Frailty Syndrome Is Associated with Increased Endothelial Activation and Post-Transplant Complications in Allo-HCT Patients

Introduction Frailty increases mortality and morbidity risks in allo-HCT patients, but its pathophysiological mechanisms remain under-studied. Previous research has linked chronic inflammation, endothelial activation and dysfunction, and frailty, particularly in older adults and those at cardiovascular risk. Given that endothelial activation -and dysfunction- occurs early post-allo-HCT due to the conditioning regimen, GVHD prophylaxis, alloreactivity, and transplant complications, this study investigates whether frailty syndrome may influence these processes. Methods From 2021 to 2023, 128 allo-HCT consecutive adults were included in the study. Patients were evaluated using the HCT Frailty Scale and categorized as fit, pre-frail, or frail based on the results. Endothelial activation was indirectly measured in all patients using the Endothelial Activation and Stress Index (EASIX), calculated from bloodworks collected at admission and on days 0, +7, +14, +21, +28, +100, and +180 after transplantation. EASIX data was complemented with the measurement of circulating endothelial activation biomarkers (von Willebrand factor antigen (VWF), soluble vascular cell adhesion molecule-1 (VCAM), regenerating islet-derived 3-alpha (REG3α), soluble tumor necrosis factor receptor I (sTNFRI), and thrombomodulin (TM)) in plasma samples of 48 consecutive patients collected at admission. Clinical information and frailty prospective data was merged with EASIX and biomarker determinations. Results The cohort median age was 55 years (IQR: 41-64), with 87 (68.0%) male patients. 31 (24.2%) had a KPS <90%, and 26 (20.3%) had an HCT-CI >3. AML was the most prevalent baseline diagnosis (n=30, 31.3%). 61(47.7%) patients underwent MAC allo-HCT, and 125 (97.7%) received peripheral blood grafts: 78 (61.0%) from HLA-matched, 24 (18.8%) from 9/10 HLA-mismatched unrelated, and 26 (20.3%) from haploidentical donors. At HCT admission, 19 (14.8%) patients were classified as frail, 61 (47.7%) as pre-frail, and 48 (37.5%) as fit. Although not statistically significant, proportions of veno-occlusive disease (11.1%, 1.6% and 2.1%, p=0.185) and transplant-associated thrombotic microangiopathy (11.1%, 4.9% and 2.1%, p=0.479) were higher in frail patients than in pre-frail and fit ones, respectively. Overall, clinically relevant aGVHD (frail and pre-frail vs. fit: Grades II-IV aGVHD: HR 5.11, P<0.01; Grades III-IV aGVHD: HR 3.64, P=0.091), cardiac events (frail and pre-frail vs. fit: HR 3.95, P=0.073), ICU admissions (frail and pre-frail vs. fit: HR 2.63, P=0.084) trend to be higher in frail and pre-frail patients than in fit ones. With a median follow-up of 15 months, 30 (23.4%) patients relapsed and 34 (26.5%) dead. Frailty was associated with worse outcomes, with 1-year OS rates for frail, pre-frail and fit patients of 40.0%, 76.7% and 85.2% (p=0.017), and respective 1-year NRM of 33.3%, 15.2% and 10.4% (P=0.269). At admission, EASIX medians were higher in frail patients than in pre-frail and fit ones, (Frail, Pre-frail, Fit patients: 1.50, 1.32, 0.82, P=0.010). The complementary analysis of the 48 patients' samples at HCT admission - moment at which 6 patients were frail, 21 pre-frail and 21 fit- revealed that frail patients had higher median values of VWF (frail, pre-frail and fit: 149, 138 and 122 U/dl, respectively), REG3α (19.5, 17.3 and 13.9 ng/dl), and VCAM (156.9, 55.2 and 85.8 ng/dl), and lower TM levels (3.1, 4.0, 4.9 ng/dl) than pre-frail and fit ones, and suggesting that frail patients had higher endothelial activation than the rest. EASIX trends according to the frailty state of patients were examined in all patients showing that EASIX globally increased from day 0 to day +7, peaked at day +21, and declined progressively by day +180. However, EASIX medians were higher in frail patients than in fit ones, and with a higher peak at day +21 than in pre-frail and fit ones (median values: 8.4, 6.8 and 5.4). Conclusions The study shows that frailty is associated with increased endothelial activation and post-transplant complications in allo-HCT patients. Although complications were more prevalent in pre-frail and frail patients, frail patients had higher mortality, indicating their limited capacity to overcome complications. Frailty should be considered when assessing and managing allo-HCT patients, and further exploring how frailty influences outcomes through endothelial activation will be valuable.