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Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy

Bone Marrow Transplantation volume 51, pages 1241–1244 (2016)Cite this article

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Hematopoietic cell transplant-thrombotic microangiopathy (HCT-TMA) is a devastating syndrome associated with transplant-related morbidity and mortality, and has similar histomorphologic features to those seen in atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP).1, 2, 3 These conditions share a common end point of microthrombotic vascular endothelial cell injury, but with differing underlying pathophysiologic mechanisms. The TMA in TTP is related to severely deficient ADAMTS13 activity and the resulting ultra-large Von Willebrand factor multimers that aggregate platelets in conditions of high shear forces. In contrast, the microthrombotic disease in aHUS is a result of complement-mediated microvascular injury and platelet activation.4 HCT-TMA typically leads to multi-organ failure, and criteria were recently issued to standardize the reporting of HCT-TMA.5, 6 Known risk factors of HCT-TMA include radiation, chemotherapy, ABO incompatibility, calcineurin inhibitors, sirolimus, viral infections and GvHD.7, 8 Common treatment approaches to HCT-TMA are largely ineffective and include withdrawal of calcineurin inhibitors, plasma exchange and intravenous immune globulin (IVIG), resulting in high mortality and morbidity rates.3, 9 We report a retrospective study of five patients who developed HCT-TMA and were treated with complement inhibition using eculizumab.

Eculizumab (Alexion, Inc., Cheshire, CT, USA) is a C5-blocking antibody that has been approved for the treatment of aHUS.10 Eculizumab is a first-in-class complement inhibitor and a humanized monoclonal antibody that binds to C5, thereby inhibiting the formation of the terminal components of the complement cascade. Recently, the use of eculizumab in pediatric patients with HCT-TMA has been reported.11 Here we describe five adult patients who developed symptoms and signs of HCT-TMA and were treated with eculizumab. Four out of five patients demonstrated improvement in hematologic and renal parameters, but two patients succumbed to infectious complications from treatment of exacerbation of pre-existing GvHD. Plasma biomarkers of complement activation were studied to assist in the clinical evaluation and the treatment of TMA.

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Acknowledgements

We acknowledge the staff of the Blood and marrow transplantation program at the Arthur G. James Cancer Hospital who helped in caring for the patients described in the manuscript.

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Authors and Affiliations

  1. Division of Hematology, The Ohio State University, Columbus, OH, USA

    S Vasu, W Blum, R Klisovic, L Andritsos, C Hofmeister, D M Benson, Y Efebera, S Jaglowski, S Penza, S Devine & S Cataland

  2. Department of Pathology, The Ohio State University, Columbus, OH, USA

    H Wu, A Satoskar & D Cohen

  3. Department of Pharmacy, James Cancer Hospital, The Ohio State University, Columbus, OH, USA

    M Puto & J Roddy

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  1. S Vasu
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Correspondence to S Vasu.

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Competing interests

SC has received research funding and honoraria from Alexion, Inc., the manufacturer of eculizumab. The remaining authors declare no conflict of interest.

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Vasu, S., Wu, H., Satoskar, A. et al. Eculizumab therapy in adults with allogeneic hematopoietic cell transplant-associated thrombotic microangiopathy. Bone Marrow Transplant 51, 1241–1244 (2016). https://doi.org/10.1038/bmt.2016.87

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