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3121 Defibrotide for the Treatment of Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome with/without Multi-Organ Dysfunction Following Chemotherapy: Results from an Ongoing Expanded Access Program

Clinical Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Transplant Toxicities
Program: Oral and Poster Abstracts
Session: 721. Clinical Allogeneic Transplantation: Conditioning Regimens, Engraftment and Acute Transplant Toxicities: Poster II
Sunday, December 6, 2015, 6:00 PM-8:00 PM
Hall A, Level 2 (Orange County Convention Center)

Nancy A. Kernan, MD1, Paul G. Richardson, MD2, Angela R. Smith, MD3, Brandon M. Triplett, MD4*, Stephan A. Grupp, MD, PhD5, Joseph H. Antin, MD6, Leslie E. Lehmann, MD7, Wei Liang, PhD8*, Robin L. Hume, MS8*, Alison L. Hannah, MD8, Bijan Nejadnik, MD8 and Robert J. Soiffer, MD9

1Pediatric BMT Service, Memorial Sloan Kettering Cancer Center, New York, NY
2Division of Hematologic Malignancy, Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
3Division of Pediatric Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN
4Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN
5Pediatric Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA
6Stem Cell/Bone Marrow Transplantation Program, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
7Center for Stem Cell Transplantation, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
8Jazz Pharmaceuticals, Palo Alto, CA
9Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA

Introduction

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning regimens for hematopoietic stem cell transplant (HSCT). Although VOD/SOS usually is thought of as a complication of HSCT, there is also a known risk in patients following chemotherapy in a non-HSCT setting. Severe hepatic VOD/SOS (ie, with multi-organ dysfunction [MOD]), may be associated with >80% mortality. Endothelial cell (EC) damage is a critical factor in the pathophysiology of VOD/SOS. Preclinical data suggest that defibrotide stabilizes ECs with direct, as well as EC-mediated, restoration of the thrombo-fibrinolytic balance. Defibrotide is approved for treatment of severe hepatic VOD/SOS in adult and pediatric patients in the European Union. In the United States, defibrotide is available as an investigational drug through an ongoing expanded-access protocol for treatment of hepatic VOD/SOS.

Methods

In the original protocol, patients were eligible if they had hepatic VOD/SOS by Baltimore criteria post-HSCT and MOD, defined by renal (tripling of creatinine levels or reduced creatinine clearance with or without dialysis) and/or pulmonary (need for oxygen supplementation with or without assisted ventilation) dysfunction. Symptoms of VOD/SOS were not considered adverse events (AEs) unless the event was considered serious. The protocol was later amended to include (1) post-chemotherapy patients with hepatic VOD/SOS; (2) patients with hepatic VOD/SOS without MOD, and (3) VOD/SOS per modified Seattle criteria. Enrolled patients received defibrotide 25 mg/kg/d in 4 divided doses for a recommended ≥21 days. Here, we describe efficacy and safety results with defibrotide for the subset of patients that developed VOD/SOS post-chemotherapy.

Results

Out of 642 patients who developed VOD/SOS and received ≥1 dose of defibrotide, 69 patients received chemotherapy without HSCT; 52% (n=36) had MOD, and 48% (n=33) did not. Median age was 8 years (range, <1 month–58.0 years), and 55 patients (80%) were ≤16 years (39 patients were children aged 2–11); 54% of patients were male. The most common primary diseases were acute lymphocytic leukemia (44%) and acute myelogenous leukemia (10%). Chemotherapeutic agents received by more than 30% of patients were vincristine, cyclophosphamide, cytarabine, doxorubicin, methotrexate and PEG-L-asparaginase. Antibody-drug conjugates linked to ozogamicin that are associated with development of VOD/SOS (gemtuzumab and inotuzumab) were received by 3 and 1 patient, respectively.

The Kaplan-Meier estimated day +100 survival rate was 77.4% (95% confidence interval, 65.4%–85.7%). For patients with MOD and without MOD, the Kaplan-Meier estimated day +100 survival rates were 74.3% (56.4%–85.7%) and 80.9% (62.3%–90.9%), respectively.

Overall, ≥1 AE was reported in 44 chemotherapy patients (63.8%). Of these, 14 (20.3%) had AEs assessed by the investigator as possibly, probably, or definitely related to defibrotide. Treatment-related AEs occurring in ≥2 patients were hypotension (4.3%), nausea (2.9%), vomiting (2.9%), and epistaxis (2.9%). Hemorrhagic AEs of any severity occurring in ≥2 patients were pulmonary (7.2%), epistaxis (5.8%), and gastric (2.9%). Serious AEs were reported in 26 patients (37.7%), most commonly multi-organ failure (7.2%), hypoxia (5.8%), and pulmonary hemorrhage (5.8%). AEs led to discontinuation in 4 patients (gastric, gastrointestinal and mouth hemorrhages, epistaxis, and hypotension). No treatment-related deaths were reported.

Conclusions

Day+100 survival of 77.4% in patients developing VOD/SOS following a variety of chemotherapy regimens without HSCT (80% of which were pediatric, primarily children) is a clinically encouraging finding. Defibrotide treatment in this group of 69 patients developing VOD/SOS post-chemotherapy was generally well-tolerated, with only 5.8% of patients discontinuing due to an AE and no treatment-related fatalities. Enrollment to the study continues.

Support: Jazz Pharmaceuticals.

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Disclosures: Kernan: Gentium S.p.A.: Research Funding . Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Richardson: Jazz Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Gentium S.p.A.: Membership on an entity’s Board of Directors or advisory committees , Research Funding ; Novartis: Membership on an entity’s Board of Directors or advisory committees ; Millennium Takeda: Membership on an entity’s Board of Directors or advisory committees ; Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees . Grupp: Novartis: Consultancy , Research Funding . Antin: Jazz Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees ; Gentium S.p.A.: Membership on an entity’s Board of Directors or advisory committees . Liang: Jazz Pharmaceuticals: Employment , Equity Ownership . Hume: Jazz Pharmaceuticals: Employment , Equity Ownership . Hannah: Jazz Pharmaceuticals: Consultancy . Nejadnik: Jazz Pharmaceuticals: Employment , Equity Ownership . Soiffer: Gentium SpA/Jazz Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees .

*signifies non-member of ASH