Endothelial Activation And Stress Index Research Articles

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...

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.

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.

Factors Associated with Prolonged CRS and Neurotoxicity after Treatment with Axicabtagene Ciloleucel

BACKGROUND While chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of high-risk B-cell malignancies, it causes significant toxicities, specifically, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Most of the research to date has focused on the identification of factors associated with the peak severity of CRS and ICANS, which does not capture the duration of these toxicities. Yet protracted toxicities are observed in a subset of patients, and risk factors predictive of CRS/ICANS duration have not been reported. To address this limitation, we have previously reported the use of a novel clinical endpoint: time to CRS and ICANS (CRS/ICANS) resolution, which captures the longitudinal impact of these toxicities while allowing for censoring in the event of early deaths (Gazeau et al, TCT, 2023). Here, we applied this framework to provide the first characterization of factors associated with time to CRS/ICANS resolution in patients receiving the FDA-approved CD19 CAR T-cell product axicabtagene ciloleucel (axi-cel). METHODS Eighty-four patients (pts) treated at the Fred Hutch Bezos Family Immunotherapy Clinic with axi-cel per the FDA label outside of a clinical trial between 1/2018 and 4/2022 were included. CRS and ICANS were graded (G) using ASTCT criteria. Cause-specific Cox regression models were used to estimate associations between 60+ pre/post-infusion patient, disease-related, laboratory variables (e.g., platelet count, creatinine, PT, PTT, CRP, IL-6, fibrinogen, ferritin), and time to CRS/ICANS resolution. Endothelial Activation and Stress Index (EASIX) score was calculated at pre-/post-infusion timepoints. Time to CRS/ICANS resolution was defined as the time from axi-cel infusion left-truncated at the time of CRS/ICANS onset until CRS/ICANS symptom resolution (first day of grade 0 for at least three consecutive days), whichever toxicity happened last, censoring for death from any cause. RESULTS Baseline characteristics and toxicity outcomes are shown in Table1. The median age at infusion was 62 (range, 25-79). Histology was large B cell lymphoma in 79 pts (94%), and follicular lymphoma in 5 pts (6%). We observed any-grade CRS in 72 pts (86%) and G≥3 CRS in 7 pts (8%). Fifty-two pts (62%) developed any-grade ICANS, and 16 pts (19%) G≥3 ICANS (G1: 15 [18%], G2: 21 [25%], G3: 15 [18%], G4: 1 [1.2%]). The median time to CRS/ICANS resolution was 10 days (95%CI: 9,11). Two pts (2%) died prior to CRS/ICANS resolution. Using univariate cause-specific Cox regression, the following pre-infusion factors were associated with longer time to CRS/ICANS resolution: lower platelet count at day 0 (HR=0.41, 95%CI: 0.17-0.98, p=0.044), higher PTT at day 0 (HR=0.05, 95%CI: 0.00-0.86, p=0.039), higher preLD creatinine (HR=0.06, 95%CI: 0.01-0.50, p=0.009) and higher EASIX score preLD (HR=0.57, 95%CI:0.35-0.94, p=0.028) and at day 0 (HR=0.52, 95%CI: 0.29-0.96, p=0.035). Cumulative incidence curves of time to CRS/ICANS resolution for select predictors are shown in Figure 1B. At the time of CRS onset, a higher ferritin level (HR=0.51, 95%CI: 0.27-0.94, p=0.031) and peak CRS severity (HR = 0.73, 95%CI: 0.55-0.97, p=0.029) were associated with longer time to CRS/ICANS resolution. Higher ferritin levels over time (time dependent HR [tdHR]=0.38, 95%CI: 0.19-0.72, p=0.004), higher PTT (tdHR=0.028, 95%CI: 0.01-0.76, p=0.028), and peak ICANS severity (HR=0.58, 95%CI: 0.046, 0.72, p&amp;lt;0.001) were associated with longer time to CRS/ICANS resolution. In a multivariable Cox model after LASSO variable selection including day 0 PTT, ferritin, EASIX score, and peak CRS severity, lower day 0 platelet count remained independently associated with longer time to CRS/ICANS resolution (HR=6.96 per log10 increase, 95%CI:1.09-44.5, p=0.04; model discrimination: C-index=0.65). CONCLUSION This is to our knowledge the first study aimed at the identification of factors associated specifically with the duration of CRS and ICANS after CD19 CAR T-cell therapy. We successfully identified pre- and post-infusion factors associated with prolonged CRS/ICANS duration after CD19 CAR T-cell therapy with axi-cel. Our findings suggest that point-of-care assessments can identify patients at risk of prolonged toxicities and could guide the use of prophylactic corticosteroids or early interventions (e.g., anakinra).

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.

Applicability and validation of different prognostic scores in allogeneic hematopoietic cell transplant (HCT) in the post-transplant cyclophosphamide era

We investigated the predictive capacity of six prognostic indices [Karnofsky Performance Status (KPS), Hematopoietic Cell Transplant-Specific Comorbidity Index (HCT-CI), Disease Risk Index (DRI), European Bone Marrow Transplantation (EBMT) and Revised Pre-Transplantation Assessment of Mortality (rPAM) Scores and Endothelial Activation and Stress Index (EASIX)] in 205 adults undergoing post-transplant cyclophosphamide (PTCy)-based allo-HCT. KPS, HCT-CI, DRI and EASIX grouped patients into higher and lower risk strata. KPS and EASIX maintained appropriate discrimination for OS prediction across the first 2 years after allo-HCT [receiver operating characteristic curve (area under the curve (AUC) > 55 %)]. The discriminative capacity of DRI and HCT-CI increased during the post-transplant period, with a peak of prediction at 2 years (AUC of 61.1 % and 61.8 %). The maximum rPAM discriminative capacity was at 1 year (1-year AUC of 58.2 %). The predictive capacity of the EBMT score was not demonstrated. This study validates the discrimination capacity for OS prediction of KPS, HCT-CI, DRI and EASIX in PTCy-based allo-HCT.

Endothelial activation and stress index as a prognostic factor of diffuse large B-cell lymphoma: the report from the nationwide multi-center Thai Lymphoma Study Group.

Several prognostic models have been introduced to predict outcomes of patients with diffuse large B-cell lymphoma (DLBCL). Endothelial activation and stress index (EASIX) is a surrogate of endothelial dysfunction which has been shown to predict outcomes of patients with various hematologic malignancies. However, the prognostic implication of EASIX for DLBCL is limited and warrants exploration. We conducted a retrospective study enrolling adult DLBCL patients including a discovery cohort from the single-centered university hospital database and a validation cohort from the independent nationwide multi-center registry. EASIX scores were calculated using creatinine, lactate dehydrogenase, and platelet levels. The receiver operating characteristic curve analysis was used to determine optimal cutoff. Statistical analysis explored the impact of EASIX on survival outcomes. A total of 323 patients were included in the discovery cohort. The optimal EASIX cutoff was 1.07 stratifying patients into low (53.9%) and high EASIX (46.1%) groups. Patients with high EASIX had worse 2-year progression-free survival (PFS) (53.4% vs. 81.5%, p<0.001) and overall survival (OS) (64.4% vs. 88.7%, p<0.001) than patients with low EASIX. Multivariate analysis revealed that older age, bulky disease, impaired performance status, and high EASIX were associated with an unfavorable OS. In the validation cohort of 499 patients, the optimal EASIX cutoff was 1.04. Similar to the discovery cohort, high EASIX score was associated with high-risk diseases, worse PFS, and inferior OS. In conclusion, EASIX score was significantly associated with survival outcomes and may be used as a simple prognostic tool to better risk-classify DLBCL.

EASIX-1year and late mortality after allogeneic stem cell transplantation

AbstractPatients with hematological malignancies who survive the first year after allogeneic stem cell transplantation (allo-SCT) without relapse have a substantial risk of nonrelapse mortality (NRM) and missing predictive markers. The Endothelial Activation and Stress Index (EASIX) predicts endothelial complications and NRM early after allo-SCT. We hypothesized that EASIX assessed 1 year after allo-SCT in survivors who were disease free may predict late NRM. Survivors who were relapse-free at 1 year after allo-SCT were retrospectively studied in 2 independent cohorts (training cohort, n = 610; merged validation cohort, n = 852). EASIX determined 1 year after allo-SCT correlated with the overall survival (OS), NRM, and relapse. Serum endothelial and inflammatory markers were measured in the training cohort and correlated with EASIX-1year, which predicted OS and NRM but not relapse risk in both the training and validation cohorts in univariable and multivariable Cox regression analyses. Brier score and c-index analyses validated the univariable EASIX effects. There was no significant interaction between EASIX-1year and incidence of chronic graft-versus-host disease (GVHD) on OS. EASIX-1year predicted the outcome irrespective of preexisting comorbidities. Principal causes of NRM in both training and validation cohorts were infections with and without GVHD as well as cardiovascular complications. EASIX-1year correlated with sCD141 and interleukin-18 but not with C-reactive protein, suppressor of tumorigenicity-2, angiopoietin-2, CXCL9, or CXCL8. To our knowledge, EASIX-1year is the first validated predictor of late overall and NRM. Patients who are high risk as defined by EASIX-1year might be considered for intensified surveillance and prophylactic measures.

Pretransplantation EASIX Score Predicts Nonrelapse and Overall Mortality of Adult Patients Undergoing Single-Unit Unrelated Cord Blood Transplantation

The Endothelial Activation and Stress Index (EASIX) is a laboratory-based score used to estimate endothelial damage occurring after hematopoietic cell transplantation (HCT). The EASIX score exhibits dynamic changes during the course of transplantation and has been identified as a predictor of nonrelapse mortality (NRM) and worse overall survival (OS) in studies focused mainly on patients who received matched related or unrelated donor allogeneic HCT. However, the role of EASIX score in the setting of cord blood transplantation (CBT) is unclear. This study examined the association between pretransplant EASIX score and post-transplantation outcomes in adult patients undergoing single-unit CBT. We retrospectively evaluated the impact of EASIX score at different time points on post-transplantation outcomes in adults following single-unit unrelated CBT between 1998 and 2022 at our institution. EASIX scores were calculated at the start of conditioning (EASIX-PRE), at day 30 post-CBT (EASIX-d30), at day 100 post-CBT (EASIX-d100), and at the onset of grade II-IV acute graft-versus-host disease (GVHD) (EASIX-GVHD II-IV). A total of 317 patients were included in this study. In the multivariate analysis, log2-EASIX-PRE (continuous variable) was significantly associated with lower risks of neutrophil engraftment (hazard ratio [HR], .87; 95% confidence interval [CI], .80 to .94; P < .001) and platelet engraftment (HR, .91; 95% CI, .83 to .99; P=.047), lower risk of grade II-IV acute GVHD (HR, .85; 95% CI, .76 to .94; P=.003), and higher risk of veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) (HR, 1.44; 95% CI, 1.03 to 2.02; P=.032). Log2-EASIX-PRE also was significantly associated with higher NRM (HR, 1.42; 95% CI, 1.08 to 1.86; P=.011) and worse OS (HR, 1.26; 95% CI, 1.08 to 1.46; P=.003), but not with relapse (HR, 1.02; 95% CI, .88 to 1.18; P=.780). Similarly, log2-EASIX-d30 (HR, 1.60; 95% CI, 1.26 to 2.05; P < .001), and log2-EASIX-d100 (HR, 2.01; 95% CI, 1.63 to 2.48; P < .001) were also significantly associated with higher NRM, but log2-EASIX-GVHD II-IV was not (HR, 1.15; 95% CI, .85 to 1.55; P=.360). Pretransplantation EASIX score is a powerful predictor of engraftment, VOS/SOS, NRM, and OS in adult patients undergoing single-unit unrelated CBT who mainly received intensified conditioning regimens. EASIX is an easily evaluable and dynamic prognostic score for accurately predicting post-transplantation outcomes in patients at any time during the course of allogeneic HCT, particularly for CBT.

EASIX Is an Accurate and Easily Available Prognostic Score in Critically Ill Patients with Advanced Liver Disease

Acute-on-chronic liver failure (ACLF) is associated with high mortality. Objective prognostic scores are important for treatment decisions. EASIX (Endothelial Activation and Stress Index) is a simple biomarker consisting of LDH, platelets, and creatinine, reflecting endothelial dysfunction after allogeneic stem cell transplantation. Considering endothelial dysfunction in the pathogenesis of ACLF, this study aimed to test the discriminative ability of EASIX in advanced liver disease. We retrospectively analysed the prognostic potential of EASIX to predict 28-day and 3-month mortality in a total of 188 liver cirrhotic patients requiring treatment at the intensive care unit. We evaluated the ability of EASIX to rule out early infections and predict the need for hemodialysis. EASIX performed moderately better than established scores in predicting 28-day mortality (AUC = 0.771) and was nearly equivalent (AUC = 0.791) to SOFA and APACHE-II in the prediction of 3-month mortality. Importantly, EASIX showed better diagnostic potential in ruling out clinically apparent infections than common proinflammatory markers (AUC = 0.861, p < 0.001) and showed suitable accuracy in predicting the need for hemodialysis (AUC = 0.833). EASIX is an accurate, objective and easily assessable biomarker for predicting mortality and complications in patients with advanced liver disease.

Comparison of Pretransplantation Prediction Models for Nonrelapse Mortality in Patients with Myelofibrosis Undergoing Allogeneic Stem Cell Transplantation

Allogeneic stem cell transplantation (alloSCT) is the only known curative treatment for myelofibrosis (MF). Risk assessment remains important for patient counseling and predicting survival outcomes for relapse and non-relapse mortality (NRM). Outcome-prediction tools can guide decision-making. Their use in MF has relied on their extrapolation from other malignancies. The primary objective of this study was to assess the performance of the HCT-CI, the augmented HCT-CI (aHCT-CI), and the Endothelial Activation and Stress Index (EASIX) in predicting non-relapse mortality (NRM) in patients with MF undergoing alloSCT. We retrospectively reviewed patients with MF undergoing alloSCT from 2012 to 2020 at the Mayo Clinic. Data were abstracted from electronic medical records. EASIX score was calculated, prior to starting conditioning therapy, and analyzed based on log2 transformed values. We evaluated the log2-EASIX scores by quartiles to assess the effect of increasing values on NRM. NRM was evaluated using competing risk analyses. We used Kaplan-Meier and log-rank method to evaluate OS. Fine-Gray model was used to determine risk factors for NRM. Comparison of performance of HCT-CI and aHCT-CI was performed by evaluation of model concordance given the high correlation between HCT-CI and aHCT-CI (r = 0.75). A total of 87 patients were evaluated. The median follow-up after alloSCT was 5 years (95% CI: 4.4 - 6.31). Patients with a high HCT-CI score had significantly increased cumulative incidence of NRM at 3-years (35.5% vs. 11.6%, P = 0.011) after alloSCT. A progressively increasing 3-year NRM was observed with an increasing aHCT-CI risk category, and patients with a high- or very-high aHCT-CI score had significantly higher 3-year NRM compared to those with intermediate or low-risk aHCT-CI scores at 3-years after alloSCT (31.9% vs. 6.52%, P = 0.004). An increasing log2-EASIX score quartile was not associated with 3-year NRM (19.0% vs. 10.1% vs. 25% vs. 14.3%, P = 0.59) and the EASIX score was not found to be a predictor of post-transplant NRM. A high HCT-CI was associated with a significantly worse 3-year OS (HR 4.41, 95%CI 1.97 - 9.87 P < 0.001). A high- or very-high aHCT-CI was significantly associated with poor 3-year OS (HR 3.99, 95% CI 1.56 - 10.22, P = 0.004). An increasing log2-EASIX score quartile group was not associated with 3-year OS (3-year OS rate: 66.7% vs. 80.4% vs. 64.6% vs. 76.2%, P = 0.57). The EASIX score should not be routinely used in patients with MF. Both the HCT-CI and the aHCT-CI are accurate in predicting long term survival outcomes in this patient population. Further studies are important to validate our findings of the role of EASIX in predicting NRM in patients with MF or other myeloproliferative neoplasms undergoing alloSCT.

130 - Day Zero Endothelial Activation and Stress Index (EASIX) Best Predicts Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Acute Myeloid Leukemia Patients

130 - Day Zero Endothelial Activation and Stress Index (EASIX) Best Predicts Allogeneic Hematopoietic Stem Cell Transplantation Outcomes in Acute Myeloid Leukemia Patients

EASIX score predicts inferior survival after allogeneic hematopoietic cell transplantation.

The Endothelial Activation and Stress Index (EASIX) is a prognostic tool that uses common clinical laboratory values and has been shown to predict non-relapse mortality (NRM) and overall survival (OS) at the onset of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We hypothesized that EASIX calculated at different time points pre- and post- HCT may predict NRM and OS, and that EASIX calculated at onset of GVHD may predict response to steroids. We evaluated the EASIX score pre- and post-HCT in 152 patients with lymphoid malignancies undergoing unmodified reduced intensity conditioning (RIC) alloHCT with uniform GVHD prophylaxis. In multivariate analysis, EASIX calculated pre-HCT was significantly associated with higher NRM (HR = 1.64, p = 0.009) and lower OS (HR = 1.33, p = 0.046). Furthermore, EASIX calculated at day 30 and at day 100 was associated with increased NRM (HR = 1.65, p < 0.001; and HR = 1.65, p < 0.001) and decreased OS (HR = 1.27, p = 0.018; and HR = 1.49, p < 0.001), independent of HCT-CI, disease and conditioning regimen. Our study shows that high EASIX scores at various time points pre- and post-HCT are significantly associated with poorer overall outcomes. EASIX provides an independent and easily accessible tool to predict outcomes that can be complementary to other measures of risk stratification for patients undergoing HCT.

Preconditioning Modified-Easix as a Predictor of Prognosis in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Allogeneic hematopoietic stem cell transplantation (alloHCT) is associated with severe complications, most of which share a common physiopathological background characterized by endothelial dysfunction. A novel risk assessment model, endothelial activation and stress index (EASIX), has been introduced as a predictor of endothelial activation. This retrospective study was performed to evaluate the predictive impact of EASIX/modified-EASIX (mEASIX) on transplant outcome. Medical records of 398 alloHCT recipients [median age: 43(17-71) years; M/F: 243/155] were examined. EASIX/mEASIX were calculated at specific time points before and after transplantation. EASIX/mEASIX were significantly associated with transplant complications including engraftment syndrome, sinusoidal obstruction syndrome, febrile neutropenia and transplant associated thrombotic microangiopathy. The probability of overall survival was significantly higher in low-preconditioning mEASIX (day -7) group (37% vs 25.2%; p = 0.008; HR: 2.057; 95% CI: 1.208-3.504). The probabilities of day30 mortality (2.9% vs 19.4%; p = 0.017; HR: 7.028; 95% CI: 1.418-34.836), day100 mortality (9% vs 33%; p = 0.004; HR: 4.469; 95% CI: 1.619-12.336) and non relapse mortality (44.8% vs 61.4%; p = 0.005; HR: 2.551; 95% CI: 1.318-4.941) were lower in low-preconditioning mEASIX (day -7) group. This retrospective cohort analysis demonstrates the significant impact of EASIX/mEASIX on transplant complications and survival. Prospective analyses are mandatory to assess the predictive role of EASIX/mEASIX in clinical practice.