A Systematic Review and Meta-Analysis of Studies of Defibrotide Prophylaxis for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome

Corbacioglu, Selim; Topaloglu, Özlem; Aggarwal, Saurabh

doi:10.1007/s40261-022-01140-y

Cited by 10 publications

(5 citation statements)

References 30 publications

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“…These patients had multiple risk factors that increased the odds of developing VOD/SOS, thereby necessitating prophylaxis with defibrotide. That said, in a separate meta-analysis of more than 3000 patients, the risk ratio for developing VOD/SOS with defibrotide prophylaxis versus control was 0.30 (95% CI: 0.12, 0.71; nominal P = 0.006) [ 22 ]. Moreover, results from a phase 3, prospective, randomised controlled study in high-risk paediatric patients demonstrated a 12% incidence of VOD/SOS by Day 30 post-HCT with defibrotide prophylaxis, while an incidence of 20% was observed in the no defibrotide control group [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

“…In total, 134/247 (54%) patients received 25 mg/kg/day of defibrotide, consistent with the dose recommended in the label; the median (IQR) dose was 25 (25,25) mg/kg/day. The median (IQR) treatment duration was 18 (11,22) days in patients with severe and 16 (8,22) days in those with very severe VOD/SOS post-HCT.…”

Section: Patient Demographics and Clinical Characteristicsmentioning

confidence: 99%

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Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study

Mohty

Blaise

Latour

et al. 2022

Bone Marrow Transplant

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Patient Demographics and Clinical Characteristicsmentioning

confidence: 99%

Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study

Mohty

Blaise

Latour

et al. 2022

Bone Marrow Transplant

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“…In terms of prophylaxis, ursodeoxycholic acid (UDA) has been associated with a significant reduction of SOS/VOD incidence in various randomized studies [75][76][77]. The use of DF as a prophylactic agent has also been shown to reduce the incidence of VOD/SOS in high-risk patients by several studies [78], whereas a systematic review by Zhang et al confirmed the lower relative risk of SOS/VOD with DF prophylaxis (risk ratio 0.47, 95% CI) [79]. A more recent meta-analysis by Cobacioglu et al confirmed a low incidence of SOS/VOD following IV DF prophylaxis regardless of age group, supporting the use of DF in the prevention of SOS/VOD [78].…”

Section: Sinusoidal Obstructive Syndrome (Sos)/veno-occlusive Disease...mentioning

confidence: 99%

“…The use of DF as a prophylactic agent has also been shown to reduce the incidence of VOD/SOS in high-risk patients by several studies [78], whereas a systematic review by Zhang et al confirmed the lower relative risk of SOS/VOD with DF prophylaxis (risk ratio 0.47, 95% CI) [79]. A more recent meta-analysis by Cobacioglu et al confirmed a low incidence of SOS/VOD following IV DF prophylaxis regardless of age group, supporting the use of DF in the prevention of SOS/VOD [78]. However, a prospective phase III study of DF prophylaxis for SOS/VOD (NCT02851407) stopped enrolment after meeting the criteria for futility although analyses are ongoing and are awaited with great interest.…”

Section: Sinusoidal Obstructive Syndrome (Sos)/veno-occlusive Disease...mentioning

confidence: 99%

Endothelial Dysfunction Syndromes after Allogeneic Stem Cell Transplantation

Vythoulkas

Tsirigotis

Griniezaki

et al. 2023

Cancers

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only therapy with a curative potential for a variety of malignant and non-malignant diseases. The major limitation of the procedure is the significant morbidity and mortality mainly associated with the development of graft versus host disease (GVHD) as well as with a series of complications related to endothelial injury, such as sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), transplant-associated thrombotic microangiopathy (TA-TMA), etc. Endothelial cells (ECs) are key players in the maintenance of vascular homeostasis and during allo-HSCT are confronted by multiple challenges, such as the toxicity from conditioning, the administration of calcineurin inhibitors, the immunosuppression associated infections, and the donor alloreactivity against host tissues. The early diagnosis of endothelial dysfunction syndromes is of paramount importance for the development of effective prophylactic and therapeutic strategies. There is an urgent need for the better understanding of the pathogenetic mechanisms as well as for the identification of novel biomarkers for the early diagnosis of endothelial damage. This review summarizes the current knowledge on the biology of the endothelial dysfunction syndromes after allo-HSCT, along with the respective therapeutic approaches, and discusses the strengths and weaknesses of possible biomarkers of endothelial damage and dysfunction.

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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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A Systematic Review and Meta-Analysis of Studies of Defibrotide Prophylaxis for Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome

Cited by 10 publications

References 30 publications

Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study

Real-world use of defibrotide for veno-occlusive disease/sinusoidal obstruction syndrome: the DEFIFrance Registry Study

Endothelial Dysfunction Syndromes after Allogeneic Stem Cell Transplantation

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

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