bluuebunny/crossref_metadata_2025_split huggingface dataset:
PRT064445 but Not Recombinant Fviia Reverses Rivaroxaban Induced Anticoagulation As Measured by Reduction in Blood Loss in a Rabbit Liver Laceration Model
Authors: Hollenbach Stanley J , Lu Genmin , Tan Siusze , Lee Gail , Athiwat Hutchaleelaha , Inagaki Mayuko , Sinha Uma 
Published: October 2019

Abstract
Abstract 3414
We used a modified rabbit liver laceration model to demonstrate the effects of PRT064445, a recombinant fXa derivative, to reverse rivaroxaban induced anticoagulation as measured by reduction of blood loss, decrease of unbound fraction of rivaroxaban in plasma and relevant pharmacodynamic markers: anti-fXa activity, prothrombin (PT) and activated thromboplastin (aPTT) times. Recombinant fVIIa (rfVIIa) was tested in the same model for comparison.
Anesthetized rabbits were administered vehicle or 1 mg/kg rivaroxaban via IV bolus injection. After 30 minutes to allow the rivaroxaban to biodistribute, vehicle, PRT064445 or rfVIIa was administered as a bolus injection followed by laceration of two liver lobes (5× each lobe: 1-cm long and 3-mm deep incisions with scalpel blade) and blood loss collected on pre-weighed gauze over 15 minutes. Blood loss due to rivaroxaban anticoagulation represented approximately 10% of the animal's total blood volume. Total rivaroxaban concentration in plasma was measured by LC-MS/MS. Free fraction of rivaroxaban (non-protein, non-PRT064445 bound) was assessed using equilibrium dialysis method followed by LC-MS/MS quantitation. Anti-fXa activity was measured using a modified chromogenic LMW heparin kit. PT and aPTT was measured using commercial reagents (HemosIL). Anticoagulation by rivaroxaban (1.65 μM average plasma concentration at 30 min time point) resulted in 2.3-fold and 1.9-fold prolongation of PT and aPTT, respectively, and increased blood loss by 3.2-fold over vehicle. PRT064445 (75 mg/rabbit) administration reduced blood loss due to rivaroxaban anticoagulation by >85% and decreased peak anti-fXa activity by 98%, PT by 74%, aPTT by 66% and the free fraction of rivaroxaban in plasma from 26% to <0.5%. In contrast, rfVIIa (150 μg/kg) had no effect on blood loss but reversed PT by 85% and aPTT by 54%. PRT064445 and rfVIIa alone had no effect on blood loss, but rfVIIa decreased PT by 35%.
These data demonstrate that PRT064445 can reduce blood loss due to rivaroxaban induced anticoagulation using a single bolus administration. Reduction of blood loss with PRT06445 correlated to the decrease in the free fraction of rivaroxaban in plasma as well as PD markers anti-fXa activity and PT, while rfVIIa decreased PT but had no effect on blood loss. These and our previous data with reversal of enoxaparin-induced anticoagulation in a rat tail transection model indicate that PRT064445 can be used as a universal antidote for both direct and indirect fXa inhibitors.

Disclosures:
Hollenbach: Portola Pharmaceuticals: Employment. Lu:Portola Pharmaceuticals: Employment. Tan:Portola Pharmaceuticals: Employment. Lee:Portola Pharmaceuticals: Employment. Athiwat:Portola Pharmaceuticals: Employment. Inagaki:Portola Pharmaceuticals: Employment. Sinha:Portola Pharmaceuticals Inc.: Employment.
Identification of Novel Adult Mesenchymal Progenitors That Can Contribute to HSC Niche
Authors: Hu Xingbin , Weng Lihong , Jung Xiaoman , Murakami Jodi , Kumar Bijender , Chen Ching-Cheng 
Published: October 2019

Abstract
Abstract 3467
The microenvironment (niche) cues hematopoietic stem cell (HSC) receives play an important role in the regulation of their decisions between self-renewal and differentiation. However, the cellular constitution of niches remains poorly understood. We identified three adult progenitor populations near the endosteum based on differential expression of cell surface markers, including CD166, CD146 and Sca1. Upon co-transplantation with fetal skeletal progenitors, Sca1+ progenitors can give rise to CD146+ and CD166+ stroma and phenotypically CXCL12 abundant reticular (CAR) cells in marrow. CD146+ and CD166+ progenitors, on the other hand, form bone without marrow cavity. Multiplex single cell qRT-PCR reveals all three progenitors expressed high levels of genes involved in HSC maintenance. In vitro co-culture assay demonstrated that all three progenitors could preserve HSC long-term multi-lineages reconstitution capability. Furthermore, disruption of stem cell factor (SCF) production in Sca1+ progenitor severely limits its ability to support HSC both in culture condition and after transplantation. Our results suggested that Sca1+, CD146+, and CD166+ mesenchymal progenitors and their progeny collaborate to provide supportive environment for hematopoiesis.

Disclosures:
No relevant conflicts of interest to declare.
CD19 Targeted Allogeneic EBV-Specific T Cells for the Treatment of Relapsed ALL in Pediatric Patients Post HSCT
Authors: Curran Kevin J. , Kernan Nancy A. , Wang Xiuyan , Taylor Clare , Doubrovina Ekaterina , Bartido Shirley , Sadelain Michel , O'Reilly Richard J. , Brentjens Renier J , Rivière Isabelle 
Published: October 2019

Abstract
Abstract 353
T cells can be genetically modified to target tumor antigens through the expression of a chimeric antigen receptor (CAR). CAR modified T cells targeting the CD19 antigen is a novel therapeutic approach for patients with relapse B-ALL following allo-HSCT. We have previously demonstrated donor derived Epstein-Barr virus specific cytotoxic T cells (EBV-CTLs) can be safely infused in patients following allo-HSCT. Following retroviral gene transfer with our CD19-specific CAR (19–28z), EBV-CTLs demonstrate in vitro cytotoxicity against CD19+ targets, retain EBV-specificity without allogeneic reactivity, and in vivo, eradicate systemic Burkitt lymphoma in a SCID/Beige murine model. Based on our preclinical studies we have initiated a phase I dose escalation clinical trial (NCT01430390) in pediatric patients with relapsed CD19+ B-ALL following allo-HSCT utilizing donor 19–28z+ EBV-CTLs. Three patients have received conditioning chemotherapy (fludarabine 25mg/m2 × 5 days) followed by infusion of CAR modified EBV-CTLs without infusion related toxicity. Subsequently, patient 1 and 3 safely received additional T cell infusions without (patient 1) and with (patient 3; cyclophosphamide) conditioning chemotherapy. Total CAR+ T cell dose for each infusion ranged from 1.4 – 4.1×105 cells/kg (1×106 total EBV-CTLs/kg per infusion). Patient 1 developed fever and biopsy proven skin GVHD (grade II) three days following his first infusion which resolved 2 weeks after starting topical steroids. Modified T cells were detected by Q-PCR in the bone marrow and peripheral blood up to 3 and 18 weeks respectively in patient 1 following first infusion, up to 2 weeks in the peripheral blood in patient 2, and have been below the limit of detection in patient 3. Patient 1 died from progressive disease 29 weeks following first infusion and patient 2 died from progressive disease 19 weeks post infusion. Patient 3, initially treated in remission following salvage chemotherapy, has no evidence of disease (NED) 15 months after last extramedullary relapse and 5 months post first infusion of 19–28z+ EBV-CTLs. These early results demonstrate the feasibility of allogeneic 1928z+ EBV-CTL infusions without the development of significant GVHD post allo-HSCT. Subsequent cohorts of patients will receive dose escalation of modified T cells and will be evaluated for safety, persistence of 19–28z+ EBV-CTLs, and for anti-tumor efficacy.

Disclosures:
No relevant conflicts of interest to declare.
Phenothiazines Induce Apoptosis in T-Cell Acute Lymphoblastic Leukemia by Activating the Phosphatase Activity of the PP2A Tumor Suppressor
Authors: Gutierrez Alejandro , Kentsis Alex , Pan Li , Baleydier Frederic , Marineau Jason , Grebliunaite Ruta , Kozakewich Elena , Reed Casie , Pflumio Francoise , Poglio Sandrine , Uzan Benjamin , Clemons Paul A. , VerPlank Lynn , An W. Frank , Burbank Jason , Norton Stephanie , Tolliday Nicola J , Steen Hanno , Bradner James E , Look A. Thomas , Aster Jon C 
Published: October 2019

Abstract
Abstract 3558
Despite the use of intensive and toxic treatment regimens, T-cell acute lymphoblastic leukemia (T-ALL) remains fatal in 25% of children and 60% of adults, highlighting the need for novel therapeutic strategies. We performed two complementary small molecule screens to identify novel T-ALL therapeutic agents: i) an in vivo zebrafish screen for small molecules toxic to MYC-overexpressing thymocytes, and ii) an in vitro screen for drugs that synergize with NOTCH inhibitors in human T-ALL cell lines. Hits common to both screens included perphenazine, an FDA-approved phenothiazine antipsychotic. Perphenazine potently induced mitochondrial apoptosis and had antileukemic activity in zebrafish T-ALL, in human T-ALL cell lines, and in primary human T-ALL lymphoblasts. However, the molecular target mediating the antileukemic activity of perphenazine appeared to be unrelated to any of its known cellular targets. To identify the relevant biologic target of perphenazine, we developed a novel method for drug target discovery, termed activity correlation proteomics, which combines native protein extraction of isotope-labeled proteomes, fluorous affinity chromatography, and quantitative mass spectrometry proteomics to relate phenotypic activities of drugs with their binding targets. Using activity correlation proteomics, we identified protein phosphatase 2A (PP2A) as the protein whose binding affinity for different phenothiazines most closely correlated with their antileukemic activity. Perphenazine was shown to activate PP2A in T-ALL cells, as assessed by rapid drug-induced dephosphorylation of multiple PP2A substrates including MYC, AKT, p70S6K, ERK, and BAD, and its effects were phenocopied by FTY720, a PP2A activator. Moreover, shRNA knockdown of PP2A scaffolding or catalytic subunits attenuated the activity of perphenazine, indicating that PP2A is required for its antileukemic activity. Our findings thus establish a novel strategy for pharmacologic activation of the PP2A tumor suppressor, and highlight its therapeutic potential in T-ALL and other cancers driven by hyperphosphorylated PP2A substrates.

Disclosures:
Off Label Use: Discovery of antileukemic activity of perphenazine mediated via activation of PP2A.
Maintenance Hypomethylating Therapy Post Allogeneic Stem Cell Transplantation Provides Favorable Progression Free Survival in High Risk Acute Myelogenous Leukemia or Non Responsive Myelodysplastic Syndrome
Authors: Sizemore Connie A. , Zhang Xu , Sanacore Melissa , Bashey Asad , Solomon Scott R. , Morris Lawrence E. , Holland H. Kent 
Published: October 2019

Abstract
Abstract 4468

Introduction
Patients with acute myelogenous leukemia (AML) or non responsive myelodysplastic syndrome (MDS) who fail to achieve a complete remission, have unfavorable cytogenetics or are refractory to therapy have a poor prognosis. Allogeneic HSCT is frequently considered a salvage option for these patients although remissions are short-lived. New strategies are needed for maintaining remission in this extremely high risk patient group. We hypothesized hypomethylating agents post allogeneic HSCT would enable patients to remain in complete remission.

Methods
Eleven patients were treated. Patient characteristics: median age, 48 years (range, 18–70 years), PBSC (n=9) or bone marrow (n=2); Diagnoses AML= 10, Non- responsive MDS=1, CIBMTR disease risk category: High [n=8], Intermediate [n=1], Low [n=2]; 36% of the patients had primary induction failure, 54% had complex molecular abnormalities with 18% of the patients having deletion 11q 23 molecular abnormality. Donors were unrelated (36%) and related (64%). All but 1 donor-recipient pairs were fully matched. Preparative regimen- busulfan based (16mg/kg or equivalent) (82%), TBI ≥ 12 Gy (9%) based or reduced-intensity haplo-identical regimen (9%). The median number of prior chemotherapy regimens was 2.5 (range, 2–6). Azacitidine (n=10) or decitabine (n=1) was selected at physician discretion as a planned prophylactic regimen post allogeneic HSCT engraftment. Initial starting doses were based on hematological conditions at the time of therapy initiation.

Results
Ten patients received azacitidine subcutaneously daily for seven days for a median of 5 cycles (range, 1–10 cycles) and one patient received decitabine 20mg/m2 intravenously for 5 days for 3 cycles. Median initial Azacitidine dose of 50 mg/m2 (range, 25–75mg/m2) daily were given at a median of 40 days (range, 38–101 days) post HSCT engraftment. Azacitidine doses were increased based on counts to a maximum dose of 75mg/m2. With a median follow-up of 24 months (range, 1.7–49 months) 6 patients are alive in complete remission. Twenty-four month progression free survival is 51% with overall survival of 76%.

Conclusion
Given the dismal results of progression free survival and overall survival following allogeneic HSCT in high risk AML or non responsive MDS, hypomethylating agents given post transplantation provide a valuable approach to prolonging remission.

Disclosures:
No relevant conflicts of interest to declare.
Decreased Pulmonary Function in Asymptomatic Long Term Survivors After Busulfan-Based Myeloablative Allogeneic Hematopoietic Stem Cell Transplant
Authors: Oh Annie L. , Patel Pritesh R. , Saraf Santosh , Sweiss Karen , Peace David , Quigley John G. , Mahmud Nadim , Dudek Steven , Rondelli Damiano 
Published: October 2019

Abstract
Abstract 4474
Pulmonary function post allogeneic hematopoietic stem cell transplant (HSCT) can be impaired by previous exposure to chemotherapy, infection, or underlying chronic graft versus host disease (cGVHD). In this retrospective study, we selected 21 long term transplant survivors with a median follow up of 48 months who had received a related (60%) or unrelated (40%) HSCT conditioned with a myeloablative busulfan-based regimen. All patients had routine pulmonary function tests (PFTs) repeated within two years from transplant and none had respiratory symptoms or a history of chronic lung infection at the time of analysis.
Median age was 45 years (range 18–54). Patients had a diagnosis of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) (52%), acute lymphoblastic leukemia (ALL) (14%), chronic myeloid leukemia (CML) (14%), non-Hodgkin lymphoma (NHL) (9%), or chronic lymphocytic leukemia (CLL) (2%). Survival rate at the time of analysis is 90%.
We initially compared single parameters of PFTs including corrected diffusion limiting capacity of oxygen (DLCO), forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity (TLC) obtained before and after transplant. Post transplant, all PFT parameters showed some degree of reduction compared to pre-transplant values (Figure 1). FEV1 and FEV1/FVC were significantly decreased (108 vs 92,p=0.04 and 86 vs 80%, p=0.04, respectively). Median values of corrected DLCO prior to and after transplant were 83% (range 55–148) and 77%(range 44–146) (p=0.2), respectively.
In order to test whether patients with >10% reduction of PFTs had an increased rate of overall cGVHD, we analyzed intra-patient changes in DLCO and FEV1 values. We then divided patients into groups with extensive, limited, or no cGVHD. No correlation was found between the degree of cGVHD and FEV1 or DLCO values.
A decrease in pulmonary function was detected in patients who received a busulfan based myeloablative HSCT despite the absence of lung infection or pulmonary cGVHD. This finding, however, did not affect long term survival.

Disclosures:
No relevant conflicts of interest to declare.
Haploidentical Transplantation (HAPLO) with Post-Transplant High-Dose Cyclophosphamide for Graft Vs Host Disease (GVHD) Prevention in the Treatment of High Risk Hematological Neoplasms
Authors: Gayoso Jorge , Kwon Mi , Serrano David , Balsalobre Pascual , Anguita Javier , Pascual Cristina , Pérez-Corral Ana , Buno Ismael , Martinez-Laperche Carolina , Castilla-Llorente Cristina , Heras Inmaculada , Pascual Maria Jesus , Caballero Dolores , Diez-Martin Jose Luis 
Published: October 2019

Abstract
Abstract 4545

Introduction:
Allogeneic transplantation is the only curative option in the treatment of multiple high risk hematologic neoplasms. Only 25–30% of patients have an HLA identical sibling donor and searching for a compatible unrelated donor or cord blood renders satisfactory results in around 60–70%. Haploidentical transplantation (HAPLO) offers a therapeutic alternative to more than 95% of such patients with the advantages of quick availability, easy programming and a committed donor.

Patients and Methods:
We evaluate the results of HAPLO with a reduced intensity conditioning regimen (Fludarabine 30 mg/m2 ×5 days (-6 to -2), Cyclophosphamide 14,5 mg/kg ×2 days (-6 and -5), IV Busulfan 3,2 mg/kg × 1–3 days (BUX, days -4 to -2) employing high doses of Cyclophosphamide post graft infussion (50 mg/kg days +3 and +4) as GVHD prophylaxis together with standard doses of cyclosporine and mycophenolate from day +5.

Results:
From Dec-2007, we have done 26 HAPLO in 4 spanish centers. Median age was 38 years (16–57), 20 were male and all were in advanced phases of their diseases (12 Hodgkin′s, 6 AML, 3 ALL, 2 MM, 1 MDS, 1 MF y 1 NHL). Previous autologous HSCT has been employed in 13 and allogeneic HSCT in 6 (2 MURD and 4 UCB). Disease status at HAPLO was CR in 8, PR in 14 and refractory in 4. Bone marrow was used in 16 and unmodified peripheral blood in 10. The haploidentical donor was patient′s mother (8), father (3), siblings (11) or other relatives (4). BUX was used in 1 dose (15), 2 doses (8) or 3 doses (2) and TBI 200 cGy in 1 case. Mean neutrophils engraftment was achieved on day +18 (13–26) and platelets >50K on day +27 (17–150) in all but 2 cases of graft failure (7.7%) due to progression (MF) or relapse (M7-AML). Main toxicities were grade 1–2 mucositis in 50%, febrile neutropenia in 75% and CMV reactivations in 58% with a 100 days NRM of 3.8% (1/26, VOD and MOF) and 10% NRM at 6 months (2/20). Grade II-IV acute GVHD appeared in 10/23 patients at risk (43%) and grade III-IV in 4/23 (17%). Chronic GVHD affected to 4/15 (27%), being extensive in 1/15 (6.7%). With a median follow-up of 9 months (1–38), 13/22 (59%) are alive in CR, progression or relapse has ocurred in 6/24 (25%). Immune reconstitution seems fast and complete in those evaluated.

Conclusions:
HAPLO with high-dose cyclophosphamide as GVHD prophylaxis is a useful alternative in the treatment of high risk hematologic tumours, with low toxicity, acceptable GVHD incidence and severity, long lasting remissions, and fast immunological reconstitution.

Disclosures:
No relevant conflicts of interest to declare.
Tandem Autologous Stem Cell Transplantation in Chemorefractory Multiple Myeloma
Authors: Garnett Catherine , Giles Chrissy , Ahmed Osman , Lasa Maialen , Auner Holger W. , MacDonald Donald , Marks Sasha , Marin David , Milojkovic Dragana , Pavlu Jiri , Bua Marco , Abdalla Saad , Kanfer Edward J , Apperley Jane , Rahemtulla Amin 
Published: October 2019

Abstract
Abstract 4554
High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is currently standard treatment for younger patients with multiple myeloma, resulting in improved survival and response rate compared to conventional chemotherapy. Disease relapse, however, remains almost inevitable and thus the role of two successive (tandem) autologous stem cell transplants has been evaluated in chemorefractory patients as a means of prolonging duration of disease response.
We retrospectively analysed the results of nine patients with chemorefractory disease treated at a single UK institution who received tandem ASCT between January 1998 and February 2009. There were six men and three women. Median age at diagnosis was 56 years (range, 42–65 years). Paraprotein isotype was IgG in eight patients and IgA in one patient. Median serum paraprotein level was 41g/L (range 12–73g/L) at presentation.
At time of 1st transplant six patients were in stable disease (SD) and three had evidence of progressive disease. Conditioning melphalan dose was 140mg/m2 in all but two patients who received 110mg/m2 and 200mg/m2. Median time between transplants was 3.7 months (range 2.3–6.4 months) with PR and SD being observed in 2/9 and 7/9 patients at time of 2nd transplant. None of the patients reached complete response (CR). One patient received melphalan 140mg/m2 prior to 2nd transplant. The remaining patients received melphalan 200mg/m2.
Median follow up after tandem transplant was 54.3 months (range 15.6 –143.6 months). No treatment related mortality was reported. At the time of analysis, six patients were still alive and under follow up with an overall survival (OS) figure for the group of 52% at 10 years from diagnosis (Figure 1). Median progression free survival (PFS) was 20 months from 2nd transplant (range 6.7–62.6 months) (Figure 2).
Tandem autologous stem cell transplant in chemorefractory patients has resulted in overall survival similar to autologous stem cell transplant in chemosensitive patients and should be considered in patients with chemorefractory disease.
Figure 1: Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma Figure 1:. Overall survival from diagnosis in patients receiving tandem autologous stem cell transplant for multiple myeloma
Figure 2: Progression free survival following tandem transplant Figure 2:. Progression free survival following tandem transplant

Disclosures:
No relevant conflicts of interest to declare.
Clinical Features, Treatment Outcomes and Prognosis of Lymphoblastic Lymphoma: A Report On 52 Patients From a Single Center in China
Authors: Li Honghua , Zhao Yu , Huang Wenrong , Bo Jian , Wang Shuhong , Jing Yu , Gao Chunji , Yu Li 
Published: October 2019

Abstract
Abstract 4556

Objective:
To investigatethe clinical features and prognostic factors, compare the treatment efficiency of chemotherapy and hematopoietic stem celltransplantation (HSCT) in Chinese patients with lymphoblastic lymphoma (LBL).

Methods:
We retrospectively analyzed clinical features, outcomes and prognosis of fifty-two patients with LBL who underwent chemotherapy (n=31) or HSCT (n=21) from January 1998 to December 2010 in our hospital.

Results:

Conclusion:
LBL is more common in young men and most patients had advanced diease at diagnosis. Clinically, it often presents with mediastinal, bone marrow and CNS involvement. More intensive ALL-like regimens appear superior to NHL-like regimens. Compared with chemotherapy, HSCT may improve overall survival. The use of HSCT in CR1 produces a trend for improved PFS. T-cell immunophenotype, elevated LDH, disease status more advanced than CR and patients without HSCT are independently associated with inferior outcomes.

Disclosures:
No relevant conflicts of interest to declare.