Between January 2018 and August 2023, 20 patients received narsoplimab for TA-TMA at the dose of 4 mg/kg. Thirteen patients were adults, with a median age of 40 (range, 32–71), and 7 patients were pediatric, with a median age of 13 (range, 5–19). All patients except two pediatric patients with sickle cell disease underwent HSCT for hematologic malignancies. Demographic and transplant characteristics are described in Table 1.

All the pediatric and adult TA-TMA were diagnosed according to the criteria proposed by Jodele and Cho, respectively. In addition, 15 (75%) patients fulfilled the criteria recently proposed by the Schoettler et al. expert panel group. The frequencies of the different diagnostic criteria met in our study population are reported in Table 2.

In our study, TA-TMA was confirmed by histologic biopsies in two adult patients. In the first case, the patient received the diagnosis of TA-TMA due to the presence of anemia, thrombocytopenia, elevated LDH, low haptoglobin, and proteinuria. Due to an intestinal perforation, this patient underwent an urgent colon resection. The biopsy of the resected sigmoid tract revealed typical signs of thrombotic microangiopathy, including gland loss, mucosal hemorrhages, and endothelial cell denudation, as commonly described in the literature [25] (Fig. 1a/b). After the surgical intervention, the patient started treatment with narsoplimab. Laboratory evidence of progressive response to treatment was documented and, following 11 doses, the patient achieved a complete laboratory and clinical response and is currently alive in complete remission.

a Loss of glands in the colon mucosa, characterized by the disappearance and atrophy of glands. Mucosal denudation, involving the loss of surface epithelium, often replaced by a single layer of regenerative enterocytes. b Widespread sloughing of epithelial cells and perivascular hemorrhages in the mucosa, indicated by the extravasation of red blood cells (RBC) from capillaries in the lamina propria. c Necrosis of the gastric mucosa and extensive ulceration. d Endothelial cell swelling, characterized by the enlargement of endothelial cells in the capillaries of the lamina propria. Sparse fungal elements in the vast necrotic area. Diffuse perivascular mucosal hemorrhage.

In the second case, the diagnosis of TA-TMA was posed due to the onset of anemia, thrombocytopenia, elevated LDH, uncontrolled hypertension, and neurological symptoms such as confusion, tremors, and lethargy. The clinical picture was further complicated by an invasive fungal infection. As the patient began to experience melena, an esophagogastroduodenoscopy was performed. The patient was under treatment with CNI (tacrolimus) and steroids (methylprednisolone 1 mg/kg). The histologic examination revealed a deepithelialized mucosa with erosions, making it difficult to exclude either gastrointestinal acute GvHD (aGvHD) or ischemic damage from intestinal TA-TMA (iTAM) [26]. Fungal hyphae and necrotic areas were also identified in the biopsy, indicating potential outcomes of widespread endothelial damage (Fig. 1c/d). Despite iTAM presenting with clinical symptoms resembling those of intestinal GvHD and often coexisting with intestinal aGvHD—a notable trigger for TA-TMA [9, 27,28,29]—our patient exhibited persistent gastric bleeding unresponsive to immunosuppressive therapy. This patient did not respond to narsoplimab and died 78 days after the diagnosis of TA-TMA.

Median time from transplant to TA-TMA was 85.5 days (range, 24–452). Risk factors for TA-TMA development such as GvHD and infections were present in a high proportion of patients. Before the diagnosis of TA-TMA and treatment with narsoplimab, 19 of the 20 patients (95%) were diagnosed with high-risk TA-TMA according to the consensus criteria in Schoettler et al. [7]. Specifically, 17 patients (85%) had a diagnosis of grade II–IV acute GvHD at a mean of 52 days (range, 14–223 days) after transplant. Sixteen patients (80%) required the start of high-dose steroids as first-line treatment and a complete GvHD response was obtained in 6 of them (5 adult patients and 1 pediatric). The remaining 10 (50%) patients were deemed steroid-refractory and started a second-line therapy for acute GvHD, ruxolitinib in most cases.

Before narsoplimab, infections were documented in 15 patients (75%) at a mean of 21 days (range, 1–267 days) after transplant, with CMV reactivation occurring in 6 patients, BK virus hemorrhagic cystitis in 7 patients, blood-stream positivity for bacteria in 4 patients, and SARS-CoV-2 with pneumonia and Clostridium difficile diarrhea in one patient each.

Thirteen patients (65%) presented with LDH levels exceeding 2 times the ULN, 10 (50%) with rUPCR ≥ 1 mg/mg, and 7 (35%) had organ dysfunction. Eighteen (90%) patients had at least two criteria for high-risk TA-TMA.

None of the adult patients discontinued CNI at the diagnosis of TA-TMA, to avoid the risk of exacerbating the concomitant GvHD. Five pediatric patients tapered or discontinued CNIs at TA-TMA diagnosis.

Narsoplimab was started at a mean of 3.5 days (range, 0–52) from TA-TMA onset. Patients received a median of 11 (range, 4–34) doses. Three patients responded after 8 doses. Thirteen patients received >8 doses, with 10 patients achieving a complete response after a median of 6 additional doses (range, 2–26). In 2 non-responders, the treatment was stopped after 4 and 5 doses, respectively, due to death. All infusions were well tolerated, and no signals of concern were reported.

Overall, the response rate was 65% (Table 3). Response rate was 62% (8/13) in adults and 71% (5/7) in pediatric patients. Improvement in laboratory TMA markers occurred in all responders. Before and after narsoplimab, median hemoglobin values were 9.1 g/dL (7.7–12.3) and 9.9 g/dL (8–12.4); median platelet count was 16,000 per microliter (range, 13,000–62,000) and 44,000 per microliter (range, 18,000–413,000), median LDH values were 531 U/L (range, 237–1201) and 324 U/L (range, 184–1061), respectively. The median time to response was 53 days (range, 9–133).

Nineteen (95%) patients were transfusion dependent at diagnosis. All responding patients were free from platelet and red-blood-cell transfusions at the end of the treatment.

Following Khaled’s criteria of renal function response [24], 9 out of 20 patients responded (45%), while the rUPCR value improvement was more impressive in pediatric than adult patients.

Among the 13 patients who responded to narsoplimab, 8 had acute GvHD with intestinal involvement of overall grade ≥ 2.

One pediatric patient had a concomitant diagnosis of poor graft function and received a second infusion of hematopoietic stem cells after 19 doses of narsoplimab. Before the stem cell boost, this patient had gained an improved renal function but no response in terms of anemia, thrombocytopenia, and LDH. The stem cell boost induced a recovery from anemia and thrombocytopenia, but a fully normalized LDH value was documented only after 30 doses of narsoplimab.

A total of 7 patients (35%) did not respond to the treatment. Within the pediatric cohort, one patient faced fatal leukoencephalopathy with persistent active TMA, leading to the discontinuation of narsoplimab after 12 administrations. Another patient died on day +36 after transplant following 5 doses of narsoplimab administered for disease progression in the context of TA-TMA, venous occlusive disease (VOD), and multi-organ failure, unresponsive to treatment with defibrotide. Two other pediatric patients initially treated with defibrotide at TA-TMA diagnosis did not respond to it. However, they subsequently started narsoplimab and responded after 8 and 12 doses, respectively. In the adult patients, nobody received other treatment for TA-TMA before narsoplimab.

Among the adults, five patients failed to respond to narsoplimab. All of them, despite intensive care, died of progressive multiorgan failure, characterized by complications such as acute respiratory failure, acute renal failure, and hemodynamic instability. At the time of death, laboratory signs of TA-TMA could still be detected. In the fifth non-responder, narsoplimab was discontinued due to inefficacy and a concomitant refractory poor graft function.

After a median follow-up time of 13 months (range, 0.36–48.16) after TA-TMA diagnosis, the OS was 70%. One-hundred-day survival was 70% in the study population and 100% among responders (Fig. 2). None of the patients included in this study experienced TA-TMA reactivation.

Overall Survival from TA-TMA diagnosis (a) and from transplant date (b).