1.
Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study
Mohty, M., Blaise, D., Peffault de Latour, R., Labopin, M., Bourhis, J. H., Bruno, B., Ceballos, P., Detrait, M., Gandemer, V., Huynh, A., et al
Bone marrow transplantation. 2022
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Abstract
Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT) conditioning. The DEFIFrance post-marketing registry study evaluated effectiveness and safety in patients who received defibrotide. It collected retrospective/prospective patient data from 53 French HCT centres from July 2014 to March 2020. Primary endpoints were survival and complete response (CR; total serum bilirubin <2 mg/dL, multiorgan failure resolution) at Day 100 post-HCT among patients with severe/very severe VOD/SOS. A secondary endpoint was evaluation of treatment-emergent serious adverse events (TESAEs) of interest. Of 798 patients analysed, 251 and 81 received defibrotide treatment for severe/very severe VOD/SOS and mild/moderate VOD/SOS post-HCT, respectively; 381 received defibrotide for VOD/SOS prophylaxis. In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated CR at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%. DEFIFrance represents the largest collection of real-world data on post-registration defibrotide use, supporting the real-world utility of defibrotide for patients with severe/very severe VOD/SOS post-HCT.
PICO Summary
Population
Adults and children receiving defibrotide for treatment or prophylaxis of veno-occlusive disease / sinusoidal obstruction syndrome (VOD/SOS) between July 2014 to March 2020 at 53 French HCT centres (n=798)
Intervention
Defibrotide for severe/very severe VOD/SOS (n=251); Defibrotide for mild/moderate VOD/SOS (n=81)
Comparison
Defibrotide for VOD/SOS prophylaxis (n=381)
Outcome
In patients with severe/very severe VOD/SOS post-HCT, Kaplan-Meier-estimated complete remission (CR) at Day 100 was 74% (95% confidence interval [CI]: 66%, 81%). At Day 100, 137/251 (55%) were alive and in CR. Kaplan-Meier-estimated Day 100 post-HCT survival was 61% (95% CI: 55%, 67%) in patients with severe/very severe VOD/SOS. TESAEs of interest occurred in 29% of these patients; VOD/SOS-related mortality at 12 months was 15%.
2.
Genetic susceptibility to hepatic sinusoidal obstruction syndrome in pediatric patients undergoing HSCT
Ansari, M., Petrykey, K., Rezgui, M. A., Vecchio, V. D., Cortyl, J., Ralph, R. O., Nava, T., Beaulieu, P., St-Onge, P., Mlakar, S. J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Sinusoidal Obstruction Syndrome (SOS) is a well-recognized and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). SOS arises from endothelial cell damage and hepatocellular injury mostly due to the transplantation conditioning regimens but also to other patient, disease and treatment-related factors. Understanding risk factors associated with the development of SOS is critical for early initiation of treatment or prophylaxis. The knowledge about genetic contribution is limited; few studies investigated so far selected set of genes. To get more comprehensive insight in the genetic component, we performed exome-wide association study using genetic variants derived from whole-exome sequencing. The analyses were performed in a discovery cohort composed of 87 pediatric patients undergoing HSCT following busulfan-containing conditioning regimen. Eight lead SNPs were identified after correction for multiple testing and subsequently analyzed in a validation cohort (n=182). Three SNPs were successfully replicated including rs17146905 (p=0.001), rs16931326 (p=0.04) and rs2289971 (p=0.03), located respectively in UGT2B10, BHLHE22 and KIAA1715 genes. UGT2B10 and KIAA1715 were retained in multivariable model while controlling for non-genetic covariates and previously identified risk variants in GSTA1 promoter. The modulation of associations by conditioning regimens was noted, KIAA1715 was dependent on the intensity of conditioning regimen, whereas the effect of UGT2B10 was equally applicable to all of them. Combined effect of associated loci was also observed (p=0.00006) with genotype-related SOS risk of 9.8. This is the first study addressing the genetic component of SOS at an exome-wide level and identifying novel genetic variations conferring higher risk of SOS, which might be useful for personalized prevention and treatment strategies.