Evaluation of Defibrotide (DF) in the Treatment of Hepatic Veno-Occlusive Disease (VOD) in Non-Stem Cell Transplant (non-SCT) Chemotherapy Patients (pts): Results From the Treatment IND (T-IND) Expanded Access Protocol and the Compassionate Use Program (CUP).

Given the potentially life-threatening nature of hepatic VOD, the lack of approved treatments for this disease and the increasing evidence indicating that DF leads to improved outcome, DF has been made available on a compassionate use basis for almost a decade and more recently via prospective expanded access programs. Although VOD is most frequent in pts post-SCT, it can be induced by chemotherapy alone. The CUP and T-IND have collected safety and outcome information from a broader pt population (n=1129 and n=333, respectively), including non-SCT pts who developed both non-severe and severe (sVOD) after chemotherapy. Demographics and results from this non-SCT population from the CUP and from an interim analysis of the T-IND are presented.

CUP pts met VOD diagnosis with at least two of the following criteria: bilirubin >2mg dL, hepatomegaly and/or ascites or an unexplained weight gain of >5%. The T-IND pts met similar criteria but required the presence of elevated bilirubin with two other criteria. Pts had non-severe and sVOD, with sVOD defined as multi-organ failure (MOF; including renal or pulmonary failure in the T-IND or additionally CNS dysfunction in the CUP). Key exclusion criteria included clinically significant bleeding/severe coagulopathy or hemodynamic instability. DF was given at 25 mg/kg/d IV (in the CUP, dosing ranged 10–80 mg/kg/day, with median dosing 25 mg/kg/d) for a minimum of 14–21 days. 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.

The current analysis is based on a total of 89 pts who developed VOD after chemotherapy (chemo) alone: 61 pts in the CUP and 28 pts in the T-IND. Pts were enrolled in CUP between December 1998 and March 2009; median age was 14 years (range 0.2–65) and 66% were male. In the T-IND the chemo pts were enrolled from December 2009 to September 2011; median age was 8 years (range 0.2–58) and 50% were male. The most common diagnosis was ALL (36% and 32%) and AML (30% and 25%) in the CUP and T-IND, respectively. Vincristine, cytarabine and cyclophosphamide were the most frequent chemotherapeutic agents associated with VOD, and with the exception of cyclophosphamide, their prior exposure was relatively similar between arms: pts in the CUP and in the T-IND, respectively, were treated with vincristine (31% and 46%), cytarabine (25% and 39%), and cyclophosphamide (16% and 61%). Median onset of VOD after chemotherapy was 19 days and 16 days in the CUP and T-IND, respectively, and sVOD was present in 46% and 50% of pts at study entry in the CUP and T-IND, respectively.

Overall, 53% (47/89) of pts achieved CR, with 53% (25/47) of pts with non-severe VOD achieving CR and 52% (22/42) of pts with sVOD achieving CR. Overall, 68% and 67% of pts were alive at D+100 (Kaplan-Meier estimate) in the CUP and T-IND, respectively, 65% and 69% of pts with non-severe VOD were alive at D+100 in the CUP and T-IND, respectively, and 72% and 64% of pts with sVOD alive at D+100 in the CUP and T-IND, respectively. When VOD outcomes were compared to the SCT population of the T-IND (Richardson PG, et al. Blood [ASH Annual Meeting Abstracts] 2011;118:487), CR was 43% in non-SCT pts vs 30% in SCT and survival was 68% vs 50%, respectively.

Toxicity proved generally manageable: 24% of pts experienced a total of eight related AEs, primarily consisting of hemorrhage (21%) and hypotension (3%). Hemorrhage included pulmonary bleeding (7%), epistaxis (7%) and GI hemorrhage (3%).

Demographic and outcome data for VOD, a frequent and life-threatening complication of SCT, has been documented from a population of 89 pts following intensive chemotherapy alone. These pts were most frequently diagnosed with ALL and AML and recipients of vincristine, cytarabine or cyclophosphamide-based chemotherapy. The use of DF for VOD, which has been shown to improve CR and survival in SCT pts, is also associated with better outcomes in pts who have not undergone transplant. Generally, DF was well-tolerated and as with prior studies, there was a low incidence of DF-associated toxicities. The use of DF in VOD following intensive chemotherapy without SCT appears promising, but more research in this predominantly pediatric patient population is needed. Enrollment to the T-IND study for this important subgroup of pts continues.

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