EFFICACY AND SAFETY OF DEFIBROTIDE TO TREAT HEPATIC VENO-OCCLUSIVE DISEASE/SINUSOIDAL OBSTRUCTION SYNDROME (VOD/SOS) POST-CHEMOTHERAPY: A POST HOC ANALYSIS OF FINAL DATA OF AN EXPANDED-ACCESS PROTOCOL
Author(s): ,
Nancy Kernan
Affiliations:
Pediatric Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center,New York,United States
,
Paul Richardson
Affiliations:
Jerome Lipper Multiple Myeloma Center, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School,Boston,United States
,
Stephan Grupp
Affiliations:
Pediatric Oncology, The Children's Hospital of Philadelphia,Philadelphia,United States
,
Joseph Antin
Affiliations:
Stem Cell/Bone Marrow Transplantation Program, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute,Boston,United States
,
Yoav Messinger
Affiliations:
Children's Hospitals and Clinics of Minnesota,Minneapolis,United States
,
Wei Liang
Affiliations:
Jazz Pharmaceuticals, Inc.,Palo Alto,United States
,
Robert Ryan
Affiliations:
Jazz Pharmaceuticals, Inc.,Palo Alto,United States
,
Robin Hume
Affiliations:
Jazz Pharmaceuticals, Inc.,Palo Alto,United States
,
William Tappe
Affiliations:
Jazz Pharmaceuticals, Inc.,Palo Alto,United States
Robert Soiffer
Affiliations:
Center for Stem Cell Transplantation, Division of Hematologic Malignancy, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School,Boston,United States
(Abstract release date: May 18, 2017) EHA Learning Center. Grupp S. Jun 25, 2017; 182095
Stephan Grupp
Stephan Grupp

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Abstract
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Abstract: S808

Type: Oral Presentation

Presentation during EHA22: On Sunday, June 25, 2017 from 09:00 - 09:15

Location: Room N104

Background
Hepatic VOD/SOS, which may be unpredictable and potentially life-threatening, is typically considered a complication of hematopoietic stem cell transplantation (HSCT), and VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post-HSCT in the European Union and to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. However, VOD/SOS can occur after chemotherapy without HSCT.

Aims
To perform a post hoc analysis of final data on safety and response to defibrotide in patients developing VOD/SOS after primary chemotherapy without HSCT (off label).

Methods
In an expanded-access protocol for patients with VOD/SOS post-HSCT or chemotherapy, with or without MOD (renal and/or pulmonary dysfunction), defibrotide 25 mg/kg/d (4 divided doses of 6.25 mg/kg) was given a recommended ≥21 days after patients provided informed consent. Post-chemotherapy subgroup survival was analyzed post hoc from the day defibrotide was started (days 0–30 after start of chemotherapy) for 70 days (because follow-up data were collected for 100 days post-chemotherapy).

Results
Of 1154 VOD/SOS patients receiving defibrotide, 137 (12%) developed VOD/SOS post-chemotherapy without HSCT. Among the 82 patients (38 with MOD) treated with DF by day 30 after start of chemotherapy, median age was 7.5 years (range, 0–68 years) and 66 (81%) were pediatric patients (≤16 years of age). Among pediatric patients, 15% were age 0-23 months, 74% were 2-11 years and 11% were 12-16 years. Most common primary diseases were acute lymphocytic leukemia (51%), acute myeloid leukemia (13%), and neuroblastoma (6%). Kaplan-Meier estimated survival at Day +70 was 74% overall (95% CI, 63–82%); 66% (49–79%) in patients with MOD and 81% (66–90%) in patients without MOD. By age subgroup, Kaplan-Meier estimated survival at Day +70 was 80% (95% CI, 68–88%) in pediatric patients (Figure) and 50% (95% CI, 25–71%) in adults.

Adverse events (AEs) were reported in 54/82 patients (66%). Hemorrhagic AEs (≥2%) were pulmonary (6%), epistaxis or mouth (4%), and hematochezia (2%). There were 22 (27%) patients with AEs assessed as being at least possibly related to defibrotide, the most common (≥2%) were pulmonary or mouth hemorrhage (4% each) and hematochezia, nausea, encephalopathy, epistaxis, or hypotension (2% each). Related AEs led to discontinuation in 6 patients and were associated with 1 death (pulmonary hemorrhage, hypotension).

Conclusion
The 74% survival rate at Day +70 in patients with VOD/SOS receiving defibrotide within 30 days of starting chemotherapy (81% in patients ≤16 years) is clinically encouraging. Of note is the 66% survival rate in patients with MOD. The defibrotide safety profile was consistent with that previously reported in the overall population of this expanded-access protocol.

 Support: Jazz Pharmaceuticals

Session topic: 29. Infectious diseases, supportive care

Keyword(s): Veno-occlusive disease, Defibrotide, chemotherapy

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