bluuebunny/crossref_metadata_2025 huggingface dataset:
VTE Prophylaxis Across the Continuum of Care in US Medical Patients at Risk of Venous Thromboembolism.
Authors: Amin Alpesh , Lin Jay , Ryan Amy
Published: October 2019

Abstract 1386

Poster Board I-408

Background:

Medical patients with chronic medical illnesses are often at risk of VTE both in-hospital and post-discharge. However, although injectable prophylaxis options are available and suitable for providing in-hospital and post-discharge prophylaxis, there is often a lack of continuity in VTE post-discharge prophylaxis. This analysis evaluated in-hospital and post-discharge VTE prophylaxis patterns for US medical patients.

Methods:

Premier's Perspective™ inpatient data were cross-matched at the individual patient level with Ingenix LabRx® outpatient data from the I3 database (January 2005-December 2007) to assess VTE prophylaxis patterns in medical patients (cancer without surgery, heart failure, severe lung disease, infectious disease) at risk of VTE (according to the American College of Chest Physicians 2004 guidelines) and with no contraindications for anticoagulation. Inpatients were assessed for any anticoagulation received in-hospital and were followed post-discharge to assess their outpatient prophylaxis use. Drug utilization and clinical practice patterns during and within 30 days after hospitalization were collected and compared descriptively between groups.

Results:

Of the 9,675 medical discharges at risk of VTE and included in this analysis, 6,185 (63.9%) did not receive any anticoagulation at all. Of the remaining 3,490 (36.1%) discharges that did receive anticoagulation, 2,045 (58.6%) received enoxaparin and 1,044 (29.9%) received unfractionated heparin (UFH) (Table). After discharge, 98.2% of all patients did not receive any prophylaxis within the following 30 days. Only 174 (1.8%) discharges received outpatient prophylaxis, with 67.8% receiving warfarin alone and 18.4% receiving enoxaparin and warfarin (Table).

Conclusion:

This analysis presents both inpatient and outpatient VTE prophylaxis patterns in real-world medical patients that are at risk of VTE. Nearly 64% of patients received no inpatient VTE prophylaxis, and less than 2% received outpatient prophylaxis. Further efforts to improve VTE prevention in hospitalized patients are required, with particular emphasis needed on the transition to outpatient prophylaxis.

Disclosures:

Amin: sanofi-aventis: Research Funding, Speakers Bureau, The authors received editorial/writing support in the preparation of this abstract funded by sanofi-aventis U.S., Inc.. Lin: sanofi-aventis: Employment. Ryan: sanofi-aventis: Research Funding.
The Tumor Suppressor Role of the Msr1 Gene in Cancer Stem Cells of Chronic Myeloid Leukemia.
Authors: Chen Yaoyu , Sullivan Con , Li Shaoguang
Published: October 2019

Abstract 188

We have previously shown that the arachidonate 5-lipoxygenase gene (Alox5) functions as a critical regulator of leukemia stem cells (LSCs) in BCR-ABL-induced chronic myeloid leukemia (CML) in mice (Chen Y, Hu Y, Zhang H, Peng C, Li S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nature Genetics 41:783-792, 2009). We believe that the Alox5 pathway represents a major molecular network in LSCs. Therefore, we decided to further dissect this pathway by comparing gene expression profiles between wild type and Alox5−/− LSCs from CML mice using the DNA microarray analysis. We identified a small group of candidate genes that were changed in expression in the absence of Alox5. Among these genes, we have identified the Msr1 gene and chosen to test the function of this gene in regulating LSC function, because this gene was up-regulated, indicating that it might play a tumor suppressor role in LSCs. In our CML mouse model, we observed that recipients of BCR-ABL transduced Msr1−/− bone marrow cells developed CML much rapidly than recipients of BCR-ABL transduced wide type bone marrow cells. To test whether this accelerated CML is related to abnormal function of LSCs, we carried out a serial transplantation assay by transferring bone marrow cells from primary recipients of BCR-ABL-transduced wild type or Msr1−/− donor bone marrow cells into secondary and next-generation of recipient mice to biologically assess the effect of Msr1 on LSCs. BCR-ABL-expressing wild type leukemia cells from bone marrow of CML mice were only able to transfer CML once, whereas BCR-ABL-expressing Msr1−/− leukemia cells were able to transfer lethal CML for five genrations. This observation indicates that BCR-ABL-expressing Msr1−/− LSCs have markedly increased stem cell function. To further compare the stem cell function, we performed the leukemia stem cell competition assay by 1:1 mixing wild type (CD45.1) and Msr1−/− (CD45.2) bone marrow cells from CML mice. At day 25 or 30 after transplantation, more than 60% and 95% of GFP+Gr-1+ cells in peripheral blood of the mice were CD45.2+Msr1−/− myeloid leukemia cells, and all these mice developed CML and died of CML derived from Msr1−/− LSCs. To confirm the tumor suppressor role of Msr1 in CML development, we co-expressed BCR-ABL and Msr1 in MSR1−/− bone marrow cells by retroviral transduction, followed by transplantation of these cells into recipient mice. The ectopically-expressed Msr1 in MSR1−/− bone marrow cells rescued the accelerated CML phenotype, and some recipient mice did not even develop the CML. Together, these results demonstrate that Msr1 plays a tumor suppressor role in LSCs. The Msr1 pathway is a novel molecular network in LSCs, and it will be important to fully study this pathway for developing curative therapeutic strategies for CML.

Disclosures:

No relevant conflicts of interest to declare.
Lymphopenia Predicts Survival in Peripheral T-Cell Lymphoma, Unspecified.
Authors: Beltran Brady , Morales Domingo , Quinones Pilar , Desposorio Carlos , Sotomayor Eduardo , Castillo Jorge
Published: October 2019

Abstract 1930

Poster Board I-953

Background: Lymphopenia is an independent prognostic factor for survival for different hematological malignancies like follicular lymphoma, Hodgkin lymphoma and diffuse large B-cell lymphoma. The role of lymphopenia at diagnosis on survival in peripheral T-cell lymphoma, unspecified (PTCLU) is not known. Methods: Eighty seven patients with a diagnosis of PTCLU were evaluated at the Edgardo Rebagliati Martins Hospital in Lima, Peru from October 1997 until April 2008. The primary objective of the study was to assess the role of lymphopenia at diagnosis in survival in cases with PTCLU. Lymphocyte count at diagnosis was obtained from the standard complete blood cell count (CBC). Lymphopenia was defined as a lymphocyte count of less than 1 × 109/L. Kaplan-Meier survival estimates and the log-rank test were performed for univariate survival analyses and Cox proportion-hazard regression test was performed for the multivariate analysis. Results: Eighty four patients with a histological diagnosis of PTCLU were included in this study. The median follow-up was 13.4 months (range 1–68 months). The sample population included 54% males and 46% females with a median age of 57 years (range 18–87 years). The median number of lymphocytes at diagnosis was 1.3 × 109/L (range 0.06–5.2 × 109/L). Lymphopenia was present in 37% of cases. In the univariate analysis, lymphopenia was identified as a poor factor for survival (median OS 59 vs. 1 month; p<0.0001). In the multivariate analysis, lymphopenia was compared to the Prognostic Index for PTCLU (PIT) and it remained as an independent predictor for survival (Hazard Ratio 4.8, 95% confidence intervals 2.2–10.6; p<0.0001). Conclusion: This study demonstrates that lymphopenia is an independent prognostic factor for survival in patients with PTCLU, suggesting that the host immune system might play a preponderant role in survival in this group of patients.

Disclosures:

No relevant conflicts of interest to declare.
Comparison of Outcomes After Allogeneic HSCT for Adult Patients with AML in Remission Using in the Conditioning Regimen Either I.V. Busulfex (BU) Plus Cyclophosphamide (Cy) or TBI Plus Cy: An- ALWP-EBMT Survey.
Authors: Nagler Arnon , Labopin Myriam , Shimoni Avichai , Volin Liisa , Bunjes Donald W. , Huynh Anne , Buzyn Agnes , Rambaldi Alessandro , Rocha Vanderson
Published: October 2019

Abstract 195

TBI/CY and oral (p.o) Bu/Cy are the traditional allogeneic HSCT (alloHSCT) myeloablative conditioning regimens for adults with AML with comparable survival and relapse probabilities. Intravenous (i.v.) Bu in contrast to p.o Bu has more predictable pharmacokinetics and a more favorable toxicity profile. Post transplantation outcomes with i.v. Bu/Cy, thus, may be superior to those achieved with TBI/Cy. In order to address these issues, the ALWP of the EBMT performed a survey comparing i.v. Bu/Cy to TBI/Cy as conditioning regimen for adult pts. with AML undergoing alloHSCT. Overall, 603 alloHSCT were analyzed. One hundred pts. underwent alloHSCT with Bu/Cy while 503 with TBI/Cy. Age was 41 (range, 18–57) and 41 (range, 16–61) years and median transplant year was 2004 (2000 – 2005) and 2003 (2000 – 2005) for the Bu/Cy and TBI/Cy groups, respectively. Disease status at alloHSCT were CR1 – 81% vs. 78% and CR2–19% vs. 22% for the Bu/Cy and TBI/Cy groups, respectively. WBC count at diagnosis was 11×109/L and 15×109/L, respectively. Regarding the cytogenetic classification, 10% and 10% were good, 60% and 55% were intermediate and 9% and 6% were poor risk, respectively (data were NA for 21%–26% of pts). Sixty nine percent and 68% of both groups underwent alloHSCT from sibling donors, while 31% and 32% from MUD, respectively. Length of follow up was 37(15–86) and 57 (1–105) months for both groups, respectively. Sixty nine percent and only 41% of the Bu/Cy and TBI/Cy groups received PB, while 31% and 59% received BM grafts, respectively (p<0.0001). Engraftment was similar in the Bu/Cy vs. the TBI/Cy groups, 95% and 96%, respectively. Cumulative incidence of TRM at 2y was 17+4% and 23+2%, respectively (p=0.23). Acute GVHD (II–IV) was also similar between the 2 groups, 28% and 32%, respectively. Two year relapse incidence was 30+5% and 22+2% for Bu/Cy vs. TBI/Cy, respectively (p=0.03) while LFS was comparable 57+5% and 61+2%, respectively (p=0.5). In multivariate analysis Cy/TBI was found to be an independent good prognostic factor for reduce relapse rate (p=0.03, HR-1.67) and there was a trend for higher TRM (p=0.16). Poor prognostic factors for LFS and TRM were age >40y, disease status (CR2 vs. CR1) and MUD vs. Sib. donor. In conclusion, in this retrospective EBMT survey outcomes of alloHSCT in adult pts. with AML in CR using either i.v Bu/Cy or TBI/Cy were comparable.

Disclosures:

No relevant conflicts of interest to declare.
Inhibition of CRM1-Mediated Nuclear Export of Transcription FACTORS by Leukemogenic NUP98 Fusion Proteins.
Authors: Takeda Akiko , Abdul-Nabi Anmaar M , Yaseen Nabeel R.
Published: October 2019

Abstract 1959

Poster Board I-982

NUP98 is a nucleoporin that plays complex roles in the nucleocytoplasmic trafficking of macromolecules. Rearrangements of the NUP98 gene in human leukemia result in the expression of numerous fusion oncoproteins whose effect on nucleocytoplasmic trafficking is poorly understood. The present study was undertaken to determine the effects of leukemogenic NUP98 fusion proteins on CRM1-mediated nuclear export. NUP98-HOXA9, a prototypic NUP98 fusion, inhibited the nuclear export of two known CRM1 substrates: mutated cytoplasmic nucleophosmin (NPMc) and HIV-1 Rev. In-vitro binding assays revealed that NUP98-HOXA9 binds CRM1 through the FG-repeat motif in a Ran-GTP dependent manner similar to but stronger than the interaction between CRM1 and its export substrates. Two NUP98 fusions, NUP98-HOXA9 and NUP98-DDX10, whose fusion partners are structurally and functionally unrelated, interacted with endogenous CRM1 in cells as shown by co-immunoprecipitation. These leukemogenic NUP98 fusion proteins interacted with CRM1, Ran, and the nucleoporin NUP214 in a manner fundamentally different from that of wild-type NUP98. NUP98-HOXA9 and NUP98-DDX10 formed characteristic aggregates within the nuclei of myeloid cells and caused aberrant localization of CRM1 to these aggregates. These NUP98 fusions caused nuclear accumulation of two transcription factors, NFAT and NFΚB, that are regulated by CRM1-mediated export. The nuclear entrapment of NFAT and NFΚB correlated with enhanced transcription from promoters responsive to these transcription factors. Taken together, the results suggest a new mechanism by which NUP98 fusions dysregulate transcription and cause leukemia, namely, inhibition of CRM1-mediated nuclear export with aberrant nuclear retention of transcriptional regulators.

Disclosures:

No relevant conflicts of interest to declare.
miRNA29a Regulates Oncogenic SKI Expression in Acute Myeloid Leukemia (AML).
Authors: Teichler Sabine , Illmer Thomas , Stiewe Thorsten , Roemhild Josephine , Neubauer Andreas
Published: October 2019

Abstract 1968

Poster Board I-991

Introduction:

AML patients with deletion of chromosome 7 (−7) or deletion of 7q (−7q) have a poor prognosis. We have found that the nuclear oncogene SKI is overexpressed in AML, especially in AML with −7/−7q. SKI acts in AML as a repressor of retinoic acid induced myeloid differentiation (Ritter et al., (2006) Leukemia). As we found SKI up regulated in AML, we asked how SKI expression may be regulated. The aim of our study was to find a molecular background for increased SKI level. On chromosome 7 is a cluster of micro-RNAs (miRNAs) localized particularly around the fragile site 7q32 (Calin et al., (2003) PNAS). Therefore we investigated whether there exists a link between expression of miRNAs localized on chromosome 7 and up regulation of SKI expression in AML.

Methods:

We used micro RNA profiling analysis, FACS, Western blot, RQ-PCR and luciferase assays to determine the role of miRNA29a in regulating SKI expression.

Results:

We found that the expression of miRNA25, miRNA29a, miRNA183 and miRNA335 was downregulated in AML patients with -7/-7q. Transfection studies with these four miRNAs in HL60 cells revealed in FACS that miRNA29a inhibits SKI expression (60,4%) compared to nonsense control (100%) and other miRNAs (miRNA25: 91%, miRNA183: 101%, miRNA335: 93%). Western blot experiments confirmed that miRNA29a reduces SKI level in HL60 cells. In keeping, miRNA29a also represses expression of the SKI target gene Nr-CaM in IFB melanoma cells. Knock down of miRNA29a using miRNA29a inhibitor molecules induces SKI expression in the high miRNA29a and low SKI expressing cell line NW1539. Luciferase assays in NW1539 and HeLa transfected with 3′UTR-constructs and HeLa cells cotransfected with miRNA29a demonstrated that miRNA29a binds to 3′UTR of SKI in vitro. Furthermore, comparison of SKI and miRNA29a expression of AML patient samples indicates that miRNA29a expression is associated with low SKI level in vivo.

Conclusion:

Our data show that miRNA29a which is located on 7q32 regulates expression of the oncogene SKI in vitro and in vivo. We suggest the deletion of miRNA29a as mechanism for up regulation of SKI in AML with -7/-7q and thus propose that in AML, this effect may contribute to the tumor suppressive function of miRNA29a.

Disclosures:

No relevant conflicts of interest to declare.
Reduced Sensitivity of the Ferroportin Q248H Mutant to Low Concentrations of Hepcidin.
Authors: Xu Min , Foster Altreisha , Diaz Sharmin , Nekhai Sergei , Gordeuk Victor R.
Published: October 2019

Abstract 2002

Poster Board I-1024

The iron exporter protein, ferroportin (Fpn), is expressed by enterocytes and macrophages. It transports iron taken up from the gut by enterocytes to portal plasma transferrin and iron recycled by macrophages to systemic plasma transferrin. Hepcidin, which is secreted by hepatocytes, interacts with Fpn, leading to its internalization and degradation. Mutations that lead to decreased production of hepcidin or that reduce the sensitivity of Fpn to hepcidin lead to higher dietary iron uptake and increased parenchymal cell iron stores. The Fpn Q248H mutation, which is common in Africans and African-Americans, has been associated with increase serum ferritin concentrations in adults and with protection from iron deficiency in Zimbabwean children (Kasvosve et al., Am J Clin Nutr. 2005 82:1102-6). Other investigators have reported that the Fpn Q248H has normal sensitivity to hepcidin concentration of 0.5 mM (Drakesmith et al., Blood 2005 106:1092-7). We hypothesized that there may be differential sensitivity on the part of Fpn Q248H to lower levels of hepcidin (0.03-0.1 uM versus 0.5 uM). We subcloned WT and Q248H ferroportins to EGFP-expression vector, transfected 293T cells and measured EGFP fluorescence in response to hepcidin. We observed about 50% less reduction of Fpn Q248H-EGFP comparing to WT Fpn in response to 0.03 mM hepcidin treatment for 3 h but the effect was lost at 0.1 mM or higher concentrations of hepcidin or when the cells were treated with hepcidin for 18 h. This observation possibly explains why this mutation was previously not identified as having lower sensitivity to hepcidin. Similar results were obtained when Fpn was detected by immunoblotting or when ferritin concentrations were measured. Ferritin concentrations were higher in monocytes and macrophages derived from patients with Fpn Q248H mutation, suggesting that there may be differential sensitivity to hepcidin of Fpn expressed on macrophages versus enterocytes. Our results suggest that Africans and African-Americans with Fpn Q248H mutation may develop higher iron stores due to lower sensitivity of this Fpn mutant to low concentrations of hepcidin.

Acknowledgments.

This work was supported by NHLBI Research Grant 2 R25 HL003679-08 from the National Institutes of Health and The Office of Research on Minority Health (to VRG) and by Howard University Seed Grant (to SN).

Disclosures:

No relevant conflicts of interest to declare.
Allogeneic Stem Cell Transplantation (allo-SCT) for Chronic Lymphocytic Leukemia: a Long Term Analysis From the Societe Francaise De Greffe De Moelle Et De Therapie Cellulaire (SFGM-TC).
Authors: Mohty Mohamad , Vernant Jean-Paul , Yakoub-Agha Ibrahim , Blaise Didier , Socié Gérard , Cordonnier Catherine , Deconinck Eric , Bourhis Jean-Henri , Guilhot François , Buzyn Agnes , Ifrah Norbert , Guyotat Denis , Harousseau Jean-Luc , Sutton Laurent , Milpied Noel-Jean , Michallet Mauricette
Published: October 2019

Abstract 201

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with a heterogeneous natural history. While some patients never require treatment or can be managed effectively with conventional chemotherapy, others experience early disease progression and death. Allo-SCT is increasingly considered as a therapeutic option for younger patients with poor-risk CLL.

This multicenter retrospective analysis assessed the long term outcome of 160 CLL patients who received allo-SCT between 1987 and 2005, and were reported to the SFGM-TC registry.

This series included 127 males (79%) and 33 females (20.6%) with a median age at CLL diagnosis of 45.5 (range, 24.4–65.1) y. The median age at time of allo-SCT was 50.9 (range, 29.8–68.3) y. Before allo-SCT, 26 patients (16.3%) received previous stem cell transplantation in the course of their disease. Patients received either a standard myeloablative conditioning regimen (n=58; 38%; Cy-TBI in 90% of cases) or a so-called reduced-intensity conditioning. A matched-related donor was used in 142 cases (89%) and PBSCs were used as source of stem cells in 92 cases (57.5%). At time of allo-SCT, only 10 patients (6.3%) were in CR1, 17 in CR2 and CR3 (10.6%), 27 in first PR (16.9%) and 106 (66.2%) in more advanced phases, including 46 patients (28.8%) in progressive disease.

With a median follow-up of 60 (range, 1.6–208) months for surviving patients, 96% of patients engrafted (ANC>500/μL) at a median of 18 (range, 1–41) days after allo-SCT. 71 patients (44.4%) experienced grade 2–4 acute GVHD, including 28 cases (17.5%) of grade 3–4 acute GVHD. 73 patients (56.2%) experienced some form of chronic GVHD. At time of last follow-up, 70 patients (43.8%) were still alive, of whom 24 (34%) were in continuous CR. Disease progression accounted for 24 deaths, while transplant-related causes (infections, n=23; GVHD, n=13; MOF, n=12; other causes, n=18) were observed in 66 cases, for a TRM rate of 41%. The KM estimates of disease-free survival (DFS) at 2, 5, and 10 years after allo-SCT were 44.3%, 39.6%, and 30.5%, respectively. Estimates of overall survival (OS) were 54.4%, 46.2%, and 35.8.1%, respectively. In a Cox multivariate analysis for OS (including demographic features, transplant and donor types, and disease status at time of allo-SCT), disease status at time of allo-SCT (CR or PR) was the most significant parameter associated with improved OS (RR=0.56; 95%CI, 0.36–0.89).

We conclude that allo-SCT has the potential to induce long-term disease control and overall survival in patients with high risk or advanced CLL.

Disclosures:

No relevant conflicts of interest to declare.
Splenectomy Exacerbates the Hypercoagulable State and Causes Significant Organ Dysfunction in Patients with Hemoglobin E/β-Thalassemia.
Authors: Atichartakarn Vichai , Chuncharunee Suporn , Archararit Napaporn , Udomsubpayakul Umaporn , Ingsathit Atiporn , Lee Ratchanee , Tunhasiriwet Anusith , Tanomsup Supachai , Aryurachai Katcharin , Ungkanont Artit , Niparuck Pimjai , Angchaisuksiri Pantep
Published: October 2019

Abstract 2014

Poster Board I-1036

Introduction:

Clinical manifestations of blood hypercoagulability, such as pulmonary arterial hypertension (PAH) and ischemic stroke, are well known in patients with thalassemia. We herein present evidence that the hypercoagulable state in β-Thalassemia disease patients is to a significant extent the result of prior splenectomy.

Patients and Methods:

One hundred and ten clinically stable hemoglobin E/β-Thalassemia outpatients, on no medication aside from folic acid and who received no blood transfusion in the preceding 4 weeks were studied. All gave written informed consent, and study protocol was approved by the institution ethics committee on studies in humans (#0774/2548). Echocardiogram was used to estimate systolic PA pressure (SPAP). Clinical features and laboratory data were stratified according to the presence or absence of the spleen, and statistical analysis was done by STATA version 10 (Stata Corp, Texas), considering a P value <0.05 as statistically significant.

Results:

Of the 110 patients, 61 were asplenic and females comprised 51% in both groups. Selected statistically significant results are shown in the table.

Conclusions:

In comparison with non-splenectomized hemoglobin E/β-Thalassemia patients, asplenic ones have higher SPAP, more severe hemolysis, more liver impairment and chronic iron overload, significant chronic low grade inflammation, and evidence of coagulation activation. Splenectomy should be more judiciously applied than heretofore, and if performed, measures to blunt or prevent a subsequent hypercoagulable and inflammatory state, which could lead to PAH should be initiated.

Disclosures:

No relevant conflicts of interest to declare.
Count Recovery in AML Patients Achieving a Complete Response.
Authors: Rosinski Steven Lawrence , Ravandi Farhad , Faderl Stefan , Garcia-Manero Guillermo , Pierce Sherry , Kantarjian Hagop M. , Estey Elihu H.
Published: October 2019

Abstract 2062

Poster Board II-39

AML is typically defined as “de novo” or “secondary”, the latter referring to patients diagnosed only after persistent blood count abnormalities (AHD) or after prior “chemotherapy” (PCT) for other illnesses. Patients with secondary AML may have a different bone marrow microenvironment leading to prolonged neutrophil and platelet recovery times following induction chemotherapy. Accordingly, we compared time from start of chemotherapy to neutrophil recovery (>1,000/μl) and platelet recovery (>100,000/μl) in 424 patients who achieved a complete response (CR) following treatment with ara-C-containing induction therapy at MD Anderson Hospital from 1995 to 2008. We divided the 424 patients as follows: (1) no AHD, no PCT (236 patients); (2) AHD, no PCT (131 patients); (3) PCT, no AHD (28 patients); and (4) AHD and PCT (29 patients). Because time to recovery may also be influenced by cytogenetics and age we subdivided patients in each of the four groups according to age (< vs. ≥ 60) and cytogenetics (normal vs. complex or -5/-7). Despite very differing CR rates, time to neutrophil recovery in patients achieving CR while statistically longer in PCT patients (p=0.05) was from a medical standpoint essentially uninfluenced by AHD and PCT status (table, median delays 2 days with PCT). Platelet recovery was affected by such status (p<0.001) being delayed by a median of 6-8 days in patients who had received PCT. Age had no effect on time to neutrophil (p=0.42) or platelet (p=0.23) recovery, while complex or -5/-7 cytogenetics had a statistically significant (p=0.002 neutrophils, 0.009 platelets) but medically insignificant (median delays of 2 days) effect on recovery time. There was no interaction between age or cytogenetics and AHD or PCT status. A similar analysis in patients who do not achieve CR would be of interest, but might be confounded by the difficulty in distinguishing between the effects of chemotherapy and those of residual AML on count recovery. Our data suggest that older patients, patients with complex or -5/-7 cytogenetics, and patients with secondary AML should not be excluded from clinical trials because of concern about prolonged time to count recovery.

Group CRs CR Rate Median Days to > 1000 Neut Median Days to > 100,000 Plt No AHD no PCT 236 68% 27 28 AHD no PCT 131 50% 27 30 PCT no AHD 28 44% 29 34 AHD + PCT 29 35% 30 36 Age < 60 255 64% 28 29 Age ≥ 60 169 48% 26 30 Normal cyto 281 69% 27 29 Complex cyto or -5/-7 143 41% 29 31

Disclosures:

No relevant conflicts of interest to declare.
Decitabine-Based Salvage Therapy in Adults with Acute Myeloid Leukemia.
Authors: Ritchie Ellen K , Arnason Jon , Feldman Eric J. , Gergis Usama S , Mayer Sebastian A , Ippoliti Cindy , Scandura Joseph M. , Roboz Gail
Published: October 2019

Abstract 2063

Poster Board II-40

Introduction:

Adults with primary refractory or relapsed acute myeloid leukemia (AML) have a poor prognosis with complete responses to salvage therapy from 13-15% and a median survival of 1.5-6 months[1, 2]. From 2006-2009, 79 patients with relapsed or refractory acute myeloid leukemia were given salvage chemotherapy with decitabine 20mg/m2 daily for 10 days or decitabine 20mg/m2 × 5 days with gemtuzumab ozogamicin (GO) 3mg/m2 on day 5 at Weill Cornell Medical Center.

Methods:

Medical records of 79 patients who received decitabine-based salvage therapy were reviewed from September 2006 through July 2009 at Weill Cornell Medical College. Survival was calculated by the Kaplan Meir method and differences in survival calculated by the log-rank test using STATA software.

Results:

Twenty-five patients received decitabine-based therapy as first salvage, 32 patients as second salvage, and 22 patients as third or greater salvage. Fifty-one patients were treated with decitabine/GO and 29 patients received decitabine alone. Median age of patients was 65.5 years with a range of 24 -89 years (first salvage 75 years, second salvage 62 years, and third or greater salvage 64 years). Median survival of all patients was 205 days, range 7-732 days. Overall 34% patients responded: 16% CR (<5% blasts in bone marrow, recovery ANC >1000 and Plts > 100,000) with median survival not yet reached; 5% CRp (< 5% blasts in bone marrow, ANC >1000 and plts < 100,000) with median survival 223 days; 13% PR (blasts 6-11%) with median survival 205 days; and 66% no response with median survival 118 days. Patients receiving first salvage had median survival 181 days with CR 13%, CRp 6%, PR 17%. Patients receiving second salvage had median survival 207 days with CR 9%, CRp 4%, PR 9%. Patients with third or greater salvage had median survival 209 days with CR 23%, CRp 0%, PR 14%. Patients receiving decitabine alone had a median survival of 209 days and those receiving decitabine/GO had a median survival of 177 days but the difference was not significant. Median survival for normal, favorable, intermediate and unfavorable cytogenetics was 282, 224, 157 and 176 days respectively (p=0.06). Conclusions: Decitabine-based treatment for relapsed and refractory AML is a low intensity alternative that has activity rivaling more intensive regimens. This retrospective study suggests that further investigation of decitabine-based salvage is warranted.

1. Sievers, E.L., et al., Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol, 2001. 19(13): p. 3244-54.

2. Giles, F., et al., Outcome of patients with acute myelogenous leukemia after second salvage therapy. Cancer, 2005. 104(3): p. 547-54.

Disclosures:

Off Label Use: Phase I trial of decitabine in AML is off-label .
VTE Prophylaxis Across the Continuum of Care in US Orthopedic Surgery Patients.
Authors: Amin Alpesh , Lin Jay , Ryan Amy
Published: October 2019

Abstract 2097

Poster Board II-74

Background:

Patients who undergo major orthopedic surgery are at significant risk of developing VTE. As 40-60% of orthopedic surgery patients develop VTE in the absence of thromboprophylaxis, evidence-based guidelines recommend pharmacological VTE prophylaxis in all patients without contraindications. As the risk of VTE persists beyond discharge in these patients, the use of LMWH and warfarin post-discharge is both suitable and recommended. However, a lack of awareness and education often leads to an absence of VTE prophylaxis post-discharge. This analysis evaluated in-hospital and post-discharge VTE prophylaxis patterns for US orthopedic surgery patients.

Methods:

Premier's Perspective” inpatient data were cross-matched at the individual patient level with Ingenix LabRx® outpatient data from the I3 database (January 2005-December 2007) to assess VTE prophylaxis patterns in major orthopedic surgery (total knee arthroplasty, total hip arthroplasty, hip fracture surgery) patients at risk of VTE (according to the American College of Chest Physicians 2004 guidelines) and with no contraindications for anticoagulation. Inpatients were assessed for the anticoagulant received in-hospital and were followed post-discharge to assess their outpatient prophylaxis use. Drug utilization and clinical practice patterns during and within 30 days after hospitalization were collected and compared descriptively between groups.

Results:

Of the 3,311 orthopedic surgery discharges at risk of VTE and included in this analysis, only 295 (8.9%) did not receive any anticoagulation at all. Of the remaining 3,016 (91.1%) discharges that did receive anticoagulation, 1,061 (35.2%) received enoxaparin, 1,028 (34.1%) received warfarin, and the remaining 927 (30.7%) received other or combination prophylaxis. However, after discharge only 1,800 (54.4%) of all patients received prophylaxis, with the majority receiving warfarin (1,028, 57.1%). The remaining 1,511 (45.6%) received no outpatient prophylaxis (Table).

Conclusion:

This analysis presents both inpatient and outpatient VTE prophylaxis patterns in real-world orthopedic surgery patients that are at risk of VTE. Although the rate of prophylaxis was high in inpatients, approximately half of all patients had no prophylaxis post-discharge. Further efforts to improve VTE prevention in discharged orthopedic surgery patients are required.

Disclosures:

Amin: sanofi-aventis: Research Funding, Speakers Bureau, The authors received editorial/writing support in the preparation of this abstract funded by sanofi-aventis U.S., Inc. . Lin:sanofi-aventis: Employment. Ryan:sanofi-aventis: Research Funding.
Pharmacological Characterization and Structure Activity Relationship of FXI Antisense Oligonucleotides in Cynomolgus Monkeys.
Authors: MacLeod Robert , Crosby Jeff , Zhao Chenguang , Gao Dacao , May Chris , Zhang Hong , Lowenberg Ester C , Levi Marcel , Monia Brett P.
Published: October 2019

Abstract 2101

Poster Board II-78

The absence of abnormal bleeding associated with congenital deficiencies of the intrinsic coagulation pathway factor, FXI, suggests that this pathway is not important for normal blood coagulation in vivo. However, recent work in mice and higher species demonstrates that the intrinsic pathway is an important contributor to pathologic intravascular thrombosis, suggesting that targeting this pathway may yield effective antithrombotic agents with high safety.

We have previously demonstrated that second generation antisense oligonucleotides (ASOs) targeting the intrinsic pathway member FXI were potent antithrombotic agents and that this activity was achieved in several mouse models of thrombosis without any increase in bleeding risk (Zhang et al. ASH 2008).

Here we characterize the pharmacological activity, chemical SAR and safety profile of FXI antisense oligonucleotides administered subcutaneously in Cynomologus monkeys. Our first monkey study was designed to address the PK/PD kinetics of FXI ASOs from a single chemical series (20 mers, 5-10-5 MOE Gapmers). Two dose escalation regimes were evaluated (1) 5mg/kg (3wks), 10mg/kg (3 wks) followed by 25 mg/kg (6wks) and (2) 5mg/kg (3wks) followed by 10mg/kg (9 wks). The subsequent study was designed to evaluate chemical SAR around the active ASOs identified in the study 1. FXI antisense oligonucleotides FXI-AS1, FXI-AS2 demonstrated dose and time dependent pharmacologic activity, including, decreased FXI mRNA in liver (up to 90%), decreased FXI protein levels and FXI activity measured in plasma, with a maximal inhibition of >80% observed at 25mg/kg on both schedules, prolonged activated partial thromboplastin times (aPTT), maximal aPTT ratio of 2.O, but no change in prothrombin time (PT) as expected. Similar to previous studies in mouse the anticoagulant activity observed from FXI depletion in monkeys was not associated with increased bleeding risk as assessed in a skin bleeding time test. Additionally, FXI ASOs had no deleterious effects on organ weights, platelets, or on measures of liver and kidney function. The second study confirmed the effects of FXI-AS1 and FXI-AS2 and demonstrated that shorter ASOs with decreased gap size were equally potent.

These results further support the development of FXI ASOs as human therapeutics for the treatment of coagulation related disorders with the potential for improved safety profiles.

Disclosures:

MacLeod: Isis Pharmaceuticals: Employment. Crosby:Isis Pharmaceuticals, Inc.: Employment. Zhao:Isis Pharmaceuticals, Inc.: Employment. Gao:Isis Pharmaceuticals, Inc.: Employment. May:Isis Pharmaceuticals, Inc.: Employment. Zhang:Isis Pharmaceuticals, Inc.: Consultancy. Lowenberg:Isis Pharmaceuticals, Inc.: Consultancy. Levi:Isis Pharmaceuticals, Inc.: Consultancy. Monia:Isis Pharmaceuticals, Inc.: Employment.
VKORC1 V66M Mutation in African Brazilian Patient Resistant to Oral Anticoagulant Therapy.
Authors: Orsi Fernanda A. , Annichino-Bizzacchi Joyce Maria , de Paula Erich Vinicius , Langley Michael R , Weck Karen
Published: October 2019

Abstract 2102

Poster Board II-79

BACKGROUND: Two enzymatic complexes are related to therapeutic response to coumarin: 1)cytocrome P-450 2C9 (CYP2C9), that metabolizes the drug; and 2)vitamin K epoxide reductase complex subunit 1 (VKORC1), targeted by coumarin. Haplotypes CYP2C9 *2 and *3 and VKORC1*2, more frequent in Caucasians, are related to coumarin sensitivity. VKORC1*3 and *4 confer resistance to the anticoagulant and are found mainly in Africandescents. MATERIAL AND METHODS: To determine genetic variability associated with altered warfarin response among Brazilian patients, sixty-two adult patients showing resistance or sensitivity to warfarin were genotyped for variants in CYP2C9 and VKORC1 associated with alteredwarfarin response. Fifty-one were users of low daily doses (¶ 2.5mg) and 11 users of high daily doses (>10mg) of warfarin.RESULTS: Among the 51 patients on low doses of warfarin, VKORC1 1639 (3673) G>A polymorphism, which defines VKORC1*2, was present in 48 (94.1%). Of these, thirty-two patients (66.7%) were Caucasians, 9 (18.7%) were of African descent, 4 (8.4%) were of both African and Brazilian-Indian descent and 3 (6.2%) were of Brazilian-Indian descent. Additionally, 27(52.9%) patients had at least one CYP2C9*2 or CYP2C9*3 allele, 21(63.6%) of Caucasians and 6 (54%) of African-descents. For the 11 patients on high doses of warfarin, 6 (54.5%) patients had at least one variant allele of VKORC1. Four patients were found with a non-coding VKORC1 polymorphism: VKOR3482(8773)C>T or VKOR 1173(6484)C>T. The VKOR 3482(8773)C>T, which defines the haplotype VKORC1*3F, was present in 2 African-descentpatients and VKOR 1173(6484)C>T, associated with VKORC1*2, was present in 3 patients. Two African-descent patients had a coding mutation Val66Met(V66M). CONCLUSION: The presence of the rare V66M mutation in two high dose outlier patients implies that this variant may be more frequent among African Brazilians and has implications for future warfarin studies in other individuals of African descent.

Disclosures:

No relevant conflicts of interest to declare.
Factor Xa and Factor VIIa Utilize Herpes Simplex Virus-Associated Tissue Factor to Increase Infection through Cellular Protease Activated Receptor 2.
Authors: Sutherland Michael R , Ruf Wolfram , Pryzdial Ed L.
Published: October 2019

Abstract 2130

Poster Board II-107

We have shown previously that purified herpes simplex type-1 (HSV1) can initiate coagulation on its surface because of tissue factor (TF) derived from the host cell and virus-encoded glycoprotein C (gC). Generation of thrombin by this viral surface pathway correlated to an increase in the susceptibility of cells to infection through a mechanism involving protease activated receptor (PAR) 1. Incomplete inhibition of the serum-mediated increase in infection by hirudin indicated that mechanisms in addition to thrombin are involved. To further investigate the importance of coagulation enzymes in HSV1 infection, the current study investigated the upstream activated coagulation factors X (FXa) and VII (FVIIa). Using a novel panel of viruses deficient in either TF and/or gC in cytolytic viral plaque assays, we examined the contribution of viral TF and gC in the FXa- or FVIIa- mediated infection of human umbilical vein endothelial cells. The addition of purified FXa resulted in up to 400% enhancement of infection when TF and gC were on the virus surface. Similarly, the effect of FVIIa was maximal when TF and gC were present, although only 150% increased. In agreement with previous studies, the addition of purified thrombin resulted in approximately a 500% increase in infection using the novel panel of viruses, which unlike FXa and FVIIa was not dependent on either viral TF or gC. Simultaneous addition of FXa/FVIIa or thrombin/FXa/FVIIa further enhanced infection to a maximum of 10-fold. FX alone had no effect on infection; however, in situ FXa generation due to the addition of FVIIa increased infection. The involvement of PAR2 was shown using inhibitory PAR2 specific antibodies which attenuated the effects of FXa and FVIIa. Anti-PAR1 inhibited the effect of thrombin, but had no effect on either FXa- or FVIIa-dependent infection. The importance of viral TF was demonstrated by inhibition of FXa or FVIIa-mediated plaque formation by anti-TF antibody, which had an insignificant effect on TF-deficient HSV1. Collectively, these data indicate that FXa and FVIIa together with TF on the virus surface may activate cellular PAR2 to increase HSV1 infection independent of thrombin.

Disclosures:

Ruf: Pfizer: Research Funding; Novo Nordisk: Research Funding.
Appropriate Timing of G-CSF Use After Mobilization Chemotherapy Significantly Increases the Yield ofCD34+ Cells in autoPBSCT.
Authors: Xu Li , Chang Chunkang , Li Xiao
Published: October 2019

Abstract 2144

Poster Board II-121

The yield of CD34+ cells collected by apheresis for autologous peripheral blood stem cell (PBSC) transplantation was greatly increased when the appropriate timing was determined to begin using G-CSF after COAEP mobilization. 29 patients with lymphoma or multiple myeloma (MM) received the same mobilization chemotherapy, including CTX 400mg/m2 d1; VDS 2 mg/ m2 d1; Ara-C 60 mg/m2 ×5d; vp-16 60 mg/m2 ×5d; and prednisone 40 mg/m2 ×5d. The control group (12 cases) received subcutaneous G-CSF (filgrastim) at the first restoration after the initial nadir of the peripheral WBC count. The experimental group (17 cases) received G-CSF during the steady rise of the WBC count (end of fluctuating after initial nadir). G-CSF was given in a single daily subcutaneous dose of 300μg until the final PBSC apheresis.When the peripheral WBC and mononuclear cell (MNC) counts reached 10.0×109/Land 1.0×109/L, respectively, leukapheresis was carried out using the COBE Spectrablood cell separator. Despite comparable treatment with alkylating agents, a significantly increased yield of CD34 positive cells was observed in the experimental group (32.0×106/kg) compared to the control group (3.1×106/kg) (P=0.0182). This result indicates the importance of appropriate timing for the use G-CSF after mobilization chemotherapy to increase the CD34+ cell yield.

Disclosures:

No relevant conflicts of interest to declare.
PU.1-Mediated Upregulation of M-CSFR Is Critical for MOZ-Leukemia Stem Cell Potential.
Authors: Aikawa Yukiko , Katsumoto Takuo , Tenen Daniel G. , Kitabayashi Issay
Published: October 2019

Abstract 216

Leukemias and other cancers possess self-renewing stem cells that help to maintain the cancer. The eradication of cancer stem cells is thought to be critical for successful anti-cancer therapy. However, there is little evidence for this. Using an acute myeloid leukemia (AML) model by introducing the leukemia-associated monocytic leukemia zinc finger (MOZ)-TIF2 fusion protein, we show here that AML can be cured by the ablation of leukemia stem cells. Chromosomal translocations that involve the MOZ gene are typically associated with the FAB-M4 or -M5 subtype of human AML and often predict a poor prognosis. While MOZ is essential for the self-renewal of hematopoietic stem cells, MOZ-fusion proteins enable the transformation of non–self-renewing myeloid progenitors into leukemia stem cells. The MOZ-fusion proteins interacted with PU.1 to stimulate the expression of macrophage-colony stimulating factor receptor (M-CSFR). Cells expressing high levels of M-CSFR (M-CSFR -high cells), but not those expressing low levels of M-CSFR, showed potent leukemia-initiating activity. Using transgenic mice expressing a drug-inducible suicide gene controlled by the M-CSFR promoter, AML was cured by ablation of the M-CSFR -high cells. Analysis of M-CSFR-deficient and PU.1-deficient mice showed that M-CSFR and PU.1 was essential to induce AML. Inhibitors for tyrosine kinases including M-CSFR slowed the progress of MOZ-TIF2-induced leukemia. Thus, M-CSFR -high cells contain leukemia stem cells, and the PU.1-mediated upregulation of M-CSFR is a useful therapeutic target for MOZ leukemia.

Disclosures:

No relevant conflicts of interest to declare.
GATA-2 L359V Mutation Is Exclusively Associated with CML Progression but Not Other Hematological Malignancies and GATA-2 P250A Is a Novel Single Nucleotide Polymorphism.
Authors: Zhang Su-Jiang , Shi Jing-Yi , Li Jianyong
Published: October 2019

Abstract 2187

Poster Board II-164

Chronic myeloid leukemia (CML) progression is characterized by occurrence of new cytogenetic and molecular abnormalities. In the previous study, we have shown the important role of GATA-2 L359V mutation in CML progression. To further ascertain the truth of transcription factor GATA-2 in hematological malignancies, we expanded our study to GATA-2 full length by directly sequencing and applied MassARRAY assay into GATA-2 L359V mutation analysis. Finally, no GATA-2 L359V mutation was found in 270 acute myeloid leukemia, 30 myelodysplastic syndrome, 50 acute lymphoblastic leukemia, 12 chronic lymphocytic leukemia, 40 CML chronic phase and 286 BCR/ABL negative myeloproliferative disorders except CML blast crisis. A new variation of GATA-2 resulted in P250A change was identified, which was not found to have statistical difference between patients with hematological malignancies and healthy control. Hence, we concluded GATA-2 L359V is exclusively associated with CML progression but not other hematological malignancies and P250A is a new single nucleotide polymorphism.

Disclosures:

No relevant conflicts of interest to declare.
CMV-Specific Immunity and CMV Complications in Seropositive HCT Recipients Depend On Donor Serostatus.
Authors: Ugarte-Torres Alejandra , Liu Yiping , Williamson Tyler , Hoegh-Petersen Mette , Quinlan Diana , Roa Lina , Khan Faisal , Russell James A. , Storek Jan
Published: October 2019

Abstract 2248

Poster Board II-225

Background:

Anti-CMV T-cells are thought to control CMV. In seropositive recipients of grafts from seropositive donors (D+R+), both na•ve and memory/effector anti-CMV T-cells are transferred with the graft. In seropositive recipients of grafts from seronegative donors (D-R+), only na•ve anti-CMV T-cells are transferred with the graft. We hypothesized that counts of anti-CMV T-cells are higher in the D+R+ compared to the D-R+ group, and that this leads to a lower incidence of CMV complications like CMV disease or CMV reactivation treated with toxic antiviral drugs, and that this may be particularly obvious in the setting of T cell depletion.

Patients and methods.

We reviewed charts of 298 seropositive recipients for CMV reactivation (pp65 antigenemia or CMV DNAemia above institutional threshold for starting preemptive therapy), recurrent CMV reactivation (above the same threshold), CMV disease, and death due to any cause. In 76 of these patients, we determined the counts of anti-CMV effector T-cells (producing INFg upon 18 h stimulation with CMV lysate in case of CD4+ T-cells or pp65 overlapping peptides in case of CD8 T+-cells). Conditioning of all patients included rabbit-anti-human thymocyte globulin (Thymoglobulin). Median follow up of the 298 patients was 19.6 months (range, 0.3 – 120.6)

Results.

As shown in Table 1, the anti-CMV T cell, in particular, CD4+ T-cell counts were higher, and the cumulative incidences of CMV reactivation, recurrent CMV reactivation and CMV disease were lower in D+R+ compared to D-R+ patients. Conclusion. Compared to D+R+ patients, D-R+ have lower counts of anti-CMV T-cells. This appears to translate into a higher risk of CMV reactivation and CMV disease. New strategies to avoid CMV complications need to be explored for D-R+ patients, eg, donor vaccination pre-transplant or infusion of anti-CMV T-cells post-transplant.

Disclosures:

No relevant conflicts of interest to declare.