In a pivotal phase II trial reported in the Journal of Clinical Oncology, Samer K. Khaled, MD, and colleagues found that narsoplimab, an inhibitor of mannan-binding lectin-associated serine protease-2, showed efficacy in the treatment of adult patients with hematopoietic stem cell transplantation–associated thrombotic microangiopathy (HSCT-TMA). On the basis of the current study, the U.S. Food and Drug Administration has initially denied approval of narsoplimab in this setting, noting that additional information would be required.

As stated by the investigators, “HSCT-TMA is a serious complication with significant mortality and no approved therapy. HSCT-TMA results from endothelial injury, which activates the lectin pathway of complement.”

Samer K. Khaled, MD

Study Details

In the international trial, 28 patients with HSCT-TMA were enrolled between August 2015 and October 2019. Patients received intravenous narsoplimab once weekly for 4 to 8 weeks. A total of 24 patients received a dose of 4 mg/kg, with 4 patients enrolled late in the trial receiving a fixed dose of 370 mg. The primary endpoint (response) required clinical improvement in two categories: (1) laboratory TMA markers (both platelet count and lactate dehydrogenase [LDH]) and (2) organ function or freedom from transfusion.

Response Rate

Among the 28 patients, 17 (61%, 95% confidence interval [CI] = 41%–79%) achieved response on the basis of improvements in both TMA markers and clinical benefit. Improvement in TMA markers was observed in 17 patients (61%), including improvement in platelet count in 14 (61%) of 23 and improvement in LDH in 21 (75%) of 28. Improvement in organ function occurred in 20 (74%) of 27 patients, including improvement in kidney function in 18 67%) of 27, and freedom from transfusion was achieved in 12 (48%) of 25.   

Survival at 100 days after HSCT-TMA diagnosis was 68% (95% CI = 48%–84%) among all patients and 94% (95% CI = 71%–100%) among responders. Median overall survival was 274 days (95% CI = 103 days–not estimable) in the total population.

Adverse Events

Adverse events were typical of those observed in patients with HSCT-TMA, with no apparent safety signals of concern. The most common type of adverse event was infection, which occurred in 71% of patients, including grade ≥ 2 infection in 61%. The most common individual adverse events of any grade were pyrexia (36%), diarrhea (32%), and vomiting (32%). Grade 3 or 4 adverse events occurred in 61% of patients. Overall, adverse events considered at least possibly related to study treatment occurred in 10 patients (36%). Adverse events led to death in four patients, due to septic shock, progressive acute myeloid leukemia, neutropenic sepsis, and graft-vs-host disease and TMA. 

The investigators concluded, “In this study, narsoplimab treatment was safe, significantly improved laboratory TMA markers, and resulted in clinical response and favorable overall survival.”

Alessandro Rambaldi, MD, of Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Omeros Corporation. For full disclosures of the study authors, visit ascopubs.org.