In this issue of Blood Advances, Matsui et al1 report that inhibition of the lectin pathway with narsoplimab, a monoclonal antibody against mannan-binding lectin–associated serine protease 2 (MASP-2), markedly improved survival in adults with high-risk transplant–associated thrombotic microangiopathy (TA-TMA) compared with a well-matched external controls from the Kyoto Stem Cell Transplantation Group (KSCTG) registry. Their comparative analysis, integrating a pivotal clinical trial (OMS721-TMA-001, NCT02222545) and an expanded-access program (EAP; NCT04247906) of narsoplimab-treated patients, provides comparative survival evaluation for MASP-2 inhibition in this rare and life-threatening posttransplant complication.
TA-TMA remains among the most lethal complications of hematopoietic cell transplantation, driven by endothelial activation, complement dysregulation, and microvascular thrombosis. Despite advances in recognition and supportive care, mortality in severe cases exceeds 80%. Terminal complement (C5) inhibition with eculizumab is used off-label, mostly in children and young adults, with encouraging yet variable responses, and drug dosing requiring close pharmacokinetic monitoring.2,3 The study by Matsui et al addresses an important question: can upstream inhibition of the lectin pathway mitigate endothelial injury in TA-TMA with acceptable therapy safety?
The authors compared overall survival among 77 adults with high-risk TA-TMA treated with narsoplimab (28 in the clinical trial receiving weekly dosing and 49 in EAP receiving 2-3 doses per week) against 121 KSCTG registry controls who did not receive narsoplimab and found a three- to fourfold reduction in mortality in narsoplimab-treated patients (hazard ratio, 0.25-0.38; P < .0001). Median survival was 41 days in controls to ≥274 days in the treated group, and 1-year survival of 16.9% in untreated controls vs 41% in clinical trial and 58% in EAP. Importantly, no new safety signals emerged despite inclusion of patients with profound immune suppression.
This rigorous effort to harmonize 2 narsoplimab-treated data sets with an externally validated registry deserves recognition. In a field historically limited to small, uncontrolled series, Matsui et al deliver a valuable effort to advance our knowledge in using MASP-2 blockade for high-risk TA-TMA.
Our knowledge on narsoplimab use for TA-TMA has been expanding in recent years. First, Khaled et al4 showed hematologic and organ responses with improved survival and favorable safety in multicenter phase 2 study using narsoplimab in adults with TA-TMA refractory to standard care. Small cohorts of real-world data from adults and children confirmed favorable safety, tolerability with some clinical benefit of narsoplimab in patients with TA-TMA especially those without graft-versus-host disease.5,6 Most recently, a multinational analysis by Schoettler et al7 reported 1-year overall survival rate of 58% in patients receiving narsoplimab as first-line therapy and 40.5% in those with more than second-line therapy. Collectively, these studies suggest that MASP-2 inhibition can be administered safely and may offer clinical benefit in severe endothelial injury after transplantation.
Although the survival signal is compelling, especially with doses being 2 to 3 times per week, the Matsui et al8 study also highlights a broader gap between clinical observations and mechanistic understanding of lectin-pathway activation in TA-TMA. To date, no complement biomarkers specific to the lectin pathway have been used to guide diagnosis or treatment. This limitation extends to most published reports on narsoplimab. Consequently, the field still lacks translational evidence identifying when lectin-pathway activation predominates or which patients are most likely to benefit from MASP-2 inhibition. These gaps do not detract from the authors’ achievement but rather define the road map for future studies integrating clinical outcomes with complement biology.
In addition, across published reports, patient selection, severity thresholds, and response criteria vary widely. Some studies include high-risk TA-TMA defined by consensus criteria (with and without testing for sC5b-9),9 whereas others use institution-specific definitions. Clinical responses range from hematologic improvement to organ recovery or survival at different time points, making cross-study comparisons difficult. The recent International Harmonization effort provides a unified diagnostic and prognostic framework that should guide future analyses.9 Only through consistent classification can therapeutic efficacy across complement-blocking strategies be accurately interpreted.
Complement activation in TA-TMA is multifactorial, involving both classical and alternative pathways that converge on C5b-9 formation. C5 inhibition directly blocks membrane-attack–complex assembly, whereas MASP-2 inhibition intervenes earlier, modifying both complement activation and thrombin generation. In practice, the challenge is deciding which pathway is driving an individual patient’s disease. As underscored in our recent review, the field urgently needs biomarkers that can 1) identify pathway predominance (lectin vs alternative vs terminal); 2) define the optimal therapeutic window before irreversible organ injury occurs; and 3) understand pharmacokinetics of therapeutic agents used for intended complement pathway blockade.10 Candidate markers such MASP-2 activity, C3d, C4d, C4 cleavage products, sC5b-9, and other endothelial injury indices (rUPCR, CXCL9, and ST2) warrant systematic evaluation. Integrating these with genomic and proteomic profiling may ultimately enable precision complement-blockade matching the inhibitor to the biology of each patient’s disease.
Matsui et al should be commended for executing a complex comparative analysis in a rare and heterogeneous condition. The findings strengthen the concept that endothelial protection through upstream complement modulation can translate into meaningful survival gains assuming that adequate drug dosing is provided. The study demonstrates that comparative analyses are informative and can be performed with rigor even in the absence of randomized trials, a practical model for severe and rare posttransplant complications where randomization is not feasible due to very high mortality without targeted interventions.
To build on these advances, future studies should embed prospective complement biomarker collection and pharmacodynamic monitoring, standardize TA-TMA severity grading and response definitions, clarify comparative efficacy and safety between MASP-2 and C5 inhibition, including sequential or combined approaches, and investigate differences in pediatric/young adult populations vs older adults. Such efforts will transform lectin-pathway inhibition from empiric therapy to mechanistically-guided precision medicine.
By demonstrating a clear survival benefit with targeted complement-blocking therapies, we can advance the field from clinical signal to comparative evidence. Recently published studies offer momentum and a challenge for the transplant community to pair clinical progress with biological clarity. Through translational integration and consensus-driven design, the full potential of precision complement blockade in TA-TMA can be realized.
Conflict-of-interest disclosure: S.J. receives consultancy from Sobi, Omeros, Novartis, and Alexion.
