Researchers have discovered that early elevation of complement factor Ba after allogeneic hemopoietic stem cell transplantation (allo-HSCT) predicts the development of transplant-associated thrombotic microangiopathy (TA-TMA), suggesting Ba levels after allo-HSCT may serve as a prognostic biomarker of the fatal complication. The report was published in Frontiers in Immunology.

 The investigators conducted a retrospective, nested case-control study of adults treated with allo-HSCT at a single center between December, 2012 and December, 2016 to evaluate the association of TA-TMA with genetic variants in 17 previously identified complement-related genes. Potential study participants (N=109), those who had allo-HSCT and for whom plasma and DNA samples were available, were matched (1:1) based on 9 pretransplant factors using propensity scoring (PS).

PS matching yielded 30 matched patients, 15 in each the TA-TMA cohort (median age, 55 years; range, 36-68 years) and non-TA-TMA cohort (58 years; 40-67 years). Diagnoses in the cohorts (TA-TMA and non-TA-TMA) included acute myeloid leukemia (20% and 33%), acute lymphoblastic leukemia (13% and 13%), myelodysplastic syndrome (20% and 13%), and other (46% and 40%). Among patients with TA-TMA, the median onset of TA-TMA was Day 25 after allo-HSCT (interquartile range, 22.5-44).


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The investigators sequenced the 17 complement-related genes from all participants. Several genetic variants with rare allele frequencies were identified in both cohorts; however, no significant differences in the percentage of patients in the TA-TMA and non-TA-TMA groups with the rare variants or in the average number of rare variants per patient were observed.

The team then evaluated the plasma concentrations of complement proteins (C3, C4, CH50, Ba, C5a, sC5b-9, CFI, CFH, and CFH-IgG) from samples that had been collected at 4 time points before and after allo-HSCT (pre-conditioning, Day 7, Day 28, and Day 60). Levels of Ba protein on post-allo-HSCT Day 7 were abnormally high and significantly higher in the TA-TMA cohort than in the non-TA-TMA cohort (mean ± standard error, 1129 ± 109 vs 584 ± 38 ng/ml; P <.001). Post-allo-HSCT Day 28 levels of C3, C4, CH50, and complement factors H and I were significantly lower in the TA-TMA cohort compared with the non-TA-TMA cohort. All other parameters were similar between the cohorts.

The team then compared the probability of overall survival (OS) and the cumulative incidence of relapse/progression and non-relapse mortality (NRM) between patients with high Ba (n=12) or low Ba (n=18). No significant differences were observed in the probability of OS and the cumulative incidence of relapse/progression; however, the cumulative incidence of NRM was significantly higher in the high Ba group than in the low Ba group (P <.01).

“We did find that Ba levels during the early phase following allo-HSCT are associated with not only TA-TMA development but also with NRM. These findings suggest that complement activation via the alternative pathway contributes to TA-TMA development, and that Ba levels during the early phase following allo-HSCT may be a novel predictive biomarker of TA-TMA development,” the authors wrote.

Disclosure: This research was supported by Alexion GK. Please see the original reference for a full list of disclosures.

Reference

Okamura H, Nakamae H, Shindo T, et al. Early elevation of complement factor Ba is a predictive biomarker for transplant-associated thrombotic microangiopathy. Front Immunol. 2021;12. doi:10.3389/FIMMU.2021.695037