Defibrotide Shows Efficacy in the Prevention of Sinusoidal Obstruction Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Study

Chalandon, Yves; Mamez, Anne‐Claire; Giannotti, Federica; Beauverd, Yan; Dantin, Carole; Mahne, Elif; Mappoura, Maria; Bernard, Fanette; Ortiz, Carmen De Ramon; Stephan, Caroline; Morin, Sarah; Ansari, Marc; Simonetta, Federico; Masouridi‐Levrat, Stavroula

doi:10.1016/j.jtct.2022.08.003

Cited by 8 publications

(7 citation statements)

References 41 publications

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“…Anticoagulants are the medicines of choice to treat patients with HSOS (Table 3), whether it is caused by drugs such as sirolimus, gemtuzumab, cyclophosphamide, or oxaliplatin, leading to drug-induced liver vascular injury [42,118,119], due to hematopoietic cell transplantation (HCT) [120][121][122], or following use of plants containing 1,2-unsaturated PAs [68,123,124]. HSOS is characterized among many other features by platelet aggravation and adhesion, damage of the endothelial cells, and the risk of occlusion of the hepatic sinusoids [68,118].…”

Section: Anticoagulantsmentioning

confidence: 99%

Treatment of Drug-Induced Liver Injury

Teschke

2022

Biomedicines

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Current pharmacotherapy options of drug-induced liver injury (DILI) remain under discussion and are now evaluated in this analysis. Needless to say, the use of the offending drug must be stopped as soon as DILI is suspected. Normal dosed drugs may cause idiosyncratic DILI, and drugs taken in overdose commonly lead to intrinsic DILI. Empirically used but not substantiated regarding efficiency by randomized controlled trials (RCTs) is the intravenous antidote treatment with N-acetylcysteine (NAC) in patients with intrinsic DILI by N-acetyl-p-aminophenol (APAP) overdose. Good data recommending pharmacotherapy in idiosyncratic DILI caused by hundreds of different drugs are lacking. Indeed, a recent analysis revealed that just eight RCTs have been published, and in only two out of eight trials were DILI cases evaluated for causality by the worldwide used Roussel Uclaf Causality Assessment Method (RUCAM), representing overall a significant methodology flaw, as results of DILI RCTs lacking RUCAM are misleading since many DILI cases are known to be attributable erroneously to nondrug alternative causes. In line with these major shortcomings and mostly based on anecdotal reports, glucocorticoids (GCs) and other immuno-suppressants may be given empirically in carefully selected patients with idiosyncratic DILI exhibiting autoimmune features or caused by immune checkpoint inhibitors (ICIs), while some patients with cholestatic DILI may benefit from ursodeoxycholic acid use; in other patients with drug-induced hepatic sinusoidal obstruction syndrome (HSOS) and coagulopathy risks, the indication for anticoagulants should be considered. In view of many other mechanistic factors such as the hepatic microsomal cytochrome P450 with a generation of reactive oxygen species (ROS), ferroptosis with toxicity of intracellular iron, and modification of the gut microbiome, additional therapy options may be available in the future. In summation, stopping the offending drug is still the first line of therapy for most instances of acute DILI, while various therapies are applied empirically and not based on good data from RCTs awaiting further trials using the updated RUCAM that asks for strict exclusion and inclusion details like liver injury criteria and provides valid causality rankings of probable and highly probable grades.

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Section: Anticoagulantsmentioning

confidence: 99%

Treatment of Drug-Induced Liver Injury

Teschke

2022

Biomedicines

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“…Strouse et al found notable differences in the cumulative incidence of grade II–IV acute GVHD at day 100 post-HCT in patients who received defibrotide versus those who did not receive defibrotide (23.1% versus 37.7%; difference, −14.6 [95% CI: −33.1, 3.9]) ( 27 ). Chalandon et al indicated that defibrotide prophylaxis significantly reduced the 1-yr cumulative incidence of aGVHD ( 28 ). Tekgündüz’s study of 195 HSCT recipients showed that the incidence of acute GVHD was 26% for patients who received defibrotide before HSCT, 40% for those who received defibrotide after HSCT, and 47% for those who received no defibrotide ( P = 0.057), with a trend toward a lower rate of severe GVHD in the pre-HSCT arm than in the other groups ( P = 0.051) ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

“…Several clinical studies have examined whether defibrotide can reduce the incidence of aGVHD ( 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ). However, the literature on randomized defibrotide assessments for GVHD prevention is relatively tiny and reports disagreeing conclusions.…”

Section: Introductionmentioning

confidence: 99%

Defibrotide impact on the acute GVHD disease incidence in pediatric hematopoietic stem cell transplant recipients

et al. 2023

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Despite advances in acute graft-versus-host disease (aGVHD) prophylaxis, current pharmacological approaches fail to prevent aGVHD. The protective effect of defibrotide on GVHD incidence and GVHD-free survival has not been sufficiently studied. 91 pediatric patients included in this retrospective study were divided into two groups based on defibrotide use. We compared the incidence of aGVHD and chronic GVHD-free survival between the defibrotide and control groups. The incidence and severity of aGVHD were significantly lower in patients who received defibrotide prophylactic administration than in the control group. This improvement was observed in the liver and intestinal aGVHD. No defibrotide prophylaxis benefit was observed in the prevention of chronic GVHD. The pro-inflammatory cytokine levels were significantly higher in the control group. Our findings suggest that prophylactic administration of defibrotide in pediatric patients significantly reduces the incidence and severity of aGVHD, with a modification of cytokine pattern, both strongly coherent with the protective drug’s action. This evidence adds to pediatric retrospective studies and preclinical data suggesting a possible defibrotide role in this setting.

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“…However, all these findings are late events in the pathology of the disease [18] and emerge after histological damage is established [19]. Prophylaxis and treatment with defibrotide (Jazz Pharmaceutical, Palo Alto, CA) have shown the most promising results in several clinical trial [20][21][22][23]. Nevertheless, treatment with defibrotide can carry significant risks, such as severe hemorrhage, especially in the context of severe thrombocytopenia present in this patient population [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Low Plasma Levels of Hyaluronic Acid Might Rule Out Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation

et al. 2023

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Background. Sinusoidal obstructive syndrome (SOS) is a potentially fatal complication secondary to hematopoietic stem cell transplant (HSCT) conditioning. Endothelial damage plasma biomarkers such as plasminogen activator inhibitor-1 (PAI-1), hyaluronic acid (HA), and vascular adhesion molecule-1 (VCAM1) represent potential diagnostic tools for SOS. Methods. We prospectively collected serial citrated blood samples (baseline, day 0, day 7, and day 14) in all adult patients undergoing HSCT at La Paz Hospital, Madrid. Samples were later analyzed by ELISA (enzyme-linked immunosorbent assay) for HA, VCAM1, and PAI-1 concentrations. Results. During sixteen months, we prospectively recruited 47 patients. Seven patients (14%) were diagnosed with SOS according to the EBMT criteria for SOS/VOD diagnosis and received treatment with defibrotide. Our study showed a statistically significant elevation of HA on day 7 in SOS patients, preceding clinical SOS diagnosis, with a sensitivity of 100%. Furthermore, we observed a significant increase of HA and VCAM1 levels on day 14. Regarding risk factors, we observed a statistically significant association between SOS diagnosis and the fact that patients received 3 or more previous lines of treatment before HSCT. Conclusions. The early significant increase in HA levels observed opens the door to a noninvasive peripheral blood test which could have the potential to improve diagnosis and facilitate prophylactic and therapeutic management of SOS before clinical/histological damage is established.

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Defibrotide Shows Efficacy in the Prevention of Sinusoidal Obstruction Syndrome After Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Study

Cited by 8 publications

References 41 publications

Treatment of Drug-Induced Liver Injury

Treatment of Drug-Induced Liver Injury

Defibrotide impact on the acute GVHD disease incidence in pediatric hematopoietic stem cell transplant recipients

Low Plasma Levels of Hyaluronic Acid Might Rule Out Sinusoidal Obstruction Syndrome after Hematopoietic Stem Cell Transplantation

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