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2067 Treatment Duration, Symptom Resolution, and Survival in Defibrotide-Treated Patients with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome after Hematopoietic Cell Transplantation: Pooled Analysis of Defifrance and EBMT PASS Registries

Program: Oral and Poster Abstracts
Session: 721. Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Toxicities: Poster I
Hematology Disease Topics & Pathways:
Biological therapies, Therapies
Saturday, December 10, 2022, 5:30 PM-7:30 PM

Mohamad Mohty, MD PhD1, Franco Locatelli, MD2, Didier Blaise, MD, PhD3, Regis Peffault De Latour4*, Myriam Labopin, MD5*, Hélène Labussière-Wallet, MD6*, Vian Amber7*, Virginie Gandemer8*, Deborah Gutierrez9*, Nalina Dronamraju10*, Jean-Hugues Dalle, MD, PhD11 and Ibrahim Yakoub-Agha12*

1EBMT Paris study office / CEREST-TC, Paris, France, Department of Hematology, Saint Antoine Hospital, Paris, France, INSERM UMR 938, Sorbonne University, Paris, France
2IRCCS Ospedale Pediatrico Bambino Gesú, Catholic University of the Sacred Heart, Rome, Italy
3Institut Paoli-Calmettes, Aix Marseille Université, Management Sport Cancer Laboratoire (MSC), Marseille, France
4Assistance Publique–Hôpitaux de Paris, Saint-Louis Hospital, Université Paris Cité, Paris, France
5EBMT Statistical Unit, Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France
6Department of Hematology, Hopital Lyon Sud, Lyon, France
7Jazz Pharmaceuticals, Oxford, United Kingdom
8University Hospital of Rennes, Rennes, France
9Jazz Pharmaceuticals, Lyon, France
10Jazz Pharmaceuticals, Philadelphia, PA
11Hôpital Robert-Debré, GHU APHP Nord et Université de Paris Cité, Paris, France
12CHU de Lille, Université de Lille, INSERM U1286, Infinite, Lille, France

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT). Defibrotide is approved for the treatment of severe hepatic VOD/SOS post-HCT in patients aged >1 month in the European Union and for hepatic VOD/SOS with renal or pulmonary dysfunction post-HCT in the United States. Clinical guidelines endorse prompt defibrotide initiation after VOD/SOS diagnosis. Outcomes from two real-world observational studies were pooled for analysis of time to diagnosis, treatment initiation and duration, and resolution of VOD/SOS in patients given defibrotide for the treatment of severe or non-severe VOD/SOS post-HCT.

DEFIFrance was an observational, post-marketing study that collected retrospective and prospective data on patients receiving defibrotide at 53 French transplant centers from July 2014 to March 2020. VOD/SOS severity was categorized retrospectively/prospectively using adult EBMT criteria in patients aged ≥18 years, and in patients aged <18 years using pediatric EBMT criteria. EBMT PASS was a multinational, prospective, observational study that enrolled defibrotide-treated patients from April 2015 to July 2018. EBMT PASS investigators graded VOD/SOS severity based on their clinical expertise. Investigators in both registries diagnosed VOD/SOS using classical/standard criteria (including, but not limited, to hyperbilirubinemia, hepatomegaly, ascites, and weight gain >5%). Since VOD/SOS grading was performed differently in the two registries, for this pooled analysis, mild/moderate and severe/very severe cases in DEFIFrance were combined with non-severe and severe cases in EBMT PASS, respectively.

Overall, 414 defibrotide-treated patients with VOD/SOS post-HCT were included (336 from DEFIFrance and 78 from EBMT PASS). The median (range) time from HCT to VOD/SOS diagnosis was 13 (interquartile range [IQR]: 8, 21) and 14 (IQR: 8, 22) days in patients with severe and non-severe VOD/SOS, respectively. Median time to initiation of defibrotide treatment after VOD/SOS diagnosis was 0 days in both severe (IQR: 0, 1) and non-severe (IQR: 0, 1) patients. 301/414 patients (73%) had resolution of VOD/SOS. Among those with severe and non-severe VOD/SOS, respectively, 208/302 (69%) and 91/108 (84%) had VOD/SOS resolution; 2 patients had missing severity data. Median time from start of defibrotide treatment to VOD/SOS resolution was 20 days (range: 3, 110) in patients with severe VOD/SOS and 15 days (range: 1, 147) in patients with non-severe VOD/SOS. Median treatment duration among patients with severe and non-severe VOD/SOS was 16.5 days (range: 1, 258) and 16 days (range: 3, 73), respectively. Among patients with resolution of VOD/SOS, symptoms resolved after Day 21 in 36% of patients with severe VOD/SOS and 23% of patients with non-severe VOD/SOS. Kaplan-Meier (KM)-estimated survival at Day 100 post-HCT among patients with severe VOD/SOS was 84% (95% confidence interval [CI]: 78%, 88%) in those who achieved VOD/SOS resolution and 14% (95% CI: 8%, 22%) in those who did not; among patients with non-severe VOD/SOS, this was 94% (95% CI: 87%, 98%) and 35% (95% CI: 15%, 57%), respectively.

Serious treatment-emergent adverse events (TEAEs) of interest occurred in 25% of patients with VOD/SOS resolution; similar safety outcomes were observed by defibrotide duration (≤21 days [25%] or >21 days [26%]). In patients treated for ≤21 days and >21 days, respectively, the most common serious TEAEs of interest by category were infection (14% and 15%) and hemorrhage (12% and 13%). Among patients with VOD/SOS resolution, the most common causes of death were infection (severe: 11%; non-severe: 2%) and GvHD (severe: 6%, non-severe: 2%).

In conclusion, time to resolution of VOD/SOS tended to be longer in patients with severe versus non-severe disease, with a substantial proportion requiring >21 days of therapy to achieve resolution. Day 100 survival was higher in patients with VOD/SOS resolution versus without, regardless of severity, highlighting the importance of obtaining resolution of VOD/SOS symptoms. The safety profile of defibrotide in the real-world setting was consistent with reports from previous studies, supporting the utility of defibrotide treatment.

Disclosures: Mohty: GSK: Honoraria; Oncopeptides: Honoraria; Pfizer,: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding. Locatelli: Jazz Pharmaceuticals: Honoraria; BlueBird bio: Speakers Bureau; Miltenyi: Speakers Bureau; Medac: Speakers Bureau; Neovii: Speakers Bureau; Amgen: Speakers Bureau; SOBI: Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Peffault De Latour: Samsung: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Keocyte: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Alexion: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Sobi: Consultancy, Honoraria. Labopin: Jazz Pharmaceuticals: Honoraria. Amber: Jazz Pharmaceuticals: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Gutierrez: Jazz Pharmaceuticals: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Dronamraju: Jazz Pharmaceuticals: Current Employment, Current equity holder in private company, Current holder of stock options in a privately-held company. Dalle: Novartis: Honoraria; Vertex: Honoraria; Sanofi: Honoraria; Medac: Honoraria; Orchard: Honoraria; Teva: Current equity holder in private company; Jazz Pharmaceuticals: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

OffLabel Disclosure: The abstract describes outcomes in patients with non-severe VOD/SOS, who are not included in the indicated population in the product label

*signifies non-member of ASH