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EASIX predicts SOS/VOD after alloSCT
ures,3 and preliminary data show that pre-emptive treat- ment with defibrotide might be effective,12 making tools to predict SOS/VOD highly desirable.
Recently, a SOS/VOD clinical risk score (age, Karnofsky status, sirolimus use, hepatitis B/C status, conditioning regimen, disease type) has been published by the Center for International Blood and Marrow Transplant Research (CIBMTR).13 However, this score has not yet been validat- ed outside of the CIBMTR database. In addition, it has been suggested that serum biomarkers, including microparticles and plasminogen activator inhibitor (PAI)- 1, may be useful to predict SOS/VOD,14-18 but validation and clinical implementation of these non-routine bio- markers will be difficult due to the lack of standardization.
We had previously developed a standard biomarker panel to assess endothelial dysfunction and activation: the Endothelial Activation and Stress Index (EASIX). EASIX is based on the simple formula “lactate dehydrogenase (LDH) (U/L) * creatinine (mg/dL) / thrombocytes (109 cells per L)” and thus calculated using three of the diagnostic parameters of thrombotic microangiopathy (TMA),19 which is another endothelial complication after alloSCT.20 EASIX has also been shown to predict mortality of patients with acute graft-versus-host disease (GvHD).19
With this background, the aim of the current study was to test the SOS/VOD predictive capacity of EASIX com- pared with that of the CIBMTR score in two independent cohorts.
Methods
Study population
For this retrospective cohort analysis, a training cohort and a validation cohort comprising consecutive adult patients who had undergone alloSCT at two independent institutions were investi- gated. Patients from the training cohort received alloSCT at the Charité - Campus Virchow Clinic, Berlin, between January 2013 and December 2015. The validation cohort consisted of patients who were allografted at the University of Heidelberg between September 2001 and December 2009. Patients undergoing alloSCT in Heidelberg after January 2010 received pravastatin and ursodeoxycholic acid (UDA) as prophylaxis of endothelial compli- cations after alloSCT. To reduce confounding influences, the vali- dation cohort was restricted to the time period before the intro- duction of pravastatin and UDA. The study was performed according to the Declaration of Helsinki, with written informed consent obtained by all eligible patients. The study has been approved by the institutional review board of both institutions.
Definitions
SOS/VOD was defined according to the 2016 European Group for Blood and Marrow Transplantation (EBMT) criteria for SOS/VOD diagnosis in adults.4 The disease score we applied for the patients classifies the disease stage of the main diseases: acute leukemia, myelodysplastic syndrome, chronic myeloid leukemia, and non-Hodgkin lymphoma/multiple myeloma. The disease stages are assigned according to the remission status at transplant or the phases of chronic myeloid leukemia. The stages include ‘early disease stage' (0), ‘intermediate disease stage’ (1), and ‘late stage disease’ (2).21
CIBMTR sinusoidal obstruction syndrome/veno-occlusive disease risk score
The SOS/VOD CIBMTR risk score has been established to
assess the risk of developing SOS/VOD after alloSCT.13 It incorpo- rates age, hepatitis B/C serology, Karnofsky performance status, use of sirolimus prophylaxis, disease, disease status at the time of transplant, and conditioning regimen. It was developed using the CIBMTR database.13 We used the ‘VOD Risk Calculator’22 and recorded the probability of SOS/VOD development for each patient in the two independent cohorts when possible.
EASIX score
The EASIX score was calculated using the formula: “LDH (U/L) *creatinine (mg/dL) / thrombocytes (109 cells per L)” as described previously, assessed at the day of alloSCT (EASIX-d0).19
Statistical analysis
The primary objective was prediction of SOS/VOD occurrence. Primary analysis was performed for the binary endpoint “cumula- tive incidence of SOS/VOD within 28 days after alloSCT” and the time-to-event endpoint “time to VOD (TTV)” which is defined as time from alloSCT to diagnosis of SOS/VOD. Secondary objec- tives were the prediction of overall survival (OS) and time to non- relapse mortality (NRM) measured from the day of alloSCT. TTV and NRM were analyzed using competing event models. The competing event for TTV is "non-SOS/VOD-mortality" defined as time from alloSCT to death without prior SOS/VOD, whereas the competing event for NRM is "time to relapse" defined as time from alloSCT to relapse of disease. Further details on statistical analyses are provided in the Online Supplementary Appendix.
Results
Patients' characteristics
The training cohort and the validation cohort consisted of 446 and 380 patients, respectively. The baseline charac- teristics are presented in Table 1. The patient cohorts were similar with regards to age, sex, conditioning regimen, and SOS/VOD incidence. However, there were significant dif- ferences in the categories donor type (more matched unre- lated donors in the training cohort), underlying disease (most frequent disease: acute myeloid leukemia, 51% and 27% in the training and validation cohort, respectively), stem cell source (bone marrow used more frequently in the validation cohort), and use of anti-thymocyte globulin (ATG) (more commonly used in the training cohort).
EASIX-d0 and sinusoidal obstruction syndrome/veno-occlusive disease risk
SOS/VOD was diagnosed in 43 patients (9.6%, median onset day [d] +9) in the training cohort and in 32 patients (8.4%, median onset d +7) in the validation cohort. In the training cohort, median EASIX-d0 in patients who later went on to develop SOS/VOD was significantly higher than in patients who did not develop SOS/VOD (40.26; interquartile range [IQR] 14.72-80.38 vs. 16.06; IQR 6.00- 36.54, P<0.0001) (Figure 1A). These findings were con- firmed in the validation cohort, where median EASIX-d0 in patients who subsequently developed SOS/VOD was also significantly higher than in patients who did not develop SOS/VOD (8.64; IQR 3.38-15.40 vs. 2.28; IQR 0.92-7.48, P<0.0001) (Figure 1B).
Increasing EASIX-d0 was significantly associated with SOS/VOD incidence in the training cohort in both univari- able (OR per log2 increase 1.39, 95%CI:1.18-1.66, P=0.0001) and multivariable analysis with the CIBMTR score as con- founder (incorporating information on 6 clinical variables)
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