P1530: PERITRANFUSIONAL C1-INHIBITOR IN PATIENTS WITH SEVERE COMPLEMENT-MEDIATED AUTOIMMUNE HEMOLYTIC ANEMIA: AN OPEN LABEL PHASE 2 TRIAL.

Abstract

Background: Complement-mediated autoimmune hemolytic anemia (AIHA) is characterized by destruction of red blood cells (RBCs) due to autoantibodies that initiate complement activation via the classical pathway. This may result in fulminant intra- and extravascular hemolysis with need for RBC transfusions, of which the efficacy can be compromised by the antibodies reacting with donor RBCs. Hemolysis induces a pro-inflammatory response that can contribute to hypercoagulability, as seen in patients with other complement-mediated hemolytic disorders such as paroxysmal nocturnal hemoglobinuria. C1-inhibitor (C1-INH; Cinryze) is an endogenous plasma regulator of the classical and lectin complement pathway approved for patients with hereditary angioedema. In a single case report and in vitro, we observed that C1-INH administration attenuated complement deposition on RBCs and subsequent hemolysis. Therefore, we hypothesized that peritransfusional administration of C1-INH in complement AIHA would reduce complement activation and hemolysis and thus improve transfusion outcome. Aims: To assess the efficacy and safety of intravenous C1-INH in patients with transfusion-dependent complement-mediated AIHA on parameters for hemolytic activity, complement activation and inflammation. Methods: We conducted a prospective, single center, phase 2 open label trial. Patients with AIHA and confirmed C3c/d-positive direct antiglobulin test, baseline hemoglobin (Hb) of ≤8 g/dL and an indication for ≥ two RBC transfusion units were included after informed consent. Treatment consisted of four peritransfusional doses of C1-INH intravenously (6000, 3000, 2000 and 1000 U) with 12 hour (hr) intervals. Blood samples at 0, 12, 24, 36, 48, 72 hrs, 7 and 14 days were analyzed for hemolytic parameters, RBC opsonization and markers of complement activation and systemic inflammation (nucleosomes and human neutrophil elastase-α1-antitrypsin complexes (HNE-α1-ATc)). Safety was monitored and scored (CTCAE version 4.0). Results: Ten patients were included in the study. At baseline, we found increased complement C3d, IgG and IgM deposition on RBCs compared to healthy controls (p=0.002, 0.005 and 0.002). Circulating C3b/c levels, nucleosomes and HNE-α1-ATc were increased compared to healthy controls (p<0.001, p=0.046 and p=0.001). C1-INH administration resulted in an increase of C1-INH antigen and -activity, peaking at 48 hrs (Fig. A). At 48 hrs after first administration, treatment significantly reduced C3d deposition on RBCs (-21%, p=0.016), but not systemic complement activation as shown by C3b/c levels (-14.96 nM, p=0.874; Fig. B). With declining C1-INH levels, C3 deposition increased again. Shortly after transfusion, Hb increased (1.59 g/dL at 12 h; p=0.008), but at 48 hrs, hemolytic and inflammation parameters did not improve (LDH -169.5 U/L, p=0.572; bilirubin total -4.306 µmol/L, p=0.987; Hb -1.217 g/dL; p=0.056; nucleosomes -17%, p=0.938; HNE-α1-ATc +21%;, p=0.297; Fig. C, D). No serious adverse events were reported. Image:Summary/Conclusion: Peritransfusional C1-INH in AIHA temporarily reduced local complement activation as evidenced by C3d deposition on RBCs, but did not affect hemolysis or systemic complement activation. Increased Hb levels at later timepoints were observed, but this effect might be confounded by additional treatments and transfusions. In conclusion, we found no (clinically) significant effect of C1-INH on hemolysis and systemic complement activation. This may be explained by the dosing of C1-INH, which possibly was too low to counter the severe complement-mediated AIHA and additional transfusion effects.