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AbstractBackgroundProstate‐specific membrane antigen (PSMA) is a well‐established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody‐drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti‐PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA‐positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate‐specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration‐resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy.MethodsA total of 119 (84 chemotherapy‐experienced and 35 chemotherapy‐naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed.ResultsPSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy‐naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy‐naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy‐naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy‐experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy‐naïve group had partial responses. The most common treatment‐related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis.ConclusionsPSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment‐related AEs included neutropenia and neuropathy.

Objective: To describe the incidence and risk factors for mortality and morbidity in patients with cirrhosis undergoing elective or emergent abdominal surgeries. Background: Postoperative morbidity and mortality are higher in patients with cirrhosis; variation by surgical procedure type and cirrhosis severity remain unclear. Methods: We analyzed prospectively-collected data from the Veterans Affairs (VA) Surgical Quality Improvement Program for 8193 patients with cirrhosis, 864 noncirrhotic controls with chronic hepatitis B infection, and 5468 noncirrhotic controls without chronic liver disease, who underwent abdominal surgery from 2001 to 2017. Data were analyzed using random-effects models controlling for potential confounders. Results: Patients with cirrhosis had significantly higher 30-day mortality than noncirrhotic patients with chronic hepatitis B [4.4% vs 1.3%, adjusted odds ratio (aOR) 2.80, 95% confidence interval (CI) 1.57–4.98] or with no chronic liver disease (0.8%, aOR 4.68, 95% CI 3.27–6.69); mortality difference was highest in patients with Model for End-stage Liver Disease (MELD) score ≥10. Among patients with cirrhosis, postoperative mortality was almost 6 times higher after emergent rather than elective surgery (17.2% vs. 2.1%, aOR 5.82, 95% CI 4.66–7.27). For elective surgeries, 30-day mortality was highest after colorectal resection (7.0%) and lowest after inguinal hernia repair (0.6%). Predictors of postoperative mortality included cirrhosis-related characteristics (high MELD score, low serum albumin, ascites, encephalopathy), surgery-related characteristics (emergent vs elective, type of surgery, intraoperative blood transfusion), comorbidities (chronic obstructive pulmonary disease, cancer, sepsis, ventilator dependence, functional status), and age. Conclusions: Accurate preoperative risk assessments in patients with cirrhosis should account for cirrhosis severity, comorbidities, type of procedure, and whether the procedure is emergent versus elective.

Abstract Background: Sickle cell disorder (SCD) and transfusion dependent beta-thalassemia (TDT) are inherited disorders of β-globin genes leading to ineffective erythropoiesis, hemolysis and multi-organ damage. Though allogenic hematopoietic cell transplantation (allo-HCT) in the only potentially curative therapy, lack of full HLA-matched donor, increased risk of myeloablative conditioning (MAC) regimen related toxicity, poor prognosis in older age groups (>14 years), and a high risk of infections and graft versus host disease (GVHD) culminating into a high transplant related mortality (TRM) preclude HCT as a treatment option for many patients. Gene therapy has been proposed as a relatively new treatment option for these monogenic disorders. It involves transfection of harvested CD34+ hematopoietic stem cells (HSC) with viral vector to transfer a normal beta globin gene, which are then transplanted back to the autologous donor. However, the available data on gene therapy is extremely variable. The purpose of this review is to evaluate the risks and outcomes of SCD and TDT patients undergoing gene therapy. Methods: A systematic search of databases using PubMed, Embase, Web of science, Cochrane database and Clinicaltrials.gov was performed on with no restrictions of language or time period. A total of 4312 articles were identified and after duplicates removal, 3508 articles were screened for relevance. Clinical studies reporting the most recent follow up results about the efficacy and safety of gene therapy in patients with hemoglobinopathies were considered for inclusion. Their quality assessment was done using the Cochrane tool, and bias was evaluated regarding the study selection, performance, detection, attrition and the reporting of the clinical trials. RESULTS (table-1): Only 7 articles qualified for the strict selection criteria with an N of 47: six studies were phase I trials (Cavazzana, M. et al 2010, Boulad, F. et al 2013, Marktel, S. et al 2017, Kwiatkowski, J. et al 2017, Cavazzana, M. et al 2017, Kanter, J. et al 2017) and one was a phase III trial (Walters, M. et al 2017). Thirty five patients (74.4%) had TDT while 12 patients (25.5%) had SCD. All these patients did not have a suitable HLA-matched HCT donor. The length of follow up was heterogeneous owing to the step wise enrollment of participants and ranged from 2-36 months. Except for 4 cases, the age of included population was >13 years. Lentivirus BB305 encoding the HbAT87Q globin gene was used for gene delivery in 81% patients (n=38). The normal beta globin gene was transduced in remaining 9 TDT cases and it involved transduction using TNS 9.3.55 vector in two cases and with GLOBE lentivirus in 7 cases. MAC with busulfan was used in 81% cases (n=38), while treosulfan+thiotepa was used in 7 cases. The non-myeloablative (NMA) conditioning with busulfan was used in only 2 cases (both TDT). Bone marrow harvest was the source of HSCs in all SCD cases. Except for 3 SCD cases in HGB-204 trial and 3 TDT cases in HGB-207 which measured the potential improvement in outcome by an increase in DP-VCN, the range of drug vector copy number (DP-VCN) was 0.3-1.5 copies per diploid genome. The total hemoglobin (HB) level at last follow up was reported for 62% cases (n=29) and it was >8.8 g/dl in all cases. Twenty-one (60%) thalassemia cases were in a transfusion (Tx) free state at last follow up, including the 7 cases (20%) who developed a complete independence from transfusions. No such Tx-free state was noted in SCD cases although they developed a reduction in the Tx-requirement and 75% SCD cases (n=9) had a 30-100% reduction in the frequency of VOCs. All the cases were alive at their recent follow up with manageable toxicity form conditioning. Acceptable safety until the median follow-up from the 7 trials was established in all cases, with no reported development of post-treatment leukemia or new malignancy in these trials. DISCUSSION: In this largest series of gene therapy for the treatment of hemoglobinopathies (to our knowledge), we find it to be clinically effective in terms of reduction in transfusion needs; data to suggest an improved OS and disease free survival is promising, however long term data is awaited. Gene therapy appears to bypass the limitations faced by allo-HCT especially a high early TRM. Randomized trials reporting the efficacy and safety outcomes with longer follow ups are urgently required. Disclosures No relevant conflicts of interest to declare.

Abstract Background: JAK2 inhibition improves splenomegaly and symptoms in patients with myelofibrosis (MF), and the JAK2 inhibitor ruxolitinib has been shown to improve both bone marrow fibrosis and survival in MF patients (Cervantes et al., 2013; Verstovsek et al., 2013). Current prognostic models such as DIPSS plus (Gangat et al., 2011) predict survival in MF based on clinical, laboratory, and cytogenetic information, but predate the era of JAK2 inhibitor use in MF. As such, their value in predicting clinical response or survival during treatment with JAK2 inhibitors remains unknown. We hypothesized that features not considered by DIPSS plus, including bone marrow fibrosis and splenomegaly, have independent effects on therapy response. We therefore conducted a retrospective analysis to create a new model to risk stratify patients with respect to their likelihood of achieving a > 50% reduction in splenic size by palpation with JAK2-inhibitor therapy. Methods: We studied a cohort of 418 patients with bone marrow biopsy-proven MF who were treated with ruxolitinib or one of four other JAK2 inhibitors. An initial cohort of 203 patients seen at University of Michigan, Stanford University, and Mayo Clinic in Scottsdale, AZ was used identify factors that would predict a clinical response to therapy. Response to therapy was evaluated at an early time point (3-4 mos) in 167 patients and at a late time point (5-12 mos) in 138 patients, with 127 patients overlapping between the two. We constructed a multivariable logistic regression model, with Bayesian variable selection, for predicting the probability of early or late splenic response to JAK2 inhibitor therapy. The model was developed with this initial group of 203 patients. The model was then validated with a cohort of 215 patients from the PERSIST1 trial (data supplied by CTI Biopharma). Results: Conclusion: We identified several factors that play a role in predicting whether or not patients with MF are likely to respond to JAK2 inhibitor therapy. The interaction between spleen size and WBC at the time of therapy initiation plays the strongest role in predicting which patients will have an early response to therapy. Additionally, our model suggests that patients who do not have a response to JAK2 inhibitor therapy by about 4 months of treatment are unlikely to develop a later response. Our model is able to discriminate between those likely to benefit after several months of therapy and those for whom a change in therapy should be considered early in their treatment course. Figure 1 The following characteristics were selected for inclusion in the prognostic model based on the data collected from our 418-patient cohort. Spleen size and white blood cell count at the time of therapy initiation were the strongest predictors of early response to JAK2 inhibitor therapy. Achievement of an early response was used to further enhance the model for the late time point (third column) and was the strongest predictor of late response. Interaction terms looked at the interdependence of variables on splenic response. Log odds ratios are provided with 95% credible intervals in parentheses. Figure 1. The following characteristics were selected for inclusion in the prognostic model based on the data collected from our 418-patient cohort. Spleen size and white blood cell count at the time of therapy initiation were the strongest predictors of early response to JAK2 inhibitor therapy. Achievement of an early response was used to further enhance the model for the late time point (third column) and was the strongest predictor of late response. Interaction terms looked at the interdependence of variables on splenic response. Log odds ratios are provided with 95% credible intervals in parentheses. Figure 2 An example of the predicted response for a hypothetical patient. The curves show the interaction of a high initial WBC (red) or a low initial WBC (green) with baseline spleen size (depicted along the X-axis) in predicting whether or not the patient will have a late response to therapy (depicted along the Y-axis). The solid lines show the probability that the patient will respond at the later time point if they had an early response. The dashed lines show the probably of a late response if the patient had not achieved a response by the early time point. Overall, a patient with a higher initial WBC and a larger baseline spleen size is less likely to respond to JAK2 inhibitor therapy. Additionally, the curves clearly separate to show that, for a given baseline WBC and spleen size, a patient who has an early response to therapy is much more likely to have a late response to therapy, whereas a patient who fails to respond early in their treatment course is much less likely to respond with further treatment. Figure 2. An example of the predicted response for a hypothetical patient. The curves show the interaction of a high initial WBC (red) or a low initial WBC (green) with baseline spleen size (depicted along the X-axis) in predicting whether or not the patient will have a late response to therapy (depicted along the Y-axis). The solid lines show the probability that the patient will respond at the later time point if they had an early response. The dashed lines show the probably of a late response if the patient had not achieved a response by the early time point. Overall, a patient with a higher initial WBC and a larger baseline spleen size is less likely to respond to JAK2 inhibitor therapy. Additionally, the curves clearly separate to show that, for a given baseline WBC and spleen size, a patient who has an early response to therapy is much more likely to have a late response to therapy, whereas a patient who fails to respond early in their treatment course is much less likely to respond with further treatment. Disclosures Boonstra: CTI Biopharma: Research Funding. Gowin:Incyte: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis: Consultancy; Ariad: Consultancy; Promedior: Research Funding; Celgene: Research Funding; Galena: Consultancy; Incyte: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding. Talpaz:Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Novartis: Research Funding; Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding.

Abstract Background: JAK2 inhibitors have been shown to improve symptoms and produce durable reductions in splenomegaly in patients with myelofibrosis (MF), and ruxolitinib has been shown to improve survival in MF patients (Cervantes et al., 2013; Verstovsek et al., 2013). Current prognostic models such as DIPSS plus (Gangat et al., 2011) predict survival in MF based on clinical, laboratory, and cytogenetic information, but their value in predicting clinical response or survival during treatment with JAK2 inhibitors remains unknown. We hypothesized that clinical features such as bone marrow fibrosis and splenomegaly may have independent effects on therapy response. Therefore, we conducted a retrospective analysis to create a new model to risk stratify patients with respect to their likelihood of responding to oral JAK2-inhibitor therapy. Methods: We studied a cohort of 203 patients with bone marrow biopsy-proven MF seen at University of Michigan, Stanford University, and Mayo Clinic in Scottsdale, AZ. These patients were all treated with ruxolitinib or an experimental JAK2 inhibitor. Our primary endpoint was defined as IWG-MRT criteria for splenic response by palpation (Tefferi et al., 2013). Response in patients with spleen size of less than 5 cm was defined as complete resolution of splenomegaly. Of the 203 patients studied, splenic response was evaluated after 3 months of therapy in 167 patients and after 6 months of therapy in 138 patients; 127 patients were in both groups. A logistic regression was performed to identify factors that would predict clinical response. Results: The following characteristics were significantly associated with spleen response at 3 and 6 months: initial spleen size, European consensus criteria grading of MF on bone marrow biopsy, initial DIPSS plus score, and initial WBC count. Cellularity on marrow biopsy was not significant. We enriched a baseline logistic model of initial dose of oral JAK2 therapy and DIPSS plus score with additional prognostic factors. We found the following clinical characteristics to be jointly associated with splenic response: normalized initial dose of oral JAK2 inhibitor, initial spleen size, DIPSS plus score, degree of fibrosis by European consensus criteria. Duration of disease from time of diagnosis to time of treatment initiation was not prognostic for splenic response. We used this model to calculate the probability of splenic response based on a risk score: Risk score = –1.18(Dose) + 0.09(Initial Spleen Size in cm) + 0.20(DIPSS-plus Points) +0.92 (if fibrosis is MF-3). The probability at 6 months can then be calculated from the risk score as follows: [1/(1+e(risk score-2.6))]. The figure demonstrates the prognostic gain of our model over a model based on DIPSS plus alone. Conclusion: With this observational study, we propose a predictive model which may serve as a clinical tool to identify which patients are most likely to benefit from JAK2 inhibitor-based therapies. Further validation in independent data sets will be required before this model can be more widely applied. Disclosures Mesa: Incyte Corporation, CTI, NPS Pharma, Inc., Gilead Science Inc., Celgene: Research Funding. Gotlib:Incyte: Consultancy, Honoraria, Research Funding, Travel Reimbursement Other; Gilead: Research Funding; Sanofi: Research Funding; Novartis: Research Funding, Travel Reimbursement, Travel Reimbursement Other. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

ABSTRACT Bilothorax is a rare condition involving drainage of bile from the biliary system into the lung's pleural space. Several cases have been reported in the literature, where the most commonly reported cause is iatrogenic injury. To date, no cases of bilothorax as a complication of liver transplantation have been reported. Given its rarity and concurrent morbidity, early recognition is paramount as this condition can quickly deteriorate into adult respiratory distress syndrome.