bluuebunny/crossref_metadata_2025_split huggingface dataset:
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
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
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
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
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
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
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
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
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
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.
Cytomegalovirus Reduces the Relapse Risk for Acute Leukemia After Transplant: There Is a Virus-Versus-Leukemia Effect.
Authors: Elmaagacli Ahmet H , Lindemann Monika , Opalka Bertram , Koldehoff Michael , Gromke Tania , Ottinger Hellmut , Ross Rudolf S. , Bauer Sebastian , Hilgendorf Inken , Beelen Dietrich W. 
Published: October 2019

Abstract
Abstract 2261
Poster Board II-238
Cytomegalovirus reactivation (HCMV) occurs frequently after hematopoetic stem cell transplantation and is associated with an increased treatment-related mortality. We aimed first to evaluate the cytotoxic effects of CMV on AML in vitro, and further, the clinical outcome of patients with AML with a documented CMV reactivation after transplant.
First, we show that HCMV infects acute leukemia cell line Kasumi-1 (AML) and SD-1 (ALL), inhibits their proliferation and induces apoptosis almost in all cells after 14 days. HCMV further inhibits the proliferation of bone marrow progenitor cells derived from healthy volunteers as demonstrated here by the reduction of the number and size of colony forming units in methylcellulose assays. The induction of apoptosis is unusual because HCMV possesses various strategies to prevent apoptosis in infected cells in order to delay their cell death and maintain its own virus replication. Apoptosis via a caspase-dependent pathway occurred although HCMV induced a significant up-regulation of the anti-apoptotic gene cFLIP and anti-stress gene Gadd45a and simultaneously down-regulation of pro-apoptotic genes p53, Bcl-2, Gadd45γ in Kasumi-1 and SD-1 cells, showing that the anti-apoptotic mechanisms of HCMV to prevent cell death failed. Concordantly, the coapplication of the caspase-specific inhibitor zVAD.fmk to HCMV- infected Kasumi-1 cells inhibited the induction of apoptosis to a great extent.
In the second part of our study we evaluated the clinical outcome of patients with AML after transplant in whom a HCMV reactivation occurred. We evaluated a homogenous group of 140 patients with AML after myeloablative conditioning, non-T cell depleted allogeneic HSCT from a HLA-identical sibling donor, and compared the clinical results to 60 patients with CML after transplant. CMV reactivation was documented by CMV-related matrix protein pp65 antigenemia test and routinely accompanied by a CMV preemptive therapy with ganciclovir.
CMV reactivation in AML patients was associated with reduced risk for relapse (11.6% v 50.5%; p&lt;0.0001) and improved overall survival estimates (73.6% v 42.5%, p=0.039), but increased risk for acute graft-versus-host-disease (GVHD) grade 2-4 (75.1% v 37.5%, p=0.004) and TRM in our analyses, whereas CML-patients had no advantageous effects. Multivariate analyses for risk of relapse confirmed CMV reactivation as an independent factor (RR 0.15, 0.03-0.67;[95% CI], p<0.013) besides chronic GVHD, disease stage, and cytogenetics.
We show here for the first time a strong anti-leukemic effect of HCMV in AML, which improves the outcome of patients after transplant, and might be defined as “virus versus leukemia effect”.

Disclosures:
No relevant conflicts of interest to declare.