Complement Inhibition Using Eculizumab to Overcome Platelet Transfusion Refractoriness in Patients With Severe Thrombocytopenia

Complement Inhibition Using Eculizumab to Overcome Platelet Transfusion Refractoriness in Patients With Severe Thrombocytopenia

Complement Inhibition Using Eculizumab to Overcome Platelet Transfusion Refractoriness in Patients With Severe Thrombocytopenia

Background: - Platelets are tiny cells in the blood that help stop bleeding. Thrombocytopenia happens when people do not have enough normal platelets. Getting a transfusion of another person s platelets can help stop too much bleeding. But because these cells are from other people, the body may reject them,putting them at risk for serious bleeding complications. This conditions is called alloimmune platelet refractoriness . There are evidence that in many patients, platelet counts fail to increase after a platelet transfusion because the transfused platelets are destroyed by the body s defence soldier, called complement . Researchers want to see if a drug, that inhibits complement, can help increase platelet levels and reduce bleeding Objectives: - To see if eculizumab increases platelet levels more after a transfusion. To see if it reduces the chance of bleeding too much. Eligibility: - Adults 18-75 years old who have thrombocytopenia and alloimmune platelet refractoriness. Design: Participants will be screened with medical history, physical exam, and blood tests. Participants will have the procedures listed below. They can have them while they are in the hospital. Or they can go to the outpatient clinic for them. Each visit may take up to 3 hours. Participants will get a meningitis vaccine if needed. Then they will get the study drug as an infusion. Participants will have a platelet transfusion. Their blood will be drawn every 24 hours until the platelet count is less than 10,000 per 1 microliter of blood. They will take antibiotics for 14 days. Participants will have a checkup and blood drawn twice a week for 2 weeks. They will get more transfusions if needed.

Platelet transfusion can be a life-saving procedure in preventing or treating serious bleeding in patients who have low and/or dysfunctional platelets. Treatment of blood cancer and other blood diseases as well as bone marrow transplantation is not possible without platelet transfusion support. Unfortunately, 20-60% of chronically transfused patients will stop responding to these transfusions putting them at risk for serious bleeding complications. Data support the concept that in many patients, platelet counts fail to increase after a platelet transfusion because the transfused platelets are destroyed by the body s complement. In order to overcome this problem, we will inhibit complement activity with the medication eculizumab that specifically binds and suppresses complement. We hypothesize that when we treat patients who have platelet refractoriness with eculizumab, the platelet counts will increase to higher numbers after platelet transfusions, decreasing the risk of bleeding complications associated with having a low platelet count.

To evaluate the safety and efficacy of eculizumab to increase the platelet increment, defined as Corrected Count Increment (CCI) >7500/μL at 10-60 min together with CCI>5000/μL at 18-24 hrs post transfusion in patients with platelet refractoriness following treatment with eculizumab and platelet transfusion.

INCLUSION CRITERIA: Ages 18-75 years inclusive. Ability to comprehend the investigational nature of the study and provide informed consent. Thrombocytopenia (due to congenital causes, bone marrow failure, hematologic malignancies, and treatment related), defined as <10k/uL without bleeding or <30K/uL with evidence of life threatening bleeding (intracranial hemorrhage, GI bleeding, pulmonary hemorrhage, uncontrolled epistaxis, hematuria). Diagnosed with immune platelet refractoriness, characterized by all of the following: Lack of adequate post-transfusion platelet count increment, defined by, CCI <7500/ul at 10-60 min, and CCI <5000/ul at 18-24 hrs (in those who had a CCI at 10-60 min greater than or equal to 5000/microl)after at least 2 consecutive transfusions. Presence of anti-HLA class A and/or B antibody. EXCLUSION CRITERIA: Active meningococcal infection. Severe psychiatric illness. Mental deficiency sufficiently severe as to make making informed consent impossible. Positive pregnancy test for women of childbearing age within 1 week. HIV positive test within 3 months Paroxysmal Nocturnal Hemoglobinuria (PNH) disease with evidence of intravascular hemolysis. Presence ITP/autoimmune thrombocytopenia Immune platelet refractoriness responsive to treatment with IVIG RE-ENROLLMENT CRITERIA: Meet response criteria to the initial treatment or second treatment Meets all initial inclusion/exclusion criteria

Vo P, Purev E, West KA, McDuffee E, Worthy T, Cook L, Hawks G, Wells B, Shalabi R, Flegel WA, Adams SD, Reger R, Aue G, Tian X, Childs R. A pilot trial of complement inhibition using eculizumab to overcome platelet transfusion refractoriness in human leukocyte antigen allo-immunized patients. Br J Haematol. 2020 May;189(3):551-558. doi: 10.1111/bjh.16385. Epub 2020 Feb 21.