bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tailored Temozolomide Therapy for Elderly Patients with Acute Myeloid Leukemia.
Authors: Medeiros Bruno C. , Gotlib Jason R. , Coutre Steven E. , Mignea Angela , Zehnder James 
Published: October 2019

Abstract
Alternative treatment modalities are greatly needed for elderly patients with acute myeloid leukemia (AML). Previous preclinical data and clinical observations show that only patients lacking expression of O6-alkylguanine-DNA alkyltransferase (AGAT) in leukemic blasts are sensitive to temozolomide. Furthermore, AGAT enzymatic activity can be significantly decreased by protracted exposure to low doses of temozolomide. Based on these data, we have designed a phase II clinical trial tailoring temozolomide therapy to elderly patients with AML according to AGAT status. AGAT promoter methylation status was determined in pretreatment leukemic samples. Patients demonstrating evidence of AGAT promoter methylation were stratified to conventional doses of temozolomide at 200mg/m2 orally x 7 days. Patients demonstrating lack of AGAT promoter methylation (unmethylated) were stratified to receive protracted doses of temozolomide (100mg/m2 orally x 14 days) followed by conventional doses of temozolomide. Those patients who achieved CR were given up to 5 similar consolidation treatments. Eleven patients have been treated to date. The median age was 78 (71–83) and 6 were male. Seven patients were newly diagnosed and 6 patients had a normal karyotype. Nine patients had an unmethylated AGAT promoter in their leukemic blasts. Correlative AGAT protein expression in leukemic blasts will be presented at the meeting. All patients had an intact mismatch repair pathway. Median HCT-CI score was 1 (0–5). Four patients (4/10) achieved a complete remission after 1 cycle of therapy (1/2 for patients with methylated AGAT promoter and 3/8 for patients with unmethylated AGAT promoter). Nonhematologic toxicities attributed were minimal. Drug-related hematologic toxicities were difficult to distinguish from disease-related cytopenias. Six patients developed neutropenic fever (four patients developed neutropenic fever before the start of therapy). Three (3/10) patients remain alive with a median duration of remission of 4.5 months (4–5 months). Four patients have died from disease progression. And two patients died of neutropenic sepsis. One patient who achieved a CR, experienced prolonged marrow aplasia (47 days) following consolidation cycle #1 and withdrew from the study. The trial is ongoing with an accrual goal of 36 patients. These preliminary results suggest that temozolomide therapy may be individually tailored to elderly patients with AML according to AGAT promoter status.
Allogeneic Stem Cell Transplantation Results in a Low Relapse Rate in Patients with Peripheral T-Cell Lymphoma.
Authors: Nickelsen Maike , Canals Carmen , Kyriakou Charalampia , Schmitz Norbert , Buzyn Agnes , Engelhardt Monika , Glass Bertram , Conde Eulogio , Lopez-Guillermo Armando , Socie Gerard , Sureda Anna 
Published: October 2019

Abstract
Patients (pts) suffering from mature (peripheral) T-cell lymphoma are known to have a poor outcome compared to pts with aggressive B-cell lymphoma when receiving conventional therapies. However, case reports and single centre experiences show promising results of allogeneic stem cell transplantation (allo SCT) for these pts. We here present a retrospective analysis of 103 pts with mature T-cell lymphoma who received an HLA-identical allo SCT in EBMT centres between 2000 and 2005. Histological subtypes of the patients were anaplastic large cell lymphoma (n=25; 4 anaplastic lymphoma kinase [ALK] positive, 11 ALK negative, 10 ALK unknown), peripheral T-cell lymphoma unspecified (n=51), angioimmunoblastic T-cell lymphoma (n=18) and aggressive T-cell lymphoma unspecified (n=9). Patients with primary cutaneous T-cell lymphoma or T-lymphoblastic lymphoma were excluded. Median follow up for surviving patients was 40 months (6–98), median age at allo SCT 42 years (18–68) and median time to allo SCT 17 months (3–233). 39 pts had failed a prior autologous SCT; 68 pts had chemosensitive disease at allo SCT (of these 15 in CR1) and 30 pts had chemorefractory or untested relapsed or progressive disease. Donors were HLA identical siblings for 73 and matched unrelated donors for 30 pts; 82 pts received peripheral blood stem cells. 54 pts were treated with reduced intensity conditioning before SCT. The cumulative incidence (CI) of acute graft versus host disease (GvHD) 100 days after SCT was 52% and had no effect on non-relapse mortality (NRM) or relapse rate (RR). 34 of 74 evaluable pts experienced chronic GvHD (14 limited, 20 extensive), CI 46% at 2 years. Introducing chronic GvHD as a time dependent covariate, this factor was associated with a higher NRM (p<0.001) and a lower RR (statistically not significant), resulting in a lower progression free survival (PFS) (p=0.001). For all patients CI of NRM and RR at 3 years were 36.7% and 24.9%, respectively, resulting in 41.4% PFS and 46.9% OS. Median time to relapse / progression was 4 (1–18) months. In multivariate COX analysis for PFS refractory disease (relative risk 3.4, p=0.001), prior failed auto SCT (relative risk 2.6, p=0.001) and poor performance status at SCT (relative risk 2.5, p=0.04) were significant adverse factors. Additionally, there were trends for T-cell depleted grafts (p=0.1), CMV status other than negative-negative (p=0.1) and reduced intensity conditioning (p=0.2) to be adverse factors. A subgroup of 39 good risk pts (good performance status, chemosensitive disease, no prior autologous SCT) had a PFS of 59%.
This retrospective analysis on allo SCT in peripheral T-cell lymphoma shows an encouraging low RR but efforts have to be made to reduce NRM. Prospective studies are warranted to further define pts who will profit from an early allo SCT.
An Open-Label Study of CEP-701 in Patients with JAK2 V617F-Positive Polycythemia Vera and Essential Thrombocytosis
Authors: Moliterno Alison R , Roboz Gail J. , Carroll Martin , Luger Selina , Hexner Elizabeth , Bensen-Kennedy Debra M. 
Published: October 2019

Abstract
Polycythemia vera (PV) and essential thrombocytosis (ET) are clonal hematopoietic stem cell disorders characterized by the over production of phenotypically normal circulating blood cells. Most PV and approximately half of ET patients harbor the activating mutation JAK2 V617F. CEP-701 is an orally available, potent low nanomolar inhibitor of both the wild-type and mutated JAK2 tyrosine kinase, with its inhibitory effect demonstrated both in enzymatic and cellular assays and in vivo, where CEP-701 significantly inhibited the growth of JAK2 V617F-positive HEL.92 xenografts in mice. These findings suggest that CEP-701 is an attractive candidate for clinical evaluation in JAK2 V617F-positive myeloproliferative disorders. The purpose of this study is to test the safety and efficacy of CEP-701 administration in JAK2 V617F positive ET and PV patients. The primary endpoint is reduction in JAK2 V617F neutrophil allele burden; secondary endpoints are reduction in phlebotomy rates, improvement in hemoglobin, white cell and platelet counts, reduction in hydroxyurea (HU) dose, and reduction in spleen size. The secondary endpoints include the pharmacokinetics and pharmacodynamics of CEP-701 and the safety of CEP-701 treatment in patients with JAK2 V617F-positive PV and ET. This is a multicenter study with an anticipated enrollment of 40 PV and ET patients. Inclusion criteria include JAK2 V617F-positive PV and ET patients; patients with PV either have a neutrophil count greater than 7,000/ul or are receiving HU, while ET patients are receiving concomitant HU. Other inclusion criteria include an ECOG performance status of 0, 1 or 2, and 18 years of age or older. Exclusion criteria include the active use of anegrelide or interferon, or a recent history of venous or arterial thrombosis. This is an 18 week trial with an optional 1 year extension period; doses will escalate from 80 mg twice daily to a maximum of 120 mg twice daily. To date, 20 subjects, 11 PV and 9 ET, comprised of 11 females and 9 males, ages 34 to 74, have enrolled. Approximately 27% of the PV patients were taking HU. The most common adverse events have been gastrointestinal (GI) and constitutional in nature. No related serious adverse events have been observed. Five patients have discontinued study participation, all for adverse events: 1 due to disease progression, 1 leg cramps, and 3 GI. To date, 7 patients have completed 18 weeks of therapy and 6 of these patients will continue to receive CEP-701 on the extension phase of the trial. Five of 8 subjects with splenomegaly have responded with reductions in spleen size evident within 6 weeks of therapy initiation. Updated results on current and future patients will be presented at the meeting.
p38 MAPK Inhibition Prevents TACE-Mediated Receptor Shedding and Improves the Hemostatic Function of Stored Platelets.
Authors: Canault Matthias , Duerschmied Daniel , Brill Alexander , Patten Ian Sean , Bergmeier Wolfgang , Wagner Denisa D. 
Published: October 2019

Abstract
Platelet transfusion is a lifesaving procedure widely used during surgery and chemotherapy. During storage platelets undergo several modifications that reduce their postransfusion survival and functionality. One important feature of this platelet storage lesion (PSL) is the shedding of surface glycoproteins such as GPIbα and GPV. We have recently demonstaretd that metalloproteinase inhibitors prevent storage-induced shedding of adhesion receptors, resulting in markedly improved postransfusion recovery and hemostatic function of platelets in mice. We now demonstrate that TNF-alpha converting enzyme (TACE/ADAM17) mediates receptor shedding from platelet stored for 18 hours at 37ºC or 22ºC. Using pharmacological inhibitors, we show that TACE -dependent shedding of GPIbα and GPV from both mouse and human platelets during storage required p38 MAP kinase signaling. In contrast, protein kinase C, Erk MAPK, and caspases were not involved. Inhibition of p38 MAPK during the storage of mouse platelets also markedly improved their posttransfusion recovery and hemostatic function in vivo. Moreover, p38 MAPK inhibition during storage of human platelets improved their adhesion to collagen under flow. Inhibition of p38 MAPK also prevented TACE-dependent shedding of GPIbα from platelets undergoing mitochondrial injury, a model for PSL. Phosphorylation of p38 MAPK was observed after platelet storage and mitochondrial injury. In summary, our data suggest that inhibition of p38 MAPK or TACE during storage may significantly improve the quality of stored platelets.
Platelet Glycoprotein 1b-1X in Hemostasis and Malignancy.
Authors: Ware Jerry , Jain Shashank 
Published: October 2019

Abstract
The platelet paradigm in hemostasis and thrombosis involves an initiation step dependent upon platelet membrane receptors binding to ligands on a damaged or inflamed vascular surface. Once bound to the surface, platelets provide a unique microenvironment supporting the accumulation of more platelets and the elaboration of a fibrin-rich network produced by coagulation factors. This paradigm has been established from decades of research. The platelet-specific receptor, glycoprotein (GP) Ib-IX, is critical in this process and can initiate the formation of a platelet-rich thrombus by tethering the platelet to a thrombogenic surface. Several ligands binding to GP Ib-IX have been identified, but von Willebrand factor (vWF) and the resultant GP Ib-IX/vWF axis has emerged as a major initiator of platelet thrombus formation in the arterial circulation. Newer, emerging data supports a role for platelets in pathological events beyond the prevention of blood loss. We have obtained data supporting the hypothesis that platelet GP Ib-IX contributes to malignancy. Knockout and transgenic mouse colonies have been generated in our laboratory and bred to C57BL/6J animals to generate several congenic strains (> 10 generation backcrosses) with dysfunctional platelet GP Ib-IX. These colonies have been used to characterize tumor metastasis and primary tumor growth in syngeneic models where the host animals are immunocompetent. The results demonstrate platelet GP Ib-IX contributes to tumorigenesis, as a functional absence of GP Ib-IX correlates with a significant reduction in the number of metastatic foci using models of experimental metastasis. In addition, an absence of GP Ib-IX significantly reduces primary tumor burden. A second series of experiments has determined that platelet GP VI, a key activation receptor on the surface of platelets also contributes to progression of experimental metastasis. The importance of metastasis in the prognosis for recovery from cancer can not be over-emphasized. Indeed, the spread of metastatic disease represents a fundamental change in significantly shortening the lifespan of patients with breast cancer. Thus, understanding the molecules that regulate metastasis identifies potential targets for therapeutic intervention that could significantly improve the prognosis for the breast cancer patient. Several decades of prior work in hemostasis and thrombosis has placed this project in a position to quickly provide new information and understanding on the links between hemostasis and cancer.
Nitric Oxide and Platelet Function.
Authors: Lowenstein Charles J. 
Published: October 2019

Abstract
Nitric Oxide (NO) is a versatile messenger molecule of the vascular system. Three different NO synthase (NOS) isoforms found in the vasculature can synthesize NO: endothelial NOS, neuronal NOS, and inducible NOS. Once produced, NO can diffuse across cell membranes and modulate the cell biology of leukocytes, endothelial cells, and platelets. NO has several classes of molecular targets, including proteins with heme moieties, such as guanyly cyclase, cysteine residues of proteins, and radicals, such as superoxide. NO influences platelets through at least two distinct pathways. NO activation of a cGMP pathway mediates NO inhibition of eicosanoid metabolism, NO suppression of gpIIb/IIIa conformational changes, and NO deactivation of thromboxane receptors. However, NO also regulates platelets by chemically modifying cysteine residues of proteins critical to platelet activation. For example, NO modifies key cysteine residues of the enzyme N-ethylmaleimide sensitive factor, thereby blocking exocytosis of alphagranules. Recent studies have shown that metabolites of NO such as nitrite may also regulate platelet function.
Donor CD4+ T Cells That Possess Both Allo- and Autoreactivity in Transplants Mediate Chronic Graft Versus Host Disease.
Authors: Zhao Dongchang , Chen Yu-Hong , Young James , Shen Elizabeth , Yi Tangsheng , Liu Hong-Jun , Chu Peiguo G. , Zeng Defu 
Published: October 2019

Abstract
Abstract 3555
Poster Board III-492
Chronic graft versus host disease (GVHD) is considered an autoimmune-like disease mediated by donor CD4+ T cells, but the role and origin of the autoreactive T cells remain controversial. Here, we report that, in a chronic GVHD model of MHC-matched DBA/2 (H-2d) donor to BALB/c (H-2d) host, donor spleen cells induced autoimmune-like chronic GVHD in thymectomized allogeneic BALB/c but not in syngeneic DBA/2 recipients. The spleen cells from the former but not the latter recipients induced autoimmune-like disease in the secondary DBA/2 recipients, indicating that autoreactive donor CD4+ T cells from transplants are expanded and contribute to chronic GVHD pathogenesis. In addition, we found that both auto- and alloreactive donor CD4+ T cells generated from primary chronic GVHD recipients via serial in vivo and in vitro expansion proliferated to donor and host DC stimulation and both induced autoimmune-like disease in syngeneic and allogeneic recipients. Furthermore, the clonal expansion and TCR spreading of the autoreactive T cells in chronic GVHD recipients were following the alloreactive T cells, as revealed by TCR-spectrum typing and skewing of TCR-CDR3 length; No dual TCR was expressed by the donor-type T cells with both allo- and autoreactivity; and the autoreactive hybridoma T clones proliferated to stimulation by both syngeneic and allogeneic DCs. Taken together, these results demonstrate that donor CD4+ T cells that possess both allo- and autoreactivity in transplants are expanded in recipients and contribute to chronic GVHD pathogenesis, and the allo- and autoreactivity of the donor T cells can be mediated by a single TCR.

Disclosures:
No relevant conflicts of interest to declare.
CCL3 and CCL4 Plasma Levels Correlate with Established Prognostic Markers in Chronic Lymphocytic Leukemia: Towards a Simple, ELISA-Based Assay for Risk Assessment.
Authors: Sivina Mariela , Hartmann Elena , Krupnik Diana , LaPushin Ruth , Keating Michael , Kipps Thomas J. , Rosenwald Andreas , Wierda William G , Burger Jan A. 
Published: October 2019

Abstract
Abstract 358

During the induction of normal immune responses, activated B cells secrete the chemokines CCL3 and CCL4 for recruitment of regulatory T cells (Nat Immunol. 2:1126-32, 2001). This may represent a mechanism enabling cognate interactions between rare antigen-specific T and B cells. We previously reported that CCL3 and CCL4 RNA and protein are induced in CLL cells by co-culture with nurselike cells and after B cell antigen receptor (BCR) cross-linking (Blood 113:3050-8, 2009). We found higher levels of CCL3 and CCL4 in ZAP-70 positive cases, and CCL3 and CCL4 secretion was abrogated by the Syk inhibitor R406. These findings suggest that CCL3/CCL4 secretion by CLL cells correlates with the signaling capacity of the BCR. Also, we previously noticed higher plasma levels of CCL3 and CCL4 in CLL patients, when compared to healthy controls.
In this study, we measured CCL3 and CCL4 plasma levels by ELISA in 351 CLL patients, and correlated CCL3 and CCL4 levels with various prognostic markers, including RAI stage, immunoglobulin heavy chain variable region gene (IgVH) mutational status, ZAP-70, β2 microglobulin, CD38, white blood count (WBC), and cytogenetic subgroups. We found that the concentrations of CCL3 and CCL4 were significantly higher in plasma samples from CLL patients who had CLL cells that used unmutated IgVH genes or that expressed ZAP-70 or CD38, or who had an advanced stage of their disease (see Table 1). For example, the mean CCL3 plasma level was 56.4 ± 8.8 pg/ml in patients with CLL cells that used unmutated IgVH (mean ± SEM, n=123) versus 14.5 ± 2.4 in patients with CLL cells that used mutated IgVH (mean ± SEM, n=139, p<0.001). The mean CCL4 level was 171.4 ± 26.3 in patients that had CLL cells that used unmutated IgVH and 92.5 ± 17.5 in patients that had CLL that expressed mutated IgVH. On the other hand, the relative absolute white cell count or presence of chromosomal abnormalities did not correlate with high plasma levels of CCL3 or CCL4. Immunohistochemistry revealed that CCL4 was predominantly expressed in proliferation centers in approximately 50% of the cases. Currently, we are evaluating whether high plasma levels of CCL3 and/or CCL4 are associated with a relatively short time from diagnosis to requiring initial treatment by the IWCLL-working group criteria. Also, we are exploring whether high plasma levels of CCL3 or CCL4 are associated with high proportions of infiltrating T cells in proliferation centers.
These studies suggest that patients can be stratified by their relative plasma levels of CCL3 and/or CCL4 and that high plasma-levels of theses chemokines define a characteristic that may be associated with aggressive disease.

Disclosures:
No relevant conflicts of interest to declare.
Nicotinamide Phosphoribosyltransferase (Nampt) Induces NAD+ / SIRT1 Mediated Deacetylation of p53 in Myeloid Cells.
Authors: Thakur Basant Kumar , Lippka Yannick , Skokowa Julia , Welte Karl 
Published: October 2019

Abstract
Abstract 3589
Poster Board III-526
Recently we found that NAMPT, a protein involved in biosynthesis of NAD+ was significantly increased in Severe Congenital Neutropenia (CN) patients treated with G-CSF as compared to healthy individuals (Skokowa et al, Nature Medicine, 2009). Increased NAD+ levels correlated with the elevated levels of SIRT1, a NAD+-dependent deacetylase involved in the deacetylation of histone and non-histone proteins. CN is considered as a pre-leukemic syndrome, since ca. 20% of CN patients develop AML/MDS. SIRT1 mediated deacetylation of p53 at the lysine 382 has been shown to attenuate the transcriptional activity of p53. We asked if inactivation of p53 by NAMPT/ NAD+ / SIRT1 dependent deacetylation plays a role in the leukemic transformation in patients suffering from CN. Here we can demonstrate that presence of NAMPT or NAD+ enhances the SIRT1 mediated deacetylation of acetylated lysine peptide in vitro. Further in 293T cells overexpression of NAMPT induces the SIRT1 mediated deacetylation of p53. Using the promyelocytic cell line NB4 we show that endogenous p53 interacts with SIRT1 and the presence of NAMPT leads to decreased acetylation of p53 at the lysine 382. The compound FK866 which specifically inhibits NAMPT has recently entered clinical trials as a potential chemotherapeutic agent. Acetylation of p53 is considered to be important for its tumor suppressor function and we asked if inhibition of NAMPT using FK866 increases the acetylation of p53. Indeed we demonstrate that the acetylation level of p53 is enhanced when NB4 cells were treated with FK866 and increased acetylation of p53 correlates with the decreased interaction between p53 and SIRT1. Treatment of NB4 with NAMPT further leads to the decreased expression of p53 target gene cyclin-dependent kinase inhibitor 1A (p21, Cip1) protein. p21 is a well known target of p53 and is involved in cell cycle arrest after the cell undergoes stress. Using p21 promoter-luciferase construct we show that SIRT1 inhibits the p53 mediated activation of p21 promoter and this inhibition was further enhanced in the presence of NAMPT or NAD+. Taken together our working hypothesis is that NAMPT/NAD+ activated SIRT1 mediates deacetylation of p53 protein thereby leading to p53 inactivation and downregulation of downstream target genes with tumor suppression functions (e.g. p21) which might possibly resulting in the leukemic transformation in CN patients.

Disclosures:
No relevant conflicts of interest to declare.