A pilot trial of complement inhibition using eculizumab to overcome platelet transfusion refractoriness in human leukocyte antigen allo-immunized patients

Abstract

Heavily transfused patients frequently develop human leukocyte antigen (HLA) allo-immunization resulting in platelet transfusion refractoriness and a high risk for life-threatening thrombocytopenia. Data suggest complement activation leading to the destruction of platelets bound by HLA allo-antibodies may play a pathophysiologic role in platelet refractoriness. Here we conducted a pilot trial to investigate the use of eculizumab, a monoclonal antibody that binds and inhibits C5 complement, to treat platelet transfusion refractoriness in allo-immunized patients with severe thrombocytopenia. A single eculizumab infusion was administered to 10 eligible patients, with four (40%) patients overcoming platelet refractories assessed measuring the corrected platelet count increment (CCI) 10-60 min and 18-24 h post transfusion. Responding patients had a reduction in the requirement for subsequent platelet transfusions and had higher post-transfusion platelet increments for 14 days following eculizumab administration. Remarkably, three of the four responders met CCI criteria for response despite receiving HLA-incompatible platelets. Our results suggest that eculizumab has the ability to overcome platelet transfusion refractoriness in patients with broad HLA allo-immunization. This study establishes proof of principle that complement inhibition can treat platelet transfusion refractoriness, laying the foundation for a large multicentre trial to assess the overall efficacy of this approach (ClinicalTrials.gov, identifier: NCT02298933).

Conflict of interest statement

Conflict of interest disclosure

The authors declare no competing financial interests.

© 2020 British Society for Haematology and John Wiley & Sons Ltd.

Figures

Fig 1.

(A) Total complement (CH50) levels pre and post eculizumab treatment. Median (horizontal lines) are shown at the two time points. (B) Response to platelet transfusion refractoriness post eculizumab in the four responding patients. One-hour (10–60-min, orange bars) and 18–24 h (blue bars) post platelet transfusion CCIs are shown in patients before and after receiving eculizumab. Responses were defined by 1-h CCI > 7500 together with the 18–24-h CCI > 5000 following a platelet transfusion. Green and red arrows indicate HLA-compatible and HLA-incompatible products, respectively.

Fig 2.

(A) Mean platelet count trajectories calculated using 221 available platelet counts measured for two weeks following eculizumab. (B) Number of platelet transfusions given two weeks pre and two weeks post eculizumab treatment.