Discontinuation Of Eculizumab Research Articles

Eculizumab as first-line treatment for patients with severe presentation of complement factor H antibody-mediated hemolytic uremic syndrome.

Complement factor H (FH) antibody-mediated hemolytic uremic syndrome (HUS) has varying prevalence globally. Plasmapheresis and immunosuppressive drugs are the standard treatment. Recently, eculizumab has been reported as an effective alternative. This study aims to report four children with FH antibody-mediated HUS managed with eculizumab plus immunosuppression as first-line therapy. A retrospective chart review was conducted for children aged ≤ 18years old with complement-mediated HUS in two referral centers. Patients with FH antibody-mediated HUS treated with eculizumab as first-line therapy were included. Four children (aged 6-11years old) were included. Dialysis was necessary in three patients. Eculizumab was administered 5-23days after onset. None of them received plasmapheresis. Prednisone and mycophenolate mofetil were added after receiving positive FH antibody results. Hematological signs and kidney function improved after the second eculizumab dose. Eculizumab was discontinued in three patients after 6months. One patient required rituximab due to persistent high FH antibody titers; discontinuation of eculizumab occurred after 15months without recurrence. No treatment-related complications were observed. During a mean 12-month follow-up (range 6-24months), no relapses were recorded and all patients ended with normal GFR. Our data suggest that a short course of 6months of C5 inhibitor might be sufficient to reverse thrombotic microangiopathy symptoms and improve kidney function in patients with severe FH antibody-mediated HUS. Simultaneously, adding immunosuppressive agents might reduce the risk of relapse and allow cessation of C5 inhibition in a shorter period of time.

Global aHUS Registry Analysis of Patients Switching to Ravulizumab From Eculizumab

Atypical hemolytic uremic syndrome (aHUS) is a progressive rare disease that, if untreated, can result in severe organ damage and death. Ravulizumab, a next-generation terminal complement inhibitor, provides immediate, complete, and sustained complement C5 inhibition. Real-world data in patients with aHUS who switched to ravulizumab from eculizumab are lacking. The Global aHUS Registry is a multicenter study (NCT01522183) collecting data on adult or pediatric patients with an aHUS diagnosis, regardless of treatment. Patient characteristics, genetic data, hematological and renal parameters, clinical events (e.g., dialysis and kidney transplantation), and adverse events (AEs) were extracted from patients who switched to ravulizumab from eculizumab up to July 3,2023. Overall, 60 patients switched to ravulizumab (adult: n= 43; pediatric: n= 17); 11 patients were excluded from effectiveness and genetic analyses (N= 49; adult: n= 40; pediatric: n= 9) because they received<3 months ravulizumab treatment and/or had >1 month between eculizumab discontinuation and ravulizumab initiation. Pathogenic complement variants were identified in 11 of 49 patients (22%); the most common was a complement factor H variant (n= 5/49 [10%]). During ravulizumab treatment, 20 AEs occurred in 13 patients, with no unexpected AEs and only 3 treatment-related AEs (infusion reaction, headaches, and fatigue). No meningococcal infections or deaths were reported. No new events of dialysis, kidney transplantation, or thrombotic microangiopathy were reported. Renal and hematological parameters remained stable after switching to ravulizumab. This is the first real-world cohort analysis of data from patients treated with ravulizumab and reinforces the real-world safety and effectiveness data of ravulizumab in patients with aHUS who switched from eculizumab.

Eculizumab treatment in paediatric patients diagnosed with aHUS after haematopoietic stem cell transplantation: a HSCT-TMA case series from Japanese aHUS post-marketing surveillance

Haematopoietic stem-cell transplantation (HSCT)-associated thrombotic microangiopathy (HSCT-TMA) is a serious complication with high mortality. Accumulating evidence suggests that complement dysregulation is potentially involved in the development of HSCT-TMA. We retrospectively analysed the clinical characteristics and outcomes of thirteen paediatric patients who were diagnosed with atypical haemolytic uremic syndrome and treated with eculizumab to manage HSCT-TMA during post-marketing surveillance in Japan. The median time from HSCT to TMA was 31 days (Interquartile range, IQR;21–58) and the median doses of eculizumab was three (IQR;2–5). Seven patients (54%) were alive at the last follow-up while six died due to complications related to HSCT. Six of seven survivors initiated eculizumab after insufficient response to plasma therapy. Following eculizumab treatment, median platelet counts and LDH levels in all survivors significantly improved and renal function improved in 4/7 patients. All survivors possessed potential risk factors of complement overactivation. During the follow-up period after eculizumab discontinuation (median;111.5 days, IQR;95–555), no TMA recurrence was observed. In this analysis, eculizumab showed benefit in over half of this paediatric patient population. Ongoing clinical studies are expected to optimize the treatment regimen of terminal complement pathway inhibitor, and it may become a therapeutic option for paediatric HSCT-TMA in the future.

Atipik Hemolitik Üremik Sendromlu Hastaların Uzun Dönem Sonuçları

Aim: Hemolytic uremic syndrome (HUS) is the clinical triad of anemia, thrombocytopenia and acute renal injury. Atypical hemolytic uremic syndrome (aHUS) is a rare disease of alternative complement pathways. It is aimed to evaluate long-term follow-up of patients with aHUS in the present study. Materials and methods: Eleven children diagnosed with aHUS were retrospectively evaluated. Demographic, clinical, and laboratory data and treatment details were reported. Results: A total of 11 patients were enrolled in the study. The mean age of patients at aHUS onset was 2.9±6 years. The mean follow-up time was 72 ± 4 months All patients had renal involvement. Extrarenal manifestations of aHUS were present in four patients. All patients had eculizumab treatment. Conclusion: Our study insight into diagnosing and managing aHUS, a very rare disease, in our pediatric patients. Genetic testing is used to improve the diagnosis of aHUS. We demonstrated the long-term efficacy and safety of eculizumab in our aHUS patients. Further studies are needed to determine the optimal time for discontinuation of eculizumab treatment.

Eculizumab Rescue Therapy in Patients With Recurrent Atypical Hemolytic Uremic Syndrome After Kidney Transplantation

Since 2016, kidney transplantation in patients with atypical hemolytic uremic syndrome (aHUS) in the Netherlands is performed without eculizumab prophylaxis. Eculizumab is given in case of posttransplant aHUS recurrence. Eculizumab therapy is monitored in the CUREiHUS study. All participating kidney transplant patients who received eculizumab therapy for a suspected posttransplant aHUS recurrence were evaluated. Overall recurrence rate was monitored prospectively at Radboud University Medical Center. In the period from January 2016 until October 2020, we included 15 (12 females, 3 males; median age 42 years, range 24-66 years) patients with suspected aHUS recurrence after kidney transplantation in this study. The time interval to recurrence showed a bimodal distribution. Seven patients presented early after transplantation (median 3 months, range 0.3-8.8 months), with typical aHUS features: rapid loss of estimated glomerular filtration rate (eGFR) and laboratory signs of thrombotic microangiopathy (TMA). Eight patients presented late (median 46 months, range 18-69 months) after transplantation. Of these, only 3 patients had systemic TMA, whereas 5 patients presented with slowly deteriorating eGFR without systemic TMA. Treatment with eculizumab resulted in improvement or stabilization of eGFR in 14 patients. Eculizumab discontinuation was tried in 7 patients; however, it was successful only in 3. At the end of the follow-up (median 29 months, range 3-54 months after start of eculizumab), 6 patients had eGFR<30 ml/min per 1.73 m2. Graft loss had occurred in 3 of them. Overall, aHUS recurrence rate without eculizumab prophylaxis was 23%. Rescue treatment of posttransplant aHUS recurrence is effective; however, some patients suffer from irreversible loss of kidney function, likely caused by delayed diagnosis and treatment and/or too aggressive discontinuation of eculizumab. Physicians should be aware that recurrence of aHUS can present without evidence of systemic TMA.

A Multicenter Study Evaluating the Discontinuation of Eculizumab Therapy in Children with Atypical Hemolytic Uremic Syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA), which has been treated successfully with eculizumab. The optimal duration of eculizumab in treating patients with aHUS remains poorly defined. We conducted a multicenter retrospective study in the Arabian Gulf region for children of less than 18 years of age who were diagnosed with aHUS and who discontinued eculizumab between June 2013 and June 2021 to assess the rate and risk factors of aHUS recurrence. We analyzed 28 patients with a clinical diagnosis of aHUS who had discontinued eculizumab. The most common reason for the discontinuation of eculizumab was renal and hematological remission (71.4%), followed by negative genetic testing (28.6%). During a median follow-up period of 24 months after discontinuation, 8 patients (28.5%) experienced HUS relapse. The risk factors of recurrence were positive genetic mutations (p = 0.020). On the other hand, there was no significant relationship between the relapse and age of presentation, the need for acute dialysis, the duration of eculizumab therapy before discontinuation, or the timing of eculizumab after the presentation. Regarding the renal outcomes after discontinuation, 23 patients were in remission with normal renal function, while 4 patients had chronic kidney disease (CKD) (three of them had pre-existing chronic kidney disease (CKD) before discontinuation, and one case developed a new CKD after discontinuation) and one patient underwent transplantation. The discontinuation of eculizumab in patients with aHUS is not without risk; it can result in HUS recurrence. Eculizumab discontinuation can be performed with close monitoring of the patients. It is essential to assess risk the factors for relapse before eculizumab discontinuation, in particular in children with a positive complement variant and any degree of residual CKD, as HUS relapse may lead to additional loss of kidney function. Resuming eculizumab promptly after relapse is effective in most patients.

Early Eculizumab Withdrawal in Patients With Atypical Hemolytic Uremic Syndrome in Native Kidneys Is Safe and Cost-Effective: Results of the CUREiHUS Study

The introduction of eculizumab has improved the outcome in patients with atypical hemolytic uremic syndrome (aHUS). The optimal treatment strategy is debated. Here, we report the results of the CUREiHUS study, a 4-year prospective, observational study monitoring unbiased eculizumab discontinuation in Dutch patients with aHUS after 3 months of therapy. All pediatric and adult patients with aHUS in native kidneys and a first-time eculizumab treatment were evaluated. In addition, an extensive cost-consequence analysis was conducted. A total of 21 patients were included in the study from January 2016 to October 2020. In 17 patients (81%), a complement genetic variant or antibodies against factor H were identified. All patients showed full recovery of hematological thrombotic microangiopathy (TMA) parameters after the start of eculizumab. A renal response was noted in 18 patients. After a median treatment duration of 13.6 weeks (range 2.1-43.9), eculizumab was withdrawn in all patients. During follow-up (80.7 weeks [0.0-236.9]), relapses occurred in 4 patients. Median time to first relapse was 19.5 (14.3-53.6) weeks. Eculizumab was reinitiated within 24 hours in all relapsing patients. At last follow-up, there were no chronic sequelae, i.e., no clinically relevant increase in serum creatinine (sCr), proteinuria, and/or hypertension in relapsing patients. The low sample size and event rate did not allow to determine predictors of relapse. However, relapses only occurred in patients with a likely pathogenic variant. The cost-effectiveness analysis revealed that the total medical expenses of our population were only 30% of the fictive expenses that would have been made when patients received eculizumab every fortnight. It is safe and cost-effective to discontinue eculizumab after 3 months of therapy in patients with aHUS in native kidneys. Larger data registries are needed to determine factors associated with suboptimal kidney function recovery during eculizumab treatment, factors to predict relapses, and long-term outcomes of eculizumab discontinuation.

Atypical hemolytic-uremic syndrome: evolution of treatment and impact of clinical and genetic characteristics on possibility of eculizumab withdrawal

Atypical hemolytic uremic syndrome (aHUS) is a rare variant of thrombotic microangiopathy (TMA) associated with uncontrolled activation of alternative complement pathway due to mutations in complement regulatory protein genes or antibodies formation to regulators. Clinical manifestations of aHUS can be triggered by infections, sepsis, pregnancy, autoimmune diseases, organ transplantation, and other complement-activating conditions. Previously, the only treatment option for aHUS was plasma therapy – fresh frozen plasma infusions or plasma exchange, but its effectiveness was insufficient. Currently, targeted treatment available – recombinant monoclonal antibodies against complement C5 protein – eculizumab with high efficiency in achieving aHUS remission, renal function recovery, and preventing TMA at kidney transplantation. For a long time, the question of the optimal duration of treatment and the possibility of eculizumab discontinuing remained unresolved. It was shown that aHUS relapses developed in 20-35 % of patients after discontinuation of complement-blocking therapy. The article presents an overview of a large number of studies of eculizumab treatment outcomes and the possibility of its withdrawal, including a French prospective multicenter study that identified risk factors for aHUS relapse after eculizumab discontinuation: the presence of rare variants of complement genes, female gender, increased soluble C5b-9 plasma level. In patients who did not have rare genetic variants, the risk of relapse was less than 5 %. In general, eculizumab discontinuation after achieving complete remission of aHUS and renal function recovery in patients with low risk of recurrence can provide better tolerability of maintenance treatment, and decrease the incidence of infectious complications and the financial burden on the healthcare system.

Complement gene variant effect on relapse of complement-mediated thrombotic microangiopathy after eculizumab cessation

AbstractEculizumab is effective for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy had been suggested, discontinuation does not universally lead to relapse. Comprehensive data evaluating risk factors for recurrence following discontinuation are limited. Our aim was to systematically review available literature assessing the role of complement genetic variants in this setting. Reports on CM-TMA and eculizumab withdrawal published before 1 January 2021, were included. Key reasons for patient exclusion were no follow-up after drug withdrawal and patients lacking complement genetic testing. Two-hundred eighty patients from 40 publications were included. Median age was 28 years, and 25 patients had a known history of renal transplant. Complement genetic variants were identified in 60%, most commonly in CFH (n = 59) and MCP/CD46 (n = 38). Of patients with a complement gene variant, 51.3% had ≥1 likely pathogenic/pathogenic variant whereas the remaining had variants of uncertain significance (VUS). Overall relapse rate after therapy discontinuation was 29.6%. Relapse rate was highest among patients with CFH variants and MCP/CD46 variants in canonical splice regions. VUS (P < .001) and likely pathogenic/pathogenic variants (P < .001) were associated with increased relapse. Presence of a renal allograft (P = .009); decreasing age (P = .029); and detection of variants in CFH (P < .001), MCP/CD46 (P < .001), or C3 (P < .001) were all independently associated with relapse after eculizumab discontinuation. Eculizumab discontinuation is appropriate in specific patients with CM-TMA. Caution should be exerted when attempting such a strategy in patients with high risk of recurrence, including a subgroup of patients with MCP/CD46 variants.

Discontinuation of Eculizumab treatment after hematological remission in patients with atypical and drug-induced hemolytic uremic syndrome.

Introduction. The aim was to evaluate the effect of therapeutic plasma exchange (TPE) and eculizumab on hematological and renal survival in atypical hemolytic uremic syndrome (aHUS), and additionally, to examine the reliability of discontinuation of eculizumab treatment.Methods. This was an observational and retrospective study of 18 patients diagnosed with aHUS.Results. The median age of the study population was 30 (22-66) years. Four of 18 patients achieved hematological remission with the TPE alone. However, one patient died after three sessions of TPE. Eculizumab was used in 13 patients and no death was observed. One year after treatment, improved kidney function was observed in 2 of 3 (66%) patients for TPE and 5 of 9 (56%) patients for Eculizumab. We discontinued eculizumab treatment in 9 patients. One of the patients who had a C3 gene mutation experienced disease relapse after Eculizumab discontinuation. None of the patients who had drug associated aHUS developed disease relapse after Eculizumab discontinuation.Conclusion. Eculizumab treatment is a life-saving therapy in aHUS. Treatment discontinuation may be considered at least six months after hematologic remission in patients who had stable renal function or no expectancy for renal survival. Moreover, drug-associated cases seem to tend not to develop disease relapse in the long term.

Complement Blockade Is a Promising Therapeutic Approach in a Subset of Critically Ill Adult Patients with Complement-Mediated Hemolytic Uremic Syndromes.

Thrombotic microangiopathy (TMA) gathers consumptive thrombocytopenia, mechanical haemolytic anemia, and organ damage. Hemolytic uremic syndromes (HUS) are historically classified as primary or secondary to another disease once thrombotic thrombocytopenic purpura (TTP), Shiga-toxin HUS, and cobalamin C-related HUS have been ruled out. Complement genetics studies reinforced the link between complement dysregulation and primary HUS, contributing to reclassifying some pregnancy- and/or post-partum-associated HUS and to revealing complement involvement in severe and/or refractory hypertensive emergencies. By contrast, no firm evidence allows a plausible association to be drawn between complement dysregulation and Shiga-toxin HUS or other secondary HUS. Nevertheless, rare complement gene variants are prevalent in healthy individuals, thus providing an indication that an investigation into complement dysregulation should be carefully balanced and that the results should be cautiously interpreted with the help of a trained geneticist. Several authors have suggested reclassifying HUS in two entities, regardless of they are complement-mediated or not, since the use of eculizumab, an anti-C5 antibody, dramatically lowers the proportion of patients who die or suffer from end-stage renal disease within the year following diagnosis. Safety and the ideal timing of eculizumab discontinuation is currently under investigation, and the long-term consequences of HUS should be closely monitored over time once patients exit emergency departments.

Eculizumab treatment and discontinuation in pediatric patients with atypical hemolytic uremic syndrome: a multicentric retrospective study.

Eculizumab is effective treatment of pediatric atypical hemolytic uremic syndrome (aHUS). However, the optimal duration of treatment is not clearlydefined. The aim of this study was to retrospectively analyze the outcome of pediatric patients with aHUS, who started eculizumab treatment but discontinued it during the follow-up period. The clinical and laboratory findings of the pediatric patients with aHUS were recorded on a web-based, national registry system, known as the Turkish aHUS Registry. The study included 63 patients who had to have received more than four doses of eculizumab duringthe acute phase of the disease. The median age at diagnosis was 3.62 (IQR: 1.29-6.14) years. During the follow-up period, 39 patients continued to receive standard eculizumab treatment (standard treatment group, treatment every 2 weeks) while 24 received an extended dose of eculizumab at three-four-week intervals (non-standard treatment group). There was no significant difference between both groups in terms of clinical and laboratory parameters. Eculizumab treatment was discontinued in 18 patients (30.7%, F/M:11/7), and the median age of these patients at diagnosis and their median follow-up duration were 4.0 (IQR:2.7-10.2) and 4.2 (IQR:2.2-7) years respectively. The median eGFR at the last visit was 110 (84.7-146.1)ml/min/1.73 m2. Fourteen patients remained in remission without any sign of the disease. Recurrence occurred in four (22.2%) patients, inwhich eculizumab was immediately started again and completeremission was achieved. Eculizumab is a successful treatment option in pediatric patients with aHUS and it can be safely discontinued with close monitoring in a selected group of patients. In case of recurrence, eculizumab should be restarted immediately to achieve complete remission.

Eculizumab discontinuation in children and adults with atypical hemolytic-uremic syndrome: a prospective multicenter study

The optimal duration of eculizumab treatment in patients with atypical hemolytic uremic syndrome (aHUS) remains poorly defined. We conducted a prospective national multicenter open-label study to assess eculizumab discontinuation in children and adults with aHUS. Fifty-five patients (including 19 children) discontinued eculizumab (mean treatment duration, 16.5 months). Twenty-eight patients (51%) had rare variants in complement genes, mostly in MCP (n = 12; 22%), CFH (n = 6; 11%), and CFI (n = 6; 10%). At eculizumab discontinuation, 17 (30%) and 4 patients (7%) had stage 3 and 4 chronic kidney disease, respectively. During follow-up, 13 patients (23%; 6 children and 7 adults) experienced aHUS relapse. In multivariable analysis, female sex and presence of a rare variant in a complement gene were associated with an increased risk of aHUS relapse, whereas requirement for dialysis during a previous episode of acute aHUS was not. In addition, increased sC5b-9 plasma level at eculizumab discontinuation was associated with a higher risk of aHUS relapse in all patients and in the subset of carriers with a complement gene rare variant, both by log-rank test and in multivariable analysis. Of the 13 relapsing patients, all of whom restarted eculizumab, 11 regained their baseline renal function and 2 had a worsening of their preexisting chronic kidney disease, including 1 patient who progressed to end-stage renal disease. A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe. It improves the management and quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment. This trial was registered at www.clinicaltrials.gov as #NCT02574403.

Outcomes of a clinician-directed protocol for discontinuation of complement inhibition therapy in atypical hemolytic uremic syndrome

Terminal complement inhibition is the standard of care for atypical hemolytic uremic syndrome (aHUS). The optimal duration of complement inhibition is unknown, although indefinite therapy is common. Here, we present the outcomes of a physician-directed eculizumab discontinuation and monitoring protocol in a prospective cohort of 31 patients that started eculizumab for acute aHUS (and without a history of renal transplant). Twenty-five (80.6%) discontinued eculizumab therapy after a median duration on therapy of 2.37 (interquartile range: 1.06, 9.70) months. Eighteen patients discontinued per protocol and 7 because of nonadherence. Of these, 5 (20%) relapsed; however, relapse rate was higher in the case of nonadherence (42.8%) vs clinician-directed discontinuation and monitoring (11.1%). Four of 5 patients who relapsed were successfully retreated without a decline in renal function. One patient died because of recurrent aHUS and hypertensive emergency in the setting of nonadherence. Nonadherence to therapy (odds ratio, 8.25; 95% confidence interval, 1.02-66.19; P = .047) was associated with relapse, whereas the presence of complement gene variants (odds ratio, 1.39; 95% confidence interval, 0.39-4.87; P = .598) was not significantly associated with relapse. Relapse occurred in 40% (2 of 5) with a CFH or MCP variant, 33.3% (2 of 6) with other complement variants, and 0% (0 of 6) with no variants (P = .217). There was no decline in mean glomerular filtration rate from the date of stopping eculizumab until end of follow-up. In summary, eculizumab discontinuation with close monitoring is safe in most patients, with low rates of aHUS relapse and effective salvage with eculizumab retreatment in the event of recurrence.

Eculizumab discontinuation in atypical haemolytic uraemic syndrome: TMA recurrence risk and renal outcomes.

BackgroundEculizumab modifies the course of disease in patients with atypical haemolytic uraemic syndrome (aHUS), but data evaluating whether eculizumab discontinuation is safe are limited.MethodsPatients enrolled in the Global aHUS Registry who received ≥1 month of eculizumab before discontinuing, demonstrated haematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analysed. The primary endpoint was the proportion of patients suffering from thrombotic microangiopathy (TMA) recurrence after eculizumab discontinuation. Additional endpoints included: estimated glomerular filtration rate changes following eculizumab discontinuation to last available follow-up; number of TMA recurrences; time to TMA recurrence; proportion of patients restarting eculizumab; and changes in renal function.ResultsWe analysed 151 patients with clinically diagnosed aHUS who had evidence of haematologic or renal response to eculizumab, before discontinuing. Thirty-three (22%) experienced a TMA recurrence. Univariate analysis revealed that patients with an increased risk of TMA recurrence after discontinuing eculizumab were those with a history of extrarenal manifestations prior to initiating eculizumab, pathogenic variants or a family history of aHUS. Multivariate analysis showed an increased risk of TMA recurrence in patients with pathogenic variants and a family history of aHUS. Twelve (8%) patients progressed to end-stage renal disease after eculizumab discontinuation; seven (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after eculizumab discontinuation.ConclusionsEculizumab discontinuation in patients with aHUS is not without risk, potentially leading to TMA recurrence and renal failure. A thorough assessment of risk factors prior to the decision to discontinue eculizumab is essential.

Determination of Relapse Risk By Complement Gene Variants after Eculizumab Discontinuation in Complement-Mediated Thrombotic Microangiopathy: A Retrospective Review

Background Eculizumab, a monoclonal antibody targeting C5, is an effective treatment for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy has been suggested, the optimal treatment schedule is unknown, while eculizumab discontinuation does not universally lead to relapse. Data evaluating risk factors associated with an increased risk of CM-TMA recurrence following eculizumab withdrawal are scarce. Prior to the eculizumab era, complement genetic studies have been used to assess morbidity and mortality in patients with CM-TMA. Our aim was to assess the impact of complement gene variants on CM-TMA relapse rate (RR) after eculizumab discontinuation. Methods Search protocols were developed for the Ovid and PubMed databases to identify existing reports on CM-TMA and eculizumab withdrawal published before February 1st 2020. Cases were cross-referenced to eliminate duplicates. Inclusion criteria included patients diagnosed with CM-TMA who had undergone eculizumab discontinuation. Reasons for exclusion were patients with no follow-up after eculizumab withdrawal and patients lacking complement gene testing. Patients undergoing eculizumab dose extension, but not discontinuation, were not included. Results Fifteen studies including 557 individuals were retrieved. Of these, 363 (65.2%) were excluded as outlined in Figure 1 and 194 cases were included in the final analysis with a global RR of 28.9% (n=56). Distribution based on gene impacted and variant type are presented in Table 1. RR was highest among patients with CFH variants (52.5% to 60%) -particularly if involving exon 22 or nonsense mutations-, MCP/CD46 variants (38.9% to 45%) -particularly if affecting splice regions-, and cases with multiple concomitant variants (57.1%) -particularly those including CFH or a CFH-CFHR1 Hybrid (Table 2). Patients with relapse were more likely to have the presence of a complement variant (p&amp;lt;0.001), history of previously resolved CM-TMA events (p=0.022), younger age (mean age 22.4 years for patients with relapse vs. 32.33 years for patients without relapse; p=0.002) and, within those with detected variants, multiple vs. single variants (p=0.002) and CFH-inclusive variants (p=0.003). On univariate analysis, complement gene variants (OR 4.217 95%CI 1.97-9.026; p&amp;lt;0.001), age &amp;lt;30 years (OR 2.346 95%CI 1.159-4.749; p=0.018), and presence of multiple variants (OR 2.06 95%CI 1.172-3.621; p=0.012) or CFH-inclusive variants (OR 3.111 95%CI 1.443-6.71; p=0.004) were associated with increased odds of CM-TMA relapse, while no prior history of additional CM-TMA events was the only factor associated with lower RR (OR 0.327 95%CI 0.123-0.87; p=0.025). Presence of complement variants (OR 4.48 95%CI 1.132-17.724; p=0.033) and CFH-inclusive variants (OR 3.045 95%CI 1.136-8.159; p=0.027) were independently associated with increased RR on multivariate analysis (Table 3). Conclusion Relapse after eculizumab discontinuation is rare in cases with no genetic variants identified but can increase to more than 80% in high-risk subgroups. Complement genetic testing is not required for CM-TMA diagnosis or for initiation of complement inhibiting therapy; however, our results demonstrate the value of complement genetic testing when stratifying risk of patients for consideration of eculizumab discontinuation. Disclosures Sridharan: Alexion: Honoraria.

Outcomes of a Clinician-Directed Protocol for Discontinuation of Complement Inhibition Therapy in Atypical Hemolytic Uremic Syndrome

Introduction : Terminal complement inhibition with a C5 inhibitor (eculizumab or ravulizumab) is the standard of care for treatment of atypical hemolytic uremic syndrome (aHUS) and leads to rapid resolution of thrombotic microangiopathy and improvement in renal function. The ideal duration of complement inhibition in aHUS is not established. Indefinite therapy is standard, though recent studies suggest that many patients with aHUS may safely discontinue therapy. Here, we present the outcomes of a physician-directed eculizumab discontinuation and monitoring protocol in a prospective cohort of 32 patients with aHUS. Methods: Consecutive patients with aHUS enrolled in the Hopkins Complement Associated Disease Registry between January 2014 and December 2019 who initiated eculizumab therapy during an acute episode of aHUS were included in the study. Patients starting eculizumab in the setting of renal transplant were excluded from the analysis. Physician directed discontinuation and monitoring was done according to the protocol outlined in Figure 1. We also evaluated relapse rate and renal outcomes and examined clinical and genetic risk factors for relapse. Results: Thirty-two consecutive patients who initiated eculizumab therapy for acute aHUS. Median age at initial diagnosis of aHUS was 44 (IQR 25, 53.5) years, 78.1% were female, and complement gene variants were present in 59.0% (13 of 22 patients with sequencing data available). Of these 32 patients, 25 (78%) discontinued eculizumab therapy after a median duration on therapy of 2.37 (IQR 1.06, 9.70) months. Six (18%) patients continued receiving it and 1 patient died during the first episode of aHUS. Of the 25 patients that discontinued eculizumab, 18 (72%) discontinued under physician direction (17 per protocol due to TMA remission including two with no renal recovery and end stage renal disease, and 1 due to non-response and a metabolic TMA thought more likely). Seven (28%) patients interrupted or discontinued therapy due to non-adherence. Overall relapse rate after eculizumab discontinuation was 20.0% (5 of 25); however, the relapse rate was higher in the case of non-adherence versus a physician directed cessation protocol (42.8% versus 11.1%, P=0.074) (Figure 2). Of the five patients who relapsed, four were re-treated and achieved remission without a decline in renal function with eculizumab; one patient died due to recurrent TMA and hypertensive emergency in the setting of non-adherence. On univariate analysis, non-adherence with therapy [OR 8.25 (95% CI 1.02 - 66.19) P=0.047] was associated with relapse while underlying complement gene variant [OR 1.39 (95% CI 0.39-4.87), P=0.598] and presence/absence of a trigger for aHUS [OR 0.66 (95% CI 0.09-4.79), P=0.687] were not significantly associated with relapse. We examined relapse rates in patients with CFH or MCP variants (40%, 2 of 5), other variants (33.3%, 2 of 6), no variants (0%, 0 of 6), and sequencing not completed (11.1%, 1 of 9) (P=0.217). These analyses are limited by the small sample size and limited number of events (5 relapses), which precluded multivariable regression analysis. Among patients that discontinued eculizumab, there was no significant decline in mean estimated glomerular filtration rate (eGFR) from the date of stopping eculizumab (47.09 + 28.28 ml/min/1.73 m2) until the most recent follow-up (56.95 + 28.02 ml/min/1.73 m2, one sided t-test P = 0.987). As seen in figure 3, improvement in eGFR (changed to a less severe eGFR category between stopping eculizumab and end of follow up) was seen in 9 of 25 patients (36%) and stable eGFR (no change in eGFR category) was seen in 15 of 25 patients (60%). Conclusion: Eculizumab discontinuation with close monitoring is safe in the majority of patients with aHUS (with native kidneys), with low rates of TMA recurrence and nearly complete salvage with eculizumab retreatment in the event of a recurrence. CFH and MCP variants may be associated with higher risk of relapse, which needs to be evaluated in larger, multicenter studies. Disclosures Moliterno: Pharmessentia: Consultancy; MPNRF: Research Funding. Chaturvedi:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Severe worsening of myasthenic symptoms after the eculizumab discontinuation

Myasthenia gravis (MG) is an autoantibody-mediated disease of the neuromuscular junction. The neuromuscular junction damage associated with MG is caused by anti-acetylcholine receptor (AChR) antibody and complements. Recently, eculizumab (an anti-C5 monoclonal antibody) was approved for patients with anti-AChR antibody-positive generalized refractory MG. Here, we report a Japanese man with MG who well responded to eculizumab, but experienced acute severe worsening of myasthenic symptoms 2months after its discontinuation. Plasmapheresis did not improve his symptoms; hence, eculizumab was re-administered, resulting in a dramatic response within a week. This is an informative case because eculizumab discontinuation in patients with MG has been very rarely reported. If eculizumab treatment is clinically well effective and AChR antibody titer does not decrease, clinicians should be aware that acute and critical deterioration of MG may occur after the eculizumab discontinuation.

Atypical Hemolytic Uremic Syndrome After Liver Transplant Treated With Eculizumab

Thrombotic microangiopathies (TMA) are a group of serious conditions that are characterized by microangiopathic hemolytic anemia and thrombocytopenia, and are often associated with acute kidney injury as well as neurologic abnormalities. There are multiple causes of TMA. TMA in a transplant patient is often attributed to calcineurin inhibitor (CNI) use and is usually treated with discontinuation of the drug. We report a case of TMA in a liver transplant patient who did not respond to CNI discontinuation or plasmapheresis but had great response to shorter than usual course of eculizumab. Eculizumab is a monoclonal antibody that prevents c5 cleavage and indirectly inhibits the formation of the membrane attack complex. Clinical response was sustained for nine months after discontinuation of eculizumab.

Atypical hemolytic uremic syndrome in Brazil: clinical presentation, genetic findings and outcomes of a case series in adults and children treated with eculizumab.

BackgroundAtypical hemolytic uremic syndrome (aHUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia and kidney injury caused by a dysregulation of the alternative complement pathway.MethodsWe conducted a multicenter nonregistry study aimed at collecting clinical, laboratory and genetic information of patients with aHUS in Brazil. Demographic data, genetic findings, treatments and outcomes are presented.ResultsThirty-four patients were included, 62% were female and 67% were Caucasian. Half of the patients had the first manifestation of aHUS before the age of 18 years (pediatric group). Among the 17 patients who had the first manifestation after the age of 18 years (adult group), 6 were kidney transplant patients. Overall, 22 patients (65%) received plasma exchange/plasma infusion (PE/PI) and 31 patients (91%) received eculizumab. Eculizumab was started later in the adult group compared with the pediatric group. Two patients stopped dialysis after PE/PI and 19 patients stopped dialysis after eculizumab despite a late start. A pathogenic/likely pathogenic variant was found in 24.3% of patients. A coexisting condition or trigger was present in 59% of patients (infections, pregnancy, hypertension, autoimmune disease and transplant), especially in the adult group. There was a 30% relapse rate after stopping eculizumab, irrespective of genetic status.ConclusionThis is the largest case series of aHUS in Brazil involving a wide range of patients for which eculizumab was the main treatment. Although eculizumab was started later than advised in the guidelines, most patients were able to stop dialysis at variable intervals. Discontinuation of eculizumab was associated with a 30% relapse of aHUS.