Eculizumab for transplant‐associated thrombotic microangiopathy in adult allogeneic stem cell transplant recipients

Rudoni, Joslyn; Jan, Anna; Hosing, Chitra; Aung, Fleur M.; Yeh, Jason

doi:10.1111/ejh.13127

Cited by 45 publications

(33 citation statements)

References 46 publications

(150 reference statements)

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“…The extensive end-organ damage seen in this cohort after treatment is more consistent with outcomes reported in an adult cohort of 10 patients treated with eculizumab for TA-TMA after allogeneic HCT. Overall survival was 60%, but only 1 patient had full organ recovery [18]. More studies are needed to examine the impact of treatment on late organ function in survivors, particularly in aHCT.…”

Section: Discussionmentioning

confidence: 99%

Thrombotic Microangiopathy Following Pediatric Autologous Hematopoietic Cell Transplantation: A Report of Significant End-Organ Dysfunction in Eculizumab-Treated Survivors

Schoettler

Lehmann

et al. 2019

Biology of Blood and Marrow Transplantation

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Transplantation-associated thrombotic microangiopathy (TA-TMA) is a known complication of autologous hematopoietic cell transplantation (aHCT), particularly in children with neuroblastoma. We describe a pediatric single-institution experience of TA-TMA after aHCT. Data were abstracted from the medical record of patients who underwent aHCT between January 1, 2008, and July 1,2018, at Boston Children’s Hospital. TA-TMA was diagnosed using either the International Working Group criteria or the “probable TA-TMA criteria” of Cho et al. Overall, 318 aHCTs were performed in 243 patients. Nine patients (3.7%) were diagnosed with TA-TMA. TA-TMA occurred most frequently in children with neuroblastoma (n = 7; 78%), all of whom were conditioned with carboplatin, etoposide, and melphalan. The median age at aHCT in children who developed TA-TMA was 3 years, 5 months (range, 18 months to 25 years). TMA was diagnosed at a median of 35 days (range, 8 to 106 days) after stem cell infusion. On a retrospective chart review using the same criteria used by the provider, patients met criteria a median of 5 days before the clinical diagnosis (range, 0 to 58 days). Eight patients had renal involvement at presentation, including nephrotic range proteinuria and severe hypertension, requiring from 2 to 6 antihypertensive medications. Two patients presented with multiorgan failure. Six patients were treated with eculizumab a median of 0 days after TA-TMA diagnosis (range, 0 to 11 days). On retrospective review, patients were treated a median of 18 days (range, 0 to 58 days) after meeting criteria for TA-TMA. Before initiation of therapy, 4 of 6 patients checked for serum complement levels had normal values, 1 had elevated CH50 and 1 had elevated sC59-b and CH50. All patients had CH50 levels within the target range (≤3 CAE) after induction therapy. Two patients (33%) had no response to eculizumab and died of multiorgan failure. The other 4 had both a hematologic response with transfusion independence (median, 6.5 weeks; range, 4 to 9 weeks) and renal response, defined as resolution of nephrotic range proteinuria (median, 21 weeks; range, 13 to 25 weeks). Among the eculizumab-treated survivors, 2 patients remained on prolonged eculizumab therapy, and one had recurrence of TA-TMA after discontinuation of eculizumab. All 4 eculizumab treated survivors have persistent organ dysfunction. Three children were treated with supportive care only; 2 died of relapsed cancer, and the third is alive with stage 2 chronic kidney disease. The median duration of follow-up after TA-TMA diagnosis was 2.5 years (range, 9 months to 4 years). The 1-year overall survival was 78% (SE = 14%). However, regardless of treatment, no survivors had complete normalization of function in all organs. Two children with normal serum CH50 and sc5b-9 levels responded to eculizumab. This report highlights the importance of maintaining a high suspicion for TA-TMA after aHCT. Further study is warranted to identify individual risk factors for TMA after aHCT, predict the response to ec...

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Section: Discussionmentioning

confidence: 99%

Thrombotic Microangiopathy Following Pediatric Autologous Hematopoietic Cell Transplantation: A Report of Significant End-Organ Dysfunction in Eculizumab-Treated Survivors

Schoettler

Lehmann

et al. 2019

Biology of Blood and Marrow Transplantation

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“…13 This has become increasingly important since the advent of a potentially disease-modifying drug, eculizumab. [14][15][16] This approach to diagnosis is challenging, because clinical features of TA-TMA are common to multiple post-HCT complications, including acute graft-versus-host disease (aGVHD) and infections. 17 These complications are also risk factors for the subsequent development of TA-TMA.…”

Section: Introductionmentioning

confidence: 99%

Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort

et al. 2020

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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.

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“…Among these included studies, five studies reported the complete response rate (CRR) for TA-TMA patients receiving Eculizumab treatment ( 19 , 20 , 24 – 26 ). The heterogeneity among included studies was substantial (I 2 = 73%, P < 0.01) and the pooled estimate of CRR was 32% (95%CI: 11–56%), which was much lower than overall response ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…However, in the study by Joslyn et al, the median duration between diagnosis and Eculizumab therapy was shorter, at four days, compared to other studies. Only one patient achieved a complete response and organ function was restored ( 19 ). This suggests that earlier initiation of Eculizumab may have no significant effect on restoring organ function.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and Safety of Eculizumab in the Treatment of Transplant-Associated Thrombotic Microangiopathy: A Systematic Review and Meta-Analysis

Zhang

Zhou

et al. 2021

Front. Immunol.

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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.

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Eculizumab for transplant‐associated thrombotic microangiopathy in adult allogeneic stem cell transplant recipients

Abstract: Early initiation of ECU may not alter the disease process enough to restore organ function, but it may prolong survival.

Cited by 45 publications

References 46 publications

Thrombotic Microangiopathy Following Pediatric Autologous Hematopoietic Cell Transplantation: A Report of Significant End-Organ Dysfunction in Eculizumab-Treated Survivors

Thrombotic Microangiopathy Following Pediatric Autologous Hematopoietic Cell Transplantation: A Report of Significant End-Organ Dysfunction in Eculizumab-Treated Survivors

Risk factors for transplant-associated thrombotic microangiopathy and mortality in a pediatric cohort

Efficacy and Safety of Eculizumab in the Treatment of Transplant-Associated Thrombotic Microangiopathy: A Systematic Review and Meta-Analysis

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