Graft-Versus-Host Disease (GVHD) and Senescence-Associated Biomarkers Correlate with Frailty and Survival in Older Adults Undergoing Hematopoietic Cell Transplantation (HCT)

Abstract

Introduction

We previously demonstrated that Fried's Frailty Phenotype (FFP) was associated with overall survival (OS) in older adults undergoing hematopoietic stem cell transplantation (HCT). We also showed that FFP is dynamic post-HCT and that declining FFP scores at 1 and 6 months correlate with inferior OS. Whether biomarkers associated with senescence-associated secretory phenotype (SASP) or graft-versus-host disease (GVHD) are associated with frailty and post-HCT outcomes in older adults remains unexplored. We examined 21 potential biomarkers related to HCT, aging, and SASP in a cohort of older adults undergoing HCT to determine their association with FFP and OS.

Methods

HCT recipients ≥ 60 years with hematologic malignancies were prospectively enrolled at our institution. FFP was assessed pre-HCT and at 1, 6, and 12 months post-HCT. Forty patients had pre-HCT, 1, 6, and/or 12-month post-HCT samples available for analysis. Biomarker selection was based on literature review and included: receptor for IL-33 (ST2), TNF-R1, TNF-RII, IL-1α, IL-1β, IL-2, IL-6, IL-7, IL-8, IL-13, IL-15, CCL2, C-X-C motif chemokine ligand 9 (CXCL9), CCL3, CCL4, PDGFAA, TNFα, VEGFα, TGFβ1, TGFβ2, and Reg3α. Biomarkers were assessed in plasma using Luminex at the aforementioned timepoints. High versus low levels for OS analyses were based on means.

Results

The median age of the cohort was 67 (range 60-75) years. Sixty percent of patients had an HCT-specific comorbidity index ≥ 3, all patients had a disease risk index of intermediate or high-risk, and 55% had mutations associated with clonal hematopoiesis. For the entire cohort, OS was 77.5% and 58.6% at 1 and 2 years, respectively. Mean ST2, TNFR1, and IL-15 levels were significantly elevated at day +28 and CXCL9 levels were significantly elevated at 6 months compared to pre-HCT levels (Figure 1A). ST2 and IL-15 levels were significantly higher in frail and pre-frail compared with fit patients (Figure 1B). While ST2 levels were not associated with GVHD development, in patients who develop GVHD after day 28 elevated ST2 levels were associated with inferior OS (p=0.023; data not shown). Higher levels of ST2 (p=0.0352), IL-6 (p<0.0001), IL-8 (p=0.0067), and IL-15 (p=0.0143) at 6-months post-HCT were associated with inferior OS compared with lower levels (Figure 2).

Conclusions

Elevations in IL-15 and ST2 were associated with frail phenotypes and higher ST2 was also associated with inferior OS after GVHD. Concentrations of ST2, IL-6, IL-8, and IL-15 at 6 months were associated with OS. Our next steps include machine learning models to identify optimal cut points to expand our understanding of the relationship of biomarkers with frailty and HCT outcomes. Further work is also needed to determine whether biomarker-guided interventions, like the initiation of ruxolitinib or other inflammatory mediators, can improve OS for older adults after HCT.