Stephan A. Grupp, MD, Ph.D., Cell Therapy and Transplant Section, The Children’s Hospital of Philadelphia speaks about the ASH 2021 Abstract – 749 A Phase 3, Randomized, Adaptive Study of Defibrotide (DF) Vs Best Supportive Care (BSC) for the Prevention of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) in Patients (pts) Undergoing Hematopoietic Cell Transplantation (HCT): Preliminary Results.
Link to Abstract:
https://ash.confex.com/ash/2021/webprogram/Paper147284.html
Introduction:
A potentially life-threatening consequence of HCT is hepatic VOD/SOS. If left untreated, VOD/SOS with multiorgan dysfunction/multiorgan failure (MOD/MOF) has a death risk of >80%. In the US, DF is approved for VOD/SOS with renal or pulmonary failure after HCT, while in the EU, it is approved for severe VOD/SOS after HCT in patients older than one month. A recent meta-analysis of over 1000 patients, including a phase 3 study in high-risk pediatric patients, found that prophylactic DF dramatically reduced the risk of VOD/SOS compared to controls. The efficacy and safety of DF vs. BSC for preventing VOD/SOS in patients undergoing HCT and at high risk of developing VOD/SOS were compared in this phase 3 research.
Methods:
Patients aged >1 month who were planned to undergo allogeneic (adult/pediatric pts) or autologous HCT (pediatric pts) who were at high risk of experiencing VOD/SOS were enrolled in this trial (NCT02851407). Patients with advanced-stage neuroblastoma or one hepatic-related EBMT risk factor underwent myeloablative conditioning (MAC). Patients with osteopetrosis or hemophagocytic lymphohistiocytosis (or a kindred condition) who were undergoing MAC, or who had previously received an ozogamicin-containing monoclonal antibody, or who had class III high-risk thalassemia, were considered very high-risk. Patients who received rapamycin for GvHD prevention were not included in the high-risk group. According to institutional norms, eligible patients were randomly assigned to either DF prophylaxis (IV DF 25 mg/kg/day for up to 21 days With BSC) or BSC. Investigators diagnosed VOD/SOS using modified Seattle criteria, which were then assessed by an Endpoint Adjudication Committee (EPAC) utilizing a blinded procedure. Pts who developed VOD/SOS were given DF till the VOD/SOS and linked MOD/MOF disappeared.
VOD/SOS-free survival by Day 30 post-HCT, as measured by EPAC, was the main goal. VOD/SOS-free survival by Day 100 post-HCT and VOD/SOS incidence by Day 30 were secondary objectives. VOD/SOS-free survival by Day 30 post-HCT was also analyzed by the investigator.
Results:
Overall, 372 participants were enrolled: 190 in the DF group (median age [range]: 13.0 [0, 72] years) and 182 in the BSC group (median age [range]: 13.0 [0, 72] years) (median age [range]: 15.0 [0, 69]). Acute lymphoblastic leukemia (26 percent vs. 28 percent), acute myeloid leukemia (27 percent vs. 24 percent), and neuroblastoma were the most common primary illnesses (14 percent vs 17 percent ). According to EPAC, the DF and BSC groups had similar Kaplan-Meier (KM)-estimated VOD/SOS-free survival by Day 30 (primary endpoint: 67 percent [95 percent Cl: 58, 74 percent] vs 73 percent [95 percent Cl: 62, 80 percent], respectively; P = 0.85) and at Day 100 (50 percent [95 percent Cl: 26, 70 percent] vs 57 percent [95 percent Cl: 37, The DF group had an 85 percent (95 percent Cl: 79, 90 percent) VOD/SOS-free survival rate by Day 30 (hazard ratio = 0.760 [95 percent CI: 0.450, 1.29]; nominal P = 0.14) and the BSC group had an 80 percent (95 percent Cl: 73, 86 percent) VOD/SOS-free survival rate by Day 30 (hazard ratio = 0.760 [95 percent CI: 0.450, 1.29]; nominal P = In 28% of VOD/SOS assessments, the EPAC and investigators disagreed. EPAC had identified VOD/SOS more frequently in both groups than investigators by Day 30 post-HCT. EPAC diagnosed 50 patients with VOD/SOS, but investigators did not; investigators identified 4 patients with VOD/SOS, but EPAC did not.
A similar percentage of patients in the DF and BSC groups (99 percent and 100 percent, respectively) experienced adverse events (AEs); the most common (>50 percent of pts) were pyrexia (61 percent and 64 percent), nausea (60 percent and 56 percent), diarrhea (58 percent and 61 percent), stomatitis (58 percent and 67 percent), and vomiting (58 percent and 67 percent) (57 percent and 52 percent ). In the DF and BSC groups, serious adverse events (SAEs) occurred in 45 percent and 43 percent of patients, respectively; AEs/SAEs reflected HCT. The DF and BSC groups had similar rates of AEs of special interest (AESI) (hypersensitivity reactions [50 percent and 45 percent, respectively], pulmonary hemorrhage [24 percent and 26 percent ], and GI bleeding [9 percent and 8 percent ]). AEs that resulted in mortality occurred in 6% of patients in each group.
Conclusions:
The primary endpoint, as measured by EPAC, showed no significant difference between the DF-treated and BSC groups; other endpoints supported this conclusion. The same percentage of patients reported AEs, SAEs, and AESIs, indicating that DF is safe in this scenario. There were no new safety signals discovered. Significant discrepancies between EPAC’s and investigators’ assessments of VOD/SOS underscore the difficulties in VOD/SOS diagnosis and muddle interpretation of the findings. Differences between the study sample and actual clinical practice, such as a lack of representation of some at-risk populations, could make it even more difficult to interpret these results.