BACKGROUND & AIMS:Angiogenesis is critical in intrahepatic cholangiocarcinoma (ICC), a highly lethal cancer with limited treatment options. Sunitinib, a multi-receptor tyrosine kinase inhibitor, has strong antiangiogenic and antitumor effects. We aimed to evaluate the efficacy and tolerability of sunitinib as a second-line treatment in chemotherapy-pretreated patients with advanced ICC. METHODS:This open-label, single-arm, phase II trial was conducted across five French centres. Eligible patients were aged ≥ 18, had advanced ICC not suitable for curative surgery and had been pre-treated with gemcitabine and/or platinum. Patients received oral sunitinib at 37.5 mg daily. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Tumour response was evaluated using RECIST v1.1, with exploratory analysis using Choi criteria. VEGF-A, VEGF-C and plasma sunitinib levels were measured. RESULTS:Fifty-three patients were included. Median OS was 9.6 months (95% CI, 6.1-13.1), median PFS was 3.7 months (95% CI, 3.1-6.4), the ORR was 14% and the DCR was 84%. Grade 3-4 cytopenias occurred in 25% of patients, hypertension in 21% and fatigue in 19%. Higher baseline levels of VEGF-A and VEGF-C correlated with longer OS. Patients with dose reductions maintained adequate drug exposure. Choi criteria, applied to 24 patients, predicted response duration better than RECIST v1.1. Baseline tumour density, assessed in 14 patients, showed a potential association with treatment responses. CONCLUSIONS:Sunitinib demonstrated efficacy and manageable toxicity as a second-line treatment in patients with advanced ICC previously treated with chemotherapy, suggesting it may represent a viable therapeutic option for this population. TRIAL REGISTRATION:ClinicalTrials.gov NCT01718327.

Sickle cell disease (SCD) and transfusion-dependent β-thalassemia (TDT) are the most prevalent monogenic disorders worldwide. Trial HGB-205 ( NCT02151526 ) aimed at evaluating gene therapy by autologous CD34 + cells transduced ex vivo with lentiviral vector BB305 that encodes the anti-sickling β A-T87Q -globin expressed in the erythroid lineage. HGB-205 is a phase 1/2, open-label, single-arm, non-randomized interventional study of 2-year duration at a single center, followed by observation in long-term follow-up studies LTF-303 ( NCT02633943 ) and LTF-307 ( NCT04628585 ) for TDT and SCD, respectively. Inclusion and exclusion criteria were similar to those for allogeneic transplantation but restricted to patients lacking geno-identical, histocompatible donors. Four patients with TDT and three patients with SCD, ages 13–21 years, were treated after busulfan myeloablation 4.6–7.9 years ago, with a median follow-up of 4.5 years. Key primary endpoints included mortality, engraftment, replication-competent lentivirus and clonal dominance. No adverse events related to the drug product were observed. Clinical remission and remediation of biological hallmarks of the disease have been sustained in two of the three patients with SCD, and frequency of transfusions was reduced in the third. The patients with TDT are all transfusion free with improvement of dyserythropoiesis and iron overload.

We analysed the therapeutic outcomes of all consecutive patients with primary central nervous system lymphoma (PCNSL) registered in the prospective French database for PCNSL and treated with intensive chemotherapy (IC) followed by autologous stem cell transplantation (IC-ASCT) between 2011 and November 2019 (271 patients recruited, 266 analysed). In addition, treatment-related complications of thiotepa-based IC-ASCT were analysed from the source files of 85 patients from 3 centers. Patients had received IC-ASCT either in first-line treatment (n = 147) or at relapse (n = 119). The median age at IC-ASCT was 57 years (range: 22–74). IC consisted of thiotepa-BCNU (n = 64), thiotepa-busulfan (n = 24), BCNU-etoposide-cytarabine-melphalan (BEAM, n = 36) and thiotepa-busulfan-cyclophosphamide (n = 142). In multivariate analysis, BEAM and ASCT beyond the first relapse were adverse prognostic factors for relapse risk. The risk of treatment-related mortality was higher for ASCT performed beyond the first relapse and seemed higher for thiotepa-busulfan-cyclophosphamide. Thiotepa-BCNU tends to result in a higher relapse rate than thiotepa-busulfan-cyclophosphamide and thiotepa-busulfan. This study confirms the role of IC-ASCT in first-line treatment and at first-relapse PCNSL (5-year overall survival rates of 80 and 50%, respectively). The benefit/risk ratio of thiotepa-busulfan/thiotepa-busulfan-cyclophosphamide-ASCT could be improved by considering ASCT earlier in the course of the disease and dose adjustment of the IC.

Busulfan (Bu) is the cornerstone of conditioning regimens prior to hematopoietic stem cell transplantation, widely used in both adults and children for the treatment of malignant and nonmalignant diseases. Despite an intravenous formulation, interindividual variability (IIV) remains high and optimal exposure difficult to achieve, especially in neonates and infants.

Background LentiGlobin gene therapy contains autologous CD34+ hematopoietic stem cells (HSCs) transduced with the BB305 lentiviral vector (LVV), encoding human β-globin with a T87Q substitution. This substitution confers anti-sickling properties to the gene therapy-derived hemoglobin (HbAT87Q) and allows for its quantification in transduced HSCs. The proof of concept for LentiGlobin gene therapy in patients with transfusion-dependent β-thalassemia (TDT) and sickle cell disease (SCD) was established in the recently completed HGB-205 study (NCT02151526). Herein, we provide the safety and efficacy outcomes and long-term follow-up data for all 7 treated patients, 4 with TDT and 3 with SCD. Methods Patients 5−35 years old with TDT (≥ 100 mL/kg of packed red blood cells [pRBCs]/year) or severe SCD (e.g., ≥ 2 acute chest syndromes [ACS] or ≥ 2 vaso-occlusive crises in the preceding year or the year before regular transfusions) were enrolled. CD34+ HSCs were obtained by mobilization and apheresis in patients with TDT or by bone marrow harvest in patients with SCD. Following collection, cells were transduced with the BB305 LVV. Patients underwent busulfan myeloablative conditioning and were infused with transduced cells. Patients were monitored for engraftment, adverse events (AEs), HbAT87Q levels, and other hematologic and clinical parameters. After 2 years in HGB-205, patients transitioned into the long-term follow-up study, LTF-303 (NCT02633943). Summary statistics are shown as median (min-max). Results As of June 2019, patients with TDT (n=4) and SCD (n=3) had a median follow-up of 49.6 (40.5-60.6) and 28.5 (25.5-52.5) months, respectively. Table 1 shows patient and drug product characteristics and several key efficacy outcomes. All patients achieved HSC engraftment. LentiGlobin safety profile was consistent with busulfan myeloablative conditioning and, in case of SCD, with the underlying disease state. The most common non-hematologic Grade ≥ 3 AEs post-LentiGlobin gene therapy (≥ 2 patients) for patients with TDT were stomatitis (n=4) and increased aspartate aminotransferase (n=2), and for patients with SCD were ACS (n=2) and vaso-occlusive pain (n=2). In all 4 patients with TDT, total Hb and HbAT87Q levels remained generally stable up to 5 years post-LentiGlobin infusion. Three of 4 patients achieved transfusion independence (TI; defined as weighted average Hb ≥ 9g/dL without pRBC transfusions for ≥ 12 months), for an ongoing duration of 56.3 (38.2-57.6) months. Weighted average total Hb during TI was 11.4 (10.5-13.0) g/dL. One patient has been off transfusions for 37.5 months and had total Hb of 7.7 g/dL, which was below the ≥ 9 g/dL requirement to meet the protocol definition of TI. At last visit, HbAT87Q levels in these 4 patients ranged from 6.2-11.2 g/dL, which contributed 73.8-86.8% of the total Hb. The first patient treated with LentiGlobin for SCD experienced one vaso-occlusive pain episode, which developed at 30 months after LentiGlobin gene therapy following a case of acute gastroenteritis with fever and dehydration. The second SCD patient had 2 serious AEs (SAEs) of ACS approximately 6 and 8 months after LentiGlobin gene therapy. The patient resumed chronic pRBC transfusions and hydroxyurea treatment and subsequently experienced 2 SAEs of vaso-occlusive pain; no additional SAEs of vaso-occlusive pain or ACS were reported during the last 16 months of follow-up after LentiGlobin infusion. The third SCD patient had no episodes of vaso-occlusive pain or ACS during 25.5 months of follow-up post-LentiGlobin gene therapy as of the data cut-off. Two patients with SCD who have been off chronic pRBC transfusions, showed improvement in hemolysis markers post-LentiGlobin treatment and stabilization of HbAT87Q expression at approximately 6 months post-LentiGlobin infusion. Total Hb levels for patients with SCD at last visit were 13.0 g/dL (patient 1), 9.4 g/dL (patient 2), and 9.8 g/dL (patient 3), with corresponding HbAT87Q contributions of 47.9%, 7.9%, and 25.8%, respectively. Summary With up to 5 years of follow-up, treatment with LentiGlobin gene therapy was well tolerated and resulted in improvement in hematologic parameters and disease-related symptoms. Further results from the completed study will be presented. Disclosures Hermine: Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Honoraria, Research Funding. Brousse:bluebird bio, Inc: Consultancy; AddMedica: Consultancy. El Nemer:Hemanext: Other: Other. Bartolucci:Novartis: Membership on an entity's Board of Directors or advisory committees; AddMedica: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; HEMANEXT: Membership on an entity's Board of Directors or advisory committees. Asmal:bluebird bio, Inc: Employment, Equity Ownership. Whitney:bluebird bio, Inc: Employment, Equity Ownership. Gayron:bluebird bio, Inc: Employment, Equity Ownership. Huang:bluebird bio, Inc.: Employment, Equity Ownership. de Montalembert:AddMedica: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ribeil:bluebird bio, Inc: Employment, Equity Ownership. Cavazzana:SmartImmune: Other: Founder.

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for some inherited disorders, including selected primary immunodeficiencies (PIDs). In the absence of a well-matched donor, HSCT from a haploidentical family donor (HIFD) may be considered. In adult recipients high-dose post-transplant cyclophosphamide (PTCY) is increasingly used to mitigate the risks of graft failure and graft-versus-host disease (GVHD). However, data on the use of PTCY in children (and especially those with inherited disorders) are scarce. We reviewed the outcomes of 27 children transplanted with an HIFD and PTCY for a PID (n = 22) or osteopetrosis (n = 5) in a single center. The median age was 1.5 years (range, .2 to 17). HSCT with PTCY was a primary procedure (n = 21) or a rescue procedure after graft failure (n = 6). The conditioning regimen was myeloablative in most primary HSCTs and nonmyeloablative in rescue procedures. After a median follow-up of 25.6 months, 24 of 27 patients had engrafted. Twenty-one patients are alive and have been cured of the underlying disease. The 2-year overall survival rate was 77.7%. The cumulative incidences of acute GVHD grade >= II, chronic GVHD, and autoimmune disease were 45.8%, 24.2%, and 29.6%, respectively. There were 2 cases of grade III acute GVHD and no extensive cGVHD. The cumulative incidences of blood viral replication and life-threatening viral events were 58% and 15.6%, respectively. There was evidence of early T cell immune reconstitution. In the absence of an HLA-identical donor, HIFD HSCT with PTCY is a viable option for patients with life-threatening inherited disorders. (C) 2019 American Society for Blood and Marrow Transplantation.

Objectives. - Because of gastric hypersecretion and/or high water-electrolytes losses, some patients require ranitidine in their parenteral nutrition (PN) mixture. Our goal was to reassess the clinical utility of adding ranitidine in NP mixtures following tensions in the supply of ranitidine for parenteral injection. Patients and methods. - A prospective clinical follow-up of patients on home parenteral nutrition (HPN) over a period of 4 months was carried out according to three criteria: "stopping", "substituting" or "maintaining" ranitidine in NP prescriptions. Results. - At the beginning of the study, 109 patients were followed on HPN program. Most of them (48 %) having short bowel syndrome (SBS). Initially, 64 patients were receiving ranitidine in association with PN. Attempt to stop IV Ranitidine was achieved in 23 patients (36 %): 2 failures led to reverse to the initial prescription. The change to the oral route involved 22 patients (34 %) with 4 failures. These failures occurred shortly after modifications, with nausea/vomiting, increased water-electrolytes losses in SBS patients. On 19 patients (30 %), ranitidine was maintained, due to insufficient intestinal absorption from children with extreme SBS, extended Hirschsprung Disease, and Chronic Intestinal Pseudo Obstruction. Conclusion. - A review of ranitidine prescriptions was conducted according to specific clinical profiles of patients. Ranitidine appears necessary for patients with severe digestive disorders. Nevertheless, an oral administration of ranitidine can be considered with clinical monitoring. (C) 2018 Association pour le developpement de la recherche en nutrition (ADREN). Published by Elsevier Masson SAS. All rights reserved.

Sickle cell disease results from a homozygous missense mutation in the β-globin gene that causes polymerization of hemoglobin S. Gene therapy for patients with this disorder is complicated by the complex cellular abnormalities and challenges in achieving effective, persistent inhibition of polymerization of hemoglobin S. We describe our first patient treated with lentiviral vector–mediated addition of an antisickling β-globin gene into autologous hematopoietic stem cells. Adverse events were consistent with busulfan conditioning. Fifteen months after treatment, the level of therapeutic antisickling β-globin remained high (approximately 50% of β-like–globin chains) without recurrence of sickle crises and with correction of the biologic hallmarks of the disease. (Funded by Bluebird Bio and others; HGB-205 ClinicalTrials.gov number, NCT02151526.)

Background: LentiGlobin Drug Product (DP) contains autologous CD34+ cells transduced with the betibeglogene darolentivec (BB305) lentiviral vector, encoding a human β-globin gene with a point mutation (AT87Q) that confers anti-sickling properties similar to those with γ-globin. Human proof of concept for LentiGlobin treatment in transfusion-dependent β-thalassemia (TDT) and severe sickle cell disease (SCD) has been established in HGB-205 (NCT02151526), the original clinical study of gene therapy for hemoglobinopathies. Here, we provide an update on 5 previously-reported patients (4 TDT, 1 SCD) as well as early data from 2 additional treated patients with SCD.

Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the molecular biology of cancer cell has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents being more specific to cancer cells were expected to be less toxic than cytotoxic agents. Targeted agents have provided clinical benefit in many GI cancer types. For example, antiangiogenics and anti-EGFR therapies have significantly improved survival of patients affected by metastatic colorectal cancer and have deeply changed the therapeutic strategy in this disease. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms (e.g., RAS mutation for anti-EGFR therapies), or to an activity restricted to some tumour settings (e.g., lack of activity in other cancer types, or on the microscopic residual disease in adjuvant setting). Many studies are negative in overall population but positive in some specific patient subgroups (e.g., trastuzumab in HER2-positive gastric cancer), illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this first part, we will focus on adenocarcinomas and squamous cell carcinomas, for which targeted therapies are mostly used in combination with chemotherapy.

Abstract Purpose: Activating KRAS mutations are frequent (>90%) in pancreatic ductal adenocarcinoma (PDAC) and drive downstream deregulation of both MAPK and PI3K-mTOR pathways. MEK inhibitors (MEKi) are under clinical evaluation in PDAC, in combination with other agents including PI3K-mTOR inhibitors. While RAS and BRAF mutations, EMT, PI3K-mTOR activation, and pERK inhibition have been suggested as predictive markers for MEKi efficacy, they are not validated in PDAC. We aimed to explore the cellular and molecular effects of MEKi GSK1120212 (GSK212) alone or in combination with PI3K-mTOR inhibitors, in PDAC cell lines and on an innovative ex vivo system. Methods: GSK212 is an allosteric non-ATP competitive MEKi, everolimus (Ev) a mTORC1 inhibitor, and BKM120 a pan-class PI3K inhibitor. Effects on proliferation were evaluated by MTT assay. Combinations were analyzed by the Chou-Talalay method. Protein expression was assessed by Western blot. Ex vivo drug assays were performed at different drug concentrations on cultures of fresh tumor tissue slices prepared from patient surgical specimens. Apoptosis and proliferation were assessed by cleaved caspase 3 (Cas-3) and MIB-1 (Ki67) immunostainings, respectively; MEKi sensitivity was defined as cleaved Cas-3 expression in 30% or more of cancer cells. Correlations between protein expressions were explored using linear regression and Pearson’s R2 calculation. Samples will be classified into PDAC subtypes according to Collisson’s, Moffit’s and Bailey’s transcriptomic signatures using non-negative matrix factorization and correlation methods. Results: MIAPaCa-2 and PANC-1 are two mesenchymal KRAS mutated/BRAF wild-type PDAC cell lines with very different response to GSK212, MIAPaCa-2 being sensitive (72h-IC50=0.009µM) and PANC-1 resistant (72h-IC50=33µM). MIAPaCa-2 was more sensitive than PANC-1 to Ev (IC50=23.3µM vs 47.0µM) and BKM120 (IC50=4.19µM vs 31.6µM). Combination of GSK212 and Ev or BKM120 for 72h resulted in synergistic effects (CI<1) in MIAPaCa-2 (MEKi sensitive) but not in PANC-1. GSK212 (0.1µM) treatment resulted in pERK extinction in both cell lines but in decreased pS6 expression only in MIAPaCa-2. Combination therapy led to extinction of pERK and pS6 in both cell lines. Apoptosis induction in MIAPaCa-2 was confirmed by PARP cleavage. Eleven tumor specimens were cultured ex vivo. We observed that: (a) GSK212 (0.1µM) treatment for 48h induced significant (≥30%) apoptosis concomitantly with a decrease in pS6 expression in MEKi sensitive tumors; (b) Ev (1µM) or BKM120 (0.1µM) exerted antiproliferative effects but did not induce apoptosis; (c) combinations resulted in higher apoptosis induction associated with a higher decrease in pS6 expression compared to MEKi alone in MEKi sensitive tumors. In sensitive tumors, cleaved Cas-3 induction was inversely correlated with pS6 expression under treatment by MEKi +/- Ev or BKM120. A R2>0.50 discriminated between sensitive and resistant tumors. There was no correlation with RAS/RAF mutation status. Predictive value of transcriptomic signatures for MEKi response will be presented. Conclusion: Response to combined MEK/mTOR pathway inhibition was not correlated with known biomarkers of response to MEKi. Besides the therapeutic potential of MEK/mTOR pathway inhibition in PDAC, this work provides the first evidence of feasibility of pharmacodynamic biomarker monitoring on fresh PDAC tissue slices. Citation Format: Cindy Neuzillet, Annemilaï Tijeras-Raballand, Anguraj Sadanandam, Pierre Bourgoin, Philippe Bourget, Pawan Poudel, Maria Serova, Armand De Gramont, Philippe Ruszniewski, Valérie Paradis, Eric Raymond, Jérôme Cros, Pascal Hammel.{Authors}. Effects of MEK inhibition alone or in combination with PI3K-mTOR pathway inhibitors in pancreatic ductal adenocarcinoma in vitro and on an innovative ex vivo fresh tumor tissue culture model. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B57.

In patients with hemoglobinopathies, transduction of hematopoietic stem cell (HSC) with a β-globin gene may induce production of functional β-globin, potentially reducing or eliminating disease symptoms. LentiGlobin™ BB305 Drug Product (DP), an investigational gene therapy product for the treatment of sickle cell disease (SCD) and β-thalassemia (βT), consists of autologous CD34+ cells transduced with the BB305 lentiviral vector. BB305 is a replication defective, self-inactivating vector using erythroid-specific globin gene regulatory elements. The vector carries an HBB gene with an anti-sickling amino acid substitution found in γ globin (T87Q) that also allows for HPLC monitoring of transgene globin levels in the subjects’ blood. HGB-205 is a phase 1/2 clinical study of safety and efficacy of LentiGlobin BB305 DP in severe SCD and transfusion-dependent βT. Subjects undergo HSC collection via bone marrow harvest (SCD) or mobilization and apheresis (βT). CD34+ cells are selected and transduced with BB305 vector to produce the DP. Subjects undergo myeloablation with IV busulfan followed by DP infusion. As of 11/10/15, 5 subjects had been treated: 1 SCD and 4 βT. No replication competent lentivirus has been detected and integration site analysis shows polyclonal reconstitution without clonal dominance at all time points to date (follow-up between 2 and 23 months). No subjects have experienced drug product-related adverse events; safety observations to date are consistent with myeloablative conditioning. The subject with SCD received 5.6 × 106 CD34+ cells/per kg from two DP lots with VCN of 1.0 and 1.2. He achieved neutrophil engraftment on Day +37 and platelet engraftment on Day +91. Prior to study treatment, he had been on prophylactic transfusions to manage severe SCD symptoms including multiple vaso-occlusive crises. He stopped transfusions at Day +88 and at 12 months post DP infusion had a total Hb of 11.7 g/dL, of which approximately 49% is anti-sickling hemoglobin (47%HbAT87Q, 2% HbF). This subject has had no post-infusion pain crises or SCD-related hospitalizations. For the βT subjects the cell dose infused was 8.8 to 13.6 × 106 CD34+ cells/per kg, with VCN between 0.8 and 2.1, with neutrophil engraftment at Day +13 to +28 and platelet engraftment at Day +17 to +24. The first two βT subjects treated had genotype β0/βE. They have been transfusion independent since ~2 weeks after DP infusion, with consistent levels of total Hb (>10g/dL) and HBAT87Q (7-8 g/dL and 9-10 g/dL). The third βT subject is homozygous for the IVS1 nt 110 G>A mutation. This subject at 4.5 months of follow-up had total Hb 8.0 g/dL and had gone ~2 months without transfusion. The fourth βT subject (β0/βE) has less than 2 months follow-up. These interim data suggest that gene therapy with LentiGlobin DP is a promising potential treatment for severe SCD and transfusion-dependent βT.

beta-globin gene disorders are the most prevalent inherited diseases worldwide and result from abnormal beta-globin synthesis or structure. Novel therapeutic approaches are being developed in an effort to move beyond palliative management. Gene therapy, by ex vivo lentiviral transfer of a therapeutic beta-globin gene derivative (beta(AT87Q)-globin) to hematopoietic stem cells, driven by cis-regulatory elements that confer high, erythroid-specific expression, has been evaluated in human clinical trials over the past 8 years. beta(AT87Q)-globin is used both as a strong inhibitor of HbS polymerization and as a biomarker. While long-term studies are underway in multiple centers in Europe and in the United States, proof-of-principle of efficacy and safety has already been obtained in multiple patients with beta-thalassemia and sickle cell disease.

The incidence of urinary tract infections caused by extended-spectrum beta-lactamase (ESBL)-producing pathogens is increasing. These infections are associated with a long hospital stay in patients undergoing urological procedures. We aimed to demonstrate that significant intraprostatic diffusion of ertapenem is achieved after a single preoperative administration. A referred sample of 19 patients requiring surgery for benign prostatic hyperplasia was prospectively included. Patients received a 1 g intravenous (i.v.) dose of ertapenem 1 h (n = 10, group A) or 12 h (n = 9, group B) before blood and prostatic samples were collected. Plasma and intraprostatic concentrations of ertapenem were measured using LC-MS/MS. Intraprostatic concentrations were considered satisfactory when higher than the MIC90 value of urinary-targeted pathogens perioperatively and for 40% of the dosing interval. The Wilcoxon test and a pharmacokinetic predictive model were used. Median plasma concentrations of ertapenem were 144.3 mg/L (95% CI 126.5-157.9) in group A and 30.7 mg/L (95% CI 22.9-36.4) in group B (P < 0.001); median intraprostatic concentrations were 16.6 mg/L (95% CI 13.3-31.4 mg/L) and 4.2 mg/L (95% CI 3.1-4.9 mg/L), respectively (P < 0.001), which were above the MIC90 values of bacteria, including ESBL-producers, during surgery and for 40% of the dosing interval. The plasma-to-prostate concentration ratio was not significantly different between groups (P = 0.97). Single-dose i.v. ertapenem reached satisfactory intraprostatic concentrations, suggesting that it could be a relevant prophylactic strategy for carriers of ESBLproducing bacteria undergoing prostatic procedures, which needs to be confirmed by further prospective trials. (C) 2016 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

The use of midostaurin, a multikinase inhibitor, has been associated with a response in 60% of patients with systemic mastocytosis, including mast-cell leukemia; the median overall survival was 28 months. A second, smaller trial in France showed a 71% response rate.

Purpose: Musculoskeletal disorders (MSD) remain the most common occupational disease in the Western countries. Beside the effects on workers themselves, MSDs may lead to high costs to enterprises and the society as a whole. Among the painful or tiring positions encountered in healthcare settings, caregivers often cite the filling of portable infusion pumps (PIP). This context was conducive to achievement of the goal of the following project: the development of a motorized apparatus designed to minimize the risk of MSDs caused by repeated gestures of filling PIPs.

Introduction: β-globin gene transfer into hematopoietic stem cells (HSCs) has the potential to reduce or eliminate the symptoms of severe sickle cell disease (SCD) and reduce or eliminate transfusion requirements in transfusion-dependent β-thalassemia (TDT). LentiGlobin Drug Product (DP) contains autologous CD34+ cells transduced with the BB305 lentiviral vector, which encodes a human β-globin gene containing a single point mutation (AT87Q) designed to confer anti-sickling properties similar to those observed with γ-globin. We previously reported proof of concept for LentiGlobin DP treatment in severe SCD and early data from 4 treated patients with TDT. We now report 18 months of follow-up for the patient with SCD and between 9 and 30 months of follow-up for the 4 patients with TDT. Patients (5-35 years of age) with severe SCD (e.g. ≥2 acute chest syndrome episodes or ≥2 vaso-occlusive crises [VOC] in preceding year/in year prior to regular transfusions) or TDT (≥100mL/kg of packed red blood cells [RBCs] per year) were enrolled. Following mobilization and apheresis (for TDT) or bone marrow harvest (for SCD), autologous CD34+ cells were transduced with the BB305 lentiviral vector. Patients underwent myeloablative conditioning with busulfan prior to infusion of the transduced cells. After infusion, patients were monitored for hematologic engraftment, vector copy number (VCN), and HbAT87Q expression. Disease-specific assessments included transfusion requirements for TDT, or VOCs and hospitalizations for SCD. Safety assessments included adverse events (AEs) and integration site analysis. Results: As of July 2016, 1 patient with severe SCD (male; 13 years old) and 4 patients with TDT (2 male, 2 female; 16-19 years old) have received LentiGlobin DP in Study HGB-205. The median LentiGlobin DP cell dose was 8.9 (range 5.6-13.6) x 106 CD34+ cells/kg with a DP VCN of 1.2 (range: 0.8-2.0) vector copies/diploid genome. Median post-infusion follow-up as of July 6, 2016 is 20.8 months (range 9.5-31.3). All subjects successfully engrafted after receiving LentiGlobin DP, with a median time to neutrophil engraftment of 17 days (range 14-38 days). VCN in peripheral blood has remained generally consistent from Month 3 in all patients with a range of 0.2 to 3.4 at last measurement. The toxicity profile observed from start of conditioning to latest follow-up remains consistent with myeloablative conditioning with single-agent busulfan, with no DP-related ≥Grade 3 AEs or serious AEs and no evidence of clonal dominance reported to date. Three patients with TDT have β0/βE genotypes and 1 is homozygous for the severe β+ mutation IVS1 nt 110 G>A. The 2 patients who have completed the 2-year primary follow-up period (both β0/βE) have not required RBC transfusions for 31 and 28 months, with total Hb of 10.9 and 13.5 g/dL, and HbAT87Q expression of 7.7 and 10.1 g/dL, respectively, at most recent study visit. Iron chelation has been discontinued and phlebotomy initiated for 1 of the patients. The remaining patient with β0/βE genotype has 9 months of follow-up and has not required transfusions since 4 days post-LentiGlobin DP infusion, achieving a total Hb of 11.3 g/dL at last study visit. The patient with the severe IVS1 genotype has 12 months of follow-up and has been free of transfusions for 9 months, with a total Hb of 8.3 g/dL at last study visit. The patient with severe SCD, who prior to study enrollment received regular RBC transfusions, has experienced no clinical symptoms or complications of SCD in the 18 months since treatment, despite discontinuing transfusions 3 months after LentiGlobin DP infusion. Total Hb in this patient was 12.5 g/dL, with 6.6 g/dL HbAT87Q (53%) and 5.7 g/dL HbS (45%) at last study visit. Compared with values at screening, unconjugated bilirubin had dropped 78% (50 to 11 μmol/L), lactate dehydrogenase had dropped 54% (626 to 287 U/L), and reticulocyte count had dropped 45% (238x109/L to 132x109/L) by Month 18. Conclusions: Data from this ongoing Phase 1/2 clinical study suggest that treatment with LentiGlobin DP can result in sustained production of therapeutic HbAT87Q, which ameliorates the clinical and biochemical effects of severe SCD and TDT, with an acceptable safety profile. Gene therapy presents a potentially promising therapy for patients with severe hemoglobinopathies. Further follow-up and additional data from patients are needed to confirm the encouraging results seen to date in this study. Disclosures Ribeil:Bluebirdbio: Consultancy; Addmedica: Research Funding. Payen:bluebird bio: Patents & Royalties. Hermine:Alexion: Research Funding; Celgene: Research Funding; Novartis: Research Funding; AB science: Consultancy, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding, Speakers Bureau. Asmal:bluebird bio: Employment, Equity Ownership. Joseney-Antoine:bluebird bio: Employment, Equity Ownership. De Montalembert:Addmedica: Research Funding; Novartis: Research Funding, Speakers Bureau. Leboulch:bluebird bio, Inc: Consultancy, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Background: In patients with hemoglobinopathies, hematopoietic stem cell (HSC) gene therapy has the potential to induce production of functional β-globin in the red blood cell lineage with the aim of reducing or eliminating the symptoms of disease. Previous results from 1 subject with severe sickle cell disease (SCD; 6 months follow-up) and 2 subjects with β0/βE-thalassemia major (up to 15 months follow-up) treated in clinical study HGB-205 suggested that transplantation with autologous CD34+ cells transduced with the LentiGlobin BB305 lentiviral vector containing an engineered βA-T87Q-globin gene (LentiGlobin BB305 Drug Product) resulted in near-normal levels of total hemoglobin (Hb) and rapid clinical improvement. Here we provide data on a new subject enrolled and additional follow-up data on the 3 subjects previously presented in Study HGB-205.