Clinical Safety and Efficacy of Narsoplimab in Pediatric and Adult Patients with Transplant-Associated Thrombotic Microangiopathy: A Real-World Experience
Authors: Castelli Marta , Mico' Maria Caterina , Grassi Anna , Algarotti Alessandra , Finazzi Maria Chiara , Rambaldi Benedetta , Meli Cristian , Rizzuto Giuliana , Pavoni Chiara , Vendemini Francesca , Verna Marta , Bonanomi Sonia , Balduzzi Adriana , Biondi Andrea , Rambaldi Alessandro , Gotti Giacomo 
Published: December 2023

Introduction
Transplant-associated thrombotic microangiopathy (TA-TMA) is a severe complication occurring after hematopoietic stem cell transplantation (HSCT), often resulting in high morbidity and mortality. There are currently no approved treatments for TA-TMA, but complement inhibition is increasingly recognized as an active treatment option in this setting. Narsoplimab (OMS721) is a fully human IgG4 antibody that binds MASP-2, the effector enzyme of the lectin pathway of the complement system. A recent pivotal trial demonstrated the safety and efficacy of narsoplimab in patients with TA-TMA. We report the results of a real-world experience with narsoplimab in a series of pediatric and adult patients with TA-TMA.
Material and methods
The diagnosis of TA-TMA was based on the following criteria (Schoettler ML, et al. Transplant Cell Ther. 2023 Mar;29(3):151-163): anemia (failure to achieve transfusion independence, hemoglobin decline by ≥1 g/dL or new-onset transfusion dependence); thrombocytopenia (failure to achieve platelet engraftment, transfusion dependence, or ≥50% reduction in baseline platelet count after full platelet engraftment); elevated lactate dehydrogenase (LDH); decreased serum haptoglobin; schistocytes in the peripheral blood smear; hypertension; and proteinuria (≥1 mg/mg random urine protein-to-creatinine ratio [rUPCR]). A positive direct Coombs test was an exclusion criterion. Narsoplimab was administered intravenously at the dose of 4 mg/kg (max 370 mg) twice weekly for at least eight doses. Response criteria were defined by improvement in both laboratory TMA markers and any clinical benefit (Khaled SK, et al. J Clin Oncol. 2022 Aug;1;40(22):2447-2457).
Results
Fifteen patients with a median age of 61 years (range, 6 - 71), 11 adults and 4 pediatrics, were treated under a compassionate use program, after ethical committee approval, between January 2018 and April 2023. All patients had previously undergone allogeneic HSCT (Table 1). All patients presented at least 4 of the 6 criteria for TA-TMA diagnosis. Fourteen patients (93%) were defined as high-risk TA-TMA for the presence of the following criteria: LDH &gt; 2 times the ULN, rUPCR ≥ 1 mg/mg, multiorgan dysfunction, concurrent acute GvHD ≥ grade 2, or infection.
Time from transplant to TA-TMA was 161 days (range, 30 - 452). Before TA-TMA, all patients had acute GvHD with a median of 116 days (range, 21 - 405) after transplant. Severe infection had been documented in 10 patients (67%) after transplant. CMV reactivation and BK virus hemorrhagic cystitis occurred in 5 and 4 patients, respectively. Twelve patients (80%) were on calcineurin inhibitors at TA-TMA onset. Fourteen patients (93%) were transfusion dependent at baseline. Patients received a median of 11 (range, 8-34) doses of narsoplimab. All infusions were well-tolerated, and no narsoplimab-related adverse events were reported.
Eleven patients responded to treatment (73%), based on the achievement of transfusion independence (10 patients) as well as on clinical and laboratory improvement, which occurred in all responders. Before and after narsoplimab, the median hemoglobin values were 9,1 g/dL (range, 7,7 - 12,3) and 10,35 g/dL (range, 9,2 - 12,4); the median platelet count was 25.000/mmc (range, 10.000 - 62.000) and 76.000/mmc (range 32.000 - 367.000); the median LDH values were 497 U/L (range 271 - 1201) and 224 U/L (range 184 - 393), respectively. The median time to response was 50 days (range, 9 - 105). One-hundred-day survival was 80% in the study population and 100% for responders (Figure 1). After treatment completion, TA-TMA never reoccurred. Three of the four patients who failed to respond, eventually died with laboratory and clinical evidence of persisting TA-TMA.
Conclusion
In this study of high-risk TA-TMA patients, the inhibition of the lectin pathway of complement activation with narsoplimab was shown to be not only an effective but also a remarkably safe treatment option with no evidence of an increased risk of infectious complications in both children and adults.