Terminal Complement Inhibitor Eculizumab Research Articles

Effect of Eculizumab on Iron Metabolism in Transfusion-independent Patients With Paroxysmal Nocturnal Hemoglobinuria

Effect of Eculizumab on Iron Metabolism in Transfusion-independent Patients With Paroxysmal Nocturnal Hemoglobinuria

Extravascular Hemolysis Due to C3-Loading in Patients with PNH Treated with Eculizumab: Defining the Clinical Syndrome

IntroductionComplement-mediated intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH) is effectively prevented by the terminal-complement inhibitor eculizumab, reducing symptoms and protecting against the clinical consequences of the disease, such as thrombosis and renal failure. Due to the continued activation of the proximal complement cascade upstream of C5, PNH red cells become opsonized with fragments of C3, leading to extravascular hemolysis and a continued transfusion requirement in a proportion of patients. Lactate dehydrogenase (LDH) is utilised as the main indicator of hemolysis in PNH but is particularly a measure of intravascular rather than extravascular hemolysis and therefore is not necessarily elevated in proportion to transfusion requirement due to C3-loading. We therefore conducted data analysis to determine whether other parameters were more indicative of extravascular hemolysis.MethodsData from patients with PNH treated in the Leeds centre of the UK PNH National Service was reviewed retrospectively. Criteria for inclusion in the analysis were treatment with eculizumab for ≥13 months, a mean platelet count >50 x 109/L and mean absolute neutrophil count >0.5 x 109/L (to exclude patients with significant bone marrow failure). Mean values for hemoglobin, absolute reticulocyte count, LDH (adjusted for upper limit of normal), total bilirubin and the proportion of PNH red cells loaded with C3 were collated covering a 48-month period. C3 loading of red cells was assessed by flow cytometry (Sutherland et al., Curr Protoc Cytom. 2015). Red cell transfusion requirements for the latest 12 months and latest eculizumab dosage were also collected.ResultsOne hundred and forty-one patients were identified for inclusion by the above criteria; 70 males and 71 females. The median hemoglobin level for all patients was 109g/l. Seventy-two percent had a mean hemoglobin below 120g/l despite treatment with eculizumab and all patients had variable amounts of C3 on their red cells demonstrating that some degree of extravascular hemolysis is always seen. During the latest 12 months, 51 (36%) patients received at least one transfusion, with 23 (16%) requiring 3 or more transfusions. Thirty (21%) patients were receiving a higher dose of eculizumab (1200mg or more every 2 weeks) due to either sub-therapeutic eculizumab levels and/or measureable terminal complement levels, assessed by the CH50, at the standard dose of 900mg every two weeks.Patients were stratified by both reticulocyte count and LDH and the means for each parameter calculated as shown in Table 1. Bilirubin, C3 loading, transfusion requirement and requirement for an increased dose of eculizumab all correlated better when stratifying by reticulocytes rather than by LDH.When patients were scored on the severity of C3 loading, bilirubin values and reticulocyte count, those with the worst (highest) joint scores were 3 times more likely to be transfused. 72/141 (51%) patients had all three of the following: reticulocyte count <230 x 109/l, bilirubin <30umol/l and less than 30% of their PNH red cells staining for C3. 55 of these 72 (76%) were not transfused in the last 12 months. In contrast 9 patients had reticulocytes >230, bilirubin ≥30 and C3-loading ≥30% and 7 of these 9 continued to require transfusions.ConclusionReticulocyte count appears to be a better indicator of extravascular hemolysis than LDH, correlating more strongly with raised bilirubin, increased C3 loading of PNH red cells and increased transfusion requirement. Using these parameters patients who are more likely to continue to require transfusion support on eculizumab can be identified. Such an approach may be used to identify patients who are more likely to benefit from inhibition of the complement cascade that could reduce the level of C3-associated extravascular hemolysis. [Display omitted] DisclosuresRichards:Alexion Pharmaceuticals, Inc.: Honoraria. Munir:Alexion Pharmaceuticals, Inc.: Honoraria; Gilled: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Roche: Honoraria. Griffin:Alexion Pharmaceuticals, Inc.: Honoraria. Arnold:Alexion Pharmaceuticals, Inc.: Honoraria. Hill:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hillmen:Roche: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding.

Discontinuation of Complement-Inhibitor Therapy in Patients with Atypical Hemolytic Uremic Syndrome

The terminal complement inhibitor eculizumab has improved the outlook for patients with atypical hemolytic uremic syndrome (aHUS), especially with

Benefits of eculizumab in AQP4+ neuromyelitis optica spectrum disorder: Subgroup analyses of the randomized controlled phase 3 PREVENT trial

BackgroundAntibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. MethodsIn the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. ResultsThe significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. ConclusionAcross a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registrationNCT01892345 (ClinicalTrials.gov).

Use of the terminal complement inhibitor eculizumab in paediatric heart transplant recipients.

Antibody-mediated rejection is a major clinical challenge that limits graft survival. Various modalities of treatment have been reported in small studies in paediatric heart recipients. A novel approach is to use complement-inhibiting agents, such as eculizumab, which inhibits cleavage of C5 to C5a thereby limiting the formation of membrane attack complex and terminal complement-mediated injury of tissue-bound antibodies. This medical modality of treatment has theoretical advantages but the collective experience in its use in the solid organ transplant community remains small. We add to this experience by combining 14 cases from 6 paediatric heart centres in this descriptive study.

Атипичный гемолитико-уремический синдром: современные представления о патогенезе, клинике, подходах к диагностике и лечению

Атипичный гемолитикоуремический синдром (аГУС) ультраредкое (орфанное) заболевание прогрессирующего течения, представляющее собой системную тромботическую микроангиопатию (ТМА) вследствие хронической неконтролируемой активации альтернативного пути комплемента. В настоящее время установлено, что генетические аномалии комплемента, которые раньше рассматривали как основную причину заболевания, являются лишь фактором, предрасполагающим к возникновению ТМА. Классическую триаду клинических проявлений аГУС составляют тромбоцитопения, микроангиопатическая гемолитическая анемия и острое повреждение почек. У большинства пациентов независимо от возраста отмечается артериальная гипертензия, основными причинами которой являются гиперренинемия вследствие ишемии ткани почек, обусловленной ТМА, и перегрузка объемом при наличии олиго/анурии. Атипичный ГУС представляет собой системную ТМА, при которой могут поражаться не только почки, но и другие жизненно важные органы головной мозг, сердце, легкие, пищеварительный тракт, глаза и др. Диагноз аГУС это диагноз исключения. Он устанавливается на основании характерной клинической картины после исключения других форм ТМА, как первичных, так и вторичных. Для исключения тромботической тромбоцитопенической пурпуры (ТТП) всем больным с ТМА необходимо определение активности ADAMTS13: снижение ее до 10 и менее является диагностическим маркером ТТП. У пациентов с аГУС и другими ТМА активность ADAMTS13 может быть снижена, однако всегда превышает 10. Инновационным подходом к лечению аГУС, используемым в клинической практике в течение последнего десятилетия, стало применение экулизумаба препарата группы комплеменингибирующих антител, который является препаратом патогенетической терапии аГУС. Экулизумаб является средством первой линии для лечения детей с установленным диагнозом аГУС, при семейном характере заболевания, наличии экстраренальных проявлений. Совершенствование методов диагностики и внедрение новых подходов к лечению позволяет быстрее заподозрить и купировать проявления аГУС, добиться стойкой ремиссии и улучшить прогноз. Atypical hemolytic uremic syndrome (aHUS) is an ultra rare (orphan) progressive disease that is a systemic thrombotic microangiopathy (TMA) due to chronic uncontrolled activation of the alternative complement pathway. It is currently established that complement genetic abnormalities that were previously considered the main cause of the disease, are only a factor predisposing to TMA occurrence. The classic triad of aHUS clinical manifestations is thrombocytopenia, microangiopathic hemolytic anemia andacute kidney damage. Most patients, regardless of age, have arterial hypertension the main reasons of hypertension are hyperreninemia (due to kidney tissue ischemia because of TMA) and volume overload in the presence of oligo/anuria. Atypical HUS is a systemic TMA that affected not only the kidneys, but also other vital organs brain, heart, lungs, digestive tract, eyes, etc. The diagnosis of aHUS is a diagnosis of exclusion that is established on the basis of specifi c clinical picture after exclusion of other forms of TMA, both primary and secondary. To exclude thrombotic thrombocytopenic purpura (TTP), all patients with TMA need to determine ADAMTS13 activity: its reducing to 10 or less is a diagnostic marker of TTP. In patients with aHUS and other TMA, ADAMTS13 activity may be reduced, but always exceeds 10. The innovative pathogenetic approach to aHUS treatment over the last decade became the application of eculizumab that is a drug from complementinhibitory antibodies group. Eculizumab is a fi rstline treatment for children with proven aHUS diagnosis, with familial disease, with extrarenal manifestations. Progress in diagnostic methods and new treatment approaches allows us to quickly suspect and stop the manifestations of aHUS, achieve stable remission and improve the prognosis.

Comparative Evaluation of Complement Factor D, C3, and C5 Inhibitors on Serum Bactericidal Activity Against Neisseria Meningitidis Isolates

Introduction: Treatment of complement-associated disorders with the terminal complement inhibitor eculizumab brings a thousand-fold elevated risk of meningococcal disease due to blockage of serum bactericidal activity (SBA) and opsonophagocytosis against Neisseria meningitidis (Nm). Vaccination against Nm is recommended for eculizumab recipients yet infection remains a risk in immunized individuals. Eculizumab was reported to inhibit killing of Nm serogroups B and C in an in vitro study with whole blood from vaccinated donors; in contrast, the investigational complement factor D (FD) inhibitor danicopan (ACH-4471), currently in phase 2 trials for treatment of disorders including paroxysmal nocturnal hemoglobinuria (PNH), had much less effect in the same study. Danicopan also showed limited effect in a separate study of SBA against unencapsulated (non-groupable) Nm strains recovered from eculizumab recipients who developed invasive meningococcal disease, whereas eculizumab blocked all observed SBA. The present study undertakes a comparative evaluation of danicopan, eculizumab, and the complement C3 inhibitor compstatin against SBA with donor sera against Nm strains comprising multiple serogroups. Methods: Serum from three donors (1-3) was obtained before and after vaccination with MenB-4C against serogroup B and conjugate vaccine against serogroups A, C, W, and Y. Five Nm isolates were tested comprising serogroups B, C, W, and Y. SBA was considered positive when bacterial viability was half or less of that observed with inactive control serum following incubation in 20% serum for one hour. Results: Partial SBA was observed in pre-vaccination sera (positive in eight of 15 serum-strain pairings) whereas post-vaccination sera were positive in nearly all cases (13 of 15). Serum donor 3 was selected for comparative inhibitor studies; pre-vaccination serum was SBA-positive against three of five Nm isolates (serogroups C, W, and Y), whereas post-vaccination serum was SBA-positive against all five. Danicopan in pre-vaccination serum inhibited SBA against two of three serogroups (W and Y), likely indicating a requirement of AP activity for amplification when anti-Nm antibody titer is low. However, danicopan in post-vaccination serum had no effect on SBA against all five Nm isolates, indicating no AP requirement when anti-Nm antibody titer is sufficient. In contrast to danicopan, compstatin and eculizumab inhibited SBA of pre-vaccination and post-vaccination serum against all Nm isolates. Conclusions: We conclude that selective FD inhibition, such as by danicopan or the second-generation FD inhibitor ACH-5228, presents a reduced risk of meningococcal disease compared with treatment with C3 or C5 inhibitors. Disclosures Zhao: Achillion Pharmaceuticals, Inc.: Employment. Patel:Achillion Pharmaceuticals, Inc.: Employment. Thanassi:Achillion Pharmaceuticals, Inc: Employment. Huang:Achillion: Employment, Equity Ownership. Podos:Achillion Pharmaceuticals, Inc: Employment.

Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab’s efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (−2.4 [1.34] and − 3.3 [0.65]); Quantitative Myasthenia Gravis (−2.9 [1.98] and − 4.3 [0.79]); Myasthenia Gravis Composite (−4.5 [2.63] and − 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (−8.6 [5.68] and − 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population.

An updated classification of thrombotic microangiopathies and treatment of complement gene variant-mediated thrombotic microangiopathy.

Conditions presenting with signs of thrombotic microangiopathies (TMAs) comprise a wide spectrum of different diseases. While pathological hallmarks are thrombosis of arterioles and capillaries, clinical signs are mechanical haemolysis, thrombocytopenia and acute renal injury or neurological manifestations. The current classification of various syndromes of TMA is heterogeneous and often does not take the underlying pathophysiology into consideration. Therefore we propose a simplified classification based on the aetiology of different syndromes leading to TMA. We propose to categorize different TMA syndromes in hereditary and acquired forms and classify them based on the genetic background or underlying conditions. Of course, this classification is not always distinctly applicable in each case and from time to time reassessment of the established diagnosis is strongly recommended. The recommended treatment of TMA in the past was plasma exchange (PE). However, recently, the terminal complement inhibitor eculizumab became commercially available and has shown promising results in different open-label studies and case series. In our centre, first-line therapy is PE; however, patients are instantly switched to complement inhibitory therapy in case of treatment failure or intolerance.

Eculizumab Is Safe and Effective as a Long-term Treatment for Protein-losing Enteropathy Due to CD55 Deficiency.

Loss of the complement inhibitor CD55 leads to a syndrome of early-onset protein-losing enteropathy (PLE), associated with intestinal lymphangiectasia and susceptibility to large-vein thrombosis. The in vitro and short-term treatment benefits of eculizumab (C5-inhibitor) therapy for CD55-deficiency have been previously demonstrated. Here we present the 18-months treatment outcomes for 3 CD55-deficiency patients with sustained therapeutic response. Three CD55-deficiency patients received off-label eculizumab treatment. Clinical and laboratory treatment outcomes included frequency and consistency of bowl movements, weight, patient/parent reports of overall well-being, and serum albumin and total protein levels. Membrane attack complex deposition on leukocytes was tested by flow cytometry, before and during eculizumab treatment. Marked clinical improvement was noted in all 3 patients with resolution of PLE manifestations, that is, diarrhea, edema, malabsorption, overall well-being, growth, and quality of life. In correlation with the clinical observations, we observed progress in all laboratory outcome parameters, including increase in albumin and total protein levels, and up to 80% reduction in membrane attack complex deposition on leukocytes (P < 0.001). The progress persisted over 18 months of treatment without any severe adverse events. CD55-deficiency patients present with early-onset diarrhea, edema, severe hypoalbuminemia, abdominal pain, and malnutrition. Targeted therapy with the terminal complement inhibitor eculizumab has positive clinical and laboratory outcomes in PLE related to CD55 loss-of-function mutations, previously a life-threatening condition. Our results demonstrate the potential of genetic diagnosis to guide tailored treatment, and underscore the significant role of the complement system in the intestine.

Post-Allogeneic Hematopoietic Stem Cell Transplantation Eculizumab as Prophylaxis Against Hemolysis and Thrombosis for Patients with Hematologic Disorders Associated with Paroxysmal Nocturnal Hemoglobinuria Clones.

Paroxysmal nocturnal hemoglobinuria (PNH) is frequently seen in the context of other aplastic anemia and myelodysplastic syndromes and is associated with hemolysis and increased thromboembolic events. Allogeneic hematopoietic stem cell transplantation (alloHCT) is the sole curative treatment but is associated with significant morbidity. The terminal complement inhibitor eculizumab reduces hemolysis and thromboembolic events and is the sole Food and Drug Administration-approved therapy for PNH. Prophylactic administration of this agent in the early post-transplantation setting to prevent hemolysis and thrombosis has not been described in the literature. We describe our institutional experience of 8 patients with PNH who underwent alloHCT and who received at least 1 dose of eculizumab within 30 days of alloHCT for prevention of thrombosis and hemolysis. One patient with underlying aplastic anemia who received bone marrow stem cells failed to engraft. Another patient experienced steroid-refractory grade IV acute graft-versus-host disease and died of a fungal infection. The other patients engrafted well; no hemolysis, thrombotic events, or infections associated with encapsulated bacteria occurred in any of the 8 patients.

Use of eculizumab in pregnancy-associated atypical hemolytic uremic syndrome

Abstract Pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) is a rare disorder, with an estimated incidence of 1 in 25,000 pregnancies [Fakhouri F, Roumenina L, Provot F, Sallee M, Caillard S, Couzi L, et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol. 2010;21:859–67.]. Unlike classic hemolytic uremic syndrome (HUS), aHUS is not related to Escherichia coli 0157:H7 infections. Rather, it arises from uncontrolled alternative complement pathway activation leading to diffuse endothelial damage. The formation of the resulting fibrin and platelet microthrombi in the vasculature leads to hemolysis, thrombocytopenia and ischemic end-organ damage in the form of acute kidney injury [Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87; Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, et al. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–81; Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60; Shen YM. Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016;14(Suppl 1):19.]. Triggers for hyperactivation of the complement pathway include infection, inflammation, malignancy, endothelium-affecting drugs, maternal-fetal hemorrhage and pre-eclampsia [Shen YM. Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome. Thromb J. 2016;14(Suppl 1):19.]. Thirty percent of individuals with aHUS are found to have mutations in the genes encoding complement regulatory proteins, such as protein factor H, complement factor I and complement 3 [Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–87; Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60.]. Outcomes of an untreated aHUS are poor: up to 50% of patients with aHUS progress to end-stage renal disease within a year and 25% die during the acute phase [Loirat C, Fremeaux-Bacchi V. Atypical hemolytic uremic syndrome. Orphanet J Rare Dis. 2011;6:60; Laurence J, Haller H, Mannucci PM, Nangaku M, Praga M, Rodriguez de Cordoba S. Atypical hemolytic uremic syndrome (aHUS): essential aspects of an accurate diagnosis. Clin Adv Hematol Oncol. 2016;14(Suppl 11):2–15.]. We present an unusual case of a 37-year-old primigravida who developed p-aHUS in the setting of hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome. She was successfully treated with a relatively novel medication; eculizumab, a terminal complement inhibitor. In contrast to previous reports of long-term treatment, she received a total of six doses of eculizumab and remained in remission at 12 months postpartum.

Thrombotic microangiopathy associated with intravenous injection of extended-release oxycodone

We describe the case of a 35-year-old man presenting with thrombotic microangiopathy (TMA) and renal impairment following, as he later disclosed, intravenous injection of oral formulation tamper-resistant extended-release oxycodone hydrochloride...

Rare genetic variants in Shiga toxin-associated haemolytic uraemic syndrome: genetic analysis prior to transplantation is essential.

We present a case of haemolytic uraemic syndrome (HUS) in a 16-year-old female with serological evidence of acute Escherichia coli O157:H7 infection. She progressed to established renal failure and received a deceased donor kidney transplant. Shiga toxin–associated HUS (STEC-HUS) does not recur following renal transplantation, but unexpectedly this patient did experience rapid and severe HUS recurrence. She responded to treatment with the terminal complement inhibitor eculizumab and subsequent genetic analysis revealed a rare variant in a complement gene. This highlights the importance of genetic analysis in patients with STEC-HUS prior to renal transplantation so that management can be individualized.

Serologic response to meningococcal vaccination in patients with paroxysmal nocturnal hemoglobinuria (PNH) chronically treated with the terminal complement inhibitor eculizumab.

Eculizumab is indicated for the therapy of patients with symptomatic paroxysmal nocturnal hemoglobinuria (PNH). Due to inhibition of terminal complement cascade, patients on eculizumab are susceptible to Neisseria meningitidis infections. The two mainstays to reduce the risk of infection are vaccination and antibiotic prophylaxis. In this retrospective study, serologic response was analyzed after vaccination with a meningococcal vaccine in 23 PNH patients (median age 36years; range 25 - 88years; 15 males, 8 females) by measuring serum bactericidal assay (SBA) using rabbit complement (rSBA) titers against meningococcal serogroups A, C, W, and Y. Serologic protection was defined by an rSBA titer ≥1:8. Forty-three percent (10/23) were vaccinated more than once due to chronic eculizumab treatment. Overall serologic response for the meningococcal serogroups was A: 78% (18/23), C: 87% (20/23), W: 48% (11/23), and Y: 70% (16/23). No meningococcal infections have been observed. As immunological response to vaccines varies, the use of serologic response analyses is warranted. Re-vaccination with a tetravalent conjugate vaccine under eculizumab therapy every 3years is essential or should be based on response rates. If meningococcal infection is suspected, standby therapy with ciprofloxacin and immediate medical evaluation are recommended. The novel vaccines covering serogroup B may even further reduce the risk for infection.

The Role of Whole-Body Magnetic Resonance Imaging (WB-MRI) in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

▪INTRODUCTION: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal blood disorder of the hematopoietic stem cells characterized by chronic, uncontrolled complement-mediated intravascular hemolysis resulting in thrombophilia with thromboembolic events (TEs) and cytopenia due to bone marrow failure. PNH is the most vicious acquired thrombophilic state and TEs represent the leading cause of morbidity and mortality in PNH. PNH clone size correlates with the possibility to acquire a thrombosis but thromboses are also present in patients (pts) with small clones. Early detection of TEs is critically to improve the outcome in PNH with the availability of the terminal complement inhibitor eculizumab.METHODS: Between Dec 2013 and Jan 2016 whole-body magnetic resonance imaging (WB-MRI) scans at 1.5 Tesla (T) (Siemens MAGNETOM® Avanto) were performed in 37 pts (51% (19/37) females; median age 44 years (range 24-73 years), median D-dimer 0.23 mg/l (range 0.2-5.1 mg/l) with either PNH (n=23) or AA/PNH-syndrome (n=14). The protocol included a cranial time-of-flight magnetic resonance angiography (TOF-MRA), an arterial and venous contrast-enhanced MRA (CE-MRA), and a T1-weighted contrast-enhanced fat-suppressed gradient-echo sequence (radial volumetric interpolated breath-hold examination (VIBE)). Median clone size of GPI-deficient granulocytes (FLAER) was 88% (range 2.6-100%) and all pts were treated according to the German PNH guidelines, including the use of the terminal complement inhibitor eculizumab (70% (26/37)), with eculizumab being initiated in 23 pts prior to MRI. In the remaining pts eculizumab was initiated post MRI for reasons other than TEs. In 64% (24/37) of the pts no TEs were documented prior to the MRI scans. Two pts had a possible clinical history of TEs, including pulmonary embolism (PE) or deep venous thrombosis (DVT). The remaining pts (29% (11/37)) had a history of venous thromboses (e.g. DVT (5/11), portal venous thromboses (4/11), or vena caval thromboses (2/11)). One pt even had a myocardial infarction and two had a cerebral venous sinus thrombosis or a thalamic infarction. Six pts (16%) had more than just one documented TE in their medical history.RESULTS: In pts with the history of TEs we did not observe a progression of the existing TEs. There was no evidence of PE throughout observation time. In pts under chronic eculizumab therapy and prior TEs, additional bone infarcts involving the lower extremities were seen in one pt. In a second pt the diagnosis of a bilateral renal infarction was made. In two pts with no history of TEs bone infarcts of the lower extremities were seen (clone size >50%). In another pt a previously undiagnosed left renal infarction was observed. Moreover, a clinical non-critical occlusion of the right posterior tibial artery was identified in one pt.CONCLUSIONS: In contrast to previous studies there was no evidence for silent major TEs (e.g. PE) at the time of analysis. We were able to identify previously undiagnosed renal and bone infarctions (overall unknown prevalence) in our cohort of PNH pts. This is the first description of bone infarctions as possible thromboembolic complications in PNH. WB-MRI scans seem to be a novel and feasible method for the assessment of the whole vascular status of a PNH pt and allow the detection of previously unidentified vascular complications. This might directly affect treatment as eculizumab is indicated in PNH pts with TEs. Furthermore, in pts with existing TEs WB-MRI scans might be implicated to document their impact prior to treatment, especially in pts with major TEs or in pts with high disease acitivity and suspicion for TEs (e.g. recurrent abdominal pain or persisting dyspnea). DisclosuresDührsen:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Röth:Alexion Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Novartis: Honoraria.

(1125) - The Use of the Terminal Complement Inhibitor Eculizumab in Pediatric Heart Transplant Recipients

(1125) - The Use of the Terminal Complement Inhibitor Eculizumab in Pediatric Heart Transplant Recipients

Complement Inhibition with Eculizumab in Patients with Cold Agglutinin Disease (CAD): Results from a Prospective Phase II Trial (DECADE Trial)

▪BACKGROUND: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia characterized by hemagglutination and complement-mediated extra- and intravascular hemolysis. Conventional therapeutic approaches, such as corticosteroids, intravenous immunoglobulin G, alkylating agents or other immunosuppressive drugs, are largely ineffective, and the therapeutic efficacy of rituximab is limited. Successful treatment of a patient with CAD with the terminal complement inhibitor eculizumab reported by us previously (Röth et al., Blood 2009) prompted us to test this novel approach in a larger number of patients.PATIENTS and METHODS: We conducted a prospective, controlled, non-randomized, multicenter phase II trial with pre- and post-treatment comparison. Inclusion criteria were symptomatic cold agglutinin-mediated hemolysis with a serum lactate dehydrogenase (LDH) level ≥ 2 x upper limit of normal and a cold agglutinin titer > 64 at 4°C. Eculizumab was given by intravenous infusion at 600 mg weekly for 4 weeks, followed 1 week later by a 900 mg dose and then 900 mg every other week through week 26. Two weeks before the first dose patients received vaccination against N. meningitidis. The primary endpoint was LDH level, secondary endpoints included transfusion requirements, parameters of intravascular hemolysis, quality of life, 6-minute walk test (6MWT), circulatory symptoms and thrombosis. The analysis was performed in the intent-to-treat population. Missing data were replaced by carrying the last observation forward. The trial was registered at http://clinicaltrials.gov as NCT01303952.RESULTS: Between 2011 and 2014 13 treatment-naïve or pretreated patients with CAD were enrolled. The median age was 74 years (range: 64 - 80), with a male-to-female ratio of 3 to 10. After treatment with eculizumab the LDH decreased from a median pre-treatment level of 572 U/L (mean ± standard deviation: 670 ± 300 U/L) by an average of 56% to a median end-of-treatment level of 327 U/L (400 ± 279 U/L; p = 0.0215, Wilcoxon signed-rank test). This was accompanied by a reduction in transfusion requirement from a median of 4.0 red blood cell units per patient in the 12-month period preceding participation in the study to 0.0 units during treatment with eculizumab. In 9 patients, transfusion requirements decreased during eculizumab therapy, in 3 patients, transfusions were required neither before nor during the study, and in one patient, transfusion requirement deteriorated (p = 0.0215, Exact McNemar's test). The result of the 6MWT improved from a median of 358 m at baseline to a median of 420 m at the end of treatment (p = 0.078). Questionnaires for quality of life showed no significant changes. During the enrollment phase, 7 thromboembolic events including 1 pulmonary embolism were recorded in a total of 4 patients; by contrast, no thromboembolic events were observed during treatment with eculizumab. A total of 37 adverse events were reported of which one was considered as probably related to eculizumab (pneumonia, patient recovered). All in all, 57% of adverse events were classified as unrelated, 5% as unlikely to be related, 32% as possibly related, and 3% as probably related to treatment. There were 4 serious adverse events.CONCLUSIONS: Treatment with eculizumab was safe and well tolerated in patients with CAD. It resulted in a statistically significant reduction in hemolysis and transfusion requirements and appeared to have a favorable impact on thromboembolic complications. The results of this trial support the notion that terminal complement activation is a relevant mediator of erythrocyte destruction in CAD. DisclosuresRöth:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Research Funding. Off Label Use: Use of eculizumab in CAD. Bommer:Alexion Pharmaceuticals: Honoraria. Hüttmann:Celgene: Other: Travel support, Speakers Bureau; Takeda: Consultancy, Other: Travel support; Gilead: Consultancy; Amgen: Consultancy, Research Funding; Roche: Research Funding. Schrezenmeier:Alexion Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Dührsen:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding.

Analysis of 3 Year Post Marketing Surveillance of Eculizumab in Japan

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a disease characterized by chronic complement-mediated hemolysis, leading to life-threatening events, such as thromboembolism (TE) and chronic kidney disease (CKD), and devastated quality of life (QOL). The terminal complement inhibitor eculizumab (ECU) was approved in Japan in 2010 under the indication to suppress hemolysis in PNH. We comprehensively report as post marketing surveillance (PMS) on the efficacy and safety of ECU administered from June 2010 to March 2013 in Japanese patients with PNH. In spite of complete blocking hemolysis, the degree of improvement of anemia by ECU treatment varies patient by patient. Analyzing the data of PMS, we investigated if patient characteristics, such as LDH, bone marrow function and renal function, can affect anemia in PNH patients treated with ECU.Methods: The PMS data of 242 patients were used for demographics and safety assessment. Of 242, 144 patients with ECU treatment at least for 1 year were analyzed for efficacy evaluation. We used platelet (PLT) count as a marker of bone marrow function and divided it into three groups, <88 (Low), 88-155 (Mid) and ≧155 x109/L (High). We also utilized CKD stage calculated by estimated GFR (eGFR) which is widely accepted as a renal function classification, eGFR <60 (CKD stage 3-5), 60-90 (CKD stage 2) and ≧90 mL/min/1.73m2 (CKD stage 0/1), according to Japanese CKD guideline.Results: In Japan LDH>1000 IU/L is commonly considered as ECU applicable severe PNH patients, but this was not correlated with other markers related to PNH severity. 41.2% of patients who started ECU had eGFR <60 mL/min/1.73m2, CKD stage 3-5. The prevalence of CKD stage 3-5 in PNH population was much higher than that of the normal Japanese population, especially in PNH patients over 65 years old. ECU treatment dramatically and quickly reduced the serum level of LDH, and 18-month (median)-teatment with ECU increased hemoglobin level by 1.9 g/dL, reduced annual transfusion units by half, made 55.3% of transfusion-dependent patients transfusion-independent, improved one CKD stage in 29% of the patients with CKD stage 3-5 and made 14% returned to CKD stage 2. Side effects of all grades associated with ECU were reported in 36.8% of patients and severe ones were observed in 8.3%, which include 10 infectious events in 8 patients. 18-month-treatment with ECU increased hemoglobin (Hb) level by 1.2 g/dL in the Low-PLT, 1.5 g/dL (p<0.001) in the Mid-PLT and 2.9 g/dL (p<0.001) in the High-PLT group and reduced annual RBC transfusion (TF) unit 21.6→11.3 (p=0.002), 11.0→7.0 and 10.0→1.1 (p<0.001), respectively. ECU augmented Hb level by 2.4 g/dL (p<0.001) in CKD stage 0/1, 2.3 g/dL (p<0.001) in CKD stage 2 and 1.1 g/dL (p=0.022) in CKD stage 3-5 and decreased annual TF units 13.4→2.9 (p<0.001), 11.5→3.3 (p=0001) and 16.5→10.4 (p=0.036), respectively.Conclusion: ECU treatment for 18 months reduced hemolysis and improved anemia, renal function and QOL. It is concluded that ECU is safe and well tolerated.Anemia in PNH would be caused not only by hemolysis but also modified by bone marrow as well as renal function. DisclosuresObara:Alexion Pharma: Research Funding. Ninomiya:Alexion Pharma: Honoraria, Research Funding. Chiba:Alexion Pharma: Research Funding. Usuki:Alexion Pharma: Speakers Bureau. Shichishima:Alexion Pharma: Honoraria, Research Funding. Nishimura:Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ohyashiki:Alexion Pharma: Honoraria, Research Funding. Nakao:Alexion Pharma: Honoraria, Research Funding. Ando:Alexion Pharma: Research Funding. Kawaguchi:Alexion Pharma: Honoraria, Research Funding. Nakakuma:Alexion Pharma: Honoraria. Hamada:Alexion Pharma: Employment. Shimono:Alexion Pharma: Employment. Kinoshita:Alexion Pharma: Honoraria. Ozawa:Alexion Pharma: Honoraria. Omine:Alexion Pharma: Honoraria. Kanakura:Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Serologic Response to Meningococcal Vaccination in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) for the Chronic Treatment with the Terminal Complement Inhibitor Eculizumab

BACKGROUND: Eculizumab is indicated for the therapy of patients with symptomatic paroxysmal nocturnal hemoglobinuria (PNH). Due to inhibition of terminal complement cascade, patients on eculizumab are susceptible to N. meningitids infections (0.48 cases per 100-patient years). The two mainstays to reduce the risk of infection are vaccination at least two weeks prior to treatment and antibiotic prophylaxis.PATIENTS/METHODS: In this retrospective study serologic response was analyzed after vaccination with a meningococcal vaccine in PNH patients (n=32) by measuring serum bactericidal antibody titers with external rabbit complement (rSBA) against meningococci serogroups A, C, W and Y. 78.1% of the patients (25/32) received a tetravalent conjugate vaccine, while 6.3% (2/32) received an unconjugated polysaccharide vaccine. In 9.4% (n=3) the type of vaccine administrated was not available. Serologic response was defined by an rSBA titer ≥1:8. In 23 patients the corresponding rSBA titers were available. 39.1% (9/23) had been vaccinated more than once due to chronic eculizumab treatment.RESULTS: Overall serologic responses independent of the time of observation for the meningococcal serogroups were: A: 78.3%, C: 86.9%, W: 47.8%, Y: 69.6%. rSBA titers varied significantly for the different time points [≤2 months (n=1): A: 100%, C: 100%, W: 100%, Y: 100%; ≤4-<6 months (n=4): A: 75%, C: 100%, W: 75%, Y: 75%; ≥6-<12 months (n=5): A: 60%, C: 40%, W: 0%, Y: 40%; ≥ 12-36 months (n=13): A: 84.6%, C: 100%, W: 53.8%, Y: 76.9%]. In 5 patients (15.6%) rSBA titers against 3 serogroups were <1:8, while 5 other patients (15.6%) had rSBA titers <1:8 against 2 serogroups at the same time. Serologic response after vaccination with an unconjugated vaccine even for the third time (n=1) prior to observation due to chronic therapy was identical to patients who had been vaccinated only once, supporting a non-immunological memory post vaccination with an unconjugated vaccine. No meningococcal infections have been observed in the analyzed cohort of eculizumab treated PNH patients so far.SUMMARY/CONCLUSIONS: Efficiency of meningococcal vaccines for the different serotypes varies significantly and serological response analyses are very useful. Revaccination with the tetravalent conjugate vaccine (Menveo®) every 3 years is recommended or should be based on the individual response. However, physicians and patients must be vigilant for meningococcal infections at all times. Furthermore, stand-by therapy with ciprofloxacin 750 mg p.o. in case of signs of meningococcal infection and immediate medical evaluation and treatment is recommended. The availability of a novel vaccine covering the B-strain (Bexsero®) may further reduce the risk of an infection. DisclosuresRoeth:Alexion: Consultancy, Honoraria, Research Funding. Duehrsen:Alexion: Honoraria.