Abstract
Background: 30-50% of heavily platelet transfused patients will ultimately develop HLA allo-immunization. Although HLA-matched platelets can be lifesaving for these patients, a substantial proportion of patients receiving partially HLA-matched platelet products develop platelet transfusion refractoriness, putting them at risk for serious bleeding complications. Recent data suggest compliment activation leading to the destruction of platelets bound by HLA allo-antibodies may play a pathophysiologic role in platelet refractoriness. Eculizumab is a monoclonal antibody that binds and inhibits C5 compliment, blocking both the classic and alternative pathways of compliment. Here we investigated whether eculizumab treatment could be used to overcome platelet transfusion refractoriness in HLA allo-immunized patients.
Methods: We conducted a one armed; phase II pilot trial (NCT02298933) in which HLA allo-immunized patients with platelet transfusion refractoriness received a single infusion of eculizumab at a dose of 1200mg. Eligible patients included adults age 18-75 with severe thrombocytopenia who had detectable HLA class I antibodies associated with platelet transfusion refractoriness (defined as a post-transfusion corrected count increment (CCI) of <7500/ul and <5000/ul at 10-60 mins and 18-24 hrs respectively that occurred following at least 2 consecutive platelet transfusions). Patients were defined to respond to therapy if one of the first 2 platelet transfusions following eculizumab infusion resulted in a CCI>7500/uL at 10-60 mins and CCI>5000/uL at 18-24 hrs post transfusion. Subjects were taken off study 14 days following eculizumab treatment. Responding patients who developed recurrent platelet refractoriness after planned study withdrawal were eligible to re-enroll on study. All patients were required meningococcal vaccination before eculizumab infusion +/- antibiotic prophylaxis to cover N. meningitidis.
Results: As of 8/2016, 8 Eculizumab infusions were administered to 7 HLA allo-immunized subjects (median age 40 yrs, range 24-71) with severe thrombocytopenia associated with platelet transfusion refractoriness. Patients had an underlying diagnosis of SAA (n=3), refractory/relapsed AML (n=2; 1 patient had just finished conditioning for a haplo-identical transplant), relapsed ALL (n=1; post MUD transplant) and high risk MDS (n=1).
Compliment, total (CH50) was the most reliable and consistent measure for complement inhibition. After Eculizumab infusion, CH50 decreased to <20U/ml in all treated patients. 3 of 8 (43%) patients had a response to therapy with platelet refractoriness resolving following 4/8 (50%) eculizumab administrations (Figures 1-3). Subject 1 received an additional 2nd treatment with eculizumab 2 months after her 1st response and again had resolution of platelet refractoriness (Figure 1A&1B).
In 3 out of 4 cases where platelet refractoriness was overcome, the administered platelet product given immediately after eculizumab treatment expressed an HLA allele for which an HLA antibody had been detected in the patient's serum. Resolution of platelet refractoriness resulted in a clinically meaningful reduction in the requirement for platelet transfusions: the median number of platelet transfusion given 2 weeks before and 2 weeks after the eculizumab infusion in responding patients was 8.5 (range 3-10) and 4.5 (range 3-5) transfusions respectively. For the non-responders, the median number of platelet transfusions given 2 weeks before and 2 weeks after the eculizumab infusion was 8 (range 7-10 ) and 9.5 (range 6-15) transfusions respectively.
Conclusions: The preliminary data from this ongoing trial suggest eculizumab may have efficacy in overcoming HLA antibody-associated platelet transfusion refractoriness. Remarkably, we observed eculizumab overcame platelet refractoriness in a subset of HLA allo-immunized patients receiving HLA mismatched platelet products that expressed an HLA allele for which an HLA antibody was detectable in the patient's serum. These data raise the possibility that eculizumab administration could be of therapeutic benefit in patients with platelet refractoriness as a consequence of newly discovered HLA antibodies, buying time for transfusion medicine departments to acquire HLA matched platelets or until platelet recovery occurs following chemotherapy or stem cell transplant.
No relevant conflicts of interest to declare.
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