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Successful use of narsoplimab to treat allogeneic transplant-associated thrombotic microangiopathy while maintaining sirolimus

Bone Marrow Transplantation (2024)Cite this article

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Hematopoietic cell transplantation-associated thrombotic microangiopathy (TA-TMA) is a unique thrombotic and inflammatory disorder that complicates the post allogeneic hematopoietic cell transplantation (alloHCT) course in up to15% of patients [1, 2], leading to a significant increase in morbidity and mortality [3]. TA-TMA has a median time-to-onset of 86 days post alloHCT [4]. Endothelial injury is the key event for TA-TMA, with subsequent endothelial cell injury propagating pro-inflammatory cytokines leading to activation of both alternative and lectin pathways of complement [5, 6]. Hemolytic anemia leading to longer-than-expected transfusion needs, thrombocytopenia and wide range of organ dysfunction characterize TA-TMA [2]. The historic lack of uniformly accepted clinical diagnostic criteria and the fact TA-TMA often coincides with other confounding complications post alloHCT that share common manifestations makes the diagnosis challenging. Efforts to build a consensus definition for TA-TMA by multiple societies have been recently published [7]. Graft-versus-host disease (GVHD) itself and the drugs typically used for prophylaxis such as calcineurin inhibitors (CNI) or mammalian target of rapamycin (mTOR) inhibitors, are often implicated in potentiating TA-TMA and complicating its diagnosis and management [8]. A growing body of evidence suggests that preexisting or novel endothelial dysfunction may create the necessary immune-inflammatory environment for TA-TMA, a process that can be exacerbated by GVHD [9, 10]. CNI cause endotheliopathy by their direct cytotoxic damage, elevated thrombomodulin and decreased prostacyclin, while mTOR inhibitors prevent endothelial repair and decrease VEGF production [11]. Withdrawal of CNI and/or mTOR inhibitors upon identifying TA-TMA has been commonly practiced as a primary intervention [12]. However, since TA-TMA can occur early in post alloHCT and/or with concomitant active GVHD, this approach can be challenging.

The use of anti-C5 monoclonal antibody eculizumab has shown promising activity in pediatric patients with TA-TMA, resulting in 66% overall survival (OS) at 1 year (compared to 16.7% in control) [13]. In adult patients with TA-TMA, small retrospective studies have reported hematological responses with eculizumab in most patients, however, with limited OS benefit, with only one third of patients alive at 30 weeks post TA-TMA diagnosis [14]. Narsoplimab (Omeros Corporation, Seattle, WA) is a novel, fully human immunoglobulin G4 monoclonal antibody that inhibits mannan-binding lectin-associated serine protease-2 (MASP2), the effector enzyme of the lectin pathway of complement. A recent phase II study evaluated the efficacy of narsoplimab prospectively in 28 patients with high-risk TA-TMA showed promising results with 61% response rate (defined as improvement in both TA-TMA markers and organ dysfunction) and 68% OS at 100 days from the date of TA-TMA diagnosis [15]. Herein, we report for the first time, a patient with high-risk TA-TMA successfully treated with narsoplimab while maintaining GVHD prophylaxis/treatment.

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Fig. 1: Linear graphs depicting the HSCT-TMA markers’ timeline upon the diagnosis, after switching tacrolimus to sirolimus, initiating narsoplimab, and the response to it.

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Data used and/or analyzed during this submission are original and they are available from corresponding author on reasonable request.

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Acknowledgements

This research was supported in part by NIH/NCI Cancer Center Support Grant P30 CA008748. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Department of Medicine, Adult Bone Marrow Transplant Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Mohammad Alhomoud, Michael Scordo & Miguel-Angel Perales

  2. Weill Cornell Medical College, New York, NY, USA

    Michael Scordo & Miguel-Angel Perales

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Contributions

MA and MAP conceptualized and wrote the paper. MS contributed to the writing of the manuscript and provided important insight. All authors reviewed and approved the final manuscript.

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Correspondence to Miguel-Angel Perales.

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Competing interests

MA has no conflicts of interest to disclose. MS served as a paid consultant for McKinsey & Company, Angiocrine Bioscience, Inc., and Omeros Corporation; received research funding from Angiocrine Bioscience, Inc., Omeros Corporation, and Amgen, Inc.; served on ad hoc advisory boards for Kite – A Gilead Company; and received honoraria from i3Health, Medscape, and CancerNetwork for CME-related activity. MAP reports honoraria from Adicet, Allogene, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, ImmPACT Bio, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Syncopation, VectivBio AG, and Vor Biopharma. He serves on DSMBs for Cidara Therapeutics, Medigene, and Sellas Life Sciences, and the scientific advisory board of NexImmune. He has ownership interests in NexImmune, Omeros and OrcaBio. He has received institutional research support for clinical trials from Allogene, Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis.

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Alhomoud, M., Scordo, M. & Perales, MA. Successful use of narsoplimab to treat allogeneic transplant-associated thrombotic microangiopathy while maintaining sirolimus. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02263-w

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