Page 202 - 2019_04-Haematologica-web

A. Radujkovic et al.
models showed a slightly improved prediction perform- ance. The corresponding prediction error curves represent- ing the Brier score over time are depicted in Online Supplementary Figure S1.
Association of asymmetric dimethylarginine levels with endothelium-related serum factors and high pre-trans- plant levels in the context of INOS polymorphisms
Samples for measurement of serum concentrations of free IL-18, soluble thrombomodulin (sCD141), and nitrates were available for 746, 776 and 375 patients, respectively. The corresponding median pre-transplant serum levels are given in Table 1. Pre-transplant ADMA levels correlated with serum levels of nitrates, free IL-18, and sCD141 (Figure 3A-C).
The concept of endothelial vulnerability involves a pro- inflammatory environment and ADMA is able to modify NO synthase and, in particular, inducible NO synthase (iNOS) activity.7,15 We analyzed whether polymorphisms in INOS modulated the observed effects of ADMA. Genotype data on INOS SNP were available for a total of 386 patients. In order to evaluate the effect of ADMA in the context of INOS polymorphisms, an optimal cut-off with regard to OS in the first year after transplantation was determined, yielding multiple cut-points (maxima) (Online Supplementary Figure S2). The maximum at 0.97 mM, which also represents the upper quartile of the ADMA distribution, was chosen to stratify patients into groups with high (≥0.97 mM) or low (<0.97 mM) ADMA levels in the context of INOS polymorphisms. There was no substantial influence of INOS SNP on the effect of ADMA on OS or NRM within the first year after allogene- ic SCT (Online Supplementary Figures S3-5).
Discussion
To the best of our knowledge, this is the first report of an association between ADMA levels measured prior to trans- plant and subsequent risk of mortality in allografted patients. ADMA is a well-characterized cardiovascular risk factor, and dysfunction of the endothelium appears to be a common finding in studies investigating the role of ADMA in (cardio-)vascular disease.10 Elevated ADMA levels have also been reported in autoimmune diseases, linking inflam- mation with autoimmunity-related vascular complica- tions.16 In renal transplant recipients, associations of increased ADMA levels with acute rejection and mortality have been observed.17,18 Furthermore, high ADMA levels were associated with pro-inflammatory conditions and were shown to predict mortality risk in critically ill and sep- tic patients.19,20 Finally, ADMA was strongly associated with all-cause mortality across different patient and general pop- ulations in recent meta-analyses.11,12
Previous studies by us and others2-5,21-23 led us to propose the hypothesis of “endothelial vulnerability” as an impor- tant contributor to the main complications of allogeneic SCT. This concept may explain why a proportion of patients with acute GvHD fail to respond to escalating immunosuppressive therapy and ultimately succumb to acute GvHD, its treatment and/or related complications.21 It denotes a risk that, in the setting of allogeneic SCT, is sub- stantiated particularly in the presence of additional chal- lenges, i.e., conditioning treatment and/or allogeneic T-cell attacks in a pro-inflammatory environment, and may result in endothelial damage that leads to perpetuating inflamma- tory end-organ destruction despite (initially) effective con- trol of T-cell activity. Since this “vulnerability” is, at least in
Table 3. Multivariable analysis of predictors of overall survival, progression-free survival and non-relapse mortality after onset of acute graft-versus-host disease (complete case analysis).
OS after acute GvHD (n=541) PFS after acute GvHD (n=530) NRM* after acute GvHD (n=530) HR(95%CI) P HR(95%CI) P HR(95%CI) P
Covariate
ADMA (per 1-log2 increase): 1st year
ADMA (per 1-log2 increase): years 2 and 3 ADMA (per 1-log2 increase): after 3 years Age at transplantation (per year)
Donor sex Female Male
Recipient sex Female Male
Donor-recipient HLA matching Mismatched
Matched
Disease stage† Early Late/intermediate
Conditioning‡ Myeloablative Reduced intensity
1.46 (1.17-1.83)
1.13 (0.73-1.76) 0.82 (0.45-1.48) 1.02 (1.01-1.03)
Ref
0.79 (0.62-1.00)
Ref
1.21 (0.95-1.53)
Ref
0.61 (0.48-0.78)
Ref
1.11(0.86-1.42) Ref
1.08 (0.45-1.48)
0.001
0.577 0.507 0.003
0.054
0.119
<0.0001
0.423
0.710
1.32 (1.07-1.63)
1.12 (0.70-1.81) 1.06 (0.56-2.02) 1.01 (1.00-1.03)
Ref
0.81 (0.64-1.03)
Ref
1.24 (0.99-1.57)
Ref
0.73 (0.57-0.93)
Ref
1.11 (0.88-1.42) Ref
1.05 (0.71-1.54)
0.010
0.633 0.860 0.013
0.081
0.065
0.010
0.378
0.847
1.36 (1.01-1.83)
1.50 (0.76-2.96) 0.65 (0.26-1.64) 1.03 (1.01-1.05)
Ref
0.71 (0.51-0.99)
Ref
1.30 (0.94-1.80)
Ref
0.55 (0.40-0.77)
Ref
0.91 (0.65-1.26) Ref
1.05 (0.58-1.89)
0.042
0.242 0.364 0.0003
0.041
0.119
0.0004
0.553
0.882
Number of events: OS after acute GvHD, n=297; PFS after acute GvHD, n=314; NRM after acute GvHD, n=159; relapse after acute GvHD, n=155. *Cause-specific hazards from a competing risks analysis for relapse and NRM after onset of GvHD. †According to Gratwohl et al.41 ‡According to Bacigalupo et al.42 ADMA: asymmetric dimethylarginine; CI: confidence interval; GvHD: graft-versus-host-disease; HLA: human leukocyte antigen; HR: hazard ratio; NRM: non-relapse mortality; OS: overall survival; PFS: progression-free survival.
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haematologica | 2019; 104(4)