Results Of The Large Prospective Study On The Use Of Defibrotide (DF) In The Treatment Of Hepatic Veno-Occlusive Disease (VOD) In Hematopoietic Stem Cell Transplant (HSCT). Early Intervention Improves Outcome - Updated Results Of a Treatment IND (T-IND) Expanded Access Protocol

Given the life-threatening nature of severe VOD (sVOD) and associated multi-organ failure (MOF), the absence of other approved therapies for this complication in the USA, and the promising results to date with DF in this setting, DF has been made available since 2007 through a prospective T-IND. The aim of the T-IND is to gather additional data on safety and response to DF in a broader patient (pt) population, including those with sVOD/MOF and those with non-severe VOD. Thus far, this is the largest prospective evaluation of DF for the treatment of sVOD/MOF in pts undergoing HSCT, and in pts who developed VOD following chemotherapy (non-HSCT pts). Here we provide an update on the efficacy and safety of DF in HSCT and non-HSCT pts, together with analysis of other clinical features of interest, including GvHD.

The original T-IND protocol required pts to have a diagnosis of VOD by Baltimore criteria (total bilirubin ≥2.0 mg/dL with ≥2 of the following: hepatomegaly, ascites or 5% weight gain) with MOF (either renal and/or pulmonary failure) following HSCT, and was amended to allow inclusion of pts with non-severe VOD (defined as no MOF) occurring either post-HSCT and post-chemotherapy. Key exclusion criteria included clinically significant bleeding or the need for >1 vasopressor. Complete response (CR) was defined as bilirubin <2 mg/dL plus resolution of MOF (if applicable). Mortality was assessed at Day +100 (D+100) in all pts. DF was given at 6.25 mg/kg IV q6h (25 mg/kg/d) with recommended treatment duration of at least 21 days (d).

The current interim analysis is based on 470 VOD pts enrolled between December 2007 and December 2012 at 75 centers, 45 of which developed VOD following chemotherapy and 425 had undergone HSCT (376 allogeneic HSCT, 89%). In HSCT patients, median age was 15 yrs (range 0.1–70), 55% were male and 18% had undergone multiple HSCTs (>1 HSCT); 284 pts had severe disease at study entry. The most common diagnosis was leukemia (29% AML; 22% ALL; 6% other). Conditioning regimen included CY (66%), BU (50%) and TBI (36%). Median onset of VOD was 15 d post-HSCT. Of HSCT pts, 35% (147/425) achieved CR and 55% (Kaplan-Meier estimate) survived to D+100. In pts with sVOD, CR was 29% and D+100 survival was 48%. For pts with non-severe VOD, CR and D+100 survival was 47% and 69%, respectively. In all HSCT pts, delay of >2 d (vs ≤2 d) in the start of DF after VOD diagnosis resulted in reduced CR (25% vs 39%, p=0.0052) and survival (Kaplan-Meier estimate) (38% vs 61%, p<0.0001). Children (≤16 years) as compared to adults had higher CR rates (41% vs 27%, p=0.0038) and better survival (60% vs 49%, p=0.0203). In the 45 non-HSCT patients, median age was 8 yrs (range 0.1–63), and 53% were male; the most common diagnosis was ALL (33%) and AML (22%). Cyclophosphamide (49%), vincristine (44%) and cytarabine (33%) were the most frequent chemotherapeutic agents associated with VOD. Median onset of VOD after chemotherapy was 14 d, and sVOD was present in 53% of pts at study entry. Of non-HSCT pts, 40% (18/45) achieved CR and 62% were alive at D+100. Toxicity proved generally manageable: 23% of pts experienced at least one related AE, primarily consisting of hemorrhage including pulmonary bleeding (6%), GI hemorrhage (7%), epistaxis (3%), hematuria (2%), and hypotension (4%). Similar to the observation of decreased GvHD in other studies, the incidence of all grade GvHD in the allogeneic HSCT pts was low at 11%.

DF therapy in sVOD/MOF pts achieved significantly improved outcome compared to that expected based upon historical data. Given the results of this large cohort of pts, early treatment with DF (i.e. within 2 d of VOD diagnosis) is recommended, and consistently improved outcome was seen in pts who have not yet progressed to sVOD. Generally, DF was well-tolerated and as with prior studies, there was a low incidence of DF-associated toxicities. These results confirm the findings of previous trials and strongly support early intervention with DF once the diagnosis of VOD is made after HSCT, which also reinforces the validity of positive studies in prophylaxis to date and suggests further trials in prevention are warranted. Outcomes in children appear to be better than in adults, supporting the importance of this agent in the pediatric population in particular. In addition, low rates of GvHD were seen and this is an important area in which further studies are planned. Enrollment to the T-IND study continues.

Richardson:Gentium : Membership on an entity’s Board of Directors or advisory committees. Hannah:Gentium: Consultancy. Hume:Gentium: Employment. Bandiera:Gentium: Employment. Heringa:Gentium: Employment. Study Group:Gentium: Employment.