blood smear. All three criteria must be met in at least two consecutive assessments separated by ≥4 weeks, and must be maintained in all subsequent assessments from the first consecutive achievement through the end of Week 26. This is defined as a sustained cTMA-R.
• Cumulative incidence and recovery rate of MODS at 6 months after diagnosis of TA-TMA [6 months after diagnosis of TA-TMA]: Over the 6-month (180-day) observation period following the diagnosis of TA-TMA, the proportion of patients with newly developed or worsened multiple organ dysfunction syndrome (MODS). This is calculated as a cumulative incidence under a competing risks model, considering death as a competing event (since patients who die cannot experience a new MODS event).
• 1-year overall survival rate after HSCT [1 year (365 days) from the date of hematopoietic stem cell infusion]: The proportion of patients who are alive at 1 year (365 days) from the date of hematopoietic stem cell infusion, among all transplanted patients in the intention-to-treat population.
• 1-year non-relapse mortality (NRM) after HSCT [1-year (365-day) after transplantation.]: The cumulative incidence of any death not attributable to disease relapse or progression within the 1-year (365-day) observation period after transplantation.
• Organ-specific functional recovery (kidney, lung, cardiovascular, etc.) [6 months after diagnosis of TA-TMA]: Following hematopoietic stem cell transplantation or a specific disease (e.g., TA-TMA), the recovery of one or more specific organ functions from a dysfunctional state during treatment or at the nadir of illness to a predefined, clinically meaningful normal or near-normal functional level, with the improvement sustained for a specified period to confirm stability.
• Safety assessments (infection, infusion-related reactions, etc. [6 months after diagnosis of TA-TMA]: Infection: Clinically significant disease caused by pathogenic microorganisms (e.g., bacteria, viruses, fungi, parasites) requiring medical intervention. Infusion-related reaction: Any adverse event occurring during the study drug infusion or within a specified time window (e.g., within 1 hour or 24 hours) after the infusion ends.
• Maximum Plasma Concentration [Cmax] of eculizumab [6 months after diagnosis of TA-TMA]: Quantitative characterization of the maximum plasma concentration \[Cmax\] of eculizumab. This describes the processes of absorption, distribution, metabolism, and excretion of eculizumab in the human body-i.e., the action of the body on the drug.
• Safety assessments (CD3+ T cells, CD19+ B cells, CD56+ NK cells) [6 months after diagnosis of TA-TMA]: Quantitative description of the effects of eculizumab treatment on the absolute counts and relative percentages of peripheral blood CD3+ T cells, CD19+ B cells, and CD56+ NK cells in patients.
• Minimum Plasma Concentration [Cmin] of eculizumab [6 months after diagnosis of TA-TMA]: Quantitative characterization of the minimum plasma concentration \[Cmin\] of eculizumab. This describes the processes of absorption, distribution, metabolism, and excretion of eculizumab in the human body-i.e., the action of the body on the drug.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age ≥18 years.
* Patients who have undergone hematopoietic stem cell transplantation for any indication within 12 months prior to enrollment.
* Meet the diagnostic criteria for TA-TMA within ≤14 days prior to enrollment (at least 4 of the following 7 criteria present simultaneously):① Lactate dehydrogenase (LDH) above the age-adjusted upper limit of normal;② Presence of schistocytes on peripheral blood smear;③ New-onset thrombocytopenia or requirement for platelet transfusions;④ New-onset anemia or requirement for red blood cell transfusions;⑤ Hypertension;⑥ Random urine protein-to-creatinine ratio (rUPCR) ≥1 mg/mg;⑦ Elevated plasma soluble C5b-9 (sC5b-9) level (≥244 ng/mL).
* Meet the criteria for high-risk TA-TMA (presence of any of the following):① Proteinuria (rUPCR ≥2 mg/mg);②Multiple organ dysfunction syndrome (MODS);③ Elevated IL-10 (≥2× upper limit of normal \[ULN\]).
* Meet the following condition: TA-TMA has not resolved after ≥72 hours of management of triggering factors/conditions, including: ① Discontinuation or dose reduction of inciting medications (e.g., calcineurin inhibitors, CNI); ② Treatment of any underlying infection; ③ Treatment of underlying acute graft-versus-host disease (aGVHD).
* Provide written informed consent.

Exclusion Criteria:

* Known hypersensitivity to eculizumab.
* Uncontrolled severe infection (including meningococcal infection).
* Prior treatment with complement inhibitors.
* Known hereditary or acquired ADAMTS13 deficiency (activity <10%).
* Disseminated intravascular coagulation (DIC).
* Respiratory failure (any cause) requiring mechanical ventilation, occurring within 72 hours prior to enrollment.
* Acute and/or chronic heart failure with ejection fraction ≤40%.
* Expected survival <48 hours.
* Any subject who, in the investigator's opinion, is not suitable for participation in this study.

• YI LUO, Principal investigator, First Affiliated Hospital of Zhejiang University