Easix-1yearas a Prognostic Index for Late Non-Relapse Mortality after Allogenichematopoietic Cell Transplantation

Introduction

Late non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation(allo-HCT) is a problem that is yet to be solved. Moreover, no efficient markers exist to predict late NRM. Vascular endothelial damage is known to be a cause of late NRM after allo-HCT. The transplant endothelial activation and stress index (EASIX) was initially established for the diagnosis of thrombotic microangiopathy. Pre-transplant EASIX (EASIX-pre) quartiles were reported to be predictive markers for early NRM after allo-HCT, but EASIX could also potentially help in the evaluation of late NRM. Since late NRM may be affected by time dependent factors that cannot be evaluated before allo-HCT, the timing of EASIX evaluation may be important. Therefore, we focused on EASIX 1 year after allo-HCT (EASIX-1year).

Aims

This study aimed to clarify the usefulness of EASIX-pre and EASIX-1year as predictive markers of late NRM and overall survival (OS) after allo-HCT.

Methods

Among 210 patients with hematological disease who underwent a first allo-HCT between 2006 and 2019at our facility, we evaluated EASIX-1year in 102(53 males and 49 females) patients who were alive after 1 year without relapse and/or withdrawal.

EASIX was calculated as LDH level (U/I) × Cre level (mg/dL) / Plt level (nL). EASIX-pre was evaluated 7-10 days before conditioning. EASIX-1year was evaluated within 1 month of 1 year after allo-HCT. Landmark analysis was used to perform statistical analysis of late NRM and OS starting 1 year after allo-HCT. Late NRM and OS assessments using EASIX-pre and EASIX-1year were performed with two risk groups based on the cutoff values from the receiver operating characteristic curve.

Forty-four patients had acute myeloid leukemia, 24 had acute lymphoblastic leukemia, 14 had myelodysplastic syndrome, 8 had malignant lymphoma, and 12 had other diseases. The median age of the patients was 40 years (range: 16-66 years). Fifty-seven patients received myeloablative conditioning and the others received reduced intensity conditioning regimens. The number of patients in each HCT-comorbidity index (HCT-CI) risk group was as follows: low risk: 51, intermediate risk: 28, and high risk: 23.

This study was performed in accordance with the Japanese Ethical Guidelines for Medical and Health Research Involving Humans and approved by the Ethical Committee of our facility.

Results

Median EASIX-pre was0.98 (0.12-24.1). The C-statistic of EASIX-pre for late NRM and OS were 0.561 (cutoff value: 0.595) and 0.591 (cutoff value: 0.766), respectively. Univariate analysis revealed that a high EASIX-pre value was not significantly associated with late NRM (5-year NRM 3.4% vs. 0%, p=0.24) and OS (5-year OS 91.3% vs. 93.5%, p=0.22). Moreover, the HCT-CI at pre-transplantation was not an indicator of late NRM (5-year NRM 10.2 % vs. 0%, p=0.29, 5-year OS 79.8% vs. 96.2%, P=0.19).

Median EASIX-1year was 0.98 (0.15-21.8). The C-statistic of EASIX-1year for late NRM and OS were 0.63 (cutoff value 2.396) and 0.663 (cutoff value 1.159), respectively. Univariate analysis revealed that a high EASIX-1year value was significantly associated with late NRM (5-year NRM 10.1% vs. 1.3%, p<0.05), but was not significantly associated with OS (5-year OS 88.3% vs. 95.2%, p=0.16).

By adjusting age, donor source, HCT-CI, chronic graft versus host disease, and conditioning in multivariate analysis, a high of EASIX-1year was extracted as the risk factor for late NRM (Hazard ratio 4.26, p<0.05). Conversely, neither EASIX-pre nor pre-transplant HCT-CI were extracted as risk factors for late NRM.

Conclusion

The present study indicated that EASIX-1year may be useful as a prognostic index for late NRM. Otherwise, pre-transplant conditions, such as EASIX-pre and pre-transplant HCT-CI, may have limited effects on late NRM.