Eculizumab is an effective therapy for PNH.

The terminal complement inhibitor eculizumab was recently shown to be effective and well tolerated in patients with paroxysmal nocturnal hemoglobinuria (PNH). Here, we extended these observations with results from an open-label, nonplacebo-controlled, 52-week, phase 3 clinical safety and efficacy study evaluating eculizumab in a broader PNH patient population. Eculizumab was administered by intravenous infusion at 600 mg every 7 ؎ 2 days for 4 weeks; 900 mg 7 ؎ 2 days later; followed by 900 mg every 14 ؎ 2 days for a total treatment period of 52 weeks. Ninety-seven patients at 33 international sites were enrolled. Patients treated with eculizumab responded with an 87% reduction in hemolysis, as measured by lactate dehydrogenase levels (P < .001). Baseline fatigue scores in the FACIT-Fatigue instrument improved by 12.2 ؎ 1.1 points (P < .001). Eculizumab treatment led to an improvement in anemia. The increase in hemoglobin level occurred despite a reduction in transfusion requirements from a median of 8.0 units of packed red cells per patient before treatment to 0.0 units per patient during the study (P < .001). Overall, transfusions were reduced 52% from a mean of 12.3 to 5.9 units of packed red cells per patient. Forty-nine patients (51%) achieved transfusion independence for the entire 52-week period. Improvements in hemolysis, fatigue, and transfusion requirements with eculizumab were independent of baseline levels of hemolysis and degree of thrombocytopenia. Quality of life measures were also broadly improved with eculizumab treatment. This study demonstrates that the beneficial effects of eculizumab treatment in patients with PNH are applicable to a broader population of PNH patients than previously studied. This trial is registered at

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Hemolysis and hemoglobinemia contribute to serious clinical sequelae in hemolytic disorders. In paroxysmal nocturnal hemoglobinuria (PNH) patients, hemolysis can contribute to thromboembolism (TE), the most feared complication in PNH, and the leading cause of disease-related deaths. We evaluated whether long-term treatment with the complement inhibitor eculizumab reduces the rate of TE in patients with PNH. Clinical trial participants included all patients in the 3 eculizumab PNH clinical studies, which recruited patients between 2002 and 2005 (n ‫؍‬ 195); patients from these studies continued treatment in the current multinational open-label extension study. Thromboembolism rate with eculizumab treatment was compared with the pretreatment rate in the same patients. The TE event rate with eculizumab treatment was 1.07 events/100 patient-years compared with 7.37 events/100 patient-years (P < .001) prior to eculizumab treatment (relative reduction, 85%; absolute reduction, 6.3 TE events/100 patient-years). With equalization of the duration of exposure before and during treatment for each patient, TE events were reduced from 39 events before eculizumab to 3 events during eculizumab (P < .001). The TE event rate in antithrombotic-treated patients (n ‫؍‬ 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P < .001). These results show that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH. This study is registered at http://clinicaltrials.gov (study ID no. NCT00122317). IntroductionIntravascular hemolysis and cell-free plasma hemoglobin have been implicated in the serious clinical sequelae of various hemolytic disorders. 1 Hemolysis is the primary clinical manifestation of the uncommon disease paroxysmal nocturnal hemoglobinuria (PNH) and has been shown to result in chronic disabling morbidities including anemia, severe fatigue, difficulty in functioning, pain, and thrombosis, all of which have a major effect on the patient's quality of life. 1-5 Paroxysmal nocturnal hemoglobinuria is defined by the acquired genetic deficiency of glycosylphosphatidylinositol (GPI)-linked proteins from the surface of blood cells. The absence of GPI-linked complement regulatory proteins on PNH erythrocytes renders them susceptible to terminal complement-mediated hemolysis.Hemolysis most likely contributes to thromboembolism (TE) in PNH, as patients with larger PNH clones have a higher incidence of TE and events have been temporally associated with increased hemolysis. 6-10 Although the mechanism is not fully understood, hemolysis has been implicated in the initiation of platelet activation and aggregation. 1 Additional in vitro studies have suggested that complement may directly activate platelets from PNH patients. 11,12 Thromboembolism is the leading cause of mortality in patients with PNH, 2,3,13-17 and an initial thrombotic event increases the relative risk of death in PNH 5-to 10-fold. 15,17 Retrospective studies suggest that, in non-Asian patients, TE accou...

From 2002 to 2007, 103 patients with primary myelofibrosis or postessential thrombocythemia and polycythemia vera myelofibrosis and a median age of 55 years (range, 32-68 years) were included in a prospective multicenter phase 2 trial to determine efficacy of a busulfan (10 mg/kg)/fludarabine (180 mg/m 2 )-based reduced-intensity conditioning regimen followed by allogeneic stem cell transplantation from related (n ‫؍‬ 33) or unrelated donors (n ‫؍‬ 70). All but 2 patients (2%) showed leukocyte and platelet engraftment after a median of 18 and 22 days, respectively. Acute graft-versushost disease grade 2 to 4 occurred in 27% and chronic graft-versus-host disease in 43% of the patients. Cumulative incidence of nonrelapse mortality at 1 year was 16% (95% confidence interval, 9%-23%) and significantly lower for patients with a completely matched donor (12% vs 38%; P ‫؍‬ .003). The cumulative incidence of relapse at 3 years was 22% (95% confidence interval, 13%-31%) and was influenced by Lille risk profile (low, 14%; intermediate, 22%; and high, 34%; P ‫؍‬ .02). The estimated 5-year event-free and overall survival was 51% and 67%, respectively. In a multivariate analysis, age older than 55 years (hazard ratio ‫؍‬ 2.70; P ‫؍‬ .02) and human leukocyte antigenmismatched donor (hazard ratio ‫؍‬ 3.04; P ‫؍‬ .006) remained significant factors for survival. The study was registered at www. clinicaltrials.gov as #NCT 00599547. (Blood. 2009;114:5264-5270)