Work

Eculizumab Response in Pediatric Transplant- Associated Thrombotic Microangiopathy- a Real- World, Multi-Institutional Experience

Year: 2025

Type: article

Abstract: Background TA-TMA is a common, severe complication of HCT in children. Eculizumab , a C5 complement inhibitor , has resulted in improved survival in some studies, but not all. The objective of this study was to determine real world response rates and outcomes of children with TA-TMA treated with eculizumab. Methods All patients with TA-TMA treated with eculizumab from January 2015 to August 2023 were included in this IRB approved, retrospective, multi-institutional study (7 sites). Hematologic and organ responses after initiation of eculizumab were defined as complete (CR), partial (PR) or no response (NR, Fig 1 ). Multi-state models were used to determine risk factors for NR to eculizumab and logistic regression models to determine the probability of organ NR after treatment using SAS 9.4 (Cary, NC). Results Of the 169 children included, the median age was 6 years (IQR 2.7 to 13.8), 46 had sinusoidal obstructive syndrome (SOS), 98 required intensive care, and 130 met high-risk criteria. TA-TMA was diagnosed a median 50 days post HCT (range 3 to 1839). 125 participants underwent an allogeneic HCT with 72 receiving bone marrow and 72 from an unrelated donor, and 71 developed grade 2-4 acute graft versus host disease (GVHD). Patients received a median of 13 doses of eculizumab (range 1 to 97) over a median of 10 weeks (range 1 to 265). Hematologic best response data were available in 163 patients, of whom 77 (48%) achieved CR a median of 66 days after treatment, 26 (16%) a PR a median of 60 days, and 58 (36%) NR ( Fig 2A). In the 153 patients with organ manifestations, the best overall organ response was CR in 68 (44%), PR in 12 (7.8%), and NR in 73 (48%) ( Fig 2B). Allogeneic HCT was a risk factor for both organ (HR 2.0, 95% CI 1.07 to 3.79) and hematologic NR (HR 2.4, 95% CI 1.01 to 5.64). Neither concurrent GVHD nor SOS were RF for NR. Multi-organ dysfunction (HR 2.2, 95% CI 1.25- 3.89) and D-dimer ≥ 574 ng/mL (HR 2.52 95% CI 1.13-5.63) at TA-TMA diagnosis were RF for no organ response. Children with HR TA-TMA had comparable response rates to the entire cohort (Fig 2C). 1-yr OS in NR was 28.4% vs 87.7% in those who achieved PR/CR (p<0.001, Fig 3 ). If patients were alive and had not achieved at minimum an organ PR by 21 days of treatment, the probability of achieving a response was <50%; in a landmark analysis on day 21, 1-yr OS was 49.8% in NR compared to 83.8% in those with a PR/CR (p <0.001). Discussion In this large, multi-institutional study, ∼50% of children demonstrated an organ or hematologic response to eculizumab, but survival in non-responders was dismal. Lack of organ response by 21 days of treatment was indicative of eculizumab treatment failure in this large real-world cohort, suggesting this may be time to consider additional or alternative therapies, though this needs to be validated. Both additional therapeutic agents for TA-TMA and biomarkers predicting response warrant additional investigation.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.jtct.2025.01.205

Institutions: Emory University, Children's Healthcare of Atlanta, University of California, San Francisco, UCSF Benioff Children's Hospital, University of California San Francisco Medical Center, Nationwide Children's Hospital, Lurie Children's Hospital, Harvard University, Dana-Farber Cancer Institute, Dana-Farber/Harvard Cancer Center, Boston Children's Hospital, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Cleveland Clinic, Aflac (United States), University of Alabama at Birmingham, UAB Medicine

Language: English

Topic: Complement system in diseases

Subfield: Immunology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $3,650

OpenAlex ID: W4407977533

FWCI: 1.114

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Cited by: 3

Related to: 10