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).

Platelet transfusion refractoriness: how do I diagnose and manage?

“…39 The complement inhibitor eculizumab has been used to increase the CCI in a limited number of transfusion refractory patients with severe thrombocytopenia. 40 Finally, in extreme cases when a patient's count must be increased for a procedure, we have resorted to an "in vivo adsorption" strategy: If a patient has a strong antibody against HLA-A2, we repeatedly transfuse an HLA-A2 positive unit to deplete the antibody, then drip-in an A2 positive unit during the procedure.…”

The association and functional relevance of genetic variation in low‐to‐medium‐affinity Fc‐gamma receptors with clinical platelet transfusion refractoriness

“…Because destruction by complement is completely independent of FcγRs, differences in the ability to fix complement may be another explanation for the discrepancy between PLT refractoriness and ITP. Recently, a pilot trial with the complement C5 inhibitor eculizumab indeed showed a positive effect in PLT refractory patients with anti‐HLA antibodies 28 . Theoretically, the difference with ITP could also derive from the possibility that FCGR polymorphisms in ITP do not determine so much the clearance rate of the platelets, but have an influence on the formation of the platelet‐specific autoantibodies, whereas the formation of antibodies in PLT refractoriness, which involves allo‐antigens not present in the recipient, is not influenced so much by FCGR polymorphisms.…”

Post–hematopoietic stem cell transplantation immune-mediated anemia: a literature review and novel therapeutics

“…Vo, et al, used eculizumab, a complement C5 inhibitor, to treat heavily alloimmunized patients with platelet transfusion refractoriness. Four of the 10 patients enrolled overcame platelet transfusion refractoriness with one dose of eculizumab [113]. Eculizumab has shown efficacy in warm antibody autoimmune hemolytic anemia and cold agglutinin disease [114,115].…”

“…Therapies targeting the complement pathway are being more frequently used in immune-mediated cytopenia. Vo et al 112 used eculizumab, a complement C5 inhibitor, to treat heavily alloimmunized patients with platelet transfusion refractoriness. Four of the 10 patients enrolled overcame platelet transfusion refractoriness with 1 dose of eculizumab.…”