Martin, Paul

Liver transplantation (LT) for alcohol associated hepatitis (AH) remains controversial. We convened a consensus conference to examine various aspects of LT for AH. The goal was not to unequivocally endorse LT for AH; instead, it was to propose recommendations for programs that perform or plan to perform LT for AH. Criteria were established to determine candidacy for LT in the setting of AH and included the following: (1) AH patients presenting for the first time with decompensated liver disease that are nonresponders to medical therapy without severe medical or psychiatric comorbidities; (2) a fixed period of abstinence prior to transplantation is not required; and (3) assessment with a multidisciplinary psychosocial team, including a social worker and an addiction specialist/mental health professional with addiction and transplantation expertise. Supporting factors included lack of repeated unsuccessful attempts at addiction rehabilitation, lack of other substance use/dependency, acceptance of diagnosis/insight with a commitment of the patient/family to sobriety, and formalized agreement to adhere to total alcohol abstinence and counseling. LT should be avoided in AH patients who are likely to spontaneously recover. Short‐term and longterm survival comparable to other indications for LT must be achieved. There should not be further disparity in LT either by indication, geography, or other sociodemographic factors. Treatment of alcohol‐use disorders should be incorporated into pre‐ and post‐LT care. The restrictive and focused evaluation process described in the initial LT experience for AH worldwide may not endure as this indication gains wider acceptance at more LT programs. Transparency in the selection process is crucial and requires the collection of objective data to assess outcomes and minimize center variation in listing. Oversight of program adherence is important to harmonize listing practices and outcomes.

Abstract Abstract 906 Background: Single-arm Phase 2 trials of DF in the treatment of severe VOD/MOF post-SCT demonstrated a complete response (CR) in 36–46% of patients (pts). A subsequent Phase 3 trial enrolling pts with more severe VOD (28%/24% with ventilator/dialysis dependence at study entry vs 5%/7%) demonstrated a CR of 24% compared to 9% in a matched Historical Control (HC); p=0.0148; Richardson ASH 2009). Given the life-threatening nature of VOD/MOF, DF was made available in the United States through a Treatment IND protocol (T-IND) in December 2007 to gather additional safety and response data. Methods: Pts were required to have a diagnosis of VOD based upon 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). Pts without a Baltimore diagnosis could enroll with biopsy-proven evidence of VOD. Eligibility criteria were expanded to permit patients with late onset VOD (VOD diagnosed after 21 days (d) or VOD/MOF after 28d post-SCT). Key exclusion criteria included clinically significant bleeding or need for >1 pressor to maintain BP. CR was defined as bilirubin < 2 mg/dL + resolution of MOF. Mortality was assessed at D+100. DF was given at 6.25 mg/kg IV q6h (25 mg/kg/d); treatment duration was recommended for at least 21d. Results: This interim analysis is based on 104 pts enrolled between14Dec2007-29Sep2009 and treated at 36 institutions. Most sites (n=23) enrolled only 1–2 pts. Nearly all pts (n=98) had undergone prior SCT; 6 had prior chemotherapy only; and 29 pts had late onset VOD post-SCT. Of the SCT pts, 69 pts enrolled in the T-IND met eligibility criteria for the original Phase 3 trial. Baseline demographics included median age 17 years (range 0.1 – 66); 59% male; and 16% with prior SCT. The most common diagnosis was leukemia (30% AML; 22% ALL; 7% other leukemia). The majority of pts had undergone allogeneic SCT (88%) with conditioning consisting of cyclophosphamide (76%), busulfan (42%) and/or TBI (41%). Mean onset of VOD post-SCT was 17 days. At entry, 20% of pts were dialysis dependent; 28% were ventilator dependent. Mean number of days of DF administration was 20 (range 2–88). Of the 104 pts, 36 (35%) achieved a CR by D+100. For the various sub-populations, the CR by D+100 rate was 24% for pts with late-onset VOD (n=29); 35% for those pts undergoing SCT (n=98); and 39% for the 69 pts who matched the entry criteria for the Phase 3 trial. Comparison of this group of 69 pts to the Phase 3 HC showed a statistically improved outcome (p=0.0007). Similar to the Phase 3 results, the CR rate was higher in pts who were not on dialysis/ventilator at study entry (41% vs 23%). Although children had previously been noted to have a higher CR rate in prior studies, the CR rate in the T-IND was similar in children compared to adults (35% and 34%, respectively). Overall D+100 mortality rate equaled 61% (n=104). Comparing the 69 pts who met Phase 3 entry criteria, D+100 mortality was 58% (p=0.0465 compared to the HC using Kaplan Meier estimates by log-rank analysis). Toxicity proved manageable: 11 pts experienced a total of 13 drug-related AEs including pulmonary hemorrhage (n=5), GI hemorrhage (n=3), hypotension (n=2), rectal hemorrhage, cerebral hemorrhage and pulmonary alveolar hemorrhage (1 pt each). Overall, 10% of pts experienced a drug-related toxicity that led to discontinuation. Similar to the observation of decreased GvHD in pediatric pts undergoing SCT who received prophylactic DF compared to best supportive care, the incidence of all grade GvHD was relatively low (8%). Conclusions: In 104 pts with severe VOD/MOF enrolled at 36 US institutions, use of DF demonstrated a 35% CR by D+100. Comparing those pts who met criteria for the Phase 3 trial to the HC used in that study, D+100 CR and survival were significantly improved in this study population. DF-associated toxicities are consistent with prior studies. Following an amendment in 30Sep2009, entry criteria for the T-IND study were expanded to permit enrollment of pts without SCT (VOD post chemotherapy) as well as pts without MOF to evaluate earlier intervention. Analysis of this group will be performed separately. Enrollment into the T-IND study continues. Disclosures: Richardson: Gentium: Membership on an entity's Board of Directors or advisory committees. Massaro:Gentium: Consultancy. Hannah:Gentium: Consultancy. Iacobelli:Gentium: Employment.

Abstract Abstract 487FN2 Background: Given the life-threatening nature of severe VOD (sVOD) and multi-organ failure (MOF), DF was made available in the US through a prospective treatment IND protocol (T-IND) to gather additional safety and response data from SCT patients (pts) with sVOD who were not eligible for a pivotal Phase 3 trial. Following completion of this Phase 3 trial, the T-IND protocol has continued and been amended to include pts who would have met eligibility criteria for the completed phase 3 trial, as well as pts with non-severe VOD and non-SCT pts who develop VOD after chemotherapy (chemo). This is the largest prospective evaluation of DF for the treatment of sVOD/MOF post SCT and non-SCT pts to date. Methods: Pts were initially required 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) that followed SCT. Following treatment of 104 pts, an amendment expanded eligibility criteria to include pts with VOD after chemo and pts with non-severe VOD (defined as no MOF). Key exclusion criteria included clinically significant bleeding or >1 pressor to maintain BP. CR was defined as bilirubin < 2 mg/dL + 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 treatment duration recommended for at least 21d. Results: This interim analysis is based on 269 pts enrolled between December 2007 and March 2011 at 67 centers. Nearly all pts (n=251) had undergone SCT (with allogeneic SCT in 225, 90%); 18 developed VOD after chemo alone. Of the 269 cases of VOD, 200 were severe at study entry, with 25% (66/269) of all pts dialysis dependent and 31% (83/269) ventilator dependent. Median age was 16 years (range 0.1 – 70); 55% were male. In the SCT pts, the most common diagnosis was leukemia (29% AML; 22% ALL; CML 3%; 4% other), with conditioning of CY (71%), BU (46%) and TBI (38%) respectively; 18% had undergone multiple SCTs (>1 SCT). Median onset of VOD was 15 d post-SCT. When presenting after chemo alone (n=18), median onset of VOD was 16 d after the first dose, most frequently after CY (61%), cytarabine (44%) and vincristine (39%), and for treatment of leukemia (AML 33%, ALL 33%, other 6%). Overall mean number of days of DF administration in all pts was 22 (range 1–88).Of 269 pts, 32% (85/269) achieved a CR and 50% [ by Kaplan-Meier estimate] survived to D+100. In the subgroup of SCT pts, 31% (78/251) achieved CR and 50% survived to D+100; 134 pts met entry criteria for the original Phase 3 trial and comparison to the Phase 3 historical control showed a statistically improved outcome in CR (30% vs 9%, p=0.0006) and D+100 survival (46% vs 25%; p=0.006). Of 200 pts with sVOD, CR was 28% and D+100 survival was 44%. In the 18 chemo only pts, CR was 39% and D+100 survival was 50%. CR rate and D+100 survival for the 69 pts with non-severe VOD were 42% and 62%, respectively. Delay of >2 d (vs < 2 d) in the start of DF after VOD diagnosis resulted in reduced CR (23% vs 35%, p=0.0339) and survival (37% vs 56%, p=0.01). Children as compared to adults had higher rates in CR (35% vs 29%) and survival (55% vs 43%). Toxicity proved generally manageable: 22% of pts experienced a total of 81 related AEs, primarily consisting of hemorrhage (19%) and hypotension (4%). Hemorrhage included pulmonary bleeding (6%), GI hemorrhage (3%), epistaxis (3%) and hematuria (3%). Similar to the observation of decreased GvHD in other studies, the incidence of all grade GvHD in the allogeneic SCT pts was 8%. Conclusions: In 269 pts with mainly sVOD/MOF, DF therapy achieved significantly improved outcome compared to an untreated historical control. Importantly, CR and survival were improved in pts who were treated within 2d of VOD diagnosis (vs. later) and in pts who had not yet progressed to sVOD. As with prior studies, there was a low incidence of DF-associated toxicities. Interestingly, the incidence of GvHD in allo-SCT pts was low, consistent with the reduction of GvHD seen in the large randomized EBMT pediatric prevention study. These results confirm the findings of previous trials and strongly support early intervention with DF once the diagnosis of VOD is made after SCT, as well as its use in pts who have not progressed to advanced MOF. The use of DF for VOD following intensive chemotherapy without SCT also appears promising, but more research in this patient population is needed. Enrollment to the T-IND study continues. Disclosures: Richardson: Gentium: Membership on an entity's Board of Directors or advisory committees. Arai:Gentium: Research Funding. Symons:Otsuka Pharmaceuticals: Research Funding. Martin:Gentium: Research Funding. Massaro:Gentium: Consultancy. D'Agostino:Gentium: Membership on an entity's Board of Directors or advisory committees. Hannah:Gentium: Consultancy. Tudone:Gentium: Employment. Hume:Gentium: Employment. Iacobelli:Gentium SpA: Employment. Soiffer:Gentium: Honoraria.