The Experts below are selected from a list of 6867 Experts worldwide ranked by ideXlab platform
Fadi Fakhouri - One of the best experts on this subject based on the ideXlab platform.
-
Eculizumab discontinuation in atypical hemolytic uremic syndrome: TMA recurrence risk and renal outcomes
Clinical Kidney Journal, 2021Co-Authors: Gema Ariceta, Fadi Fakhouri, Andrew M. Siedlecki, David J. Cohen, Lisa Sartz, Benjamin Miller, Vasilis Nikolaou, Gianluigi ArdissinoAbstract:ABSTRACT Background Eculizumab modifies the course of disease in patients with atypical hemolytic uremic syndrome (aHUS), but data evaluating whether Eculizumab discontinuation is safe are limited. Methods Patients enrolled in the Global aHUS Registry who received ≥1 month of Eculizumab before discontinuing, demonstrated hematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analyzed. The primary endpoint was the proportion of patients suffering thrombotic microangiopathy (TMA) recurrence after Eculizumab discontinuation. Additional endpoints included: eGFR 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. Results We analyzed 151 patients with clinically diagnosed aHUS who had evidence of hematologic 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; 7 (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after Eculizumab discontinuation. Conclusions Eculizumab 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.
-
Outcomes in patients with atypical hemolytic uremic syndrome treated with Eculizumab in a long-term observational study
BMC Nephrology, 2019Co-Authors: Jan Menne, Yahsou Delmas, Fadi Fakhouri, Christoph Licht, Åsa Lommelé, Enrico E. Minetti, François Provôt, Eric Rondeau, Neil S. Sheerin, Jimmy WangAbstract:There are limited long-term outcome data in Eculizumab-treated patients with atypical hemolytic uremic syndrome (aHUS). We report final results from the largest prospective, observational, multicenter study of patients with aHUS treated with Eculizumab. Patients with aHUS who participated in any of five parent Eculizumab trials and received at least one Eculizumab infusion were eligible for enrollment in a long-term follow-up study. Rates of thrombotic microangiopathy (TMA) manifestations off versus on Eculizumab were evaluated. Additional endpoints included change from baseline estimated glomerular filtration rate (eGFR), long-term renal outcomes, and serious targeted treatment-emergent adverse events. Among 93 patients (0–80 years of age), 51 (55%) remained on Eculizumab and 42 (45%) discontinued; for those who discontinued, 21 (50%) reinitiated therapy. Patients who reinitiated Eculizumab had similar baseline clinical characteristics to patients who remained on Eculizumab, with higher likelihood of genetic/autoimmune complement abnormalities, more prior TMAs, and longer disease course versus those who did not reinitiate. Mean eGFR improved rapidly and remained stable for up to 6 years on Eculizumab. In patients who discontinued, there was a trend toward decreasing renal function over time from discontinuation. Additionally, off-treatment TMA manifestation rates were higher in those aged
-
Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study
Clinical Kidney Journal, 2019Co-Authors: Jan Menne, Yahsou Delmas, Fadi Fakhouri, Christoph Licht, Enrico E. Minetti, François Provôt, Eric Rondeau, John Kincaid, Chris Mix, Neil S. SheerinAbstract:Background : Eculizumab, a terminal complement inhibitor, is approved for atypical haemolytic uraemic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy (TMA). Methods : In 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. Results : Of 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. Conclusions : As 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.
-
Eculizumab Use for Kidney Transplantation in Patients With a Diagnosis of Atypical Hemolytic Uremic Syndrome
Kidney International Reports, 2019Co-Authors: Andrew M. Siedlecki, Christoph Licht, Johan Vande Walle, Véronique Frémeaux-bacchi, Nicole M. Isbel, Jennifer James Eggleston, David J. Cohen, Gema Ariceta, Gianluigi Ardissino, Fadi FakhouriAbstract:Introduction Recurrence of atypical hemolytic uremic syndrome (aHUS) in renal allografts is common, leading to dialysis and graft failure. Pretransplant versus posttransplant initiation of Eculizumab treatment in patients with aHUS has not been rigorously investigated. We hypothesized Eculizumab pretransplant would reduce dialysis incidence posttransplant. Methods Of patients enrolled in the Global aHUS Registry (n = 1549), 344 had ≥1 kidney transplant. Of these, 188 had received Eculizumab. Eighty-eight patients (47%) were diagnosed with aHUS and received Eculizumab before, and during, their most recent transplant (group 1). A total of 100 patients (53%; group 2) initiated Eculizumab posttransplantation. This second group was subdivided into those diagnosed with aHUS before (n = 52; group 2a) or after (n = 48; group 2b) their most recent transplant. Results Within 5 years of transplantation, 47 patients required dialysis; the risk of dialysis after transplantation was significantly increased in group 2b (hazard ratio [HR] 4.6; confidence interval [CI] 1.7–12.4) but not 2a (HR 2.3; CI 0.9–6.2). Graft function within 6 months of transplantation was significantly better in group 1 (median estimated glomerular filtration rate of 60.6 ml/min per 1.73 m2) compared with 31.5 and 9.6 ml/min per 1.73 m2 in groups 2a (P = 0.004) and 2b (P = 0.0001), respectively. One meningococcal infection (resolved with treatment) and 3 deaths (deemed unrelated to Eculizumab) were reported. Conclusions Outcomes for transplant patients with aHUS treated with Eculizumab were improved compared with previous reports of patients with aHUS not treated with Eculizumab. Our findings suggest delayed aHUS diagnosis and therefore treatment is associated with an increased risk of dialysis posttransplantation and reduced allograft function.
-
Pathogenic Variants in Complement Genes and Risk of Atypical Hemolytic Uremic Syndrome Relapse after Eculizumab Discontinuation
Clinical Journal of the American Society of Nephrology, 2017Co-Authors: Fadi Fakhouri, Yahsou Delmas, François Provôt, Marc Fila, Christelle Barbet, Valérie Châtelet, Cédric Rafat, Mathilde Cailliez, Julien Hogan, Aude ServaisAbstract:BACKGROUND AND OBJECTIVES: The complement inhibitor Eculizumab has dramatically improved the outcome of atypical hemolytic uremic syndrome. However, the optimal duration of Eculizumab treatment in atypical hemolytic uremic syndrome remains debated. We report on the French atypical hemolytic uremic syndrome working group's first 2-year experience with Eculizumab discontinuation in patients with atypical hemolytic uremic syndrome. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: Using the French atypical hemolytic uremic syndrome registry database, we retrospectively identified all dialysis-free patients with atypical hemolytic uremic syndrome who discontinued Eculizumab between 2010 and 2014 and reviewed their relevant clinical and biologic data. The decision to discontinue Eculizumab was made by the clinician in charge of the patient. All patients were closely monitored by regular urine dipsticks and blood tests. Eculizumab was rapidly (24-48 hours) restarted in case of relapse. RESULTS: Among 108 patients treated with Eculizumab, 38 patients (nine children and 29 adults) discontinued Eculizumab (median treatment duration of 17.5 months). Twenty-one patients (55%) carried novel or rare complement genes variants. Renal recovery under Eculizumab was equally good in patients with and those without complement gene variants detected. After a median follow-up of 22 months, 12 patients (31%) experienced atypical hemolytic uremic syndrome relapse. Eight of 11 patients (72%) with complement factor H variants, four of eight patients (50%) with membrane cofactor protein variants, and zero of 16 patients with no rare variant detected relapsed. In relapsing patients, early reintroduction (≤48 hours) of Eculizumab led to rapid (
Peter Hillmen - One of the best experts on this subject based on the ideXlab platform.
-
Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome 10 year pharmacovigilance analysis
British Journal of Haematology, 2019Co-Authors: Gérard Socié, Camille L. Bedrosian, Peter Hillmen, Mariepierre Cabytosi, Jing L Marantz, Alexander Cole, Christoph Gasteyger, Arshad Mujeebuddin, Johan Vande Walle, Hermann HallerAbstract:Eculizumab is the first and only medication approved for paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) treatment. However, Eculizumab safety based on long-term pharmacovigilance is unknown. This analysis summarises safety data collected from spontaneous and solicited sources from 16 March 2007 through 1 October 2016. Cumulative exposure to Eculizumab was 28 518 patient-years (PY) (PNH, 21 016 PY; aHUS, 7502 PY). Seventy-six cases of meningococcal infection were reported (0·25/100 PY), including eight fatal PNH cases (0·03/100 PY). Susceptibility to meningococcal infections remained the key risk in patients receiving Eculizumab. The meningococcal infection rate decreased over time; related mortality remained steady. The most commonly reported serious nonmeningococcal infections were pneumonia (11·8%); bacteraemia, sepsis and septic shock (11·1%); urinary tract infection (4·1%); staphylococcal infection (2·6%); and viral infection (2·5%). There were 434 reported cases of Eculizumab exposure in pregnant women; of 260 cases with known outcomes, 70% resulted in live births. Reporting rates for solid tumours (≈0·6/100 PY) and haematological malignancies (≈0·74/100 PY) remained stable over time. No new safety signals affecting the Eculizumab benefit-risk profile were identified. Continued awareness and implementation of risk mitigation protocols are essential to minimise risk of meningococcal and other Neisseria infections in patients receiving Eculizumab.
-
Long-term treatment with Eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival
Blood, 2011Co-Authors: Richard Kelly, Anita Hill, Louise Arnold, Gemma L Brooksbank, Stephen J. Richards, Matthew J. Cullen, Lindsay D Mitchell, Dena Cohen, Walter M Gregory, Peter HillmenAbstract:Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder with increased mortality and morbidity resulting from intravascular hemolysis. Eculizumab, a monoclonal antibody against the complement protein 5, stops the intravascular hemolysis in PNH. We evaluated 79 consecutive patients treated with Eculizumab in Leeds between May 2002 and July 2010. The survival of patients treated with Eculizumab was not different from age- and sex-matched normal controls ( P = .46) but was significantly better than 30 similar patients managed before Eculizumab ( P = .030). Three patients on Eculizumab, all over 50 years old, died of causes unrelated to PNH. Twenty-one patients (27%) had a thrombosis before starting Eculizumab (5.6 events per 100 patient-years) compared with 2 thromboses on Eculizumab (0.8 events per 100 patient-years; P P
-
Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low level extravascular hemolysis occurring through c3 opsonization
Haematologica, 2010Co-Authors: Anita Hill, Richard Kelly, Louise Arnold, Stephen J. Richards, Matthew J. Cullen, Russell P. Rother, Peter HillmenAbstract:Background Paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia characterized by intravascular hemolysis which has been demonstrated to be effectively controlled with Eculizumab. However, lactate dehydrogenase levels remain slightly elevated and haptoglobin levels remain low in some patients suggesting residual low-level hemolysis. This may be due to C3-mediated clearance of paroxysmal nocturnal hemoglobinuria red blood cells through the reticuloendothelial system. Design and Methods Thirty-nine samples from patients not treated with Eculizumab and 31 samples from patients treated with Eculizumab were obtained (for 17 of these 31 samples there were also samples taken prior to Eculizumab treatment). Membrane bound complement was assessed by flow cytometry. Direct antiglobulin testing was carried out using two methods. Lactate dehydrogenase was assayed to assess the degree of hemolysis. Results Three of 39 patients (8%) with paroxysmal nocturnal hemoglobinuria not on Eculizumab had a positive direct antiglobulin test, while the test was positive in 21 of 31 (68%) during Eculizumab treatment. Of these 21 patients who had a positive direct antiglobulin test during Eculizumab treatment, 17 had been tested prior to treatment; only one was positive. Flow cytometry using anti-C3 monoclonal antibodies was performed on the 21 direct antiglobulin test-positive, Eculizumab-treated patients; the median proportion of C3-positive total red blood cells was 26%. Among the Eculizumab-treated patients, 16 of the 21 (76.2%) with a positive direct antiglobulin test received at least one transfusion compared with one of ten (10.0%) of those with a negative test ( P <0.01). Among the Eculizumab-treated patients, the mean hemoglobin value for the 21 with a positive direct antiglobulin test was 9.6±0.3 g/dL, whereas that in the ten patients with a negative test was 11.0±0.4 g/dL ( P =0.02). Conclusions These data demonstrate a previously masked mechanism of red cell clearance in paroxysmal nocturnal hemoglobinuria and suggests that blockade of complement at C5 allows C3 fragment accumulation on some paroxysmal nocturnal hemoglobinuria red cells, explaining the residual low-level hemolysis occurring in some Eculizumab-treated patients.
-
Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low level extravascular hemolysis occurring through c3 opsonization
Haematologica, 2010Co-Authors: Anita Hill, Richard Kelly, Louise Arnold, Stephen J. Richards, Matthew J. Cullen, Russell P. Rother, Peter HillmenAbstract:Background Paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia characterized by intravascular hemolysis which has been demonstrated to be effectively controlled with Eculizumab. However, lactate dehydrogenase levels remain slightly elevated and haptoglobin levels remain low in some patients suggesting residual low-level hemolysis. This may be due to C3-mediated clearance of paroxysmal nocturnal hemoglobinuria red blood cells through the reticuloendothelial system.Design and Methods Thirty-nine samples from patients not treated with Eculizumab and 31 samples from patients treated with Eculizumab were obtained (for 17 of these 31 samples there were also samples taken prior to Eculizumab treatment). Membrane bound complement was assessed by flow cytometry. Direct antiglobulin testing was carried out using two methods. Lactate dehydrogenase was assayed to assess the degree of hemolysis.Results Three of 39 patients (8%) with paroxysmal nocturnal hemoglobinuria not on Eculizumab had a positive direct antiglobulin test, while the test was positive in 21 of 31 (68%) during Eculizumab treatment. Of these 21 patients who had a positive direct antiglobulin test during Eculizumab treatment, 17 had been tested prior to treatment; only one was positive. Flow cytometry using anti-C3 monoclonal antibodies was performed on the 21 direct antiglobulin test-positive, Eculizumab-treated patients; the median proportion of C3-positive total red blood cells was 26%. Among the Eculizumab-treated patients, 16 of the 21 (76.2%) with a positive direct antiglobulin test received at least one transfusion compared with one of ten (10.0%) of those with a negative test (P
-
Eculizumab, a terminal complement inhibitor, improves anaemia in patients with paroxysmal nocturnal haemoglobinuria.
British Journal of Haematology, 2008Co-Authors: Jörg Schubert, Gérard Socié, Peter Hillmen, Jeff Szer, Alexander Röth, Neal S. Young, Modupe O. Elebute, Giacomo Gianfaldoni, Paul Browne, Robert GellerAbstract:In paroxysmal nocturnal haemoglobinuria (PNH), chronic destruction of PNH red blood cells (RBCs) by complement leads to anaemia and other serious morbidities. Eculizumab inhibits terminal complement-mediated PNH RBC destruction by targeting C5. In the phase III, double-blind, placebo-controlled, TRIUMPH study, Eculizumab reduced haemolysis, stabilized haemoglobin levels, reduced transfusion requirements and improved fatigue in patients with PNH. Herein, we explored the effects of Eculizumab on measures of anaemia in patients from the TRIUMPH study and the open-label SHEPHERD study, a more heterogeneous population. Eculizumab reduced haemolysis regardless of pretreatment transfusion requirements and regardless of whether or not patients became transfusion-dependent during treatment (P < 0.001). Reduction in haemolysis was associated with increased PNH RBC counts (P < 0.001) while reticulocyte counts remained elevated. Eculizumab-treated patients demonstrated significantly higher levels of haemoglobin as compared with placebo in TRIUMPH and relative to baseline levels in SHEPHERD (P < 0.001 for each study). Eculizumab lowered transfusion requirement across multiple pretreatment transfusion strata and eliminated transfusion support in a majority of both TRIUMPH and SHEPHERD patients (P < 0.001). Patients who required some transfusion support during treatment with Eculizumab showed a reduction in haemolysis and transfusion requirements and an improvement in fatigue. Eculizumab reduces haemolysis and improves anaemia and fatigue, regardless of transfusion requirements.
Jack F M Wetzels - One of the best experts on this subject based on the ideXlab platform.
-
Case Report: Variable Pharmacokinetic Profile of Eculizumab in an aHUS Patient.
Frontiers in immunology, 2021Co-Authors: Romy N. Bouwmeester, Elena B. Volokhina, Jack F M Wetzels, Kioa L. Wijnsma, Caroline Duineveld, Lambertus P. Van Den Heuvel, Mendy Ter Avest, Rob Ter Heine, N.c.a.j. Van De KarAbstract:Background With the introduction of Eculizumab, a C5-inhibitor, morbidity and mortality improved significantly for patients with atypical hemolytic uremic syndrome (aHUS). In view of the high costs, actual needs of the drug, and increasing evidence in literature, aHUS patients can be treated according to a restrictive Eculizumab regimen. We retrospectively analyzed the pharmacokinetic and dynamic parameters of Eculizumab in one patient in time, emphasizing various factors which could be taken into account during tapering of treatment. Case presentation A nowadays 18-year-old male with a severe, frequently relapsing form of atypical HUS due to a hybrid CFH/CFHR1 gene in combination with the homozygous factor H haplotype, required chronic plasma therapy (PT), including periods with plasma infusion, from the age of onset at 5 months until initiation of Eculizumab at the age of 11 years. A mild but stable chronic kidney disease (CKD) and 9 years of disease remission enabled prolongation of Eculizumab interval. At the age of 15 years, a sudden yet multifactorial progression of chronic kidney disease (CKD) was observed, without any signs of disease recurrence. However, an acquired glomerulocystic disease, a reduced left kidney function, and abnormal abdominal venous system of unknown etiology were found. In addition, after an aHUS relapse, an unexpected increase in intra-patient variability of Eculizumab concentrations was seen. Retrospective pharmacokinetic analysis revealed a change in Eculizumab clearance, associated with a simultaneous increase in proteinuria. Conclusion High intra-patient variability of Eculizumab pharmacokinetics were observed over time, emphasizing the necessity for adequate and continuous therapeutic drug monitoring in aHUS patients. Eculizumab serum trough levels together with complement activation markers (CH50) should be frequently assessed, especially during tapering of drug therapy and/or changing clinical conditions in the patient. In addition, an increase in proteinuria could result in urinary Eculizumab loss, indicating that urinary monitoring of Eculizumab may be important in aHUS patients with an unexplained decline in serum concentrations.
-
Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use
Pediatric Nephrology, 2019Co-Authors: Kioa L. Wijnsma, Caroline Duineveld, Jack F M WetzelsAbstract:With the introduction of the complement C5-inhibitor Eculizumab, a new era was entered for patients with atypical hemolytic uremic syndrome (aHUS). Eculizumab therapy very effectively reversed thrombotic microangiopathy and reduced mortality and morbidity. Initial guidelines suggested lifelong treatment and recommended prophylactic use of Eculizumab in aHUS patients receiving a kidney transplant. However, there is little evidence to support lifelong therapy or prophylactic treatment in kidney transplant recipients. Worldwide, there is an ongoing debate regarding the optimal dose and duration of treatment, particularly in view of the high costs and potential side effects of Eculizumab. An increasing but still limited number of case reports and small cohort studies suggest that a restrictive treatment regimen is feasible. We review the current literature and focus on the safety and efficacy of restrictive use of Eculizumab. Our current treatment protocol is based on restrictive use of Eculizumab. Prospective monitoring will provide more definite proof of the feasibility of such restrictive treatment.
-
Safety and effectiveness of restrictive Eculizumab treatment in atypical haemolytic uremic syndrome.
Nephrology Dialysis Transplantation, 2017Co-Authors: Kioa L. Wijnsma, Elena B. Volokhina, N.c.a.j. Van De Kar, Caroline Duineveld, Lambertus P. Van Den Heuvel, Jack F M WetzelsAbstract:Background Atypical haemolytic uremic syndrome (aHUS) is a rare but severe form of thrombotic microangiopathy as a consequence of complement dysregulation. aHUS has a poor outcome with high mortality and >50% of patients developing end-stage renal disease. Since the end of 2012, these outcomes have greatly improved with the introduction of Eculizumab. Currently the duration of treatment is debated. Most guidelines advise lifelong treatment. However, there is no hard evidence to support this advice. Historically, a substantial number of aHUS patients were weaned of plasma therapy, often without disease recurrence. Moreover, the long-term consequences of Eculizumab treatment are unknown. In this retrospective study we describe 20 patients who received a restrictive treatment regimen. Methods All aHUS patients who presented in the Radboud University Medical Center, Nijmegen, The Netherlands, between 2012 and 2016 and who received Eculizumab are described. Clinical, diagnostic and follow-up data were gathered and reviewed. Results Twenty patients (14 adults, 6 children) with aHUS have received Eculizumab. Eculizumab was tapered in all and stopped in 17 patients. aHUS recurrence occurred in five patients. Due to close monitoring, recurrence was detected early and Eculizumab was restarted. No clinical sequela such as proteinuria or progressive kidney dysfunction was detected subsequently. In total, Eculizumab has been discontinued in 13 patients without aHUS recurrence, of which 5 are event free for >1 year. With this strategy ∼€11.4 million have been saved. Conclusions A restrictive Eculizumab regimen in aHUS appears safe and effective. Prospective studies should further evaluate the most optimal treatment strategy.
-
Eculizumab dosing regimen in atypical HUS: Possibilities for individualized treatment
Clinical Pharmacology & Therapeutics, 2017Co-Authors: Elena B. Volokhina, Jack F M Wetzels, Kioa L. Wijnsma, R.g. Van Der Molen, Nel Roeleveld, T. J. A. N. Van Der Velden, J.h.c. Goertz, Fred C.g.j. Sweep, Roger J. M. Brüggemann, N.c.a.j. Van De KarAbstract:Recent studies indicate that Eculizumab is often given in excess to atypical hemolytic uremic syndrome (aHUS) patients. Individualization of treatment is thus highly requested; however, data on the pharmacokinetics and pharmacodynamics of Eculizumab remain limited. We analyzed 11 patients during induction (weekly), maintenance (2-weekly), and tapering (every 3-8 weeks) phases of treatment. The trough Eculizumab levels increased with each additional dose during the induction phase (depending on body weight). During maintenance, high Eculizumab concentrations of up to 772 μg/mL were observed. The levels decreased with each following dose during tapering (3- and 4-week intervals); however, three patients maintained target Eculizumab levels over long time periods (30-48 weeks). At intervals of 6-8 weeks, target Eculizumab levels were no longer attained. Serum samples with Eculizumab concentrations ≥50 μg/mL showed adequate complement blockade. Our data provide essential insight for optimization of Eculizumab dosing schemes and lessening of therapy burden for the patients and cost of the treatment.
-
Cost-effectiveness of Eculizumab treatment after kidney transplantation in patients with atypical haemolytic uraemic syndrome.
Nephrology Dialysis Transplantation, 2017Co-Authors: Jan A J G Van Den Brand, Jacobien C Verhave, Eddy M Adang, Jack F M WetzelsAbstract:Background: Kidney transplantation in patients with atypical haemolytic uraemic syndrome (aHUS) is frequently complicated by recurrence of aHUS, often resulting in graft loss. Eculizumab prophylaxis prevents recurrence, improving graft survival. An alternative treatment strategy has been proposed where Eculizumab is administered upon recurrence. We combined available evidence and performed a cost-effectiveness analysis of these competing strategies. Methods: A cost-effectiveness analysis using a decision analytical approach with Markov chain analyses was used to compare alternatives for aHUS patients with end-stage renal disease (ESRD): (i) dialysis treatment, (ii) kidney transplantation, (iii) kidney transplantation with Eculizumab therapy upon recurrence of aHUS, (iv) kidney transplantation with Eculizumab induction consisting of 12 months of prophylaxis and (v) kidney transplantation with lifelong Eculizumab prophylaxis. We assumed that all patients received a graft from a living donor and that recurrence probability was 28.4% within the first year of transplantation. Results: At 8.34 quality-adjusted life years (QALYs) gained and a cost of euro402 412, kidney transplantation without Eculizumab was the least costly alternative. By comparison, dialysis was more costly and resulted in fewer QALYs gained. Eculizumab upon recurrence resulted in 9.55 QALYs gained at a cost of euro425 097. The incremental cost-effectiveness ratio (ICER) was euro18 748 per QALY. Both Eculizumab induction and lifelong Eculizumab were inferior to Eculizumab upon recurrence, as both resulted in fewer QALYs gained and higher costs. Conclusions: Kidney transplantation is more cost effective than dialysis to treat ESRD due to aHUS. Adding Eculizumab treatment results in a substantial gain in QALYs. When compared with Eculizumab upon recurrence, neither Eculizumab induction nor lifelong Eculizumab prophylaxis resulted in more QALYs, but did yield far higher costs. Therefore, Eculizumab upon recurrence of aHUS is more acceptable.
Ashley Teusink - One of the best experts on this subject based on the ideXlab platform.
-
variable Eculizumab clearance requires pharmacodynamic monitoring to optimize therapy for thrombotic microangiopathy after hematopoietic stem cell transplantation
Biology of Blood and Marrow Transplantation, 2016Co-Authors: Sonata Jodele, Tsuyoshi Fukuda, Kana Mizuno, Alexander A Vinks, Benjamin L Laskin, Jens Goebel, Bradley P Dixon, Ranjit S Chima, Russel Hirsch, Ashley TeusinkAbstract:Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor Eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of Eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with Eculizumab. We measured Eculizumab serum concentrations, total hemolytic complement activity, and plasma sC5b-9 concentrations. Population PK/PD analyses correlated Eculizumab concentrations with complement blockade and clinical response and determined interindividual differences in PK parameters. We also compared transplant survival in patients treated with Eculizumab (n = 18) with patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n = 11). In the PK analysis, we found significant interpatient variability in Eculizumab clearance, ranging from 16 to 237 mL/hr/70 kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, was a significant determinant of Eculizumab clearance and disease response. Sixty-one percent of treated patients had complete resolution of TMA and were able to safely discontinue Eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared with untreated patients (56% versus 9%, P = .003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but Eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. Our Eculizumab dosing algorithm, including pr-treatment plasma sC5b-9 concentrations, patient's actual body weight, and the first Eculizumab dose (mg), accurately determined Eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide Eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.
-
Eculizumab therapy in children with severe hematopoietic stem cell transplantation associated thrombotic microangiopathy
Biology of Blood and Marrow Transplantation, 2014Co-Authors: Sonata Jodele, Tsuyoshi Fukuda, Kana Mizuno, Alexander A Vinks, Benjamin L Laskin, Jens Goebel, Bradley P Dixon, Ashley Teusink, Fred G Pluthero, Lily LuAbstract:Abstract We recently observed that dysregulation of the complement system may be involved in the pathogenesis of hematopoietic stem cell transplantation–associated thrombotic microangiopathy (HSCT-TMA). These findings suggest that the complement inhibitor Eculizumab could be a therapeutic option for this severe HSCT complication with high mortality. However, the efficacy of Eculizumab in children with HSCT-TMA and its dosing requirements are not known. We treated 6 children with severe HSCT-TMA using Eculizumab and adjusted the dose to achieve a therapeutic level >99 μg/mL. HSCT-TMA resolved over time in 4 of 6 children after achieving therapeutic Eculizumab levels and complete complement blockade, as measured by low total hemolytic complement activity (CH50). To achieve therapeutic drug levels and a clinical response, children with HSCT-TMA required higher doses or more frequent Eculizumab infusions than currently recommended for children with atypical hemolytic uremic syndrome. Two critically ill patients failed to reach therapeutic Eculizumab levels, even after dose escalation, and subsequently died. Our data indicate that Eculizumab may be a therapeutic option for HSCT-TMA, but HSCT patients appear to require higher medication dosing than recommended for other conditions. We also observed that a CH50 level ≤ 4 complement activity enzyme units correlated with therapeutic Eculizumab levels and clinical response, and therefore CH50 may be useful to guide Eculizumab dosing in HSCT patients as drug level monitoring is not readily available.
Sonata Jodele - One of the best experts on this subject based on the ideXlab platform.
-
variable Eculizumab clearance requires pharmacodynamic monitoring to optimize therapy for thrombotic microangiopathy after hematopoietic stem cell transplantation
Biology of Blood and Marrow Transplantation, 2016Co-Authors: Sonata Jodele, Tsuyoshi Fukuda, Kana Mizuno, Alexander A Vinks, Benjamin L Laskin, Jens Goebel, Bradley P Dixon, Ranjit S Chima, Russel Hirsch, Ashley TeusinkAbstract:Thrombotic microangiopathy (TMA) after hematopoietic stem cell transplantation (HSCT) associated with terminal complement activation, as measured by elevated plasma terminal complement (sC5b-9) concentrations, has a very high mortality. The complement inhibitor Eculizumab may be a therapeutic option for HSCT-associated TMA. We examined the pharmacokinetics and pharmacodynamics (PK/PD) of Eculizumab in children and young adult HSCT recipients with TMA and activated complement to determine drug dosing requirements for future efficacy trials. We analyzed prospectively collected laboratory samples and clinical data from 18 HSCT recipients with high-risk TMA presenting with complement activation who were treated with Eculizumab. We measured Eculizumab serum concentrations, total hemolytic complement activity, and plasma sC5b-9 concentrations. Population PK/PD analyses correlated Eculizumab concentrations with complement blockade and clinical response and determined interindividual differences in PK parameters. We also compared transplant survival in patients treated with Eculizumab (n = 18) with patients with the same high-risk TMA features who did not receive any targeted therapy during a separate prospective observational study (n = 11). In the PK analysis, we found significant interpatient variability in Eculizumab clearance, ranging from 16 to 237 mL/hr/70 kg in the induction phase. The degree of complement activation measured by sC5b-9 concentrations at the start of therapy, in addition to actual body weight, was a significant determinant of Eculizumab clearance and disease response. Sixty-one percent of treated patients had complete resolution of TMA and were able to safely discontinue Eculizumab without disease recurrence. Overall survival was significantly higher in treated subjects compared with untreated patients (56% versus 9%, P = .003). Complement blocking therapy is associated with improved survival in HSCT patients with high-risk TMA who historically have dismal outcomes, but Eculizumab pharmacokinetics in HSCT recipients differ significantly from reports in other diseases like atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. Our Eculizumab dosing algorithm, including pr-treatment plasma sC5b-9 concentrations, patient's actual body weight, and the first Eculizumab dose (mg), accurately determined Eculizumab concentration-time profiles for HSCT recipients with high-risk TMA. This algorithm may guide Eculizumab treatment and ensure that future efficacy studies use the most clinically appropriate and cost-efficient dosing schedules.
-
Eculizumab therapy in children with severe hematopoietic stem cell transplantation associated thrombotic microangiopathy
Biology of Blood and Marrow Transplantation, 2014Co-Authors: Sonata Jodele, Tsuyoshi Fukuda, Kana Mizuno, Alexander A Vinks, Benjamin L Laskin, Jens Goebel, Bradley P Dixon, Ashley Teusink, Fred G Pluthero, Lily LuAbstract:Abstract We recently observed that dysregulation of the complement system may be involved in the pathogenesis of hematopoietic stem cell transplantation–associated thrombotic microangiopathy (HSCT-TMA). These findings suggest that the complement inhibitor Eculizumab could be a therapeutic option for this severe HSCT complication with high mortality. However, the efficacy of Eculizumab in children with HSCT-TMA and its dosing requirements are not known. We treated 6 children with severe HSCT-TMA using Eculizumab and adjusted the dose to achieve a therapeutic level >99 μg/mL. HSCT-TMA resolved over time in 4 of 6 children after achieving therapeutic Eculizumab levels and complete complement blockade, as measured by low total hemolytic complement activity (CH50). To achieve therapeutic drug levels and a clinical response, children with HSCT-TMA required higher doses or more frequent Eculizumab infusions than currently recommended for children with atypical hemolytic uremic syndrome. Two critically ill patients failed to reach therapeutic Eculizumab levels, even after dose escalation, and subsequently died. Our data indicate that Eculizumab may be a therapeutic option for HSCT-TMA, but HSCT patients appear to require higher medication dosing than recommended for other conditions. We also observed that a CH50 level ≤ 4 complement activity enzyme units correlated with therapeutic Eculizumab levels and clinical response, and therefore CH50 may be useful to guide Eculizumab dosing in HSCT patients as drug level monitoring is not readily available.
