Page 138 - 2021_02-Haematologica-web

S. Jiang et al.
ies, patients with high EASIX-d0 scores might benefit from closer monitoring of emerging clinical SOS/VOD signs and early interventions.
EASIX-d0 has to be put into perspective with the CIBMTR SOS/VOD clinical risk score, which has been recently described as a predictive tool to identify patients at high risk of developing SOS/VOD.13 The CIBMTR score has been established using a large sample from the CIBMTR database and consists of select baseline parame- ters which are partly fixed (age, hepatitis B/C serology, Karnofsky performance score, diagnosis, disease status at transplant) and partly subject to intervention (use of sirolimus, conditioning regimen). It has been shown to be predictive for SOS/VOD but not for NRM and OS.13 In the present study, the CIBMTR score exhibited only a weak association with SOS/VOD incidence and no association with NRM or OS. One explanation for this discrepancy might be that the two European cohorts investigated in the current study differed in some respects from the CIBMTR cohort. First, in vivo T-cell depletion with ATG was administered in most patients in the two European cohorts, whereas the majority of the CIBMTR patients did not receive ATG for GvHD prophylaxis.13 Second, most patients in our two cohorts were conditioned with reduced intensity conditioning (RIC), whereas only a minority of patients from the CIBMTR database received an RIC regimen.13 Third, sirolimus was administered in 8% of the patients from the CIBMTR database,13 whereas none of our patients received sirolimus prophylaxis. This is relevant because sirolimus was a risk factor for SOS/VOD development in the CIBMTR analysis. In addi- tion, registry data might be prone to consistency deficits, while we had immediate access to the primary data ensur- ing the high quality of the data used in our study. Of note, the CIBMTR score has been primarily validated in a large population. We have validated the current EASIX-VOD score in smaller cohorts. Therefore, further validation is needed. The EBMT is currently conducting a prospective non-interventional study on the value of the EASIX score to predict alloSCT-related endothelial complications. Furthermore, we expect that data from several retrospec- tive cohorts in different centers will soon be available.
Based on previous publications on the efficacy of UDA and statins in the protection of the endothelium,23,24 the Heidelberg alloSCT group decided to administer pravas- tatin and UDA as prophylaxis for alloSCT recipients trans- planted after January 2010. UDA is a synthetic bile acid that reduces the incidence of SOS/VOD, and is associated with less liver toxicity and better survival rates.3,25 Statins have not been extensively studied for the prevention of endothelial complications. However, its pleiotropic effects include, besides the inhibition of cholesterol synthesis, improving endothelial function, reducing oxidative stress and inflammation, and decreasing thrombogenic proper- ties.26,27 Statins may therefore be beneficial in the preven- tion of endothelial complications. Accordingly, we
observed a reduction of endothelial post-transplant com- plications, as previously shown in TMA20 and refractory GvHD28 upon implementation of statin/UDA endothelial prophylaxis.
In the present study, the SOS/VOD incidence was markedly reduced after the introduction of pravastatin/UDA prophylaxis. These protective effects, both in terms of SOS/VOD risk reduction and lower NRM and overall mortality, were particularly pronounced in patients with high EASIX-d0 scores, as compared to high- risk patients who did not receive pravastatin/UDA. This suggests that patients at high risk for SOS/VOD may ben- efit most from prophylactic SOS/VOD strategies.
Limitations of our study are its retrospective design and the validation in only one independent cohort of patients with similar patients' characteristics, which are typical for adult European alloSCT transplant centers. Therefore, the results cannot be extrapolated to pediatric alloSCT popu- lations. Since EASIX-d0 is very easy to assess, any trans- plant center now has the opportunity to evaluate its potential in their respective patient population and we hope that more data on different patient populations, including pediatric patients or haploidentical transplanta- tion, will soon be available. To facilitate this process, we have created the EASIX-d0 SOS/VOD calculator for free public use (http://biostatistics.dkfz.de/EASIX/).
In conclusion, EASIX-d0 seems to be an easy-to-use bio- marker for identifying patient populations at high risk for SOS/VOD, and thus could be a promising tool both for clinical trials and tailored monitoring strategies. Statin/UDA endothelial prophylaxis could be an option to overcome the increased SOS/VOD risk indicated by high EASIX-d0 scores.
Disclosures
Olaf Penack has received research support and honorarium as a speaker from Jazz Pharmaceuticals. Thomas Luft has received research support from Jazz Pharmaceuticals and Neovii.
The remaining authors declare no competing interests.
Contributions
SJ, OP and TL designed the study, performed research, analysed data and wrote the manuscript; DS, AR and JM-L per- formed research; TT analyzed data; IWB, LB, CM-T and PD designed the study and edited the manuscript. All authors have read the manuscript and have agreed to submit it.
Acknowledgments
The authors would like to thank Jazz Pharmaceuticals for financial support.
Funding
This study was partly financially supported by Jazz Pharmaceuticals. The company played no role in the acquisition or analyses of data. Jazz was not involved in the writing or edit- ing of the manuscript.
References
1. Mohty M, Malard F, Abecassis M, et al. Sinusoidal obstruction syndrome/veno- occlusive disease: current situation and per- spectives - a position statement from the
European Society for Blood and Marrow
posing factors. Hepatology. 1984;4(1):116- Transplantation (EBMT). Bone Marrow 122.
Transplant. 2015;50(6):781-789.
2. Mcdonald GB, Sharma P, Matthews DE,
Shulman HM, Thomas ED. Venocclusive disease of the liver after bone marrow trans- plantation: diagnosis, incidence, and predis-
3. Carreras E. How I manage sinusoidal obstruction syndrome after haematopoietic cell transplantation. Br J Haematol. 2014; 168(4):481-491.
4. Mohty M, Malard F, Abecassis M, et al.
452
haematologica | 2021; 106(2)