Eculizumab is an effective therapy for PNH.

Eculizumab is safe and well tolerated in patients with PNH. This antibody against terminal complement protein C5 reduces intravascular hemolysis, hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life in patients with PNH.

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events (TEs) and chronic kidney disease (CKD). The long-term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3-year survival estimate of 97·6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86·9% at 36 months), reflecting inhibition of chronic haemolysis. TEs decreased by 81·8%, with 96·4% of patients remaining free of TEs. Patients also showed a time-dependent improvement in renal function: 93·1% of patients exhibited improvement or stabilization in CKD score at 36 months. Transfusion independence increased by 90·0% from baseline, with the number of red blood cell units transfused decreasing by 54·7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival.

Paroxysmal nocturnal hemoglobinuria (PNH) is a debilitating and life-threatening disease in which lysis of PNH red blood cells frequently manifests with chronic hemolysis, anemia, and thrombosis. Renal damage in PNH is associated with chronic hemosiderosis and/or microvascular thrombosis. We determined the incidence of renal dysfunction or damage, defined by stages of chronic kidney disease (CKD), in a large cohort of PNH patients and evaluated the safety and efficacy of the complement inhibitor eculizumab in altering its progression. Renal dysfunction or damage was observed in 65% of the study population at baseline with 21% of patients with later stage CKD or kidney failure (glomerular filtration rate [GFR] 60 ml/min/1.73 m 2 ; Stage 3, 4, or 5). Eculizumab treatment was safe and well-tolerated in patients with renal dysfunction or damage and resulted in the likelihood of improvement as defined as categorical reduction in CKD stage (P < 0.001) compared with baseline and to placebo (P 5 0.04). Improvement in renal function was more commonly seen in patients with baseline CKD Stages 1-2 (67.1% improvement, P < 0.001) although improvement was also observed in patients with CKD Stages 3-4 (P 5 0.05). Improvements occurred quickly and were sustained for at least 18 months of treatment. Patients categorized at CKD Stages 3-5 did not worsen during treatment with eculizumab. Overall, 40 (21%) of 195 patients who demonstrated renal dysfunction or damage at baseline were no longer classified as such after 18 months of treatment. Administration of eculizumab to patients with renal dysfunction or damage was well tolerated and was usually associated with clinical improvement. Am. J. Hematol. 85:553-559, 2010. V

Rabbit antithymocyte globulin (rATG; thymoglobulin, Genzyme) in combination with cyclosporine, as first-line immunosuppressive therapy, was evaluated prospectively in a multicenter, European, phase 2 pilot study, in 35 patients with aplastic anemia. Results were compared with 105 age-and disease severitymatched patients from the European Blood and Marrow Transplant registry, treated with horse ATG (hATG; lymphoglobulin) and cyclosporine. The primary end point was response at 6 months. At 3 months, no patients had achieved a complete response to rATG. Partial response occurred in 11 (34%). At 6 months, complete response rate was 3% and partial response rate 37%. There were 10 deaths after rATG (28.5%) and 1 after subsequent HSCT. Infections were the main cause of death in 9 of 10 patients. The best response rate was 60% for rATG and 67% for hATG. For rATG, overall survival at 2 years was 68%, compared with 86% for hATG (P ‫؍‬ .009). Transplant-free survival was 52% for rATG and 76% for hATG (P ‫؍‬ .002). On multivariate analysis, rATG (hazard ratio ‫؍‬ 3.9, P ‫؍‬ .003) and age more than 37 years (hazard ratio ‫؍‬ 4.7, P ‫؍‬ .0008) were independent adverse risk factors for survival. This study was registered at www.clinicaltrials.gov as NCT00471848. (Blood. 2012;119(23): 5391-5396) IntroductionHistorically, horse antithymocyte globulin (hATG) has been the preferred animal source of ATG as first-line treatment for acquired aplastic anemia (AA) patients who are ineligible for hematopoietic stem cell transplantation (HSCT). For severe AA (SAA), the combination of ATG and cyclosporine (CSA) results in a response rate of 60% to 75% of patients, and the response is superior to using either agent alone. [1][2][3][4][5] The addition of G-CSF to the combination of ATG and CSA has shown no significant benefit either in terms of response or survival, 6-8 although it may reduce infectious complications and duration of hospital admission. 6 For patients with nonsevere AA (NSAA) who are transfusion dependent, the combination of ATG and CSA is superior to CSA alone, with a higher response rate, higher blood counts, and improved disease-free survival. 9 Rabbit ATG (rATG) is more commonly used for a second course after relapse or lack of response to a first course of hATG. Response to a second course for nonresponse to a first course varies from 30% to 77% 10,11 and only 11% in children. 12 In contrast, in patients relapsing after a first course, the response to a second course is 65%. 11,13 Until 2007, there were 2 preparations of hATG, namely, lymphoglobulin (Genzyme) and ATGAM (Pfizer). The most commonly used preparation of rATG (thymoglobulin, Genzyme) uses the same immunogen as lymophoglobulin; horses or rabbits are immunized with human thymocytes obtained at the time of cardiac surgery from newborn infants. rATG is more immunosuppressive than hATG; it results in more prolonged lymphopenia, 14 and it is more effective at preventing and treating acute renal allograft rejection. 15 We undertook a European study conducted by th...