Eculizumab Treatment Research Articles

Benefits and Limitations of Long-Term Eculizumab Treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH): Real-World Data from Large Cohort Study in Russia

▪Background: Anticomplement C5 therapy with eculizumab is the standard of treatment of patients (pts) with active hemolytic PNH. However, there are few data on long-term complement inhibition efficacy and current PNH prognosis from real-world clinical practice.Objectives: The aim of this study was to evaluate long-term eculizumab efficacy and PNH outcomes in the large cohort in Russia.Methods: As of August 1, 2018, a total of 354 pts with hemolytic PNH were observed in the I.P. Pavlov First St. Petersburg State Medical University in cooperation with the local hematological service in 75 regions of Russia (n=344), as well as in Belarus, Kazakhstan, Kyrgyzstan, Ukraine, Tajikistan (n=10) (Table 1). The analysis was conducted in the whole cohort and separately in the prospective phase after November 2011 with the eculizumab availability in Russia.We analyzed indications and access to anticomplement C5 therapy according to National guidelines (2014), frequency and causes of discontinuation of therapy, cumulative incidence of independence from transfusions with allo-HSCT as competing risk, frequency of breakthrough hemolysis (BTH) and intensive extravascular hemolysis, overall survival (OS) and causes of mortality.Results: According to the current National guidelines (2014), 323 pts had at least one indication for therapy with eculizumab: thrombosis (n=89, 25 %), transfusion-dependent hemolytic anemia (n=261, 74 %), acute kidney injury (AKI, n=69, 19 %), chronic kidney disease (CKD, n=244/304, 80 %) including CKD stage ≥ 2 (n=66/304, 22 %), pulmonary hypertension (n=66/265, 25 %) and pregnancy (n=22). Due to differences in regional support for rare diseases, only 204 (63%) pts had access to therapy with eculizumab. In addition, 19 pts received novel anti-C5 agent in clinical trial and were excluded from analysis. Allogeneic HSCT was performed in 24 pts, including 2 cases of MDS/AML evolved from AA/PNH and 17 cases of severe AA/PNH with eculizumab bridging in the prospective phase.With the median duration of eculizumab therapy of 3.4 years (0.2-6.1) the independence from RBC transfusions (TI) was achieved in 109 of 154 initially transfused pts (71 %) with a cumulative incidence of 61 % (95 % CI, 52-68) and 69 % (95 % CI, 60-76) after 12 and 24 months of therapy respectively. The median hemoglobin level at last follow-up were 6.6 (4.0-9.7), 10.5 (range, 7.1-15.4) and 12.1 g/dl (8.9-14.0) in patients who did not reach the TI, who reached the TI and were never transfused, respectively (p =0.0001).BTH was documented in 36 of 184 evaluated pts (20 %), including 16 and 20 cases with and without obvious triggers respectively. Intensive extravascular hemolysis with bilirubin level > 2xULN persisted in 31 % pts. Temporary or permanent discontinuation of eculizumab treatment occurred in 58 pts due to death (n=11), allogeneic BMT (n=17), spontaneous clone reduction (n = 4), absence of new indications 6 months after delivery (n=4), and terminating access to treatment (n=22). All pts of the latter group developed a relapse of intensive intravascular hemolysis, which in 3 cases was complicated by AKI (n=1), stroke (n=1) and myocardial infarction (n=1).OS was assessed in the prospective phase after 2011. A total of 24/203 (12 %) pts died which resulted in 5-year OS of 87% (CI 95 %, 81-92). Treatment with eculizumab significantly improved OS (Fig.1). The 5-year OS rate was 91% (CI 95 %, 85-98) in pts treated with eculizumab and 74 % (CI 95 %, 63-85) in never-treated pts (p=0.0003). There were significant differences in the causes of death between pts receiving and not receiving eculizumab: related to thrombosis 1/7 (14 %) vs 9/17 (53 %), AA and MDS 4/7 (57%) vs 5/17 (29 %).Conclusions: The results of the study show both the high efficacy and limitations of treatment with eculizumab for PNH in real-world practice. Prospectively confirmed significant improvement of the overall survival on eculizumab stress the need for faster and wider access to costly therapy. Nevertherless, a number of limitations, including BTH and extravascular hemolysis, lack of control of bone marrow failure and further clonal evolution, determine the relevance of next-generation complement inhibitors and risk-adjusted allogeneic HSCT as a curative option. [Display omitted] DisclosuresKulagin:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria.

Iron Overload in Patients with Paroxysmal Nocturnal Hemoglobinuria

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal bone marrow disorder caused by a somatic mutation in PIGA that leads to a marked deficiency or absence of the complement regulatory proteins CD55 and CD59. The disease manifests with intravascular hemolysis, anemia and thrombosis. PNH is characterized by diverse changes in iron metabolism. Chronic hemolysis leads to the massive iron loss due to hemoglobinuria and hemosiderinuria, whereas frequent transfusions in severely anemic, transfusion-dependent patients might cause the development of iron overload.Aim: to assess iron metabolism in PNH patients based on both laboratory parameters and MRI data.Methods: the study group included 28 PNH patients (pts) followed up in our Center between 2015 and 2017. Laboratory parameters including hemoglobin (Hb), reticulocytes (RET), erythrocyte and granulocyte PNH clone sizes and LDH levels were analyzed. Iron metabolism was characterized by measurement of serum ferritin (SF), transferrin, iron concentration, total iron binding capacity (TIBC), transferrin saturation (TS). Multiecho gradient-echo T2* magnetic resonance imaging (T2* MRI) was performed to assess both liver and kidney iron load. All pts were divided into 3 cohorts: №1 - pts on treatment with eculizumab, №2 - pts who received eculizumab in the past and №3 - eculizumab naïve pts.Results:Сohort №1 included 2 pts (2 women) aged 39 and 64 yrs. Hb level was 9,3 and 9,9 g/dl, RET count - 9,6 and 10%, LDH level - 570 and 650 U/l. Erythrocyte PNH clone size was 99 and 72%, and granulocyte PNH clone size was 99 and 87%.Cohort №2 consisted of 6 pts (2 men and 4 women, median age 39 yrs (31 - 53)) which had a history of eculizumab treatment. The median duration of eculizumab treatment in these pts was 23 months, the median time of treatment cessation (due to administrative reasons) was 6 months before study assessments. The medians of laboratory parameters were as follows: Hb = 7,7 g/dl, RET count = 6,6%, LDH level = 3296 U/l (1580 - 7444), erythrocyte PNH clone size = 36%, granulocyte PNH clone size = 98%.Cohort №3 consisted of 20 untreated pts (15 men and 5 women, median age 35 yrs (29 - 58)). The medians of laboratory parameters: Hb = 8,4 g/dl, RET count = 8,5%, LDH level = 4130 U/l (670 - 8322), erythrocyte PNH clone size = 52%, granulocyte PNH clone size = 93%.Serum iron metabolism indices in all patient cohorts are reported in Table 1. Based on the analysis of the measured serum iron metabolism indices, 3 types of iron metabolism disturbances were identified in pts of the study group (n=28): iron deficiency (14% of pts), iron overload (21% of pts) and divergent changes (65% of pts). T2* MRI was performed in 23 pts. Signs of liver iron overload were revealed in 35% pts whereas signs of kidney iron overload were detected in 91% pts. T2* MRI data was analyzed within each of the patient cohorts, results are reported in Table 1.Conclusion: the results of our pilot study demonstrate that in PNH patients laboratory parameters are not sufficient to assess iron metabolism. T2* MRI is a noninvasive and accurate technique which should be considered as a method of choice to quantify tissue iron overload. Kidney iron overload was detected in all PNH patients who did not receive eculizumab at the moment of the analysis and was absent in 2 patients on eculizumab. Thus, hemosiderin deposition in the renal cortex might play an important role in the development of renal involvement including the formation of interstitial fibrosis and chronic kidney disease. [Display omitted] DisclosuresLukina:Sanofi Genzyme: Honoraria, Other: Principal investigator in the eliglustat Phase 2, ENGAGE, ENCORE, and EDGE trials; receives travel reimbursement; member of advisory boards, Research Funding.

Economic Benefit of Early Inhospital Diagnosis and Treatment Initiation of Eculizumab in aHUS

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, potentially life-threatening disease often requiring hospital or intensive care unit (ICU) admission. Previously outcomes were poor with 56% of adults progressing to end-stage renal disease or death within one year of disease onset, regardless of plasma exchange/plasma infusion. Eculizumab (Soliris®, Alexion Pharmaceuticals, Inc., New Haven, CT, USA), a monoclonal antibody directed against complement C5, is the only approved treatment for aHUS. It has demonstrated significant improvement in clinical outcomes, including rescue or preservation of renal function, particularly with early initiation. However, difficulty in the differential diagnosis of aHUS has contributed to significant delays in instituting effective therapy. We hypothesize that patients initiating treatment on Day 8 of their hospital stay or later [late initiators (LI)] consume more inpatient resources and have greater hospital costs compared to those that initiate therapy earlier [early initiators (EI)].OBJECTIVE: To evaluate the impact of early versus late initiation of eculizumab treatment for patients with aHUS admitted to a hospital.METHODS: Patients with an inpatient hospitalization in the Premier Perspective® Hospital Database (Oct 2011 - March 2016) with a diagnosis code for hemolytic uremic syndrome (HUS) and/or thrombotic microangiopathy (TMA) (International Classification of Diseases, Clinical Modification 9th Revision [ICD-9-CM]: 283.11 or 10th Revision [ICD-9-CM]: D59.3 and ICD-9-CM 446.6/ICD-10-CM M31.1, respectively), and evidence of eculizumab use for aHUS during the hospitalization were included. Patients who had eculizumab use in the hospital outpatient setting within the preceding 6 months were excluded from the analysis. Patients were further validated as aHUS by an expert clinician prior to inclusion in the analysis. EI were defined as having received eculizumab within 7 days of admission; LI received eculizumab on Day 8 or later. Cutoff at 8 days was chosen due to time it takes in general to receive results of an ADAMTS13 activity test, which is used to distinguish between thrombotic thrombocytopenic purpura and other TMAs. The primary outcome measures were discharge status, days in intensive care unit (ICU), time from initiation to discharge, readmission rates, dialysis use, and total hospital costs. Multivariable regression (logit and log-linear gamma) models were fit to the data to control for potential confounding variables like patient demographics and comorbid conditions.RESULTS: A total of 150 (67.6%) LI and 72 (32.4%) EI were identified. Patient characteristics and descriptive statistics of the cohorts are shown in the Table. LI were older and a lower proportion were <18 years of age. While a similar proportion of patients were admitted to ICU, LI spent longer in the ICU. Although the number of days to live discharge from eculizumab initiation was similar between groups, the total hospital length of stay (LOS) for LI was much greater versus EI. Significantly more LI than EI received dialysis and were readmitted within 90 days of initial hospitalization. Multivariable regression analyses demonstrated significant differences in dialysis use and hospital costs in the LI versus EI groups. LI had 3.2 (OR 1.4, 7.3) times the odds of receiving dialysis during hospitalization (versus EI) and had estimated total hospital costs (least squares mean) that were $17,781 higher ($103,557 versus $85,776).CONCLUSIONS: Late initiation of eculizumab in patients with aHUS results in greater resource utilization and higher hospital costs than those for early initiators of treatment. This suggests that processes should be implemented to expedite results of required lab tests such as ADAMTS13 activity test, for rapid differential diagnosis of aHUS to institute timely and appropriate treatment.This study was funded by Alexion Pharmaceuticals Inc. [Display omitted] DisclosuresDonato:Alexion Pharmaceuticals Inc: Employment, Equity Ownership. Ryan:2CTI Clinical Trial and Consulting: Consultancy, Other: I am an employee of 2CTI Clinical Trial and Consulting Services Inc. who is a consultant for Alexion. Irish:2CTI Clinical Trial and Consulting Services: Consultancy, Other: During this study, I was an employee of 2CTI Clinical Trial and Consulting Services Inc. who is a consultant for Alexion. Gasteyger:Alexion Pharma GmbH: Employment, Equity Ownership. L'Italien:Alexion Pharmaceuticals, Inc.: Equity Ownership, Other: Former employee and current stockholder of Alexion Pharmaceuticals, Inc. . Laurence:Alexion Pharmaceuticals Inc: Consultancy.

A Prospective Analysis of Breakthrough Hemolysis in 2 Phase 3 Randomized Studies of Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria

A Prospective Analysis of Breakthrough Hemolysis in 2 Phase 3 Randomized Studies of Ravulizumab (ALXN1210) Versus Eculizumab in Adults with Paroxysmal Nocturnal Hemoglobinuria

Pre-Transplant Genetic Susceptibility in Adult Allogeneic Hematopoietic Cell Transplant Recipients: Incidence and Clinical Relevance in Transplant-Associated Thrombotic Microangiopathy

Introduction: Transplant-associated thrombotic microangiopathy (TA-TMA) is a potentially life-threatening complication of allogeneic hematopoietic cell transplantation (HCT). In light of encouraging results by complement inhibition treatment, a few studies and case series have reported complement-related genetic variants in patients with TA-TMA. However, several issues remain undisclosed, regarding both the incidence of such variants and the clinical importance of pre-transplant genetic profiling. Within this context, we hypothesized that pre-transplant genetic susceptibility is evident in adult TA-TMA patients but not in their donors or control transplanted patients and also investigated the association of genetic variants with response to treatment and survival.Methods:To this end, we enrolled consecutive adult allogeneic HCT recipients diagnosed with TA-TMA according to the International Working Group criteria between 2014-2017. Patients were managed based on institutional policy with conventional treatment including withdrawal of calcineurin or mTOR inhibitors, steroid administration and/or plasma infusion/plasma exchange. To test our hypothesis, we also studied donors of the enrolled patients with available samples and age- and sex-matched control HCT recipients. Genomic DNA was extracted from pre-transplant peripheral blood samples of TA-TMA patients, donors and controls. Probes were designed using the Design studio (Illumina). The amplicons cover the exonic regions of complement regulatory genes (complement factor H/CFH, CFH-related, CFI, CFB, CFD, C3, CD55, C5, CD46, thombomodulin/THBD) and TMA-associated ADAMTS13, spanning 15 bases into the intronic regions. After quality assessment, each sample was treated independently in order to produce the appropriate mapping of the reads against the human reference genome hg19. Variant calling was performed using the Genome Annotation Toolkit and variant annotation using annovar together with supplemental databases. Variants with minor allele frequency lower than 1% were considered rare.Results:We studied 30 patients that presented TA-TMA at median + 73 (9-540) days with full hematopoietic constitution, 18 donors of our patients and 30 controls, without significant differences in transplant characteristics (Table).Donors of patients presented significantly lower number of detected (p=0.039) and rare (p=0.049) variants per sample, as well as variants in exonic, splicing or UTR regions (p=0.025) compared to TA-TMA patients. In control patients, we also observed a significantly lower number of rare variants in ADAMTS13 (p=0.002), CD46 (p=0.001), CFH (p=0.010), CFI (p=0.031) and CFB (p=0.016) compared to TA-TMA patients (Graph). Variants previously reported to be pathogenic in TMAs were found in ADAMTS13 and CFB. While heterozygous pathogenic mutations were present in both TA-TMA and control samples, homozygous pathogenic mutations were evident only in 4 TA-TMA patients (p=0.038).Regarding clinical outcomes, 21 of 30 TA-TMA patients (70%) were refractory to conventional treatment. Refractory patients presented a significantly increased incidence of variants in exonic, splicing or UTR regions (p=0.045) compared to responders. 12 patients received eculizumab based on institutional policy. Despite initial laboratory response to eculizumab treatment, only 4 of 12 survived. 19 out of 30 patients succumbed to treatment-related mortality, which was also associated with significantly increased number of variants in exonic, splicing or UTR regions (p=0.012).Conclusions:Increased incidence of pathogenic, rare and exonic variants in TA-TMA patients supports a relevant role for genetic susceptibility that is not evident in control HCT recipients or patients' donors. This, combined with the finding that exonic variants were associated with refractoriness to treatment and increased mortality, indicates that pre-transplant genetic profiling may be useful to intensify monitoring and early intervention in high-risk patients. In this complex setting, the functional and clinical role of genetic variants needs to be further investigated in prospective studies. [Display omitted] DisclosuresGavriilaki:European Hematology Association: Research Funding. Stamatopoulos:Gilead: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

An adult case of atypical hemolytic uremic syndrome presented with posterior reversible encephalopathy syndrome: Successful response to late-onset eculizumab treatment.

Atypical hemolytic uremic syndrome is a rare and progressive disease caused by uncontrolled alternative complement activation. Dysregulatıon of the complement activation results in thrombotic microangiopathy and multiorgan damage. A 29-yearold woman who was admitted with complaints of vomiting and headache was detected to have acute renal failure with microangiopathic hemolytic anemia (MAHA). After the diagnosis of atypical hemolytic uremic syndrome (aHUS), she was treated with plasma exchange (PE) and hemodialysis (HD). She has experienced hypertensionrelated posterior reversible encephalopathy syndrome (PRES) at the second plasma exchange. She was initiated on eculizumab therapy because of no response to PE on the 34th days. Her renal functions progressively improved with eculizumab treatment. Dependence on dialysis was over by the 4th month. Dialysis free-serum Creatinine level was 2.2 mg/dL [glomerular filtration rate (e-GFR): 30 mL/min/1.73 m2] after 24 months.Neurological involvement (PRES, etc.) is the most common extrarenal complication and a major cause of mortality and morbidity from aHUS. More importantly, we showed that renal recovery may be obtained following late-onset eculizumab treatment in patient with aHUS after a long dependence on hemodialysis.

Outbreak of Shiga toxin-producing Escherichia-coli-associated hemolytic uremic syndrome in Istanbul in 2015: outcome and experience with eculizumab

This study aims to identify epidemiological and clinical characteristics of patients and report our experience with eculizumab treatment during an outbreak of hemolytic uremic syndrome (HUS) caused by Shiga toxin-producing Escherichia coli (STEC) in Istanbul in 2015. Thirty-two children (21 females, median age 3.25years) were included in this study. Demographic, clinical and laboratory data, and treatment details were retrospectively collected. Renal outcomes were assessed at last follow-up visit. To assess the effect of eculizumab on prognosis of STEC-HUS, subgroup analysis was performed on patients who required dialysis. A high number of cases occurred within a certain region of Istanbul. Stool samples were cultured from 21 patients (65%), and enteroaggregative E. coli (EAEC; n = 7) and enterohemorrhagic E. coli (EHEC; n = 3) strains were detected. Rates of dialysis treatment, neurological manifestations, and death were 59%, 25%, and 3%, respectively. Mean follow-up duration was 8.6 ± 2.6months (range 3-12months). None of the patients (n = 25) was on dialysis at the final visit. The complete renal recovery rate was 54%. Nine patients were treated with eculizumab. At final follow-up visit, no differences in estimated glomerular filtration rate, proteinuria level, or hypertension incidence were observed between patients treated with eculizumab and those not treated with eculizumab. An outbreak of EAEC occurred in a specific region of Istanbul. Livestock markets were suspected as the source. Evidence for beneficial effects of eculizumab on renal outcome was not clear in this cohort.

Antibody Inhibition of Properdin Prevents Complement-Mediated Intravascular and Extravascular Hemolysis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a serious blood disorder characterized by dysregulated complement activation on blood cells. Eculizumab, the current standard therapy and a humanized anti-C5 mAb, relieves anemia and thrombosis symptoms of PNH patients by preventing complement-dependent intravascular hemolysis (IVH). However, up to 20% of PNH patients on long-term eculizumab treatment still suffer from significant anemia and are transfusion dependent because of extravascular hemolysis (EVH) of C3-opsonized PNH erythrocytes. In this study, we show that function-blocking anti-properdin (P) mAbs dose-dependently inhibited autologous, complement-mediated hemolysis induced by factor H dysfunction. Furthermore, anti-human P (hP) mAbs potently and dose-dependently inhibited acidified serum-induced hemolysis of PNH erythrocytes (Ham test). In contrast to erythrocytes rescued by anti-C5 mAb, nonlysed PNH erythrocytes rescued by anti-P mAb incurred no activated C3 fragment deposition on their surface. These results suggested that anti-P mAbs may prevent EVH as well as IVH of PNH erythrocytes. To test the in vivo efficacy of anti-hP mAbs in preventing EVH, we generated a P humanized mouse by transgenic expression of hP in P knockout mice (hP-Tg/P-/-). In a murine EVH model, complement-susceptible erythrocytes were completely eliminated within 3 d in control mAb-treated hP-Tg/P-/- mice, whereas such cells were protected and persisted in hP-Tg/P-/- mice treated with an anti-hP mAb. Collectively, these data suggest that anti-P mAbs can inhibit both IVH and EVH mediated by complement and may offer improved efficacy over eculizumab, the current standard therapy for PNH.

Failure of first meningococcal vaccination in patients with atypical haemolytic uraemic syndrome treated with eculizumab

The C5 complement inhibitor eculizumab is a first-line treatment in atypical haemolytic uraemic syndrome (aHUS). Therapy with eculizumab is associated with a highly increased risk for meningococcal infection. Therefore, vaccination is highly recommended before beginning treatment. Efficacy of quadrivalent meningococcal vaccines (MenACWY) in patients treated with the C5 complement inhibitor eculizumab in aHUS has not yet been determined. Patients with aHUS received one dose of a MenACWY conjugate vaccine before eculizumab treatment commenced. Bactericidal titres against meningococcal serogroups A, C, W and Y were determined using baby rabbit complement in 25 patients. Full immune response to meningococcal vaccination was detected in five patients (20%), while seven patients (28%) showed no immune response in any of the tested serogroups. The remaining 13 patients showed incomplete immune response with proof of protective antibody titres for one to three serogroups without perceptible preference for any serogroup. Bactericidal titres after re-vaccination were available for 17 patients. Nine patients with incomplete immune response after first vaccinations showed protective antibody titres for all serogroups after re-vaccination. Kidney function had improved in >50% of patients at the time of re-vaccination compared with the time of first vaccination and immunosuppressive therapy was only applied to re-vaccinated patients following kidney transplantation. Immunogenicity of first quadrivalent meninongococcal vaccination is insufficient in patients with aHUS. Booster response is promising, but incomplete. Therefore, establishing antibiotic prophylaxes seems pivotal.

Correction to: Effects of eculizumab treatment on quality of life in patients with paroxysmal nocturnal hemoglobinuria in Japan.

In the original publication of this article, Tables2, 3 and 4 were published incorrectly. The corrected tables 2, 3 and 4 are given in the following pages.

Clinical and genetic predictors of atypical hemolytic uremic syndrome phenotype and outcome

Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, life-threatening disease. The Global aHUS Registry collects real-world data on the natural history of the disease. Here we characterize end-stage renal disease (ESRD)-free survival, the rate of thrombotic microangiopathy, organ involvement and the genetic background of 851 patients in the registry, prior to eculizumab treatment. A sex-specific difference was apparent according to age at initial disease onset as the ratio of males to females was 1.3:1 for childhood presentation and 1:2 for adult presentation. Complement Factor I and Membrane Cofactor Protein mutations were more common in patients with initial presentation as adults and children, respectively. Initial presentation in childhood significantly predicted ESRD risk (adjusted hazard ratio 0.55 [95% confidence interval 0.41-0.73], whereas sex, race, family history of aHUS, and time from initial presentation to diagnosis, did not. Patients with a Complement Factor H mutation had reduced ESRD-free survival, whereas Membrane Cofactor Protein mutation was associated with longer ESRD-free survival. Additionally extrarenal organ manifestations occur in 19%-38% of patients within six months of initial disease presentation (dependent on organ). Thus, our real-world results provide novel insights regarding phenotypic variables and genotypes on the clinical manifestation and progression of aHUS.

Atypical hemolytic-uremic syndrome as one of the causes of acute kidney injury in pregnant women.

Analysis of clinical manifestations, course and outcomes of obstetric aHUS. 45 patients with aHUS development during pregnancy or immediately after childbirth were observed between 2011 and 2017, age from 16 to 42 years. All patients had AKI (serum creatinine 521,5±388,0 µmol/l, oliguria or anuria that required initiation of hemodialysis). 93.3% pts had extrarenal manifestations of TMA with the development of multiple organ failure (MOF). The mean number of damage organs was 3,7±1,2. In all patients, the development of aHUS was preceded by obstetric complications, surgery, infection, etc. In the outcome: 53.4% women showed complete recovery of renal function, 11.1% developed CKD 4-5 stages, 35.5% had dialysis-dependent end-stage renal failure (ESDR). Maternal mortality was 23.9%. Perinatal mortality was 32.6%. The early start of eculizumab treatment (within 1-2 weeks from the onset of aHUS), compared with therapy start after 3 weeks, increased the chances of favorable outcome for mother in 5.33 times, and the chances for normalization of renal function in 48.7 times. Obstetric aHUS is characterized by the development of AKI in 100% of cases. In most patients, the obstetric aHUS occurs with the development of MOF. Timely diagnosis of aHUS and immediate treatment by eculizumab allows not only to save the life of patients, but also completely restore their health.

Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study.

BackgroundEculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA).MethodsIn five parent studies, eculizumab effectively prevented TMA and improved renal and haematologic outcomes in patients with aHUS; therefore, these patients could enrol in this long-term, prospective, observational and multicentre study. The primary endpoint was the TMA manifestation rate off and on eculizumab post-parent study. Post hoc analyses evaluated rates during labelled versus non-labelled dosing regimens, and in those with versus without identified complement abnormalities. Serious targeted treatment-emergent adverse events (TEAEs) were evaluated.ResultsOf 87 patients in the current study, 39 and 76 had off- and on-treatment periods, respectively; 17 (44%) with off periods reinitiated eculizumab. TMA manifestation rate per 100 patient-years was 19.9 off and 7.3 on treatment [hazard ratio (HR), 4.7; P = 0.0008]; rates were highest off treatment and lowest during labelled regimens. TMA manifestations with hospitalizations/serious AEs occurred more frequently off versus on treatment. TMA rates were higher among patients with identified complement abnormalities (HR, 4.5; P = 0.0082). Serious targeted TEAEs occurred at similar rates off and on treatment.ConclusionsAs expected, patients with aHUS have increased risk of TMA manifestations after discontinuation of eculizumab or in the setting of non-labelled eculizumab dosing. Collectively, results show that maintaining eculizumab treatment minimizes risk of TMA, particularly in patients with identified complement abnormalities. Future studies are needed to further characterize TMA and longer term outcomes on labelled or non-labelled eculizumab regimens and after discontinuation of treatment.

Extra-Renal manifestations of atypical hemolytic uremic syndrome in children.

Atypical hemolytic uremic syndrome (aHUS) is a chronic disease characterized by thrombotic microangiopathy and a high risk of end-stage kidney disease. Dysregulation and/or excessive activation of the complement system results in thrombotic microangiopathy. Interest in extrarenal manifestations of aHUS is increasing. This study aimed to determine the clinical characteristics of patients with extrarenal manifestations of aHUS in childhood. This study included 70 children with extrarenal manifestations of HUS from the national Turkish aHUS Registry. The demographics, clinical characteristics, genetic test results, all treatments, and renal/hematologic status of aHUS patients with extrarenal involvement were recorded. The most common extrarenal manifestation was neurological system involvement (n = 46 [27.2%]), followed by gastrointestinal (n = 20 [11.8%]), cardiovascular (n = 12 [7%]), and respiratory (n = 12 [7%]) involvement. The patients with neurological involvement had a higher mortality rate and a lower estimated glomerular filtration rate (eGFR) than the other patients at last follow-up. Eculizumab (with or without plasma exchange/plasma infusion) treatment increased the renal and hematologic recovery rates. The most common and serious extrarenal manifestation of aHUS is neurological involvement and treatment outcome findings presented herein are important to all relevant clinicians.

Successful 7-Year Eculizumab Treatment of Plasmapheresis-Resistant Recurrent Atypical Hemolytic-Uremic Syndrome due to Complement Factor H Hybrid Gene: A Case Report

Atypical hemolytic-uremic syndrome (aHUS) is an extremely rare disease, and up to 70% of the patients have a genetic mutation in the encoding components of complement activation or anti-complement factor H autoantibodies. The risk of recurrence after kidney transplantation is 10% to 80%. Eculizumab, a monoclonal antibody that binds complement protein C5, has shown to be highly effective in patients with aHUS; however, there are only few reports on the efficacy and safety of long-term eculizumab treatment in children with recurrent aHUS. Only 3 case reports regard treatment in patients with complement factor H (CFH/CFHR1/CFHR3) hybrid gene. This report presents the efficacy and safety of long-term eculizumab treatment in a child with recurrent aHUS who has been successfully treated with eculizumab for more than 7 years. The patient presented as a 9-year-old with aHUS due to CFH/CFHR1/CFHR3 hybrid gene and received deceased donor kidney transplantation. After the transplantation, he experienced recurrence of aHUS 2 months later. Daily plasma exchanges were ineffective in the transplanted kidney; the patient became anuric and hemodialysis was needed. Eculizumab was started as therapy and led to complete remission of aHUS including restoration of diuresis. Eculizumab has been given as therapy for 7 years. The young patient is in a sustained remission without any adverse events. This patient is only the sixth patient reported with recurrent aHUS due to CFH/CFHR1/CFHR3 hybrid gene and is the patient with the longest remission of recurrent aHUS ever published.

Adverse outcomes in obstetric-atypical haemolytic uraemic syndrome: a case series analysis

Objective: The aim of this case series is to raise awareness of obstetric-related atypical haemolytic uraemic syndrome (aHUS) amongst obstetricians and gynaecologists.Study design: Data from 20 consecutive patients, aged 19–38, with obstetric-aHUS manifestation during or immediately after pregnancy are reported. Patients were diagnosed and treatment was initiated between 2012 and 2016.Results: Presentation of aHUS was mainly preceded by preeclampsia and/or haemolysis, elevated liver enzymes and low platelet count syndrome, other obstetric complications, or by diarrhoea. Thrombotic microangiopathy (TMA) was evident in all patients with signs of microangiopathic haemolysis (sharp decline in haemoglobin; mean 67 g/L), elevated lactate dehydrogenase (LDH; mean 2953.1 U/L), schistocytosis, thrombocytopenia (mean platelet count 52.5 × 109/µL), and acute kidney injury (AKI) (hypercreatininaemia, mean 456.4 µmol/L; oliguria or anuria). The majority of patients (80%) initially presented with arterial hypertension. Diagnosis of obstetric-aHUS was complicated, as multiple organs were affected. Time taken to make the diagnosis of aHUS delayed the initiation of fresh-frozen plasma infusions and plasma exchange (80% of patients) and subsequent eculizumab treatment (40% of patients). Maternal mortality was high (35%) as was foetal mortality (25%).Conclusions: Obstetric-aHUS is a serious condition characterized by multiple organ failure (MOF) and a high mortality rate. Presentation of obstetric-aHUS is preceded by various precipitating factors, suggesting pregnancy complications, and not the pregnancy per se, often induce aHUS in women with a genetic predisposition to its development. A delay in the correct diagnosis and initiation of the most effective treatment can have serious consequences, reinforcing the need to raise awareness of obstetric-aHUS.

Eculizumab treatment in severe pediatric STEC-HUS: a multicenter retrospective study.

Hemolytic uremic syndrome related to Shiga-toxin-secreting Escherichia coli infection (STEC-HUS) remains a common cause of acute kidney injury in young children. No specific treatment has been validated for this severe disease. Recently, experimental studies highlight the potential role of complement in STEC-HUS pathophysiology. Eculizumab (EC), a monoclonal antibody against terminal complement complex, has been used in severe STEC-HUS patients, mostly during the 2011 German outbreak, with conflicting results. On behalf of the French Society of Pediatric Nephrology, we retrospectively studied 33 children from 15 centers treated with EC for severe STEC-HUS. Indication for EC was neurologic involvement in 20 patients, cardiac and neurologic involvement in 8, cardiac involvement in 2, and digestive involvement in 3. Based on medical status at last follow-up, patients were divided into two groups: favorable (n = 15) and unfavorable outcomes (n = 18). Among patients with favorable outcome, 11/14 patients (79%) displayed persistent blockade of complement activity before each EC reinjection. Conversely, in patients with unfavorable outcome, only 9/15 (53%) had persistent blockade (p = n.s.). Among 28 patients presenting neurological symptoms, 19 had favorable neurological outcome including 17 with prompt recovery following first EC injection. Only two adverse effects potentially related to EC treatment were reported. Taken together, these results may support EC use in severe STEC-HUS patients, especially those presenting severe neurological symptoms. The study, however, is limited by absence of a control group and use of multiple therapeutic interventions in treatment groups. Thus, prospective, controlled trials should be undertaken.

Hemolytic uremic syndrome with dual caution in an infant: cobalamin C defect and complement dysregulation successfully treated with eculizumab.

Hemolytic uremic syndrome (HUS) is a clinical syndrome characterized by hemolytic anemia, thrombocytopenia, and acute kidney injury. Atypical hemolytic uremic syndrome (aHUS) is a devastating disease with significant mortality and high risk of progression to end-stage kidney disease. It is mostly caused by dysregulation of the alternative complement pathway. Cobalamin C (Cbl C) defect is a genetic disorder of cobalamin metabolism and is a rare cause of HUS. We present a 6-month-old male infant who was admitted to the pediatric intensive care unit (PICU) due to restlessness, severe hypertension, anemia, respiratory distress, and acute kidney injury. Metabolic screening revealed elevated plasma homocysteine levels, low methionine levels, and methylmalonic aciduria, and the patient was diagnosed as having HUS secondary to Cbl C defect. Additionally, complement factor H (CFH) and complement C3 levels were decreased. The infant was treated with betaine, hydroxycobalamin, and folic acid. After treatment, the homocysteine and methylmalonic acid levels were normalized but hemolysis and acute kidney failure persisted. He required continued renal replacement treatment (CRRT) and plasma exchange due to thrombotic microangiopathy (TMA). Therefore, we considered a second mechanism in the pathogenesis as complement dysregulation and gave eculizumab to the patient. After eculizumab treatment, the renal and hematologic indices improved and he was free of dialysis. To the best of our knowledge, our patient is the first to have Cbl C defect-HUS accompanied by complement dysregulation, who responded well to eculizumab therapy.

Atypical Hemolytic Uremic Syndrome in Children Aged

Background: There are limited data on infants with atypical hemolytic uremic syndrome (aHUS). The aim of this study was to determine the clinical and laboratory features, and to evaluate treatment modalities and outcomes in infants with aHUS. Materials and Methods: Relevant data on patients with onset of aHUS at age <2 years were obtained from the Turkish Pediatric aHUS Registry. Results: Among the 146 patients included in the Registry, 53 (36%) (23 male and 30 female) were enrolled for the study. Age at disease onset was ≤1 year in 29 of the patients. In all, 21 (40%) of the patients developed neurological symptoms. Disease-causing mutations were noted in 14 (36%) of the 39 patients in which genetic analysis was performed. Plasma therapy was performed in 42 (79%) patients; eculizumab therapy was administered to treat the first episode of aHUS in 33 (62%) patients and in 5 patients as the first- line therapy. In total, 38 (72%) patients received renal replacement therapy (RRT), 3 (6%) died due to acute illness, and 4 (8%) were discharged from hospital with RRT. Follow-up visit data were available for 46 patients and the median duration was 23 months (range 3–129 months). End-stage renal disease developed only in 1 patient. Proteinuria and hypertension persisted in 17 (37%) and 20 patients (44%) respectively. Eculizumab treatment was continued in 25 of the 39 patients during the follow-up period. Conclusion: One-third of the aHUS patients had disease onset during infancy. The prognosis of this life-threatening disease seems to get better with improved treatment modalities.

Eculizumab treatment for ischemic enteritis accompanied with paroxysmal nocturnal hemoglobinuria: a case report and literature review

Eculizumab treatment for ischemic enteritis accompanied with paroxysmal nocturnal hemoglobinuria: a case report and literature review