Long Term Treatment with Eculizumab In Paroxysmal Nocturnal Hemoglobinuria (PNH): Sustained Efficacy and Improved Survival
Authors: Kelly Richard J , Hill Anita , Mitchell Lindsay D , Richards Stephen John , Arnold Louise M , Valters Gemma L , Cullen Matthew , Cohen Dena R , Gregory Walter M , Hillmen Peter 
Published: October 2019

Abstract
Abstract 639
PNH is an acquired clonal hemolytic anemia associated with severe symptoms, life-threatening thrombosis, pulmonary hypertension (PH), chronic renal impairment (CRI) and bone marrow failure resulting in reduced quality of life (QoL) and survival (median: 10 – 15 years). Eculizumab is a monoclonal humanized antibody that inhibits terminal complement activity and thereby prevents intravascular hemolysis, reduces transfusions, improves QoL and protects against PH, CRI and thromboses. Eculizumab was approved for PNH in 2007 as a result of studies with short follow-up and with no information on it's impact on survival.
We present data on 79 patients treated with eculizumab from the Leeds PNH Center between May 2002 – July 2010 including 34 patients from the clinical trials and a further 45 treated since, funded in England by the National Commissioning Group (NCG) or locally in Scotland and Wales. The NCG indications for treatment include transfusion-dependent hemolysis (4 or more transfusions in 12 months) or significant PNH-related complications (i.e. thrombosis or renal failure) regardless of transfusion history. Three patients did not fulfil these criteria but were treated for profound symptoms as agreed with the NCG. Forty men and 39 women were treated for a mean of 39 months (1-98). Median age at diagnosis was 37yo (12-79) and at initiation of eculizumab was 46yo (14-84). Median granulocyte clone size at the start of eculizumab was 96.38% (41.78-99.98). Patient survival on eculizumab was compared with age and sex matched controls obtained using data from the UK Office of National Statistics. We previously published that there was a significantly worse survival for PNH patients compared to matched controls with ~ 50% of patients dying as a result of PNH (Hillmen et al., NEJM 1995). In the current series there was no difference in mortality between patients on eculizumab and the normal population (P=0.46; Fig 1). Patients over 70yo had worse survival (P=0.0042) with none of the 45 patients under the age of 50yo dying. Three patients died: a 55yo man from metastatic caecal carcinoma diagnosed prior to eculizumab, a 76yo woman who died from pneumionia following a long history of recurrent bronchopneumonia prior to eculizumab and a 79yo man with a preceding history of ischaemic heart disease who died from cardiac failure. Three patients have had a clonal evolution of their PNH, 1 to acute myeloid leukemia and 2 to myelodysplasia. Two patients have stopped eculizumab: - 1 due to pre-existing aplastic anemia and 1 with spontaneous remission of his PNH. Seventy four patients remain on eculizumab to date.Figure 1Kaplan-Meier survival plots depicting PNH patients on eculizumab compared to age and sex matched controlsFigure 1. Kaplan-Meier survival plots depicting PNH patients on eculizumab compared to age and sex matched controls
There were 34 thrombotic episodes in 21/79 patients (27%) prior to eculizumab and only 2 thromboses since. Importantly primary prophylaxis with warfarin has now been stopped in 21 patients (mean duration of 8.4 months (range: 1–25) and total of &gt; 14 years) with no thromboses occurring. Seven patients had thrombosis within 12 months prior to starting eculizumab and they had no further thromboses on therapy. Therefore eculizumab is effective in preventing new, or evolution of pre-existing thrombosis, and appears to remove the need for primary prophylactic anticoagulation. We have not systematically stopped the anticoagulation of patients with a previous history of thrombosis. Patients had a mean of 19.9 units transfused (0-156) in the 12 months before eculizumab. Of the 64 patients on eculizumab for at least a year, 43 (67%) have been transfusion independent for &gt;12 months. Twenty one patients still needing transfusions had a significant (P=0.028) reduction in their mean requirement of 24.6 (4-52) units in the 12 months before eculizumab compared to a mean of 14.6 (2-50) units in the last 12 months.
Eculizumab is well tolerated long-term (&gt; 8 years of therapy) with continued improvement in PNH associated symptoms, reduction in transfusion requirements and a higher proportion of transfusion independent patients than previously seen. There is a significant reduction in the development of thromboembolism on eculizumab therapy and importantly we have been able to stop primary prophylaxis with warfarin in 21 patients without any thrombotic complications. We demonstrate for the first time that eculizumab has a major impact on survival in PNH so that survival is comparable to an age- and sex-matched control population.

Disclosures:
Kelly: Alexion Pharmaceuticals: Honoraria. Hill:Alexion Pharmaceuticals: Honoraria, Speakers Bureau. Richards:Alexion Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Arnold:Alexion Pharmaceuticals: Honoraria. Hillmen:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.