Endothelial Activation And Stress Index Research Articles

Impact of met-haemoglobin and oxidative stress on endothelial function in patients with transfusion dependent β-thalassemia

Transfusion dependent β-thalassemia is a genetic blood disorder characterized by chronic anaemia. Blood transfusion is lifesaving but comes at a cost. Iron overload emerges as a prime culprit as a free radicals damage endothelial cells. Chronic anaemia further disrupts oxygen delivery, exacerbating the oxidative stress. Increased levels of met-haemoglobin and malondialdehyde compromise endothelial function. This research sheds light on the impact of met-haemoglobin and oxidative stress on endothelial function in 50 patients with transfusion dependent β-thalassemia major compared to 50 healthy individuals as control. Blood samples were collected & subjected to CBC, biochemical analysis including creatinine, ferritin, CRP, LDH, and HCV antibodies. Oxidative stress was assessed using met-haemoglobin & malondialdehyde. Endothelial dysfunction was evaluated by endothelial activation and stress index (EASIX). EASIX, met-haemoglobin and malondialdehyde were significantly increased in patients (1.44 ± 0.75, 2.07 ± 0.2, 4.8 ± 0.63; respectively) compared to the control (0.52 ± 0.24,0.88 ± 0.34,0.8 ± 0.34; respectively). Significant strong positive correlation was found between EASIX and met-haemoglobin, malondialdehyde, serum ferritin and CRP (P = 0.00, r = 0.904, P = 0.00, r = 0.948, P = 0.00, r = 0.772, P = 0.00, r = 0.971; respectively. Met-haemoglobin as well as EASIX should be routinely estimated to assess endothelial function especially before the decision of splenectomy. Antioxidant drugs should be supplemented.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR), Growth Differentiation Factor-15 (GDF-15), and Soluble C5b-9 (sC5b-9) Levels Are Significantly Associated with Endothelial Injury Indices in CAR-T Cell Recipients

Endothelial injury indices, such as Endothelial Activation and Stress Index (EASIX), modified EASIX (m-EASIX), and simplified EASIX (s-EASIX) scores, have been previously associated with chimeric antigen receptor-T (CAR-T) cell immunotherapy complications. Soluble urokinase-type plasminogen activator receptor (suPAR), growth differentiation factor-15 (GDF-15), and soluble C5b-9 (sC5b-9) have been described as markers of endothelial injury post-hematopoietic stem cell transplantation. In the current study, we examined whether suPAR, GDF-15, and sC5b-9 levels were associated with endothelial injury indices in adult CAR-T cell recipients. The levels of these markers were measured in patients before CAR-T cell infusion and in healthy individuals with immunoenzymatic methods. We studied 45 CAR-T cell recipients and 20 healthy individuals as the control group. SuPAR, GDF-15, and sC5b-9 levels were significantly higher in the patients’ group compared to the healthy control group (p < 0.001, in all comparisons). SuPAR levels at baseline were associated with the m-EASIX scores calculated at the same time point (p = 0.020), while suPAR and GDF-15 concentrations were correlated with EASIX scores at day 14 post-infusion (p < 0.001 in both comparisons). Moreover, sC5b-9 levels were correlated with the s-EASIX scores at infusion (p = 0.008) and the EASIX scores at day 14 (p = 0.005). In our study, sC5b9, suPAR, and GDF-15 levels were found to reflect endothelial injury in CAR-T cell recipients.

Effect of Endothelial Activation and Stress Index(EASIX) on Prognosis of Peripheral T-Cell Lymphoma Patient

To investigate the effect of endothelial activation and stress index (EASIX) on the prognosis of patients with angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), and to compare the clinical characteristics of patients in the low EASIX and high EASIX groups. The clinical data of 59 newly diagnosed AITL and PTCL-NOS patients admitted to the Affiliated Hospital of Xuzhou Medical University from January 2010 to September 2021 were retrospectively analyzed. The optimal cut-off value of EASIX was determined by receiver operating characteristic (ROC) curve; The chi-square test was used to analyze the correlation between EASIX and clinical features of patients with AITL and PTCL-NOS; The Kaplan-Meier survival curve was used to analyze the overall survival (OS) and progression-free survival (PFS) of the patients; Univariate and multivariate analyses were performed by using Cox proportional hazards model. The optimal cut-off value of EASIX was 0.95, based on which the patients were divided into a low EASIX (<0.95) group and a high EASIX (≥0.95) group. Compared with the low EASIX group, the high EASIX group had a higher proportion of patients with advanced Ann Arbor stage, higher risk according to IPI, elevated LDH, hypoproteinemia, anemia, B symptoms,extranodal involvement, and bone marrow involvement. Survival analysis showed that the OS and PFS of patients in the high EASIX group were significantly shorter than those in the lower EASIX group(P <0.001). The multivariate analysis showed that EASIX was an independent risk factor for OS ［HR=7.217 (95%CI : 1.959-26.587), P =0.003］ and PFS ［HR=2.718(95%CI : 1.032-7.161), P =0.043］ of PTCL patients. High EASIX in newly diagnosed patients with AITL and PTCL-NOS suggests a poor prognosis, and high EASIX is a risk factor affecting prognosis of the patients.

EASIX-guided risk stratification for complications and outcome after CAR T-cell therapy with ide-cel in relapsed/refractory multiple myeloma

BackgroundChimeric antigen receptor (CAR) T-cell therapy has demonstrated significant benefits in the treatment of relapsed/refractory multiple myeloma (RRMM). However, these outcomes can be compromised by severe complications, including cytokine release...

EASIX and m-EASIX predict CRS and ICANS in pediatric and AYA patients after CD19-CAR T-cell therapy

AbstractCytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) are complications of CD19-directed chimeric antigen receptor (CD19-CAR) T-cell therapy. The Endothelial Activation and Stress Index (EASIX) and modified EASIX (m-EASIX) scores have been retrospectively proven to be predictive of CRS and ICANS in adult CAR T-cell recipients. However, these scores have not been evaluated in pediatric cohorts. We retrospectively report on 76 pediatric and adolescent and young adult (AYA) patients with relapsed/refractory B-cell acute lymphoblastic leukemia treated with CD19-CAR T cells at St. Jude Children’s Research Hospital or John’s Hopkins Hospital. Data included patient, disease, and treatment characteristics. EASIX and m-EASIX scores were calculated at days –5 before, 0, and +3 after CAR T-cell infusion. CRS and ICANS occurred in 47 and 17 patients, respectively. At all evaluated time points, the median EASIX scores were higher for patients who developed severe CRS and any grade ICANS, and the median m-EASIX scores were higher in patients who developed severe CRS and severe ICANS than those with no/mild CRS/ICANS. Receiver operating characteristic curve analysis showed that both scores were strong predictors of CRS, especially severe CRS, at all time points. Any grade and severe ICANS were best predicted by both scores at day +3. m-EASIX uniformly outperformed EASIX, except for predicting any grade ICANS. Our results validate the potential utility of EASIX and m-EASIX scores for predicting CAR T-cell–related complications for pediatric and AYA patients.

Early defibrotide therapy and risk factors for post-transplant veno-occlusive disease/sinusoidal obstruction syndrome in childhood.

Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complications of hematopoietic cell transplantation (HCT). We studied the impact of early defibrotide (DF) therapy on the outcomes of pediatric patients with VOD/SOS after transplantation, focusing on recent immunotherapies. A total of 111 pediatric patients who underwent HCT for malignant disease between February 2017 and March 2023 at Kyushu University Hospital were included. Among 111 patients of less than 20years of age who underwent HCT for malignancy at a single institution between 2017 and 2023, VOD/SOS occurred in 25 (23%) patients. VOD/SOS developed more frequently in the post-DF era (2020-2023, n=58) than in the pre-DF era (31% vs. 13%, p=.04). The proportion of patients with relapsed/refractory acute lymphoblastic leukemia (ALL) was higher in the post-DF era than in the pre-DF era (44% vs. 8%, p=.04). Early DF therapy that was started at two European Society for Blood and Marrow Transplantation diagnostic criteria reduced the severity of VOD/SOS (p<.01) in comparison to non-early therapy started at less than two criteria. A multivariate analysis indicated that a history of cytokine release syndrome (odds ratio [OR]=10.4, p=.01) and juvenile myelomonocytic leukemia (OR=8.98, p=.04), but not an endothelial activation and stress index (EASIX) score of greater than 0.85, were independent risk factors for VOD/SOS. Early DF therapy improves the severity and survival outcomes of post-transplant VOD/SOS in children. However, its incidence is increasing in the era of immunotherapy for progressive diseases.

EASIX (endothelial activation and stress index) predicts mortality in patients with coronary artery disease.

Coronary interventions reduce morbidity and mortality in patients with acute coronary syndrome. However, the risk of mortality for patients with coronary artery disease (CAD) additionally depends on their systemic endothelial health status. The 'Endothelial Activation and Stress Index' (EASIX) predicts endothelial complications and survival in diverse clinical settings. We hypothesized that EASIX may predict mortality in patients with CAD. In 1283 patients undergoing coronary catheterization (CC) and having a diagnosis of CAD, EASIX was measured within 52days (range -1year to -14days) before CC and correlated with overall survival. In an independent validation cohort of 1934 patients, EASIXval was measured within 174days (+ 28days to + 11years) after CC. EASIX predicted the risk of mortality after CC (per log2: hazard ratio (HR) 1.29, 95% confidence interval: [1.18-1.41], p < 0.001) in multivariable Cox regression analyses adjusting for age, sex, a high-grade coronary stenosis ≥ 90%, left ventricular ejection fraction, arterial hypertension and diabetes. In the independent cohort, EASIX correlated with EASIXval with rho = 0.7. The long-term predictive value of EASIXval was confirmed (per log2: HR 1.53, [1.42-1.64], p < 0.001) and could be validated by integrated Brier score and concordance index. Pre-established cut-offs (0.88-2.32) associated with increased mortality (cut-off 0.88: HR training: 1.63; HR validation: 1.67, p < 0.0001 and cut-off 2.32: HR training: 3.57; HR validation: 4.65, p < 0.0001). We validated EASIX as a potential biomarker to predict death of CAD patients, irrespective of the timing eitherbefore or after catheterization.

Surrogates of Endothelial Injury Predict Survival After Post-transplant Cyclophosphamide

Post-transplant cyclophosphamide (PT-Cy) is becoming the standard of care for preventing graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplant (alloHCT). Cyclophosphamide is associated with endothelial injury. We hypothesized that the endothelial activation and stress index (EASIX) score, being a marker of endothelial dysfunction, will predict non-relapse mortality (NRM) in alloHCT patients receiving PT-Cy for GVHD prophylaxis. We evaluate the prognostic ability of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and EASIX scores, and report other factors influencing survival, in patients with hematologic malignancies undergoing alloHCT and receiving PT-Cy-based GVHD prophylaxis. Adult patients with hematologic malignancies who underwent alloHCT and received PT-Cy for GVHD prophylaxis at the three Mayo Clinic locations were included in this study. We retrospectively reviewed the Mayo Clinic database and the available electronic medical records to determine the patient, disease, and transplant characteristics. An HCT-CI score of ≥3 was considered high. The EASIX score was calculated from labs available between day -28 (of alloHCT) to the day of starting conditioning and analyzed on log2 transformed values. A log2-EASIX score ≥2.32 was considered high. The cumulative incidence of NRM was determined using competing risk analysis, with relapse considered as competing risk. Overall survival (OS) from transplant was determined using Kaplan-Meier and log-rank methods. Cox-proportional hazard method was used to evaluate factors impacting survival. A total of 199 patients were evaluated. Patients with a high log2-EASIX score had a significantly higher cumulative incidence of NRM at 1 year after alloHCT (34.5% versus 12.3%, P = .003). Competing risk analysis showed that a high log2-EASIX score (HR 2.92, 95% CI 1.38 to 6.17, P = .005) and pre-alloHCT hypertension (HR 2.15, 95% CI 1.06 to 4.36, P = .034) were independently predictive of 1 year-NRM. Accordingly, we combined the two factors to develop a composite risk model stratifying patients in low, intermediate, and high-risk groups: 111 (55.8%) patients were considered low-risk, 76 (38.2%) were intermediate and 12 (6%) were high-risk. Compared to patients in the low-risk group, the intermediate (HR 2.38, 95% CI 1.31 to 4.33, P = .005) and high-risk (HR 5.77, 95% CI 2.31 to 14.39, P < .001) groups were associated with a significantly inferior 1-year OS. Multiorgan failure (MOF) was among the common causes of NRM (14/32, 43.8%) particularly among patients with prior pulmonary comorbidities [7 (50%) patients]. Our study shows that EASIX score is predictive of survival after PT-Cy. The novel EASIX-HTN composite risk model may stratify patients prior to transplant. MOF is a common cause of NRM in patients receiving PT-Cy, particularly among patients with pulmonary comorbidities.

Association between Age-Adjusted Endothelial Activation and Stress Index and Intensive Care Unit Mortality in Patients with Severe COVID-19.

Endothelial activation and stress index (EASIX) reflects endothelial dysfunction or damage. Because endothelial dysfunction is one of the key mechanisms, a few studies have shown the clinical usefulness of original and age-adjusted EASIX (age-EASIX) in patients with coronavirus disease 2019 (COVID-19). We aimed to evaluate the clinical utility of age-EASIX in predicting intensive care unit (ICU) mortality in critically ill patients with COVID-19 in South Korea. Secondary analysis was performed using clinical data retrospectively collected from 22 nationwide hospitals in South Korea between January 1, 2020, and August 31, 2021. Patients were at least 19 years old and admitted to the ICU for severe COVID-19, demanding at least high-flow nasal cannula oxygen therapy. EASIX [lactate dehydrogenase (U/L)×creatinine (mg/dL)/platelet count (109 cells/L)] and age-EASIX (EASIX×age) were calculated and log2-transformed. The mean age of 908 critically ill patients with COVID-19 was 67.4 years with 59.7% male sex. The mean log2 age-EASIX was 7.38±1.45. Non-survivors (n=222, 24.4%) in the ICU had a significantly higher log2 age-EASIX than of survivors (8.2±1.52 vs. 7.1±1.32, p&lt;0.001). log2 age-EASIX was significantly associated with ICU mortality (odds ratio, 1.541; 95% confidence interval, 1.322 to 1.796; p&lt;0.001) and had a better area under the receiver operating characteristic curve than of the sequential organ failure assessment (SOFA) score in predicting ICU mortality (0.730 vs. 0.660, p=0.001). Age-EASIX is significantly associated with ICU mortality and has better discriminatory ability than the SOFA score in predicting ICU mortality.

EASIX is an effective marker in predicting mortality of traumatic brain injury patients

BackgroundThe Endothelial Activation and Stress Index (EASIX) is a novel marker of endothelial injury and correlates with survival of various patients. The endothelial dysfunction plays an important role on the pathophysiological process of traumatic brain injury (TBI). This study was designed to explore the prognostic value of EASIX on TBI patients.Methods358 TBI patients hospitalized in the West China hospital between October 2018 and October 2022 were enrolled for this study. The EASIX was calculated based on the formula: lactate dehydrogenase (U/L) × creatinine (mg/dL)/platelets (109 cells/L). The univariate and multivariate logistic regression with forward method was performed to explore the association between EASIX and mortality. A prognostic model was developed combining significant risk factors in the multivariate logistic regression. The receiver operating characteristic (ROC) curve was used to compare the predictive accuracy of the EASIX and the developed model.ResultsThe 30-day mortality of enrolled 358 TBI patients was 51.1%. Non-survivors had higher EASIX than survivors (p < 0.001). The multivariate logistic regression confirmed seven risk factors for mortality of TBI including injury mechanism (p = 0.010), GCS (p < 0.001), glucose (p < 0.001), EASIX (p = 0.017), subdural hematoma (p = 0.012), coagulopathy (p = 0.001). The AUC of EASIX, SOFA, GCS was 0.747, 0.748 and 0.774, respectively. The AUC of developed predictive model was 0.874 with the sensitivity of 0.913 and specificity of 0.686.ConclusionsThe EASIX is a reliable marker for predicting mortality of TBI patients. The predictive model incorporating EASIX is helpful for clinicians to evaluate the mortality risk of TBI patients.

Evaluation of Circulating Endothelial Cells as Direct Marker of Endothelial Damage in Allo-Transplant Recipients at High Risk of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome

Sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD), is a rare but potentially fatal complication following allogenic hematopoietic cell transplantation (allo-HCT). Timely identification of SOS/VOD to allow for prompt treatment is critical, but identifying a VOD-predictive biomarker remains challenging. Given the pivotal role of endothelial dysfunction in SOS/VOD pathophysiology, the CECinVOD study prospectively evaluated levels of circulating endothelial cells (CECs) in patients undergoing allo-HCT with a myeloablative conditioning (MAC) regimen to investigate the potential of CEC level in predicting and diagnosing SOS/VOD. A total of 150 patients from 11 Italian bone marrow transplantation units were enrolled. All participants were age >18 years and received a MAC regimen, putting them at elevated risk of developing SOS/VOD. Overall, 6 cases of SOS/VOD (4%) were recorded. CECs were detected using the Food and Drug Administration-approved CellSearch system, an immunomagnetic selection-based platform incorporating ferrofluid nanoparticles and fluorescent-labeled antibodies, and were defined as CD146+, CD105+, DAPI+, or CD45-. Blood samples were collected at the following time points: before (T0) and at the end of conditioning treatment (T1), at neutrophil engraftment (T2), and at 7 to 10 days postengraftment (T3). For patients who developed VOD, additional samples were collected at any suspected or proven VOD onset (T4) and weekly during defibrotide treatment (T5 to T8). A baseline CEC count >17/mL was associated with an elevated risk of SOS/VOD (P = .04), along with bilirubin level >1.5 mg/mL and a haploidentical donor hematopoietic stem cell source. Postconditioning regimen (T1) CEC levels were elevated (P = .02), and levels were further increased at engraftment (P < .0001). Additionally, patients developing SOS/VOD after engraftment, especially those with late-onset SOS/VOD, showed a markedly higher relative increase (>150%) in CEC count. Multivariate analysis supported these findings, along with a high Endothelial Activation and Stress Index (EASIX) score at engraftment (T2). Finally, CEC kinetics corresponded with defibrotide treatment. After the start of therapy (T4), CEC levels showed an initial increase in the first week (T5), followed by a progressive decrease during VOD treatment (T6 and T7) and a return to pre-SOS/VOD onset levels at resolution of the complication. This prospective multicenter study reveals a low incidence of SOS/VOD in high-risk patients compared to historical data, in line with recent reports. The results from the CECinVOD study collectively confirm the endothelial injury in allo-HCT and its role in in the development of SOS/VOD, suggesting that CEC level can be a valuable biomarker for diagnosing SOS/VOD and identifying patients at greater risk of this complication, especially late-onset SOS/VOD. Furthermore, CEC kinetics may support treatment strategies by providing insight into the optimal timing for discontinuing defibrotide treatment.

Plasma from patients undergoing allogeneic hematopoietic stem cell transplantation promotes NETOSIS in vitro and correlates with inflammatory parameters and clinical severity.

NETosis, the mechanism by which neutrophils release extracellular traps (NETs), is closely related to inflammation. During the allogeneic hematopoietic stem cell transplantation (allo-HSCT), different stimuli can induce NETs formation. Inflammation and endothelial injury have been associated with acute graft-versus-host disease (aGVHD) and complications after allo-HSCT. We focus on the study of NETosis and its relation with cytokines, hematological and biochemical parameters and clinical outcomes before, during and after allo-HSCT. We evaluate the capacity of plasma samples from allo-HSCT patients to induce NETosis, in a cell culture model. Plasma samples from patients undergoing allo-HSCT had a stronger higher NETs induction capacity (NETsIC) than plasma from healthy donors throughout the transplantation process. An optimal cut-off value by ROC analysis was established to discriminate between patients whose plasma triggered NETosis (NETs+IC group) and those who did not (NETs-IC group). Prior to conditioning treatment, the capacity of plasma samples to trigger NETosis was significantly correlated with the Endothelial Activation and Stress Index (EASIX) score. At day 5 after transplant, patients with a positive NETsIC had higher interleukin (IL)-6 and C-reactive protein (CRP) levels and also a higher Modified EASIX score (M-EASIX) than patients with a negative NETsIC. EASIX and M-EASIX scores seek to determine inflammation and endothelium damage, therefore it could indicate a heightened immune response and inflammation in the group of patients with a positive NETsIC. Cytokine levels, specifically IL-8 and IL-6, significantly increased after allo-HSCT with peak levels reached on day 10 after graft infusion. Only, IL-10 and IL-6 levels were significantly higher in patients with a positive NETsIC. In our small cohort, higher IL-6 and IL-8 levels were related to early severe complications (before day 15 after transplant). Although early complications were not related to NETosis by itself, NETosis could predict overall non-specific but clinically significant complications during the full patient admission. In summary, NETosis can be directly induced by plasma from allo-HSCT patients and NETsIC was associated with clinical indicators of disease severity, cytokines levels and inflammatory markers.

Modified EASIX scores predict severe CRS/ICANS in patients with acute myeloid leukemia following CLL1 CAR-T cell therapy.

Chimeric antigen receptor T (CAR-T) cell therapy targeting CLL1 has been considered a potent weapon for patients with acute myeloid leukemia (AML). This study aims to evaluate the efficacy and toxicity of CLL1 CAR-T cell therapy in a larger cohort, with particular attention to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Among the 32 patients assessed for efficacy, complete remission occurred in 71.88% (23/32) of cases and undetectable minimal residual disease in 14 patients. The CRS developed in all patients, with 8 individuals experiencing ICANS. Severe CRS and ICANS were observed in 11 and 2 patients, respectively. Furthermore, the Endothelial Activation and Stress Index (EASIX) and its derivatives measured before and after CLL1 CAR-T cell infusion were employed for predicting the severe complications. Significant differences were observed in EASIX scores on the day before lymphodepletion (Day BL, P = 0.023), -1 (P < 0.001), +1 (P < 0.001), and +3(P = 0.014); sEASIX scores on Day BL (P = 0.007), -1 (P < 0.001), +1 (P < 0.001), and +3 (P < 0.001); and mEASIX score on Day -1 (P = 0.004) between patients with mild and severe CRS/ICANS. Additionally, there was a significant difference in mEASIX scores between responders and non-responders on Day BL (P = 0.004) and Day -1 (P = 0.044). Our findings indicate that pre- and post-infusion assessments of EASIX/mEASIX/sEASIX scores serve as reliable prognostic indicators for severe CRS/ICANS and treatment response following CLL1 CAR-T cell therapy, which can assist physicians in implementing preemptive treatment strategies for potential severe complications and screening patients who are suitable candidates for CLL1 CAR-T cell therapy. EASIX/mEASIX/sEASIX scores serve as reliable prognostic indicators for severe CRS/ICANS following CLL1 CAR-T cell therapy. The preinfusion mEASIX scores of CLL1 CAR-T cells can effectively predict treatment response.

Endothelial Activation and Stress Index (EASIX) to predict mortality after allogeneic stem cell transplantation: a prospective study

BackgroundWe previously reported that the “Endothelial Activation and Stress Index” (EASIX; ((creatinine×lactate dehydrogenase)÷thrombocytes)) measured before start of conditioning predicts mortality after allogeneic hematopoietic stem cell transplantation (alloSCT) when used as...

Routinely Calculable Biomarkers Are Associated with the Development of Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation

Introduction: Sinusoidal obstruction syndrome (SOS) is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). As the immediate initiation of SOS treatment has been shown to be associated with a better prognosis, SOS prediction is clinically important. Biomarkers composed of some routine parameters, such as the aspartate aminotransferase to platelet ratio index (APRI), fibrosis-4 index (FIB-4), and albumin-bilirubin (ALBI), have been widely used to evaluate various hepatic diseases. However, the contribution of these hepatic biomarkers to the prediction and diagnosis of SOS has not been estimated yet. Here, we investigated whether routinely calculable biomarkers, endothelial activation and stress index (EASIX), APRI, FIB-4, ALBI, model for end-stage liver disease (MELD), and MELDNa were associated with the development of SOS. Patients and Methods: A total of 141 patients (corresponding to 161 transplant cases) who underwent allogeneic HSCT at our institution between January 2012 and December 2022 were retrospectively analyzed. The median age at transplantation was 52 years (range: 19-69). The primary diseases included AML (n = 59), ALL/LBL (n = 34), MDS (n = 20), malignant lymphoma (n = 15), plasma cell neoplasm (n = 4), CML/MPN (n = 10), bone marrow failure (n = 3), and others (n = 16). The graft sources were from 30 related and 131 unrelated donors. The numbers of bone marrow, peripheral blood, and cord blood sources were 65, 29, and 67, respectively. Conditioning consisted of myeloablative (n = 68) and reduced-intensity (n = 93) regimens. Haplo-identical transplantation was not performed in this cohort. SOS was diagnosed according to the European Society for Blood and Marrow Transplantation diagnostic criteria 2023. The baseline value of each biomarker before conditioning was compared between the SOS-developing and non-SOS groups, using the Kruskal-Wallis test and a post-hoc test with the Bonferroni method. To evaluate the contribution of biomarkers on SOS diagnosis, we configured matched paired controls from non-SOS cases (three non-SOS controls per SOS case), adjusting for age, sex, last follow-up day, HLA mismatch, and hematopoietic cell transplantation-specific comorbidity index. The values of biomarkers in the SOS and matched paired control groups were compared using the Mann-Whitney U test. In the present study, the negative sign of ALBI was reversed for convenience in analysis. Results and Discussion: Twenty cases were diagnosed to have developed clinical SOS (10 classical SOS and 10 late onset SOS cases). All biomarkers at baseline were significantly different for classical SOS versus non-SOS cases. The median values of EASIX, APRI, FIB-4, ALBI, MELD, and MELDNa were 8.70 vs 1.09 (range: 0.57-24.68 vs 0.22-34.10, P &amp;lt; 0.001), 4.97 vs 0.60 (range: 0.33-32.07 vs 0.11-10.30, P &amp;lt; 0.001), 10.80 vs 1.84 (range: 1.37-38.01 vs 0.31-44.69, P &amp;lt; 0.001), 1.84 vs 2.43 (range: 0.83-3.71 vs 1.33-3.27, P = 0.012), 8.0 vs 7.0 (range: 6-12 vs 6-17, P = 0.028), and 9.5 vs 7.0 (range: 6-18 vs 6-17, P = 0.025), respectively. Moreover, among SOS cases, biomarkers at SOS diagnosis were significantly different compared with those of matched paired controls. The median values were 33.67 vs 3.90 (range: 4.54-252.18 vs 0.28-87.22, P &amp;lt; 0.001), 9.90 vs 1.79 (range: 3.33-127.33 vs 0.19-23.94, P &amp;lt; 0.001), 43.00 vs 6.80 (range: 7.91-182.27 vs 0.60-54.92, P &amp;lt; 0.001), 1.06 vs 2.02 (range: 0.37-1.88 vs 0.52-3.19, P &amp;lt; 0.001), 14.0 vs 7.0 (range: 10-30 vs 6-23, P &amp;lt; 0.001), and 16.5 vs 8.5 (range: 10-31 vs 6-29, P &amp;lt; 0.001), respectively. These results indicate that these biomarkers are associated with SOS, as well as support its diagnosis. As these biomarkers were concise, rapidly calculable, and dispensable with special techniques, their use might be clinically superior to other tests. Conclusion: These routinely calculable biomarkers are associated with the development of SOS. Furthermore, these biomarkers are clinically useful for diagnosis of SOS. Further studies are required to improve the performance and discover an optimal biomarker.

Easix Score Correlates With Endothelial Dysfunction Biomarkers and Predicts Risk of Acute Graft-Versus-Host Disease After Allogeneic Transplantation

Plasma biomarkers of endothelial dysfunction have been postulated for the diagnosis and prognosis of acute graft-versus-host disease (aGVHD). However, their use is not validated in clinical practice yet. The endothelial activation and stress index (EASIX), a simple score based on routine laboratory parameters, is considered to be an indirect marker of endothelial damage. High value of EASIX was correlated with worse non-relapse mortality (NRM) and overall survival (OS) and a high risk of sinusoidal obstructive syndrome and transplant-associated thrombotic microangiopathy (TA-TMA). This study investigates the predictive value of plasma biomarkers and the EASIX score for the prediction of aGVHD. We assessed vascular cell adhesion molecule-1 (VCAM-1), tumor necrosis factor receptor 1 (TNFR1), and VWF:Ag plasma levels and the EASIX score before allogeneic hematopoietic stem cell transplantation (allo-HSCT) and on days 0, 3, 7, 14, and 21 in an experimental cohort (n = 33). EASIX was transformed to a base-2 logarithm to perform the analysis. For the most relevant biomarkers, we estimate the optimal cutoff values and the discriminatory ability to differentiate patients with high-risk of aGVHD. The conclusions obtained in the experimental cohort were validated in a large cohort of 321 patients at the same institution. Plasma biomarkers and EASIX showed similar post-transplantation dynamics consisting of a progressive increase. Multivariate analysis showed an association between high TNFR1 levels and Log-2 EASIX score on day 7 after transplantation with an increased likelihood of developing aGVHD (hazard ratio [HR] = 1, P = .002; HR = 2.31, P = .013, respectively). Patients with TNFR1 ≥1300 ng/mL (HR = 7.19, P = .006) and Log2-EASIX ≥3 (HR = 14.7, P <.001) at day 7 after transplantation were more likely to develop aGVHD with high predictive accuracy (C-index of 74% and 81%, respectively). In the validation cohort, patients with Log2-EASIX ≥3 on day 7 after transplantation presented a significantly higher incidence of grade II-IV aGVHD (HR = 1.94, P = .004) independent of GVHD prophylaxis (HR = 0.38, P = .004), conditioning regimen (HR = 0.59, P =.02) and type of donor (HR = 2.38, P = .014). Differential degree of endothelial damage can be measured using both EASIX score and plasma biomarkers in the early post-transplantation period. Patients at risk of developing aGVHD could be easily identified by a high EASIX score. Both indicators of endothelial activation represent a promising approach to predict aGVHD.

Population-Based External Validation of the EASIX Scores to Predict CAR T-Cell-Related Toxicities.

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61-0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment.

Endothelial Activation and Stress Index in adults undergoing allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide-based prophylaxis

Background aimsPost-transplant cyclophosphamide (PTCY)-based prophylaxis is becoming widespread for allogeneic hematopoietic cell transplantation (allo-HCT) performed independently of the selected donor source. In parallel, use of the Endothelial Activation and Stress Index (EASIX)—considered a surrogate parameter of endothelial activation—for predicting patient outcomes and clinical complications is gaining popularity in the allo-HCT setting. MethodsWe first investigated whether the dynamics of EASIX after allo-HCT differ between patients receiving PTCY and patients receiving other prophylaxis. We then investigated whether the predictive capacity of EASIX persists in PTCY-based allo-HCT. A total of 328 patients transplanted between 2014 and 2020 were included, and 201 (61.2%) received PTCY. ResultsEASIX trends differed significantly between the groups. Compared with patients receiving other prophylaxis, patients receiving PTCY had lower EASIX on day 0 and higher values between day 7 and day 100. In patients receiving PTCY, higher EASIX correlated significantly with higher non-relapse mortality (NRM) and lower overall survival (OS) when measured before and during the first 180 days after allo-HCT. In addition, higher EASIX scores measured at specific time points were predictors of veno-occlusive disease (VOD), transplant-associated thrombotic microangiopathy (TA-TMA) and grade 2–4 acute graft-versus-host disease (aGVHD) risk. ConclusionsThis study demonstrates how EASIX trends vary during the first 180 days after allo-HCT in patients receiving PTCY and those not receiving PTCY and validates the utility of this index for predicting NRM, OS and risk of VOD, TA-TMA and grade 2–4 aGVHD in patients receiving PTCY.

Easix Indices Predict CRS and Overall Survival in Adult CAR-T Cell Recipients

Background: Immunotherapy with Chimeric Antigen Receptor T cells (CAR-Τ) is worldwide commercially available for refractory B cell malignancies, with continuously expanding indications.Given that cytokine release syndrome (CRS) and neurotoxicity (ICANS) are encountered in many CAR-T recipients both in trials and real-world setting, novel predictive and prognostic markers are highly needed. Aim: To this end, we hypothesized that EASIX (Endothelial Activation and Stress Index) and the most recently described modified EASIX (mEASIX) would be associated with severe CRS, ICANS and/or Overall Survival (OS) in the real-world setting. Methods: We collected data from consecutive adult patients (pts) from six transplant centers in Greece. Tisagenlecleucel and axicabtagene ciloleucel were administered since 2020, and brexucabtagene autoleucel since 2022. All pts received lymphodepleting therapy before CAR-T cell infusion with combination of cyclophosphamide and fludarabine. For patient monitoring as well as for prophylaxis and treatment of side effects, the EBMT and MD Anderson guidelines were adopted. EASIX (lactate dehydrogenase [LDH; U/L] x creatinine [mg/dL]/platelet [PLT] count; 10 9/L]) and mEASIX (which replaces creatinine with CRP [mg/dL]) were calculated before lymphodepletion (baseline), at day of infusion (0), and day 14 (14). The following variables were analyzed: age, gender, disease type and phase, product type, time from collection to product arrival and to infusion, progression-free (PFS) and overall survival (OS), laboratory markers at pre-specified time-points (LDH, creatinine, platelets, ferritin, CRP). Data cut-off date was end of June 2023, with at least 1 month of follow-up post infusion. Multivariate models were not performed due to multicollinearity issues. Results: Ninety pts, aged 49 (18-75) years, received commercial CAR-T cell products (33 tisagenlecleucel, 37 axicabtagene ciloleucel, 11 brexucabtagene autoleucel) for refractory/relapsed DLBCL (56), PMBCL (5), TFL (8), B-ALL (10), or MCL (11) after a median of 3 (1-9) previous lines of treatment including autologous (n=13) or allogeneic (n=7) transplantation. Severe (grade 3-4) CRS and ICANS were noted in 21% and 39%, respectively. Severe CRS was associated with mEASIXbaseline (p=0.025), and CRPbaseline (p=0.001), EASIX14 and m-EASIX14 (p&amp;lt;0.001). Both mEASIXbaseline and m-EASIX14 were able to predict severe CRS in ROC curve (AUC=0.768, p=0.032 and AUC=0.712, p=0.027). Severe ICANS did not correlate with EASIX indices, except for a trend towards statistically significant association with EASIX14 (p=0.054). On the other hand, severe ICANS was associated with increased LDH at baseline (p=0.001). With a median follow-up of 6.6 (1-42) months, 1-year PFS and OS were 33.2% and 62.5% respectively. Baseline values of ferritin and LDH, CRP values at all time-points, EASIX14 and mEASIX14 were associated with OS. Both EASIX indices predicted death in ROC curves. Similarly, EASIX14 was associated with PFS. Conclusions: This multicenter study, based on real-world experience with CAR-T cell therapy, confirms the predictive value of EASIX and mEASIX not only for life-threatening complications but also for survival outcomes. The implementation of EASIX may therefore aid in the selection of patients who are candidates for interventions to mitigate untoward sequelae of CAR-T therapy.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) and Growth Differentiation Factor-15 (GDF-15) Leves Are Significantly Associated with Edothelial Injury Indices in Adult Allogenic Hematopoietic Cell Transplantation Recipients

Introduction: Endothelial dysfunction is a common denominator of graft-versus-host disease (GVHD) and transplant-associated thrombotic microangiopathy (TA-TMA). Among endothelial injury indices, the Endothelial Activation and Stress Index (EASIX) has been studied in allogeneic hematopoietic cell transplantation recipients (allo-HCT) recipients, while others including suPAR and GDF-15 have been determined only in other patient populations with hematologic diseases, such as in patients with Multiple Myeloma, AL- amyloidosis and Sickle Cell Disease. We hypothesized that suPAR and GDF-15 would reflect endothelial injury in allo-HCT recipients. Methods: We enrolled consecutive adult TA-TMA (classified according to current standardized criteria), acute and/or chronic graft-versus-host-disease (GVHD), control allogeneic hematopoietic cell transplantation (alloHCT) recipients and apparently healthy individuals of similar age and gender in a 1:1:1:1 ratio. Plasma was collected and stored immediately at -80 oC at the first day of confirmed TA-TMA or GVHD diagnosis and at a similar post-transplant period in control recipients. EASIX [lactate dehydrogenase (U/L) × creatinine (mg/dL)/thrombocytes (10⁹ cells per L)] was calculated at day 0, 30, 100 and at last follow-up. Soluble C5b-9/membrane attack complex, suPAR and GDF-15 levels were measured using immunoenzymatic techniques. Results: We studied 20 TA-TMA, 20 GVHD, 20 control alloHCT patients, and 20 healthy controls. We found significantly higher suPAR and GDF-15 levels in TA-TMA and GVHD patients compared to alloHCT and healthy controls (p&amp;lt;0.001, Bonferroni's correction). Then, we further analyzed characteristics of the alloHCT population. TA-TMA developed at a median of 125 post-transplant day (range 9-2931); whereas the first day of confirmed GVHD diagnosis was at a median of 78 post-transplant day (range 16-145). Both GDF-15 and suPAR concentrations were associated with EASIX at day 100 (r=0.351, p=0.012 and r=0.338, p=0.015, respectively) and last follow-up (r=0.473, p&amp;lt;0.001 and r=0.410, p=0.020, respectively). Among the laboratory values used to calculate EASIX (LDH, creatinine, platelets), suPAR was associated with creatinine and platelets at day 100 and last follow-up; while GDF-15 only with platelets at both time points, suggesting that the association with EASIX is not driven by laboratory values per se. Interestingly, only suPAR and not GDF-15 levels was associated with soluble C5b-9 levels (p=0.013), a marker reflecting high risk in TA-TMA. Conclusion: Our study shows for the first time that suPAR and GDF-15 reflect endothelial injury in allo-HCT recipients. In accordance with other patient populations, suPAR emerges as a marker of renal dysfunction, characterizing high-risk in endothelial injury syndromes and in particular, TA-TMA. However, prior to their clinical usefulness, these biomarkers must undergo through rigorous validation in multiple cohorts.