Survival Outcomes in Adult and Pediatric Patients Who Experienced Thrombotic Microangiopathy after Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis

Introduction

Thrombotic microangiopathy (TMA) is a severe, life-threatening, systemic complication after hematopoietic stem cell transplantation (HSCT), characterized by heterogeneous manifestations and a complex underlying pathophysiology resulting in multiorgan failure and death (Meri, 2022). The diagnosis of HSCT-TMA is challenging due to symptoms overlapping with other conditions and the absence of universally accepted diagnostic criteria, leading to a poor prognosis owing to delays in the onset of treatment (Meri, 2022). Moreover, the survival and clinical outcomes are poor, with a mortality rate of >50% at 1 year post-HSCT (Schoettler, 2022). Currently, there are no approved treatments for HSCT-TMA. This systematic literature review and meta-analysis aimed to assess the survival of patients with HSCT-TMA managed with non-biologic therapies.

Methods

A search strategy was implemented in February 2023 in the MEDLINE and Embase databases, comprising keywords and indexed terms for the population (HSCT-TMA) and study designs of interest (randomized controlled trials, single-arm trials, and observational studies). Studies published in the past 10 years were considered for eligibility screening. Eligible studies fit the pre-determined Population, Intervention, Comparator, Outcome, Study design (PICOS) criteria and described survival outcomes for patients with HSCT-TMA, either untreated or those who received non-biologic therapy. The database search was supplemented with a search for conference abstracts from the past 2 years and a manual search to identify recent publications as of June 2024. A meta-analysis was performed by fitting parametric survival curves to the reconstructed Kaplan-Meier curves from the included studies. The median duration of survival and survival rates at 6, 12, and 24 months were

calculated using the model that exhibited the best fit. Statistical heterogeneity was evaluated using the I² test. Meta-analysis was grouped by adult, pediatric, and combined cohorts.

Results

Of the 49 studies that met the eligibility criteria and were included in the systematic review, 31 unique studies were included in the meta-analysis. In adults, the median (range) survival time from TMA to death per the Weibull model was 0.17 (0.07-0.24) years, with an estimated survival rate of 26% at 6 months, 12% at 12 months, and 4% at 24 months. The median survival time from HSCT to death in adults per the Gompertz model was 0.61 (0.38-1.01) years, with an estimated survival rate of 55%, 38%, and 27% at 6, 12, and 24 months, respectively. For the pediatric population, only one study met the inclusion criteria, which reported a median (range) survival of 0.20 (0.14-NA) years, and survival rates of 18% at 6 months, and 17% at both 12 and 24 months from TMA diagnosis. The median duration of survival from TMA to death per the Weibull model in the mixed adult and pediatric population was 0.50 (0.15-1.66) years, with an estimated survival rate of 50% at 6 months, 36% at 12 months, and 22% at 24 months.

Conclusions

The findings from themeta-analysis confirmed that patients diagnosed with HSCT-TMA who received non-biologic therapies had poor survival outcomes. Due to heterogeneity in study populations, varying definitions used to diagnose TMA, and lack of standardized approach for reporting outcomes, it was difficult to compare studies, which is reflected in the small number of studies being included in the meta-analysis and the variability in outcomes. The findings further highlight the unmet need for timely diagnosis of HSCT-TMA as well as novel therapies to manage these patients.

Dandoy:Alexion: Honoraria, Research Funding; Omeros: Honoraria. Hyman:Alexion Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company; Vertex Pharmaceuticals: Ended employment in the past 24 months. Ayers:Broadstreet HEOR: Current Employment, Other: Broadstreet HEOR received funding from Alexion to conduct this work. Cheung:Broadstreet HEOR: Current Employment, Other: Broadstreet HEOR received funding from Alexion to conduct this work. Kennedy:Broadstreet HEOR: Current Employment, Other: Broadstreet HEOR received funding from Alexion to conduct this work. Messali:Alexion, AstraZeneca Rare Disease: Current Employment.