The Prognostic Calculator Easix Predicts Acute Gvhd, Non-Relapse Mortality and Overall Survival in Adult Patients Undergoing Reduced Intensity Conditioning Allogeneic HCT

Abstract

Keywords Allogeneic transplantation; endothelial damage; biomarkers. Background Endothelial damage is associated with severe complications and increased risk of death after allogeneic hematopoietic cell transplantation (AlloHCT). The recently developed Endothelial Activation and Stress Index (EASIX) is a prognostic tool that uses clinical lab values and has been shown to predict non-relapse mortality (NRM) and overall survival (OS) at onset of acute graft versus host disease (aGVHD) in reduced intensity (RIC) alloHCT (Luft, Lancet Haematol 2017). We hypothesized that EASIX may be valuable for more broadly predicting aGVHD, NRM and OS after AlloHCT, beyond time of onset of aGVHD. Design We evaluated 152 adult patients who received an unmodified RIC AlloHCT from a related or unrelated donor with uniform GVHD prophylaxis of sirolimus/tacrolimus and low-dose MTX for treatment of lymphoid malignancies, between April 2008 and May 2017. The EASIX formula (LDH*Creatinine/platelet counts) was calculated at multiple timepoints (pre-HCT, day 30, day 100, onset TMA and aGVHD). For all EASIX assessments post-HCT, a landmark analysis was conducted at the given timepoint A log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. A one-unit increase in log2 EASIX is associated with a doubling (one-fold increase) of EASIX on the original scale. Kaplan-Meier, cumulative incidence, and cox modeling (cause specific for NRM and aGVHD) were used to evaluate EASIX as it relates to outcomes of interest. Relapse and death or relapse were considered competing risks for NRM and aGVHD respectively. Results The median age at transplant was 54 years (range 23-78), 70% were males, a majority had non-Hodgkin lymphoma (68%), and most had sensitive disease at time of HCT (CR=56%; PR=33%). All patients, except two, received peripheral blood stem cells. Sixty-three patients had an HLA-identical related donor, while the remaining 89 had an unrelated donor transplant (HLA-matched in 75 patients, and HLA-mismatched in 14 patients). HCT-CI was 0 in 49 patients, 1-2 in 41 and ≥ 3 in 62 patients. With a median follow-up in surviving patients of 5.4 years (range, 0.8-10), the 1 and 3 years OS rate was 84.2% (95% CI, 77.3-89.1) and 67.9% (95% CI, 59.6-74.8), respectively. The NRM rate at 1 and 3 years was 7.9% (95% CI, 4.3-12.9) and 16.4% (95% CI, 10.9-22.8), respectively. The 1-year cumulative incidences of grades 1-4, 2-4 and 3-4 aGVHD were 56.6% (95% CI, 48.3-64.1), 42.1% (95% CI, 34.2-49.8) and 7.9% (95% CI, 4.3-12.9), respectively. Post-HCT thrombotic microangiopathy was only observed in 13 patients, representing too few events for EASIX analysis. As expected, HCT-CI was significantly associated with both OS and NRM. Pre-HCT EASIX was significantly associated with increased NRM (HR=1.60 [95% CI, 1.15-2.23], p=0.005) and aGVHD grade 1-4 and 2-4 (HR=1.33 [95% CI, 1.08-1.64], p=0.006 and HR=1.39 [95% CI, 1.10-1.75], p=0.005; respectively), but not OS or grade 3-4 aGVHD (Table 1). EASIX at day 30 and day 100 was significantly associated with both OS and NRM (Figures 1-4). Furthermore, confirming the results of Luft, EASIX calculated at onset of any grade aGVHD was significantly associated with OS (HR=1.34 [1.10-1.63], p=0.004) and NRM (HR=1.47 1.11-1.94], p=0.007). Finally, there was no correlation between HCT-CI and EASIX score. Conclusions We conclude that the EASIX formula, calculated at various timepoints pre and post AlloHCT, is significantly associated with NRM and OS. Pre-HCT EASIX also predicts risk of aGVHD, confirming prior results, EASIX at onset of acute GVHD is a predictor of NRM and OS in adult recipients RIC AlloHCT. EASIX provides an independent and easily accessible tool to predict important AlloHCT outcomes that can be used in addition to HCT-CI to better risk stratify patients. Disclosures Sauter: Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Perales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees; Novartis: Other: Personal fees.

External validation and comparison of multiple prognostic scores in allogeneic hematopoietic stem cell transplantation

“…Validation studies of each of these scores have been published, [19][20][21][22][23] however, few direct comparisons on the same population have rarely been performed, and mostly include 2 or 3 scores (HCT-CI and EBMT or PAM). 6,14,[24][25][26][27] Furthermore, methodologies have varied; Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD) guidelines, 17,28 which outline best practices for model development and validation, are inconsistently followed.…”

Modified EASIX predicts severe cytokine release syndrome and neurotoxicity after chimeric antigen receptor T cells

“…1 EASIX assessed pre-HCT has also been shown to predict significant fluid overload after transplant and increased risk of acute graft-versushost-disease and to be associated with non-relapse mortality and overall survival after allo-HCT. [2][3][4][5] Patients who develop chimeric antigen receptor (CAR) T-cell-related severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) exhibit hemodynamic instability and coagulopathy, with evidence of endothelial activation and increased blood-brain barrier permeability. 6 Several inflammatory cytokines and markers of coagulopathy have been shown to correlate with the onset of severe CRS and/or ICANS, such as interferon-g, interleukin-6 (IL-6), IL-1, IL-10, monocyte chemoattractant protein-1 (MCP-1), and angiotensin-2 (Ang-2).…”

Pretransplantation EASIX predicts intensive care unit admission in allogeneic hematopoietic cell transplantation

“…16 Additionally, a higher EASIX score at days 130 and 1100 post-RIC alloHCT has been associated with grade II to IV acute GVHD, higher NRM, and poorer OS. 17 No association was observed between EASIX-PRE and the probability of TAM, SOS, or acute GVHD onset during the posttransplantation phase. The association between EASIX-PRE and increased risk of TAM was reported in a large cohort of 755 adults treated with alloHCT.…”

“…The EASIX score comprises 3 biomarkers of endothelial dysfunction (LDH, creatinine, and platelets) and, when evaluated before alloHCT (EASIX-PRE), predicts OS and NRM. 12,14,17 Endothelial dysfunction is a common pathologic mechanism of many severe infectious and noninfectious alloHCTrelated complications. 14 Because the endothelium plays a major role in a patient's systemic response to infection and organ failure onset, 19 we hypothesized that EASIX-PRE could predict the development of severe organ dysfunction that would require specific support in the ICU.…”

“…13,14 Furthermore, it has been used to predict transplantation complications when evaluated at different time points after alloHCT. [15][16][17] Because endothelial syndromes can lead to organ dysfunction and a subsequent need for advanced support measures, we hypothesized that EASIX-PRE could predict the probability of clinically relevant complications that would require intensive care unit (ICU)-specific treatments. Therefore, the goal of the present study was to validate the predictive power of EASIX-PRE for overall survival (OS) and nonrelapse mortality (NRM) in a cohort of adults undergoing alloHCT and explore the ability of the score to predict relevant transplantationrelated complications such as ICU admission.…”