Narsoplimab, a Mannan-Binding Lectin-Associated Serine Protease-2 Inhibitor, for the Treatment of Adult Hematopoietic Stem-Cell Transplantation–Associated Thrombotic Microangiopathy

Khaled, Samer K.; Claes, Kathleen; Goh, Yeow Tee; Kwong, Yok Lam; Leung, Nelson; Mendrek, Włodzimierz; Nakamura, Ryotaro; Sathar, Jameela; Ng, Edmund; Nangia, Narinder; Whitaker, Steve; Rambaldi, Alessandro

doi:10.1200/jco.21.02389

Cited by 54 publications

(34 citation statements)

References 22 publications

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“…Further, as a result of possible cross talk between systems, LP inhibitors may be of particular interest in bleeding patients with complement dysregulation. Narsoplimab (OMS721) is a human monoclonal IgG4 inhibitor of MASP2, which has recently completed a phase II study assessing its effectiveness in patients with TMA [97][98][99]. Data from this phase II study of 28 patients suggest that narsoplimab improves laboratory markers of TMA and organ function and may have a beneficial effect on overall survival in patients with HSCT-TMA [97][98][99].…”

Section: Hsct-tma: Future Treatments Targeting Complementmentioning

confidence: 99%

“…Narsoplimab (OMS721) is a human monoclonal IgG4 inhibitor of MASP2, which has recently completed a phase II study assessing its effectiveness in patients with TMA [97][98][99]. Data from this phase II study of 28 patients suggest that narsoplimab improves laboratory markers of TMA and organ function and may have a beneficial effect on overall survival in patients with HSCT-TMA [97][98][99]. However, overall physiologic concentrations of active LP molecules are low, suggesting it may play a minor role in HSCT-TMA pathogenesis, and there may be a risk of reduced efficacy in conditions such as HSCT-TMA because of the apparent involvement of all complement pathways in pathogenesis [97,98].…”

Section: Hsct-tma: Future Treatments Targeting Complementmentioning

confidence: 99%

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The Role of Complement in HSCT-TMA: Basic Science to Clinical Practice

et al. 2022

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Section: Hsct-tma: Future Treatments Targeting Complementmentioning

confidence: 99%

Section: Hsct-tma: Future Treatments Targeting Complementmentioning

confidence: 99%

The Role of Complement in HSCT-TMA: Basic Science to Clinical Practice

et al. 2022

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“…In a recent study of 19 patients with TA-TMA treated with Narsoplimab, survival at day 100 was significantly better compared to historical controls (53% vs. 10%). Disease markers (platelet count, haptoglobin and LDH) also improved in the Narsoplimab group [ 75 ]. Despite the limitations of the study (small cohort, no information on the use of immunosuppressants and lack of specific dose regimen), Narsoplimab received a Breakthrough Therapy Designation from the US FDA in 2022 for the treatment of TA-TMA after allo-HSCT.…”

Section: Current Therapeutic Approachesmentioning

confidence: 99%

Transplant-Associated Thrombotic Microangiopathy in the Context of Allogenic Hematopoietic Stem Cell Transplantation: Where We Stand

Λαζανά

2023

IJMS

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Transplant-associated thrombotic microangiopathy (TA-TMA) constitutes a significant contributor to the increased morbidity and mortality after allogenic hematopoietic stem cell transplantation (allo-HSCT). TA-TMA is a heterogenous disease, characterized by the triad of endothelial cell activation, complement dysregulation and microvascular hemolytic anemia, which may affect all organs. The lack of consensus diagnostic criteria, along with the common clinical features mimicking other diseases that complicate allo-HSCT, make the diagnosis of TA-TMA particularly challenging. Significant effort has been made to recognize specific risk factors predisposing to the development of TA-TMA and to identify serum biomarkers predicting the development of the disease. With regard to treatment, therapeutic plasma exchange (TPE) has been traditionally used, although with doubtful efficacy. On the other hand, the pivotal role of complement activation in the pathophysiology of TA-TMA has led to the exploration of the therapeutic potential of complement inhibitors in this setting. Eculizumab has been proposed as a first-line therapeutic agent in TA-TMA, owing to the very promising results in both pediatric and adult clinical trials. Pharmacokinetic and pharmacodynamic studies and CH50 levels are of paramount importance in the allo-HSCT setting, as a different dosing schedule (more intensive—in dose and frequency—at the beginning) seems to be required for successful outcomes. Furthermore, Narsoplimab, a MASP-2 inhibitor, recently received a Breakthrough Therapy Designation from the FDA for the treatment of TA-TMA after allo-HSCT. Finally, the decision to withdraw the CNIs, although initially advised by the Bone and Marrow Transplant Clinical Trials Network Committee, remains debatable owing to the controversial results of recent clinical trials. This review summarizes the current updates on pathophysiology, diagnosis and therapeutic approaches and emphasizes future goals and perspectives.

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“…Narsoplimab has been used in COVID-19 patients [ 78 ], showing a reduction of endothelial cell damage. In a single-arm open-label pivotal trial (NCT02222545), in which 28 adult patients with TA-TMA received narsoplimab, a response rate of 61% was observed [ 79 ].…”

Section: Complement System Involvementmentioning

confidence: 99%

Complement System as a New Target for Hematopoietic Stem Cell Transplantation-Related Thrombotic Microangiopathy

et al. 2022

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Thrombotic microangiopathy (TMA) is a complication that may occur after autologous or allogeneic hematopoietic stem cell transplantation (HSCT) and is conventionally called transplant-associated thrombotic microangiopathy (TA-TMA). Despite the many efforts made to understand the mechanisms of TA-TMA, its pathogenesis is largely unknown, its diagnosis is challenging and the case-fatality rate remains high. The hallmarks of TA-TMA, as for any TMA, are platelet consumption, hemolysis, and organ dysfunction, particularly the kidney, leading also to hypertension. However, coexisting complications, such as infections and/or immune-mediated injury and/or drug toxicity, together with the heterogeneity of diagnostic criteria, render the diagnosis difficult. During the last 10 years, evidence has been provided on the involvement of the complement system in the pathophysiology of TA-TMA, supported by functional, genetic, and therapeutic data. Complement dysregulation is believed to collaborate with other proinflammatory and procoagulant factors to cause endothelial injury and consequent microvascular thrombosis and tissue damage. However, data on complement activation in TA-TMA are not sufficient to support a systematic use of complement inhibition therapy in all patients. Thus, it seems reasonable to propose complement inhibition therapy only to those patients exhibiting a clear complement activation according to the available biomarkers. Several agents are now available to inhibit complement activity: two drugs have been successfully used in TA-TMA, particularly in pediatric cases (eculizumab and narsoplimab) and others are at different stages of development (ravulizumab, coversin, pegcetacoplan, crovalimab, avacopan, iptacopan, danicopan, BCX9930, and AMY-101).

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Narsoplimab, a Mannan-Binding Lectin-Associated Serine Protease-2 Inhibitor, for the Treatment of Adult Hematopoietic Stem-Cell Transplantation–Associated Thrombotic Microangiopathy

Cited by 54 publications

References 22 publications

The Role of Complement in HSCT-TMA: Basic Science to Clinical Practice

The Role of Complement in HSCT-TMA: Basic Science to Clinical Practice

Transplant-Associated Thrombotic Microangiopathy in the Context of Allogenic Hematopoietic Stem Cell Transplantation: Where We Stand

Complement System as a New Target for Hematopoietic Stem Cell Transplantation-Related Thrombotic Microangiopathy

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