Thrombotic Microangiopathy Following Pediatric Autologous Hematopoietic Cell Transplantation: A Report of Significant End-Organ Dysfunction in Eculizumab-Treated Survivors.
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. Three 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 eculizumab, and capture long-term sequelae in survivors.
Schoettler M
，Lehmann L
，Li A
，Ma C
，Duncan C
... -
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Case report: A family of atypical hemolytic uremic syndrome involving a CFH::CFHR1 fusion gene and CFHR3-1-4-2 gene duplication.
Mutations in the complement factor H (CFH) gene are associated with complement dysregulation and the development of atypical hemolytic uremic syndrome (aHUS). Several fusion genes that result from genomic structural variation in the CFH and complement factor H-related (CFHR) gene regions have been identified in aHUS. However, one allele has both CFHR gene duplication and CFH::CFHR1 fusion gene have not been reported. An 8-month-old girl (proband) presented with aHUS and was treated with ravulizumab. Her paternal grandfather developed aHUS previously and her paternal great grandmother presented with anti-neutrophil cytoplasmic antibody-associated vasculitis and thrombotic microangiopathy (TMA). However, the proband's parents have no history of TMA. A genetic analysis revealed the presence of CFH::CFHR1 fusion gene and a CFHR3-1-4-2 gene duplication in the patient, her father, and her paternal grandfather. Although several fusion genes resulting from structural variations of the CFH-CFHR genes region have been identified, this is the first report of the combination of a CFH::CFHR1 fusion gene with CFHR gene duplication. Because the CFH-CFHR region is highly homologous, we hypothesized that CFHR gene duplication occurred. These findings indicate a novel pathogenic genomic structural variation associated with the development of aHUS.
Tasaki Y
，Tsujimoto H
，Yokoyama T
，Sugimoto N
，Kitajima S
，Fujii H
，Hidaka Y
，Kato N
，Maruyama S
，Inoue N
，Wada T
... -
《Frontiers in Immunology》
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