Pediatric transplant–associated thrombotic microangiopathy health care utilization and implications of eculizumab therapy∗
Ontology highlight
ABSTRACT:
SUBMITTER: Schoettler M
PROVIDER: S-EPMC10912836 | biostudies-literature | 2023 Dec
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:In patients with pregnancy-associated complement gene variant-mediated thrombotic microangiopathy (cTMA), terminal complement blockade is used for treatment of cTMA flares during pregnancy or following delivery. We report pregnancy and delivery outcomes of 2 genetically high-risk patients with cTMA, including 1 kidney transplant recipient, during ongoing eculizumab therapy. In both patients, the first manifestation of cTMA occurred independent from pregnancy. One patient has a history of 2 uneventful pregnancies with prophylactic plasma infusions, and the other has a history of early abortion during long-term eculizumab therapy following kidney transplantation. Overall, pregnancy and delivery outcomes under ongoing eculizumab therapy in our 2 patients with preserved kidney function were excellent as compared with other patients reported in the literature. Eculizumab plasma concentrations were maintained in the therapeutic range during pregnancy and were also detectable in cord blood. Results of cord blood analysis showed deficient complement activity, with low factor and regulator levels, most likely reflecting the age of the neonates and presence of eculizumab in cord blood. In conclusion, pregnancy during ongoing eculizumab treatment appeared to be safe in 2 women with a history of high-risk genetic cTMA and excellent kidney function, even following kidney transplantation.
| S-EPMC7380370 | biostudies-literature
Project description:BackgroundGemcitabine is a broadly used chemotherapeutic agent that can cause a rare but life-threatening complication called thrombotic microangiopathy (TMA). Early recognition is crucial as therapy options are limited.Case descriptionWe report the case of a 46-year-old patient with pancreatic adenocarcinoma who presented with severe anemia and thrombocytopenia as well as acute kidney injury. A diagnosis of gemcitabine-induced TMA was made. He became rapidly transfusion and dialysis dependent. Despite discontinuation of gemcitabine and treatment with high-dose corticotherapy as well as plasmapheresis, no improvement in both renal and hematological parameters was seen. Treatment with eculizumab was initiated. One week after the first administration, the patient no longer required packed cells nor platelet transfusions and one month later, dialysis could be discontinued. After five doses, treatment with eculizumab was stopped. Four months later, his serum creatinine was 1 mg/dL.ConclusionsThis case report illustrates the promising beneficial effects of eculizumab in gemcitabine-induced TMA, both regarding transfusion dependence as well as improvement in renal function, thereby allowing further therapy options in patients with an active malignancy.
| S-EPMC9830318 | biostudies-literature
Project description:BackgroundGemcitabine is a broadly prescribed chemotherapy, the use of which can be limited by renal adverse events, including thrombotic microangiopathy (TMA).MethodsThis study evaluated the efficacy of eculizumab, a monoclonal antibody targeting the terminal complement pathway, in patients with gemcitabine-induced TMA (G-TMA). We conducted an observational, retrospective, multicenter study in 5 French centres, between 2011 and 2016.ResultsTwelve patients with a G-TMA treated by eculizumab were included. The main characteristics were acute renal failure (100%), including stage 3 acute kidney injury (AKI, 58%) and renal replacement therapy (17%), hypertension (92%) and diffuse oedema (83%). Eculizumab was started after a median of 15 days (range 4-44) following TMA diagnosis. A median of 4 injections of eculizumab was performed (range 2-22). Complete hematological remission was achieved in 10 patients (83%) and blood transfusion significantly decreased after only one injection of eculizumab (median of 3 packed red blood cells (range 0-10) before treatment vs 0 (range 0-1) after one injection, P < 0.001). Two patients recovered completely renal function (17%), and 8 achieved a partial remission (67%). Compared to a control group of G-TMA without use of eculizumab, renal outcome was more favourable. At the end of the follow up, median eGFR was 45 vs 33 ml/min/1.73m2 respectively in the eculizumab group and in the control group.ConclusionsThese results suggest that eculizumab is efficient on haemolysis and reduces transfusion requirement in G-TMA. Moreover, eculizumab may improve renal function recovery.
| S-EPMC8293501 | biostudies-literature
Project description:Transplant-associated thrombotic microangiopathy (TA-TMA) is a well-recognized complication of hematopoietic cell transplantation (HCT). Diagnosis is challenging and in the absence of a tissue biopsy, TA-TMA is provisionally diagnosed by meeting clinical criteria. In this study, we describe the prevalence, outcomes, and risk factors for meeting 2 different diagnostic criteria for TA-TMA and for increased transplant-related mortality (TRM). In this retrospective study of 307 pediatric HCT patients, records were reviewed for the first 100 days after HCT. Patients who were diagnosed with TA-TMA by a provider during this time were included. In addition, the Cho et al criteria (2010) and Jodele et al (2014) TA-TMA criteria were applied retrospectively. Eight patients (2.6%) were diagnosed with TA-TMA by their provider. However, on retrospective review, 20% and 36% met the Cho and Jodele criteria for TA-TMA, respectively. Overall survival was significantly worse (P < .0001) and TRM was significantly higher in patients who met criteria for TA-TMA (MC-TA-TMA) (P < .0001). After controlling for comorbid conditions, MC-TA-TMA (hazard ratio [HR], 10.9; P = .0001) and grade 3/4 acute graft-versus-host-disease (aGVHD) (HR 3.5; P = .01) remained independently associated with increased TRM. Among allogeneic HCT recipients, features associated with an increased risk for MC-TA-TMA included ≥2 HCT, concurrent grade 3/4 aGVHD and concurrent infections. Among patients who MC-TA-TMA, LDH ≥2 times the upper limit of normal (P = .001), the need for ≥2 antihypertensive medications (P < .0001), and acute kidney injury (P = .003) were associated with significantly increased TRM.
| S-EPMC7284101 | biostudies-literature
Project description:This study aimed to identify a risk profile for development of transplant-associated thrombotic microangiopathy (TA-TMA) in children undergoing hematopoietic stem cell transplantation (HSCT). Between 2013 and 2016, 439 children underwent 474 HSCTs at 2 supraregional United Kingdom centers. At a median of 153 days post-HSCT, TA-TMA occurred among 25 of 441 evaluable cases (5.6%) with no evidence of center variation. Sex, underlying disease, intensity of the conditioning, total body irradiation-based conditioning, the use of calcineurin inhibitors, venoocclusive disease, and viral reactivation did not influence the development of TA-TMA. Donor type: matched sibling donor/matched family donor vs matched unrelated donor vs mismatched unrelated donor/haplo-HSCT, showed a trend toward the development of TA-TMA in 1.8% vs 6.1% vs 8.3%, respectively. Presence of active comorbidity was associated with an increased risk for TA-TMA; 13% vs 3.7% in the absence of comorbidity. The risk of TA-TMA was threefold higher among patients who received >1 transplant. TA-TMA rates were significantly higher among patients with acute graft-versus-host disease (aGVHD) grades III to IV vs aGVHD grade 0 to II. On multivariate analysis, the presence of active comorbidity, >1 transplant, aGVHD grade III to IV were risk factors for TA-TMA (odds ratio [OR]: 5.1, 5.2, and 26.9; respectively), whereas the use of cyclosporine A/tacrolimus-based GVHD prophylaxis was not a risk factor for TA-TMA (OR: 0.3). Active comorbidity, subsequent transplant, and aGVHD grades III to IV were significant risk factors for TA-TMA. TA-TMA might represent a form of a vascular GVHD, and therefore, continuing control of aGVHD is important to prevent worsening of TA-TMA associated with GVHD.
| S-EPMC7284098 | biostudies-literature
Project description:Transplant-associated thrombotic microangiopathy (TA-TMA) is an endothelial injury syndrome that complicates hematopoietic stem cell transplant (HSCT). Morbidity and mortality from TA-TMA remain high, making prevention critical. We describe our retrospective single-center experience of TA-TMA after pediatric allogeneic HSCT and present a novel pre-HSCT risk-stratification system and prophylaxis regimen. From January 2012 through October 2019, 257 patients underwent 292 allogeneic HSCTs. Prospective risk stratification was introduced in December 2016. High-risk (HR) patients were treated with combination prophylaxis with eicosapentaenoic acid and N-acetylcysteine. The 1-year cumulative incidence of TA-TMA was 6.3% (95% confidence interval [CI], 3.2-9.4). Age ≥10 years, myeloablative conditioning with total body irradiation, HLA mismatch, diagnosis of severe aplastic anemia or malignancy, prior calcineurin inhibitor exposure, and recipient cytomegalovirus seropositivity were found to be pre-HSCT risk factors for development of TA-TMA. Before routine prophylaxis, TA-TMA rates were significantly different between the HR and standard-risk groups, at 28.2% (95% CI, 0-12.7) vs 3.2% (0.1-6.3), respectively (P < .001). After introduction of prophylaxis, the 1-year cumulative incidence of TA-TMA in the HR group decreased to 4.5% (95% CI, 0-13.1; P = .062, compared with the incidence before prophylaxis). Multicenter pediatric studies are needed to validate these risk criteria and to confirm the efficacy of the prophylactic regimen.
| S-EPMC8095147 | biostudies-literature
Project description:BackgroundTransplant-associated thrombotic microangiopathy (TA-TMA) is a dangerous and life-threatening complication in patients undergoing hematopoietic stem cell transplantation (HSCT). Eculizumab has been used in the treatment of TA-TMA, and several studies have confirmed the benefit of Eculizumab in patients with TA-TMA. However, the results remain controversial. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Eculizumab for TA-TMA.Materials and methodsWe searched PubMed and Embase for studies on the efficacy and safety of Eculizumab in TA-TMA patients. Efficacy outcomes consisted of overall response rate (ORR), complete response rate (CRR), and survival rate at the last follow-up (SR). Safety outcomes were adverse events (AEs), including infection, sepsis, impaired liver function, infusion reactions, and death.ResultsA total of 116 patients from six studies were subjected to meta-analysis. The pooled estimates of ORR, CRR, and SR for TA-TMA patients were 71% (95% CI: 58-82%), 32% (95% CI: 11-56%), and 52% (95% CI: 40-65%), respectively. Only one patient presented with a severe rash, and infection was the most common AEs. The main causes of death were infection and GvHD.ConclusionCurrent evidence suggests that Eculizumab improves SR and ORR in patients with TA-TMA and that Eculizumab is well tolerated. However, the number of studies is limited, and the findings are based mainly on data from observational studies. Higher quality randomized controlled trials and more extensive prospective cohort studies are needed.
| S-EPMC7856300 | biostudies-literature
Project description:Background. Primary thrombotic microangiopathy includes hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli, atypical hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Methodology. A retrospective study that included patients younger than 18 years diagnosed with primary thrombotic microangiopathy between 2011 and 2021. Results. Thirty patients were included, of which 63% corresponded to a hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli, and 30% to the atypical hemolytic uremic syndrome. The median age was 2.8 years and female sex predominated at 57%. On admission to the emergency room, fever and fatigue were the most frequent symptoms (93%), followed by oliguria and anuria (80%). 48% of patients received hemodialysis during their care. Mortality was estimated at 13%. Conclusion. This study constitutes the largest series of primary thrombotic microangiopathy in the pediatric population of Latin America, where the etiological and clinical behavior of this condition is described.
| S-EPMC11650636 | biostudies-literature
Project description: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.
| S-EPMC4716886 | biostudies-literature
Project description: Not available
| S-EPMC8116759 | biostudies-literature