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Traumatic brain injury (TBI) is a global health problem, for which there are no approved therapies. Advances in acute clinical care have improved post-TBI survival, yet many patients are left with chronic TBI-related disabilities (i.e. chronic TBI). Existing treatments that focus on rehabilitation and symptom management do not modify the disease and have limited effectiveness. Consequently, chronic TBI-related disabilities remain a significant unmet medical need. Cell therapies have neuroprotective and neurorestorative effects which are believed to modify the disease. In this article, we review the safety and efficacy of cell therapies in early-phase clinical studies that have shown potential to improve outcomes in acute to chronic phases of TBI.

To determine minimally clinically important differences (MCIDs) for Disability Rating Scale (DRS), Fugl-Meyer Upper Extremity Subscale (FM-UE), Fugl-Meyer Lower Extremity Subscale (FM-LE), and Fugl-Meyer Motor Scale (FMMS) in patients with chronic motor deficits secondary to traumatic brain injury (TBI).Retrospective analysis from the 1-year, double-blind, randomized, surgical sham-controlled, Phase 2 STEMTRA trial (NCT02416492), in which patients with chronic motor deficits secondary to TBI (N = 61) underwent intracerebral stereotactic implantation of modified bone marrow-derived mesenchymal stromal (SB623) cells. MCIDs for DRS, FM-UE, FM-LE, and FMMS were triangulated with distribution-based, anchor-based, and Delphi panel estimates.Triangulated MCIDs were: 1) -1.5 points for the Disability Rating Scale; 2) 6.2 points for the Fugl-Meyer Upper Extremity Subscale; 3) 3.2 points for the Fugl-Meyer Lower Extremity Subscale; and 4) 8.4 points for the Fugl-Meyer Motor Scale.For the first time in the setting of patients with chronic motor deficits secondary to TBI, this study reports triangulated MCIDs for: 1) DRS, a measure of global outcome; and 2) Fugl-Meyer Scales, measures of motor impairment. These findings guide the use of DRS and Fugl-Meyer Scales in the assessment of global disability outcome and motor impairment in future TBI clinical trials.

ObjectiveTo determine whether chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow–derived mesenchymal stromal/stem cells (SB623).MethodsThis 6-month interim analysis of the 1-year double-blind, randomized, surgical sham–controlled, phase 2 Stem Cell Therapy for Traumatic Brain Injury (STEMTRA) trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multicenter trial (n = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, or 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (n = 61), and efficacy was assessed in the modified intent-to-treat population of randomized patients who underwent surgery (n = 61; SB623 = 46, control = 15).ResultsThe primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (least square [LS] mean) 8.3 (standard error 1.4) vs 2.3 (standard error 2.5) for control at 6 months, the LS mean difference was 6.0 (95% confidence interval 0.3–11.8, p = 0.040). Secondary efficacy endpoints improved from baseline but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25).ConclusionsSB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls.ClinicalTrials.gov Identifier:NCT02416492.Classification of EvidenceThis study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of conditioning during hematopoietic stem cell transplantation (HSCT) or chemotherapy without HSCT, with a historically reported mean incidence of 13.7% post-HSCT. Typical symptoms of VOD/SOS may include hyperbilirubinemia, painful hepatomegaly, weight gain, and ascites. Defibrotide, a polydisperse mixture of predominantly single-stranded polydeoxyribonucleotides, is currently the only therapy approved to treat hepatic VOD/SOS with pulmonary/renal dysfunction (ie, multiorgan dysfunction/multiorgan failure [MOD/MOF]) following HSCT in the United States and to treat severe hepatic VOD/SOS post-HSCT in the European Union. In preclinical and human studies, defibrotide has demonstrated profibrinolytic, antithrombotic, anti-inflammatory, and angio-protective actions, thus promoting an anticoagulant phenotype of the endothelium that protects and stabilizes the function of endothelial cells. In a phase 3, historically controlled, multicenter trial in adults and children with VOD/SOS and MOD/MOF (defibrotide: n = 102; controls treated before defibrotide availability: n = 32), defibrotide resulted in significantly greater day +100 survival following HSCT (38.2%) vs controls (25.0%; propensity analysis-estimated between-group difference: 23%; P = .0109). The most common adverse events (AEs) were hypotension and diarrhea; rates of common hemorrhagic AEs were similar in the defibrotide and historical control group (64% and 75%, respectively). In a phase 3 prophylaxis trial, defibrotide was found to lower incidence of VOD/SOS in children (not an approved indication) and reduce the incidence of graft-versus-host disease. This review describes the development and clinical applications of defibrotide, focusing on its on-label use in patients with VOD/SOS and MOD/MOF after HSCT.

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a progressive, potentially fatal complication of conditioning for haematopoietic stem cell transplant (HSCT). The VOD/SOS pathophysiological cascade involves endothelial-cell activation and damage, and a prothrombotic-hypofibrinolytic state. Severe VOD/SOS (typically characterized by multi-organ dysfunction) may be associated with >80% mortality. Defibrotide is approved for treating severe hepatic VOD/SOS post-HSCT in the European Union, and for hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States. Previously, defibrotide (25 mg/kg/day in 4 divided doses for a recommended ≥21 days) was available through an expanded-access treatment protocol for patients with VOD/SOS. Data from this study were examined post-hoc to determine if the timing of defibrotide initiation post-VOD/SOS diagnosis affected Day +100 survival post-HSCT. Among 573 patients, defibrotide was started on the day of VOD/SOS diagnosis in approximately 30%, and within 7 days in >90%. The relationship between Day +100 survival and treatment initiation before/after specific days post-diagnosis showed superior survival when treatment was initiated closer to VOD/SOS diagnosis with a statistically significant trend over time for better outcomes with earlier treatment initiation (P < 0·001). These results suggest that initiation of defibrotide should not be delayed after diagnosis of VOD/SOS.

Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multiorgan failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin level > 2.0 mg/dL by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any noninfectious pulmonary abnormality. Patients with severe VOD were divided into 2 groups for analysis: those treated with defibrotide (n = 41) and those not treated with defibrotide (n = 55). Patients in the nondefibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival rate at day +100 was 39% (95% CI, 24.8% to 54.3%) in patients receiving defibrotide and 30.9% (95% CI, 19.5% to 43.6%) in those not receiving defibrotide. Resolution rate of VOD at day +100 was 51% in the defibrotide group and 29% in the nondefibrotide group (difference, 22.1%; 95% CI, 2.6% to 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD.

Sinusoidal obstruction syndrome (SOS) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT) associated with significant morbidity and mortality. Healthcare utilization, costs, and mortality were assessed in HSCT patients diagnosed with SOS, with and without multi-organ dysfunction (MOD).This retrospective observational study identified real-world patients undergoing HSCT between January 1, 2009 and May 31, 2014 using the Premier Healthcare Database. In absence of a formal ICD-9-CM diagnostic code, SOS patients were identified using a pre-specified definition adapted from Baltimore and Seattle criteria and clinical practice. Severe SOS (SOS/MOD) and non-severe SOS (SOS/no-MOD) were classified according to clinical evidence for MOD in the database.Of the 5,418 patients with a discharge diagnosis of HSCT, 291 had SOS, with 134 categorized as SOS/MOD and 157 as SOS/no-MOD. The remaining 5,127 patients had HSCT without SOS. Overall SOS incidence was 5.4%, with 46% having evidence of MOD. Distribution of age, gender, and race were similar between the SOS cohorts and non-SOS patients. After controlling for hospital profile and admission characteristics, demographics, and clinical characteristics, the adjusted mean LOS was 31.0 days in SOS/MOD compared to 23.9 days in the non-SOS cohort (medians = 26.9 days vs 20.8 days, p .001). The adjusted mean cost of SOS/MOD patients was $140,653, which was $41,702 higher than the non-SOS cohort (medians = $105,749 vs $74,395, p .001). An almost 6-fold increased odds of inpatient mortality was associated with SOS/MOD compared to the non-SOS cohort (odds ratio = 5.88; 95% CI = 3.45-10.33).Limitations of retrospective observational studies apply, since the study was not randomized. Definition for SOS was based on ICD-9 diagnosis codes from a hospital administrative database and reliant on completeness and accuracy of coding.Analysis of real-world data shows that SOS/MOD is associated with significant increases in healthcare utilization, costs, and inpatient mortality.

Background Bapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease. Methods We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) e4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. Results There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE e4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE e4 allele carriers but not in noncarriers. Conclusions Bapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE e4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).

Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (≤16 years) and adult (>16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was generally well tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MOD symptoms, the most commonly reported treatment-emergent adverse event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD.

e15614 Background: CAR-T cells has emerged as novel cancer treatment, particularly for hematologic malignancies. However, treatment of solid tumors using redirected T-cells remains challenging. We developed a novel T-cell platform ET140202 targeting AFP/MHC complex enhanced by GPC3-guided co-stimulation. Herein we report a case study of ET140202 for a male subject with 3 liver HCC lesions, multiple lung metastases and with no response to sorafenib and regorafenib. Methods: The schedule and dose of ET140202 T cell infusion was summarized in Fig 1a. The subject received 16 i.v. infusions of ET140202 T cells at doses ranging from 0.42-6 ×106 cells/kg, totaling 2.461×109 cells. Vital signs, blood cell count, and blood chemistry were monitored on Days 1, 3, 7, and 14. Clinical responses were assessed at Month 1, 3, 5, 9 and 12. Results: T-cell expansion was observed shortly after each infusion. No treatment-related Grade 3 or higher AEs observed. Grade 1 or 2 events that were possibly attributable to therapy included dry mouth, dry skin peeling from hand and foot, and voice hoarseness and oral mucosal ulceration. All events resolved in 3-5 days with symptomatic treatment. At Day 40, the subject developed Grade 2 mucositis, which improved in 5 days following vitamin C treatment and oral hygiene care. The subject did not experience any signs of CRS or neurotoxicity. Cytokines including IL-2, IL-6, GM-CSF, INFg and TNFa were below detection at most time points post-infusion. All 3 liver lesions regressed at month 5 and the regression persisted to the last follow-up timepoint at month 12. All 4 lung nodules appeared to slightly increase in size at month 1, which may be attributed to pseudo-progression and substantially decreased at month 5. The decrease of the lung lesions also persisted to month 12. AFP levels were increased above the baseline shortly after T-cell infusion, possibly due to the lysis of tumor and gradually decreased to the normal level of 10 ng/mL on Day 135 and persisted to the last follow-up on day 365. Conclusions: ET140202 T cells has the potential to be used safely and effectively in AFP+/HLA-A2+ HCC to induce regression of primary and metastatic lesions.

e18540 Background: CML can progress to blast crisis in which the disease behaves like an acute leukemia. A novel chimeric T-cell therapy ET019002 is built upon Eureka Therapeutics ARTEMIS platform and co-expressed with an additional anti-CD19 scFv fused to the CD28 protein. ET019002 demonstrated superior preclinical anti-tumor activities to the classical anti-CD19 CAR-T cells. Herein we describe the first-in-human clinical study of ET019002 in a blast crisis of CML subject with T315I mutation, breast, skin, nasal sinus, liver, CNS involvement and heavily previous lines of therapy. Methods: The subject received infusions of ET019002 T cells at the dose of 1x106 receptor+ T cells/kg on Day 0, 66 and 122. The primary objective is safety and the secondary objectives include ET019002 T-cell engraftment and anti-tumor efficacy. Results: The subject developed a transient fever and chills with a maximum temperature of 40.2°C 4 days post the 1st infusion. Fever was resolved within 3 days after giving NSAIDs. No inflammatory cytokines except IL-6 were elevated during the study. IL-6 elevated 4 days post the 1st infusion, reached peak level at 507.18 pg/ml on Day 6 and decreased to 37 pg/ml on Day 8. This was not seen after the 2nd and the 3rd infusion. Lumps from breast and skin disappeared and the enlarged liver and spleen were back to normal size. Bone marrow biopsy at day 12 showed lymphoblast cells were significantly decreased from baseline of 38% to the level of 1%. The leukemic cells in cerebrospinal fluid were cleared on Day 14. The copy number of tumor-related fusion gene BCR-ABL/ABL was reduced from 1.489 x 100 to 3.942 x 10-5. However, 2 months post the 1st infusion, BCR-ABL/ABL rebounded to 3.795 x 10-4. The 2nd infusion showed no effect on the relapse of the leukemia in molecular level. The 3rd infusion resulted in CR which relapsed 1 month post the infusion. Flow cytometry analysis showed the loss of CD19 on the leukemic cells. Conclusions: Repeated infusion of autologous ET019002 was safe and achieved a three-month CR after the ET019002 T cells therapy, which could provide a window for the patient to receive curative therapies such as bridging allogeneic hematopoietic stem cells. Clinical trial information: NCT03642496.

e14013 Background: Despite the success in hematological malignancies, immunotherapy of solid tumors using redirected T cells such as CAR-T remains challenging due to the lack of a unique tumor antigen, inefficient trafficking of CAR T cells to tumor sites and the presence of immunosuppressive tumor microenvironment. ET140202 is a novel T-cell platform that targets AFP/MHC complex with GPC3-guided co-stimulation aiming to improve the specificity and efficacy. Herein we report a case study of ET140202 for a subject with AFP+ recurrent HCC previous treated with surgery and 2 TACE therapies. Baseline imaging showed multiple nodules on segment 7 of right lobe with enlarged lymph nodes in hepatic hilar region. Methods: From 9/25/18 to 1/29/19 the subject first received 2 intra-hepatic artery infusions (i.a.) of ET140202 T cells at the dose of 3×106 cells/kg followed by 4 i.v. infusions at the dose of 6×106 cells/kg. No lymphodepleting chemotherapy was given prior to T-cell infusion. Vital signs, blood cell count, and blood chemistry were monitored on Days 1, 3, 7, and 14. Clinical responses were assessed at Month 1, 2, 3, 4, 6, 9, 12 and 24. Results: Vital signs are normal after each infusion. No treatment-related Grade 2 or higher AEs observed. Grade 1 events that were possibly attributable to therapy included transient elevation of AST and bilirubin 58 days post the 1st infusion. Both events resolved in 4 days without treatment. The subject did not experience any clinical signs of CRS or neurotoxicity. Month 1, 2, and 3 follow-ups showed that the number and size of the liver nodules slowly increased overtime. Month 4 follow-up showed that the size of liver nodules decreased more than 50% of baseline and resulted in PR based on RECIST criteria. The AFP level elevated in the subject after infusion and reached the peak of 2097 ng/mL 55 days post 1st infusion, gradually dropped to 905 ng/mL on day 67, elevated to the 2nd peak of 2660 ng/mL and gradually decreased to 1235 ng/mL at the last follow-up on day 130. Conclusions: Repeated infusion of ET140202 T cells via i.a. and i.v. routes is safe and shows early sign of efficacy 4 months post initiation of the treatment in AFP+/HLA-A2+ HCC subject.

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable and potentially fatal complication of hematopoietic cell transplantation (HCT) or nontransplantation-associated chemotherapy/radiotherapy. In cases of severe hepatic VOD/SOS, typically defined by associated multiorgan failure (MOF, also known as multiorgan dysfunction), mortality exceeds 80%. Preclinical and early clinical data have provided a rationale for defibrotide treatment in hepatic VOD/SOS. Based on this evidence and in recognition of the dismal prognosis for these patients, defibrotide was made available through an international multicenter compassionate-use program conducted from December 1998 to March 2009. Physicians participating in the program voluntarily provided demographic and outcome data for patients given defibrotide. Efficacy and safety analyses were performed using the data received for 710 treated patients. Defibrotide was given at 10, 25, 40, 60, or 80 mg/kg/day for a median of 15 days (range, 1 to 119 days). By Kaplan-Meier analysis, the estimated overall day +100 survival was 54% (58% in the 25 mg/kg/day dose group). Adverse events (AEs) were reported in 53% of patients. The most common AEs were MOF, progression of hepatic VOD/SOS, sepsis, and graft-versus-host disease, which were consistent with the AEs expected for this patient population. No clinically meaningful trends in AEs were identified by gender, age, or dose group. Safety and efficacy results were consistent with prior studies of defibrotide in hepatic VOD/SOS, and subgroup analyses lend support to the use of the 25 mg/kg/day dose. (C) 2016 American Society for Blood and Marrow Transplantation.

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n = 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day +100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8;P= .0109, using a propensity-adjusted analysis). Observed day +100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6;P= .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%]) was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day +100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This trial was registered at www.clinicaltrials.gov as #.

Although Remicade (infliximab) is costly relative to non-biologic therapy, its impact on healthcare resource utilization and mucosal healing may make it a cost-effective option. This study aimed to compare gastrointestinal (GI)-related healthcare resource utilization and severity of mucosal damage before and during infliximab therapy in Crohn's disease (CD) or ulcerative colitis (UC) patients.A retrospective chart review was conducted at 14 gastroenterology practices from across the country, which varied in practice sizes and types. Patients were aged ≥18 years, diagnosed with CD or UC, and had an infliximab index date between January 1, 2005 and September 30, 2007. GI-related utilization 12 months before and 12 months after the index date was compared. Endoscopic disease severity was categorized based on blinded review of abstracted reports.Results from 268 patients indicated significantly lower rates of surgery (29.7% to 9.9%, p 0.0001, CD; 24.4% to 12.8%, p = 0.042, UC) and colonoscopy (54.4% to 17.6%, p 0.0001, CD; 50.0% to 22.1%, p = 0.0007, UC) during infliximab therapy. The rates of hospitalizations in UC (15.1% to 3.5%, p = 0.0124) and radiology assessments in CD (23.1% to 10.4%, p = 0.006) also decreased. Based on severity data from 183 procedures, greater proportions of patients had normal or mild ratings during infliximab treatment compared with pre-treatment.This retrospective descriptive study is limited by the type and quantity of information available in patient charts from 14 gastroenterology clinics during the first year of infliximab treatment. In addition, the number of patients with pre-treatment and post-treatment disease severity information was too small to make comparisons among disease severity groups. Further information about the severity of disease and the extent of mucosal healing could be helpful in determining the effect of therapy on resource utilization in future research.GI-related resource utilization was significantly lower and attenuation of mucosal damage severity was observed during infliximab treatment compared with the pre-treatment period.

Background: Chimeric antigen receptor (CAR) T-cell is rapidly emerging as a promising new therapy for cancer. Although it can induce rapid clinical responses, it is also associated with cytokine release syndrome (CRS), the most commonly observed toxicity, which in some cases can lead to life-threatening multi-organ failure. To ameliorate these problems we developed a novel chimeric T-cell therapy platform, the ARTEMIS™ platform, which functionally matches the potency of CAR T-cells, but dramatically reduces the release of cytokines upon killing of target-positive tumor cells. Herein, we describe the first-in-human clinical study of anti-CD19-ARTEMIS, ET190L1-ARTEMISTM, in relapsed and refractory (r/r) B-cell lymphoma. Methods: This dose escalating study is a single-center clinical study to evaluate the safety and efficacy of ET190L1-ARTEMIS T cells in patients with r/r CD19+ non-Hodgkin lymphoma, including diffused large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic lymphoma, and splenic marginal zone lymphoma. All patients received conditioning chemotherapy of cyclophosphamide and fludarabine followed by a single infusion of ET190L1-ARTEMISTM T cells at the dose of 1x106, 3x106, and 6x106 ARTEMIS+ T cells per kilogram respectively. The primary endpoint is safety and estimation of the maximum tolerated dose of ET190L1-ARTEMISTM T cells. Secondary objectives include ARTEMIS T-cell engraftment and response assessment by Lugano criteria. Results: Manufacturing was successful for all patients. As of July 18, 2018, 21 patients received autologous ET190L1-ARTEMIS T cells, 3 were infused with 1 × 106 (low dose), 13 received 3 × 106 (medium dose) and 5 received 6 × 106 (high dose) ARTEMIS+ T cells/kg. Expansion of ARTEMIS T cells after infusion was observed in all patients by qPCR and flow cytometry using anti-idiotype antibody. No dose-limiting toxicities and no greater than Grade 2 drug-related adverse events (AEs) were observed. Inflammatory-related cytokines in blood including IL-2, IL-4, IL-6, IL-8, IL-10, IFNgamma, TNFalpha, and GM-CSF were below detection level in most time points post infusion. AEs consisted of transient fever (38 ~ 39.2°C) from 1 to 4 days post infusion in 9 patients, transient grade 1 skin rash (1 × 106/kgcohort) in one patient. All of these AEs were limited and spontaneously resolved, except in 3 patients where symptomatic treatment for fever was given. No hypotension or any other clinical signs of CRS or neurotoxicity were observed. No anti-IL6 drug was given nor any hospitalization for AEs were needed. One patient with a large lymphoma mass on the right side of the neck experienced transient hand-tremor and unilateral tongue numbness on the right side, possibly due to the rapid shrinkage of tumor nodules around the neck (Table 1). Efficacy assessment was planned at 1, 2, 3, 6, 9, 12 18 and 24 months post infusion. All subjects (n=21) completed 1st month efficacy assessment: 11/21 (52%) responders, with 6/11 (55%) complete remission (CR) and 5/11 (45%) partial remission (PR). Of the 11 responders at 1 month, 8 completed 3rd month efficacy assessment, with 6/6 CRs maintained CR and 2/2 PRs had disease progression. Of the 11 responders at 1 month, 6 completed 6th month efficacy assessment, with 5/6 CRs maintained CR and 1/6 CRs releapsed. Of the 2 SDs at 1 month, 1 progressed at 4.5 month (Table 2). The median follow up time is 3 months and the range of follow up time is 1-8 months. Conclusions: The interim results show that ET190L1-ARTEMISTM T cell therapy is safe and demonstrated promising efficacy in r/r B-cell lymphoma patients at the current dose and schedule, including 11/21 responders and excellent safety profile, with no CRS and neurotoxicity observed. The durability of these efficacy and safety results will be assessed in longer follow up. Clinical trial information: NCT02658929 Disclosures Long: Eureka Therapeutics, Inc.: Employment. Liu:Eureka Therapeutics, Inc.: Employment, Equity Ownership. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Rizzieri:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nejadnik:Eureka Therapeutics, Inc.: Employment. Zhu:Beijing Cancer Hospital: Employment. Liu:Eureka Therapeutics, Inc.: Employment, Equity Ownership.

3049Background: To ameliorate CRS commonly associated with CAR T-cell therapy, we developed a novel T cell therapy, the ARTEMIS platform, which functionally matches the potency of CAR-T cells, but ...

Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is an unpredictable, potentially life-threatening complication of conditioning regimens for hematopoietic stem cell transplant (HSCT). Severe hepatic VOD/SOS (ie, with multi-organ dysfunction [MOD]), may be associated with >80% mortality. Defibrotide (DF) is approved for treatment of severe hepatic VOD/SOS in the European Union. In the United States, DF is available through an ongoing expanded-access protocol. Methods DF treatment for hepatic VOD/SOS with MOD is being assessed in a clinical program in pediatric and adult patients, including a phase 2 dose-finding trial, a pivotal phase 3 study of DF compared to historical controls (HC), and a single-arm expanded-access program. In the phase 2 dose-finding study, patients were randomized to receive 25 or 40 mg/kg/day. In the other 2 studies, treated patients received DF 25 mg/kg/d. DF was given in 4 divided doses for a recommended ≥14 days (dose-finding trial) or ≥21 days (pivotal and expanded-access studies). VOD/SOS was defined in each study by Baltimore and/or modified Seattle criteria. Here, we report results for treatment with DF 25 mg/kg/day in pediatric patients (aged ≤16y) with VOD/SOS plus MOD post-HSCT across these 3 studies. Results A pooled efficacy analysis included 255 pediatric patients with VOD/SOS and MOD post-HSCT who received DF 25 mg/kg/d in the dose-finding trial (n=22), pivotal trial (n=44), and expanded-access program (n=189). Among patients, 29.8% (n=76) were aged 0-23 mo, 48.6% (n=124) aged 2-11y, and 21.6% (n=55) aged 12-16y. 83.9% received allogeneic transplants (98.7% of patients aged 0-23 mo; 66.7% of patients aged 2-11y; 100% of patients aged 12-16y) and 16.1% received autologous transplants (1.3%, 0-23 mo; 32.3%, 2-11y; none, 12-16y). Acute leukemia (41.2%) was the most common primary disease (23.7%, 0-23 mo; 40.3%, 2-11y; 67.3%, 12-16y). At day +100 following HSCT, the survival rate in the overall pediatric population was 51.4% (95% CI, 45.2%-57.5%; n=131/255). Day +100 survival by age subgroup was 52.6% (95% CI, 41.4%-63.9%; n=40/76) in patients aged 0-23 mo, 53.2% (95% CI, 44.4%-62.0%; n=66/124) in those aged 2-11y, and 45.5% (95% CI, 32.3%-58.6%; n=25/55) in patients aged 12-16y. A safety analysis pooled data from the dose-finding and the pivotal trials, which incorporated on-site data monitoring, included 65 children who received DF at a dose of 25 mg/kg/day and 14 children in the HC group. At least 1 AE was reported for 93.8% (61/65) of DF-treated patients from these trials (95.5%, 0-23 mo; 89.7%, 2-11y; 100%, 12-16y), and for all HC patients. Overall AE profiles were generally similar between treated and HC patients. In these 2 trials, 67.7% of pediatric patients receiving 25 mg/kg/day DF had ≥1 serious AE (77.3%, 0-23 mo; 58.6%, 2-11y; 71.4%, 12-16y). Treatment-related AEs (TR-AEs) were reported in 44.6% of patients (31.8%, 0-23 mo; 44.8%, 2-11y; 64.3%, 12-16y). The most common TR-AE overall was pulmonary alveolar hemorrhage (2 patients per age group: 9.1%, 0-23 mo; 6.9%, 2-11y; 14.3%, 12-16y). AEs leading to death were reported for 49.2% (32/65) of patients from these 2 trials (72.7%, 0-23 mo; 31.0%, 2-11y; 50.0%, 12-16y) and 57.1% of HC patients (8/14; 40.0%, 0-23 mo; 85.7%, 2-11y; none, 12-16y). In the expanded-access program, ≥1 serious AE occurred in 98 (51.9%) patients ≤16y old; TR-AEs occurred in 41 (21.7%) of patients ≤16y old, most commonly pulmonary hemorrhage (6.9%), gastrointestinal hemorrhage (3.7%), and hypotension (3.7%). Conclusions In this pooled analysis of data from pediatric patients with VOD/SOS and MOD enrolled in 3 DF studies, day +100 survival was generally consistent across pediatric age subgroups. The safety profile in pediatric patients with VOD/SOS and MOD was generally consistent with what would be expected for this critically ill population. Support: Jazz Pharmaceuticals. Disclosures Kernan: Gentium S.p.A.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Grupp:Novartis: Consultancy, Research Funding. Banerjee:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding.

e18565 Introduction: Hydroxyurea (HU) is deemed first-line cytoreductive therapy for patients with essential thrombocythemia (ET) at high-risk for vascular complications with 20-25% of patients developing HU intolerance/ resistance (HUIR). Up to one-third of patients taking anagrelide, often the 2nd line drug of choice, are also unable to tolerate its side effects (cardiovascular and gastrointestinal). A review of the medical literature suggests widespread support for individualized treatment plans in ET with multiple options, including HU, anagrelide, interferon and busulfan, but little is known about physician practice. Methods: We contracted with a research company to perform an internet survey of 20 academic and 20 community hematologists to assess treatment practices for HUIR ET patients. We assumed a 25% rate of resistance to anagrelide. Results: Academic and community physicians reported 22% and 25% HUIR rates, respectively. An estimated 60% and 44% of HUIR patients in academic and community settings, respectively, would undergo treatment with an agent other than anagrelide (interferon, busulfan, or ruxolitinib) in 2nd or 3rd line treatments. Physicians not using anagrelide as 2nd line therapy also would not use it as 3rdline therapy. Anagrelide is used more frequently in the community setting. Conclusions: About 50% of HUIR patients are treated with agents other than anagrelide as 2nd/ 3rdline therapy. Reasons for practice variation in the treatment of ET remain poorly understood. [Table: see text]

We studied modulation of release of nitric oxide (NO) into nasal passages by physical characteristics (airflow, temperature, humidity) or gases (oxygen, carbon dioxide) in nasal air of humans. Each characteristic or gas in nasal air was changed during voluntary soft palate elevation (to isolate nasal passages). Increasing airflow through the nose caused incremental increases in NO release from 211+/-23 nl/(min x m(-2)) at 1 L/min to 312+/-40 nl/(min x m(-2)) at 22 L/min (P0.001, n = 6). Decreased humidity (dry airflow, 1-22 L/min) reduced NO release only at the highest airflow rate. Changing temperature (range 46 to 0 degrees C) had no effect on NO release. Hypoxia (below 4% O2) rapidly and reversibly decreased NO release (200+/-40 nl/(min x m(-2)) at 21% O2 versus 99+/-17 nl/(min x m(-2)) at 0% O2 for 3 min, (P0.001, n = 5). Carbon dioxide (5%) reduced NO release slightly. We conclude that airflow, reduced humidity, carbon dioxide concentration, and oxygen concentration modulate NO release into nasal passages.

Introduction: VOD (also known as Sinusoidal Obstruction Syndrome) is a potentially life threatening complication of hematopoietic stem-cell transplantation (HSCT). Severe VOD (sVOD), defined as VOD with evidence of multi-organ dysfunction (MOD), leads to high morbidity and mortality in HSCT patients. This study assessed healthcare utilization and costs associated with VOD in patients undergoing HSCT. Methods: A retrospective cohort study was conducted using the Premier research database and had a starting population of all patients with inpatient HSCT between January 1, 2009 and May 31, 2014. The VOD cohort ("all-VOD") included those who also had at least one discharge diagnosis indicating liver injury or at least two diagnoses for VOD symptoms, such as hyperbilirubinemia and/or hepatomegaly, during the study period. sVOD patients were identified using diagnoses for multi-organ dysfunction and were a subset of the VOD cohort. The non-VOD cohort was all patients from the starting cohort who did not have evidence of VOD. Primary outcomes were total hospitalization costs, hospital length of stay (LOS), and inpatient mortality. Secondary outcomes were intensive care unit (ICU) costs, ICU LOS, 30-day all-cause readmission rates and associated costs. Unadjusted descriptive analysis included Chi-squared or Wilcoxon Rank Sum tests for comparisons between cohorts, with non-VOD as the reference group. Multivariable analysis estimated the association between VOD status and primary outcomes, adjusting for differences in demographic, hospital, and clinical characteristics. Generalized linear models (GLM) were applied for total costs and LOS, and logistic regression was used for inpatient mortality. Recycled prediction was used to calculate the adjusted outcomes by VOD status. Results: A total of 5,418 patients had inpatient HSCT during the study period. The study included 291 all-VOD patients (134 sVOD and 157 non-severe VOD), in addition to 5,127 patients without evidence of VOD. Unadjusted descriptive analysis found that the all-VOD cohort had higher hospital costs (Median: $119,594, IQR: $59,793-$220,461) and longer LOS (Median: 28 days, IQR: 20-41) than the non-VOD cohort (Median cost: $62,747, IQR: $40,590-$120,974, p Discussion: This analysis is subject to limitations of administrative data. Since there is no diagnostic code for VOD, we used clinical judgment to sort through the codes most likely to be related to VOD/sVOD. Notably, the 40% mortality in the sVOD group is considerably lower than the approximately 80% mortality reported in the literature. One important reason for this difference is that our analysis measured mortality during initial HSCT hospitalization, while the higher rates in the literature are based on 100-day mortality. Additionally, our algorithm may have yielded less severe disease compared to the literature. Conclusions: VOD and sVOD were associated with increased healthcare utilization and costs compared with the HSCT patients without VOD. sVOD patients also had almost 6 times higher odds of inpatient mortality compared with patients without VOD. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Dvorak: Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Cao:Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Lipkin:Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Robinson:Premier Research Services: Employment; Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership.

Introduction Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of conditioning regimens for hematopoietic stem cell transplant (HSCT). Although VOD/SOS usually is thought of as a complication of HSCT, there is also a known risk in patients following chemotherapy in a non-HSCT setting. Severe hepatic VOD/SOS (ie, with multi-organ dysfunction [MOD]), may be associated with >80% mortality. Endothelial cell (EC) damage is a critical factor in the pathophysiology of VOD/SOS. Preclinical data suggest that defibrotide stabilizes ECs with direct, as well as EC-mediated, restoration of the thrombo-fibrinolytic balance. Defibrotide is approved for treatment of severe hepatic VOD/SOS in adult and pediatric patients in the European Union. In the United States, defibrotide is available as an investigational drug through an ongoing expanded-access protocol for treatment of hepatic VOD/SOS. Methods In the original protocol, patients were eligible if they had hepatic VOD/SOS by Baltimore criteria post-HSCT and MOD, defined by renal (tripling of creatinine levels or reduced creatinine clearance with or without dialysis) and/or pulmonary (need for oxygen supplementation with or without assisted ventilation) dysfunction. Symptoms of VOD/SOS were not considered adverse events (AEs) unless the event was considered serious. The protocol was later amended to include (1) post-chemotherapy patients with hepatic VOD/SOS; (2) patients with hepatic VOD/SOS without MOD, and (3) VOD/SOS per modified Seattle criteria. Enrolled patients received defibrotide 25 mg/kg/d in 4 divided doses for a recommended ≥21 days. Here, we describe efficacy and safety results with defibrotide for the subset of patients that developed VOD/SOS post-chemotherapy. Results Out of 642 patients who developed VOD/SOS and received ≥1 dose of defibrotide, 69 patients received chemotherapy without HSCT; 52% (n=36) had MOD, and 48% (n=33) did not. Median age was 8 years (range, The Kaplan-Meier estimated day +100 survival rate was 77.4% (95% confidence interval, 65.4%-85.7%). For patients with MOD and without MOD, the Kaplan-Meier estimated day +100 survival rates were 74.3% (56.4%-85.7%) and 80.9% (62.3%-90.9%), respectively. Overall, ≥1 AE was reported in 44 chemotherapy patients (63.8%). Of these, 14 (20.3%) had AEs assessed by the investigator as possibly, probably, or definitely related to defibrotide. Treatment-related AEs occurring in ≥2 patients were hypotension (4.3%), nausea (2.9%), vomiting (2.9%), and epistaxis (2.9%). Hemorrhagic AEs of any severity occurring in ≥2 patients were pulmonary (7.2%), epistaxis (5.8%), and gastric (2.9%). Serious AEs were reported in 26 patients (37.7%), most commonly multi-organ failure (7.2%), hypoxia (5.8%), and pulmonary hemorrhage (5.8%). AEs led to discontinuation in 4 patients (gastric, gastrointestinal and mouth hemorrhages, epistaxis, and hypotension). No treatment-related deaths were reported. Conclusions Day+100 survival of 77.4% in patients developing VOD/SOS following a variety of chemotherapy regimens without HSCT (80% of which were pediatric, primarily children) is a clinically encouraging finding. Defibrotide treatment in this group of 69 patients developing VOD/SOS post-chemotherapy was generally well-tolerated, with only 5.8% of patients discontinuing due to an AE and no treatment-related fatalities. Enrollment to the study continues. Support: Jazz Pharmaceuticals. Disclosures Kernan: Gentium S.p.A.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States.. Richardson:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis: Consultancy, Research Funding. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees. Liang:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Introduction: Hepatic VOD, also known as Sinusoidal Obstruction Syndrome, is a potentially life threatening complication of hematopoietic stem cell transplantation (HSCT). Severe VOD (sVOD), defined as VOD with evidence of multi-organ dysfunction, leads to high morbidity and greater than 80% mortality (Coppell 2010) in HSCT patients. The purpose of this study was to develop an approach, in the absence of a specific diagnosis code, to identify VOD and sVOD in a hospital administrative database and to measure incidence among HSCT patients. Methods: A retrospective cohort study was conducted using the Premier Healthcare Database, which contains more than 535 million patient encounters (inpatient and outpatient). The starting population was all patients with inpatient HSCT between January 1, 2009 and May 31, 2014 (n=5,418). Since there is currently no diagnosis code for VOD, we used clinical experience (CD, BN) to develop a coding algorithm to identify VOD within the database. In order to be categorized as having VOD, patients with HSCT had to have at least one code from the group B1, indicating hepatic or thromboembolic disease AND at least two codes from group B2, which is focused on VOD diagnosis criteria used in clinical practice (Figure 1). To more accurately identify VOD and exclude alternate etiologies of the liver abnormalities, patients with graft versus host disease (GVHD) (ICD-9 279.50) or TPN cholestasis (ICD-9 576.2 and TPN identified in charge master) were excluded. To qualify for sVOD, VOD patients also had to have at least one code from group C (Figure 1). Results: This algorithm identified 291 VOD patients (5.4% of the HSCT patients) (Figure 1). Forty-six percent (n=134) of those VOD patients, or 2.5% of the total HSCT patients, had codes consistent with sVOD. The incidence of VOD among pediatrics (≤ 17 years old) was 6.4% and the incidence in adults (18+) was 5.3%. The mean age and standard deviation (SD) in the no-VOD and VOD groups was 50.6 (SD 18.4) and 50.6 (SD 19.2), respectively (p=0.97) and the mean age in the sVOD group was 47.7 (SD 21.4) (p=0.08 compared to no-VOD). Among non-VOD patients 8.6% were < 17 years, compared to 10.3% in all-VOD (p=0.647) and 14.9% in sVOD (p=0.096). Among allogeneic HSCT patients, 7.2% had VOD, including 3.6% with sVOD, while only 4.4% of patients with autologous HSCT had VOD, including 1.8% with sVOD. Discussion: The incidence of VOD found in this study was lower than some literature estimates. Coppell et al., using a systematic literature review from 1979 through 2007, found an overall VOD incidence of 13.7%, with higher incidence in patients with allogeneic HSCT (12.9%) than in autologous (8.7%). However, this estimate includes older studies in a time when more intensive conditioning led to higher rates of VOD. Furthermore, our criteria were designed to identify patients with high certainty of VOD. In a more recent study in which 271 patients received reduced intensity conditioning for allogeneic HSCT, the cumulative incidences of VOD and sVOD were 8.9% and 1.5%, respectively (Tsirigotis 2014). Limitations: This analysis is subject to limitations of administrative data. Since there is no diagnostic code for VOD, we used clinical judgment to sort through diagnosis and procedures codes that could be associated with complications of HSCT to find the most likely codes related to VOD and sVOD. The lower incidence in our analysis may have been the result of relatively restrictive methodology designed to identify VOD patients with a high degree of certainty based on diagnosis codes. Conclusion: VOD is a potentially life threatening complication of HSCT and was found in 5% of inpatient HSCT procedures, half of which were deemed severe with multi organ dysfunction, in the 5-year period ending in mid-2014. Disclosures Dvorak: Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Cao:Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis; Premier Research Services: Employment. Lipkin:Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis; Premier Research Services: Employment. Robinson:Jazz Pharmaceuticals: Other: Premier Research Services received funding from Jazz Pharmaceuticals for data access, study design, and analysis; Premier Research Services: Employment. Villa:Jazz Pharmaceuticals: Employment, Equity Ownership.

Background: Single breath diffusing capacity for carbon monoxide (Dco) is commonly used as a simple method of assessing overall pulmonary gas exchange properties. Studies of Dco in bronchial asthma have yielded conflicting results. Objective: To study Dco and to determine the factors influencing Dco in patients with asthma. Methods: Dco was prospectively measured in 80 consecutive never-smoker patients with uncomplicated stable asthma. The topographic distribution of lung perfusion was determined in 10 asthmatics and 10 controls, with a Xe-133 radionuclide scan. Results: The mean (SD) value of Dco was increased to 117 (17) percent of predicted values; individual values were either within or above normal limits; diffusion was also elevated at 116 (19) percent after correction for alveolar volume (transfer coefficient, D/VA). The Dco was not correlated with atopic status, duration of asthma, or results of spirometric tests; there was a weak negative correlation between D/VA and FEV(1) or residual volume. There was a better perfusion of the upper zones of the lungs in asthmatics as compared with controls. Among the asthmatics, there was a strong positive correlation between Dco and the apex to base perfusion ratio (r=0.975). Conclusions: Dco is normal or high among never smoker patients with uncomplicated asthma; elevated Dco may be attributed to a better perfusion of the apices of the lungs; the latter could result from two mutually nonexclusive mechanisms: an increase in pulmonary arterial pressure and/or a more negative pleural pressure generated during inspiration as a consequence of bronchial narrowing. The unexpected finding of high Dco should raise the possibility of bronchial asthma in patients with otherwise undiagnosed conditions.

Objective To evaluate the healthcare costs and resource utilization associated with pediatric Crohn’s disease (PCD) from a payer perspective. Methods A retrospective analysis was conducted using claims from 1 January 2003 through 31 December 2006 from the HealthCare Partners database. Patients were younger than 18 years of age, had a new diagnosis of PCD, and continuous health plan eligibility 6 months before and 12 months after the disease index date (the date of the first claim with a PCD diagnosis). For comparison, a non-PCD cohort was matched on age, sex, and birthday (within 30 days). Results Data from 30 patients with PCD and 10,864 non-PCD controls were included. The total cost per member per month (PMPM) for the PCD cohort was $2,547 compared with $101 for the non-PCD cohort. Inpatient admissions accounted for the largest portion (54%) of the total cost PMPM for PCD patients. There were 500 admissions per thousand members per year (PTMPY) for the PCD cohort and 11 admissions PTMPY for the non-PCD cohort. The average lengths of stay were 7.6 and 4.4 days for the PCD cohort and the non-PCD cohort, respectively, and the inpatient costs PMPM were $1,409 and $18, respectively. Costs and resource utilization were also higher for PCD patients treated with systemic therapies. Conclusion PCD was associated with higher costs and resource utilization, compared with non-PCD controls, primarily driven by inpatient stays. Treating PCD appropriately before the disease progresses to a level requiring hospitalization may help reduce the costs associated with this disease.

We characterized the nasal contribution to exhaled nitric oxide (NO) at rest and during breathholding in humans. Exhaled NO was greater during nose breathing (141 +/- 17 nl/min/M2, mean +/- SEM) compared with mouth breathing (68 +/- 6 nl/min/M2, n = 8, p < 0.001). After voluntary closure of the soft palate (VCSP) to eliminate nasal NO, exhaled NO from the mouth decreased further (30 +/- 4 nl/min/M2, p < 0.001). Release of NO into nasal passages during VCSP (217 +/- 19 nl/min/M2) was greater than exhaled NO during nasal breathing (141 +/- 17 nl/min/m2, p < 0.001), suggesting that nasal NO is taken up by the respiratory tract. During mouth breathing or nose breathing, NO concentrations sampled with a bronchoscope were higher in the nasopharynx than at the epiglottis or in the trachea in five subjects. Increased peak exhaled NO after a breathhold (33 +/- 7 ppb) was reduced (10 +/- 4 ppb, p < 0.001) after balloon occlusion of the nasopharynx. NO concentration during breathholding increased to a greater extent in the nasopharynx than in the pharynx or trachea. We conclude that the majority of exhaled NO at rest and during a breathhold originates in the nasopharynx.

Gastrointestinal manifestations associated with chronic idiopathic inflammatory demeylinating polyradiculoneuropathy (CIIDP)

Background: Severe hepatic veno-occlusive disease (VOD, also referred to as sinusoidal obstruction syndrome) with associated multi-organ failure (MOF) is a life-threatening complication of hematopoietic stem cell transplant (HSCT) and has an associated mortality rate >80%. Defibrotide has been shown to have a protective effect on injured endothelium and to restore the thrombo-fibrinolytic balance. In severe VOD, defibrotide has improved complete response (CR) rates and survival at Day +100 post HSCT compared with historical controls, and has also been shown to have a favorable safety profile. In the EU, defibrotide is now approved for the treatment of severe hepatic VOD in HSCT therapy. It is indicated in adults, adolescents, children, and infants >1 month of age. In the USA, there are currently no approved therapies for this complication; however, defibrotide has been made available since 2007 through an expanded access protocol directed treatment IND (T-IND). The aim of the T-IND is to gather additional data on safety and efficacy of defibrotide in a broader patient population, including those with severe VOD/MOF post HSCT, non-severe VOD post HSCT, and VOD following chemotherapy in the non-HSCT setting. This is the largest prospective evaluation of defibrotide for the treatment of VOD. Here we provide an update on the safety of defibrotide from this ongoing study. Methods: The original T-IND protocol required patients 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; the study was amended to allow inclusion of patients with non-severe VOD (defined as no MOF) occurring either post-HSCT or post-chemotherapy. Key exclusion criteria include clinically significant bleeding or the need for >1 vasopressor. Defibrotide was given as a 2-hour infusion at 6.25 mg/kg IV every 6 hours (25 mg/kg/d) with a recommended minimum treatment duration of 21 days. Results: The current interim safety analysis is based on 612 patients enrolled between December 2007 and December 2013 (including 99 in 2013) for whom safety data is available and who received ≥1 dose of defibrotide. Across the USA, over the course of the study approximately 86 centers were active to enroll patients. Median patient age was 12 years (range 2 to 18 years, 34.9% aged >18 to 65 years, and 1.2% aged >65 years. Patients were primarily male (55.8%) and predominantly white (65.6%). Overall, 454 patients (74.2%) reported ≥1 treatment emergent adverse events (AEs). Of these, 138 patients (22.5%) had AEs that investigators assessed as related (possibly, probably, or definitely) to study medication. Related AEs in >2.0% were pulmonary hemorrhage (4.7%), gastrointestinal hemorrhage (3.6%), epistaxis (3.1%), and hypotension (2.8%). Serious AEs (SAEs) were reported by 368 patients (60.1%). The majority of SAEs were assessed as not related to study treatment; 82 patients (13.4%) had an SAE at least possibly related to study treatment, most commonly pulmonary hemorrhage (3.9%) and gastrointestinal hemorrhage (2.9%). AEs leading to death occurred in 254 patients (41.5%); these AEs were deemed by the investigators to be possibly related to study medication in only 17 patients (2.8%). Previously reported efficacy data at D +100 in 425 patients evaluable for outcome have shown survival of 55% (by Kaplan-Meier estimate) for patients following HSCT, and survival of 62% (by Kaplan-Meier estimate) in 45 patients following chemotherapy (without HSCT), respectively. Conclusions: Defibrotide therapy in patients with VOD was generally well tolerated in this population, with manageable toxicity, and promising results seen in terms of response and survival. Safety results from prior studies, which have also been associated with a low incidence of defibrotide-associated toxicities, have proven very consistent with the favorable tolerability profile seen in this largest experience to date. Enrollment to the T-IND study continues; updated results will be presented at the meeting. Support:Jazz Pharmaceuticals Off-Label Use Defibrotide is an investigational treatment for hepatic veno-occlusive disease in the United States. Disclosures Richardson: Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals Inc.: Research Funding. Off Label Use: Defibrotide is an investigational treatment for veno-occlusive disease in the United States.. Antin:Dana-Farber Cancer Institute: Employment; Tempera: Consultancy; Enlivex: Consultancy. Lehmann:Dana Farber/Boston Children's Hospital: Employment. Bandiera:Gentium S.p.A.: Employment. Hume:Jazz Pharmaceuticals Inc.: Employment. Hannah:Jazz Pharmaceuticals: Consultancy. Nejadnik:Jazz Pharmaceuticals: Employment. Study Group:Gentium S.p.A.: Employment.

Introduction Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), is a rare and potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Severe cases, historically defined by multi-organ dysfunction (MOD), may be associated with mortality rates of >80%. There is no FDA-approved treatment for VOD/SOS. Defibrotide (DF) has a proposed mechanism of action that includes stabilization of endothelial cells and restoration of thrombo-fibrinolytic balance. Earlier analyses of a pivotal phase 3 trial of DF in VOD/SOS plus MOD (Richardson et al. Blood. 2009;114:Abstract 654) underpinned approval of DF in the EU to treat severe hepatic VOD/SOS after HSCT. Additional data were obtained at the request of US health authorities. Here we present the final analysis: day +100 survival (primary endpoint) and complete response (CR; secondary). Methods This was a multicenter, open-label, phase 3 historical control (HC) study assessing DF. Eligible patients met Baltimore VOD/SOS criteria (total bilirubin ≥2.0 mg/dL with ≥2 of: hepatomegaly, ascites, or 5% weight gain) by day +21 post-HSCT, plus MOD (renal [trebling of creatinine levels, reduced creatinine clearance, or dialysis] and/or pulmonary [oxygen saturation ≤90%, need for oxygen supplementation/ventilator dependence]) by day +28 post-HSCT. Exclusion criteria included severe graft-versus-host disease (GvHD) of liver or gut, clinically significant bleeding, or need for ≥2 pressors. HC patients were reviewed for inclusion/exclusion criteria in a sequential review of medical charts starting 6 months prior to use of DF at each site; a blinded medical review committee made the final determination of HCs unequivocally meeting criteria for VOD/SOS with MOD. DF dose was 25 mg/kg/d in 4 divided 2-hour IV infusions q6h; recommended treatment duration was ≥21 days. Primary endpoint was day +100 survival. CR by day +100 was a secondary endpoint. Treatment difference in survival and CR rates and their 95% confidence intervals were estimated using propensity-stratified and weighted (Koch-adjusted) estimates of differences in proportions that account for baseline prognostic factors of survival (ie, ventilator and/or dialysis dependency at entry, age ≤/>16 years, transplant type, and prior HSCT). Analyses included patients treated with DF and HCs. Results There were 102 patients in the DF group and 32 cases selected as HCs. Baseline characteristics were similar in the DF and HC groups: mean age (26 and 25 years; 43% and 44% ≤16 years), allogeneic graft (88% and 84%), prior HSCT (13% and 9%), ventilator- and/or dialysis-dependent at study entry (33% and 22%), myeloablative conditioning (87% and 94%), and the most common underlying diseases (acute leukemias: 45% and 47%), respectively. In the DF-treated group, common GvHD medications included tacrolimus (49%), methotrexate (41%), and cyclosporine (38%); in the HC group, common medications were cyclosporine (72%) and methotrexate (63%). Survival at day +100 in the DF and HC groups was 38% and 25%, respectively. The propensity-stratified difference in survival was 23.0% (95.1% CI, 5.2-40.8, P = .0109). Respective observed CR rates by day +100 were 25.5% and 12.5%, and the propensity-stratified difference in CR was 19.0% (95.1% CI, 3.5-34.6, P = .0160). Comparing the earlier EU and final analyses, the survival rates at day +100 in each group did not vary; however, the propensity adjusted final analysis provided a different level of statistical significance. Day +100 CR rates in the original analysis were slightly lower in both arms at 24% and 9% due to increased data capture to investigate CR; the P value was essentially unchanged. For the DF group, 45% had an adverse event (AE) at least possibly related to study drug, and 21% had a serious AE at least possibly related to study drug. In this very sick population, percentages of patients with ≥1 AE leading to death were similar between DF and HC patients (64% and 69%), as were hemorrhagic AEs (64%, 75%) and hypotension (39%, 50%). Conclusions Based on observed study data and using a propensity-adjusted rate difference estimator, patients treated with DF had a 23% reduction in risk of death by day +100 and 19% improvement in CR rate. Overall incidence of hemorrhage and fatal AEs were similar between groups with AEs consistent with those expected in this critically ill population. Support: Jazz Pharmaceuticals. Disclosures Richardson: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Marizomib, pmalidomide, and low dose dexamethasone in RR MM. Defibrotide is an investigational treatment for hepatic veno-occlusive disease/sinusoidal obstruction syndrome in the United States. . Kernan:Gentium S.p.A.: Research Funding. Grupp:Novartis: Consultancy, Research Funding. Guinan:Gentium SpA/Jazz Pharmaceuticals: Other: My institution received fees for research.. Martin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium SpA/Jazz Pharmaceuticals: Research Funding. Steinbach:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Krishnan:Celgene: Consultancy, Speakers Bureau; BMS: Consultancy; Janssen: Consultancy; Onyx: Speakers Bureau; Jazz: Consultancy; Millenium: Speakers Bureau. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding. Rodriguez:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Doyle:Gentium SpA/Jazz Pharmaceuticals: Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. D'Agostino:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Massaro:Gentium SpA/Jazz Pharmaceuticals: Consultancy. Miloslavsky:Jazz Pharmaceuticals: Employment, Equity Ownership. Hume:Jazz Pharmaceuticals: Employment, Equity Ownership. Iacobelli:Gentium SpA: Employment. Nejadnik:Jazz Pharmaceuticals: Employment, Equity Ownership. Hannah:Gentium SpA: Other: Personal fees during conduct of the study.. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.