bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predictors of Outcome In Adult Patients with Acute Myeloid Leukemia In First Relapse,
Authors: Ravandi Farhad , Faderl Stefan , Pierce Sherry , Garcia-Manero Guillermo , Brandt Mark , Shan Jianqin , Kadia Tapan , Borthakur Gautam , Estrov Zeev , o'Brien Susan , Cortes Jorge E. , Kantarjian Hagop M. 
Published: October 2019

Abstract
Abstract 3569
Treatment of patients with acute myeloid leukemia (AML) in first relapse has remained challenging and although relatively high response rates have been reported using selected combination chemotherapy regimens, long term leukemia-free survival has been less than 20% in most studies. A number of predictors of outcome have been reported of which the most significant are duration of first CR (CR1), cytogenetics at diagnosis, age at relapse, and whether allogeneic stem cell transplant (SCT) was performed in CR1 (Breems, DA, JCO, 2005). We sought to examine predictors of outcome after first relapse of AML incorporating some of the more recent relevant covariates such as molecular data, when available. From January 2000 to March 2010, 447 patients with AML (excluding acute promyelocytic leukemia) in first relapse were seen at the University of Texas – MD Anderson Cancer Center (MDACC) and have available survival data; 275 received therapy at MDACC and 66 (24%) achieved a second CR (CR2), with 14 (5%) patients achieving CR without platelet recovery (CRp2). For the overall population, the median survival from relapse is 5 months (range, 1 to 103+) and the median follow-up in surviving patients is 34.3 months (range, 5 to 103+). On univariate analysis, the following factors predicted survival in first relapse: the duration of CR1 (p<0.001), unfavorable cytogenetics at diagnosis (p<0.001) and having NPM1+/FLT3- status at diagnosis (p=0.001), as well as the following variables at relapse: age (p< 0.001), WBC (p<0.001), platelets (p=0.005), peripheral blood blast % (p<0.001), bone marrow blast % (p<0.001), performance status (p<0.001), creatinine (p<0.001), LDH (p<0.001) and albumin (p<0.001). Having FLT3-ITD at diagnosis and undergoing allogeneic stem cell transplant in CR1 were of borderline significance (p value for both =0.08). On multivariate analysis, taking into account only variables with a p<0.1, duration of CR1, age at relapse, unfavorable cytogenetics at diagnosis, and LDH as well as bone marrow blast % at relapse were significant (p<0.001). Positive FLT3-ITD at diagnosis was also significant (p=0.04). When multivariate analysis was conducted in the subset of 121 patients with complete FLT3 and NPM1 mutational status at diagnosis, neither the NPM1+/FLT3- status, nor having FLT3-ITD at diagnosis remained significant. In conclusion, we confirm that the most important predictors for survival in first relapse are duration of CR1, age at relapse, unfavorable cytogenetics, and possibly FLT3-ITD at diagnosis, as well as percentage of bone marrow blasts and LDH at relapse.

Disclosures:
No relevant conflicts of interest to declare.
A Meta-Analysis of CAG (cytarabine, aclarubicin, G-CSF) Regimen for the Treatment of 1045 Patients with Leukemia in China and Japan,
Authors: Wei Guoqing , Ni Wanmao , Chiao Dicky , Huang He , Cai Zhen , Liu Delong 
Published: October 2019

Abstract
Abstract 3638

Background:
CAG regimen (cytarabine, aclarubicin, G-CSF) has been commonly used in China and Japan for the treatment of AML and MDS. This study is to summarize the data and to analyze the efficacy as well as the toxic effects of CAG regimen in acute leukemia (AL) and MDS pts.

Methods:
The databases of PubMed, Wanfang Data, as well as American Society of Hematology (ASH) annual meeting abstracts were searched for articles published in English, Chinese and Japanese languages between January 1995 and December 2010. Eligible studies were relevant clinical trials on AL and MDS pts treated with CAG regimen. Complete remission (CR) rates and odds ratio (OR) were compared through a meta-analysis using a random-effects or fixed-effects model.

Results:
37 trials with a total of 1045 AL and MDS pts were included for analysis. Among the 1045 pts treated with CAG, 819 pts were AML, 215 pts were de novo MDS or transformed AML (MDS/tAML), 6 pts were ALL, and 5 pts were biphenotypic acute leukemia (BAL). The AML CR rate of CAG from 29 studies was 58.0% (95% CI, 53.1%-62.7%). The MDS/t-AML CR rate from 12 studies was 45.7% (95% CI, 39.0%-52.4%). The AML CR rate was significantly better than that of MDS /tAML (Q=8.072, p<0.01). Among 819 AML pts, 327 pts were newly diagnosed, 370 pts were relapsed/refractory (R/R) AML. The AML status was not specified in the rest 122 pts. Interestingly, no significant difference in CR rates was noted between the newly diagnosed (57.0%, 95% CI 51.5%-62.3%) and R/R AML pts (60.1%, 95% CI 50.5%-68.9%) (Q=0.312, p>0.05). The CR rate for the 367 elderly AML pts was 52% (95% CI 51.5%-62.3%). The CR rate was also significantly higher in pts with favorable (64.5%, 95% CI 38.8%-83.9%) and intermediate (69.6%, 95% CI 60.4%-77.5%) cytogenetics than those with unfavorable one (29.5%, 95% CI 19.7%-41.8%) (p<0.05). There were 7 trials that compared the CR rates of CAG regimen with those of other induction regimens in AML pts. Surprisingly, the CR rate of CAG was significantly higher than those of other induction regimens (OR 2.425, 95% CI, 1.515–3.880). CAG regimens were well tolerated with cardiotoxicity in 0.42% cases (4/954) and early death occurred in 4.40% cases (44/1000).

Conclusions:
CAG regimen induced significantly higher CR rates in AML than in MDS pts. The CR rates of CAG regimen was significantly better than those of other induction regimens in AML pts. This regimen was well tolerated with low cardiotoxicity and early death rate.

Disclosures:
No relevant conflicts of interest to declare.
Dematin Is Essential for Calcium Mobilization in Platelets
Authors: Wieschhaus Adam Joseph , Breton Guy Le , Chishti Athar H 
Published: October 2019

Abstract
Abstract 365
Dematin is an actin binding protein that was originally identified in the human erythrocyte membranes; however, dematin polypeptides are detectable in many non-erythroid cells. In erythrocytes, dematin is located at the spectrin-actin junctions thus linking the skeleton to the plasma membrane. This junctional complex serves to maintain both erythrocyte shape and membrane stability. Dematin is phosphorylated by multiple protein kinases, including the cAMP-dependent protein kinase and protein kinase C, and its actin bundling activity is regulated by phosphorylation. Dematin is also an excellent substrate of calpain-1, a calcium-dependent cysteine protease. Because of the functional similarities between the core components of the membrane skeleton in erythrocytes and platelets, we sought to investigate the physiological function of dematin in platelets. The remodeling of the actin cytoskeleton is known to regulate platelet activation and secretion of platelet granule contents. Western blotting demonstrated abundant expression of the ∼52 kDa polypeptide of dematin in both human and mouse platelets. To evaluate the functional role of dematin in platelets, we utilized the dematin headpiece knockout (HPKO) mouse model previously generated in our laboratory. Headpiece domain of dematin is an actin binding module sharing sequence similarity with the villin-family of cytoskeletal proteins. Importantly, the in vivo deletion of the headpiece domain of dematin resulted in substantial diminution of calcium mobilization in response to multiple agonists of platelet activation (Fig. 1). The reduced calcium mobilization in HPKO platelets was associated with significant inhibition of the platelet aggregation and granule secretion pathways. The HPKO platelets exhibit decreased activation of both the integrin αIIbβ3 receptor and RhoA upon platelet stimulation. Moreover, the HPKO platelets display aberrant morphology upon spreading on the fibrinogen and vWF-coated surfaces. Consistent with these findings, the HPKO mice show a significant clot retraction defect associated with a general tail bleeding phenotype. Mechanistically, the basal level of cAMP remained unaltered in the HPKO platelets suggesting the independence of the observed phenotype upon changes in the cAMP concentration. Immunofluorescence analysis indicated that dematin is associated with two platelet membrane compartments known to be involved in calcium fluxes, i.e., the dense tubular system (DTS) and the plasma membrane. Studies are currently in progress to identify the dematin-associated complex in platelets by Western blotting and proteomics approaches. Together, these results unveil dematin as a novel regulator of calcium homeostasis in platelets with functional implications for the development of new anti-platelet therapies.

Disclosures:
No relevant conflicts of interest to declare.
Expression of Phospholipse C Gamma 2 in Diffuse Large B-Cell Lymphomas,
Authors: Huynh Minh Quang , Kaiser Ulrich , Goßmann Jennifer , Neubauer Andreas 
Published: October 2019

Abstract
Abstract 3667
Cell survival and proliferation of diffuse large B-cell lymphomas (DLBCL) are dependent on the NF-κB signaling pathway. Antigen binding of the B-cell receptor (BCR) leads to phosphorylation of Src tyrosine kinases, resulting in PLCg2 activation, which is important for regulation of NF-κB through the protein kinase C (PKC). The PLC-PKC cascade also activates the Ras signaling pathway. There are several clinical studies showing that inhibition of PKCβ with the specific inhibitor Enzastaurin could be a promising new therapy target for DLBCL. To our knowledge, there are little data about the role of PLCg2 in DLBCL. It has been shown that the activity of Syk and PLCg2 are well correlated with sensitivity of DLBCL to dasatinib.
Our study performed immunohistological staining of PLCg2 in 86 primary DLBCL. PLCg2 was strongly expressed in 54 out of 86 cases (63%) and weakly expressed in 28 cases (32%). Only 4 cases (5%) were negative for PLCg2. In three DLBCL cell lines (SuDHL-4, SuDHL-6 and U2932) we could show an inhibitory effect of the PLC-inhibitor U73122 on cell proliferation. Treatment in combination with Enzastaurin or the Src-inhibitor pp2 had an additive effect on cell proliferation compared to U73122 alone.
In conclusion, PLCg2 is strongly expressed in a great subset of DLBCL. Inhibition of PLCg2 could be, at least in these cases, a new target for lymphoma treatment.

Disclosures:
No relevant conflicts of interest to declare.
Phase I Trial Evaluating the Safety and Biological Activity of Iboctadekin (rhIL-18) in Combination with Rituximab in Patients with CD20+ B Cell Non-Hodgkin's Lymphoma,
Authors: Robertson Michael J. , Bauman John , Gardner Olivia , Jonak Zdenka , Struemper Herbert , Germaschewski Fiona , Koch Kevin M. , Murray Sharon , Weisenbach Jill , Toso John 
Published: October 2019

Abstract
Abstract 3697

Background:
Iboctadekin (recombinant human interleukin-18; rhIL-18) is an immunostimulatory cytokine with anti-tumor activity in preclinical animal models. Phase I clinical trials have demonstrated that rhIL-18 is well-tolerated as monotherapy for patients with advanced solid tumors. Preclinical and clinical data indicate that rhIL-18 acts a costimulatory cytokine that may be optimally used in combination with other agents such as monoclonal antibodies. Methods: Patients with CD20+ B-cell non-Hodgkin's lymphoma (NHL) were given rituximab 375 mg/m2 IV weekly for 4 consecutive weeks in combination with rhIL-18 (in six dose cohorts of 1, 3, 10, 20, 30, and 100 mcg/kg) IV weekly for 12 weeks. Eligible patients had disease which progressed after standard therapy or for which there was no effective standard treatment. Assessments included safety/tolerability, pharmacokinetics, pharmacodynamics (serum cytokines, peripheral blood phenotypic markers and tumor biomarkers), immunogenicity, and anti-tumor activity. Results: Nineteen patients were enrolled on study (10 follicular NHL, 5 mantle cell lymphoma, 2 diffuse large B-NHL, 2 other subtypes). The combination was well-tolerated with a safety profile similar to that observed with rituximab or rhIL-18 given as monotherapy. The pharmacodynamic response is as expected based on results of prior clinical trials of rhIL-18 as monotherapy for cancer. Using the IWC response criteria, two (11%) of 18 evaluable patients had complete responses (CR) and 3 (16%) had partial responses (PR). Six (33%) patients had stable disease. Overall response rate for follicular lymphoma was 33% (1 CR, 2 PR). Conclusions: The combination of rhIL-18 and rituximab is safe, well-tolerated, and induces potent biological activity. A maximum tolerated dose of rhIL-18 was not identified. Further study of rhIL-18 plus rituximab in patients with CD20+ B cell malignancies is warranted.

Disclosures:
Bauman: GlaxoSmithKline: Employment, Equity Ownership. Gardner:GlaxoSmithKline: Employment, Equity Ownership. Jonak:GlaxoSmithKline: Employment, Equity Ownership. Struemper:GlaxoSmithKline: Employment, Equity Ownership. Germaschewski:GlaxoSmithKline: Employment, Equity Ownership. Koch:GlaxoSmithKline: Employment, Equity Ownership. Murray:GlaxoSmithKline: Employment, Equity Ownership. Toso:GlaxoSmithKline: Employment, Equity Ownership.
The Role of Imatinib Plasma Level in the Achievment of Complete Cytogenetic Response (CCyR) in Chronic Myeloid Leukemia (CML) Therapy
Authors: Kutsev Sergey , Oxenjuk Oxana , Mordanov Sergey , Shatokhin Yuri , Pospelova Tatiana , Khoroshko Nina , Turkina Anna 
Published: October 2019

Abstract
Abstract 3789

Background.
The treatment of patients with chronic phase (CP) Ph-positive chronic myeloid leukemia (CML) with imatinib has resulted in high rates of cytogenetic and molecular responses. There are evidences that the achievement of CCyR and MMR to imatinib therapy is related with Imatinib plasma level (IPL) in some studies1,2 but not in others 3. This discrepancy may be possibly explained by the heterogeneity in the analysed cohort patients differing with respect to the phase of the disease and imatinib dose.
The Aim of our study was to elucidate the trough role of IPL in the achievement of CCyR in homogeneous cohort of CP CML patients.

Methods.
IPL were detected in 321 CP CML patients with Imatinib treatment duration more than 12 months (the median – 90,3). Imatinib doses was 400 mg QD. The age of patients was 54,6 (24–76). Male/female ratio was 157/164. All patients gave informed consent before blood sampling. Blood samples were collected in 21–27h after the last Imatinib dose intake. Imatinib concentrations (C trough) were determined by validated LC/MS/MS method.

Results.
The patients were subdivided in 4 quartiles (Q): Q1 (n=81) with IPL 0 – 670 ng/ml, Q2 (n=80) with IPL 671 – 1042ng/ml, Q3 (n=80) with IPL 1043 – 1362ng/ml, Q4 (n=80) with IPL 1363 – 3826/ml. The results of imatinib treatment in each quartile were estimated according ELN recommendation. The obtained findings have shown that 48,1% CP CML patients in Q1 have achieved CCyR whereas 77,5%, 81,3% and 85% - in Q2,Q3 and Q4 respectively (Fig.1.).

Conclusion.
Our findings show that the achievement of CCyR in large cohort of CP CML patients (n=321) on imatinib with 400 mg/QD depends on IPL. The low level of IPL may indicate the nonadherence of some CML patients as well as some intrinsic mechanisms of imatinib plasma concentration decrease.

Disclosures:
Kutsev: Novartis: Research Funding, Speakers Bureau. Pospelova:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Khoroshko:Novartis: Speakers Bureau.
Activation of Chromatin Structure Upstream PU.1 Gene and in Vitro Differentiation in High Risk Myelodysplastic Syndrome Following 5-Azacytidine,
Authors: Stopka Tomas , Curik Nikola , Burda Pavel , Vargova Karin , Pospisil Vit , Vlckova Petra , Savvulidi Filipp , Necas Emanuel , Hájková Hana , Haskovec Cedrik , Belickova Monika , Cermak Jaroslav , Trneny Marek , Jonasova Anna 
Published: October 2019

Abstract
Abstract 3791
Use of DNA demethylating agent 5-azacytidine (AZA) in high risk Myelodysplastic syndromes (MDS) represents an important strategy yet not fully understood at molecular levels. Previous work demonstrated that normal progenitors treated by DNA demethylation agent Decitabine upregulated a key hematopoietic transcription factor PU.1. This was potentiated in presence of granulocyte colony stimulating factor (G-CSF) prior the DNA demethylation (Hu et al. 2010). Similarly, Decitabine administered to multiple myeloma cells resulted in DNA demethylation and upregulation of PU.1 gene (Tatetsu et al. 2007). To advance our understanding of molecular events mediated by AZA in MDS we measured effect of AZA on transformed cell lines (OCI-M2, SKM-1, MOLM-13, HNT-34, F-36P) and monitored the hematopoietic transcriptional program. We herein present evidence that AZA, while inducing efficiently cell cycle arrest and apoptosis of MDS tumor cells, stimulates also the expression of PU.1 and its target C/EBPa that is followed by acquisition of the myeloid differentiation program. Gene derepression of PU.1 is marked by epigenetic modifications at the upstream regulatory element (URE) of PU.1. G-CSF potentiated effects of AZA in MOLM-13 and SKM-1 cells. The effects of G-CSF and other cytokines (such as M-CSF or GM-CSF) on monocytic versus granulocytic lineage commitment of MDS cells are currently tested. To advance our study on the patient level we used primary high risk MDS CD34+ cells (N=36). Tumor cells with the lowest PU.1 expression displayed partial methylation at URE and incomplete sensitivity to AZA/G-CSF-mediated in vitro differentiation. We observed that patients with permissive chromatin at URE and higher PU.1 (and C/EBPa) levels responded significantly better to AZA/G-CSF in vitro. Currently we enrolled more patients in order to ask whether permissive PU.1 locus predicts responsiveness to AZA and whether it associates with different clinical patient outcome. (Grants: IGA NT10310-3/2009, MPO FR-TI2/509, GAUK251135 82210 & 251070 45410, SVV-2011-262507).

Disclosures:
No relevant conflicts of interest to declare.
IER3 Expression in Childhood Myelodysplastic Syndrome,
Authors: de Vries Andrica , Zwaan Christian M. , van Oorschot Astrid Danen- , de Haas Valerie , Hasle Henrik , Locatelli Franco , De Moerloose Barbara , Polychronopoulou Sophia , Stary Jan , Schmugge Markus , Dworzak Michael , Zecca Marco , Beverloo H. Berna , Niemeyer Charlotte M , Pieters Rob , van den Heuvel Marry M. 
Published: October 2019

Abstract
Abstract 3817

Background:
Childhood myelodysplastic syndrome (MDS) is a rare disease accounting for less than 5% of all hematological malignancies. In about 50% of the MDS cases an abnormal karyotype is found by conventional karyotyping, of which chromosome 6 is involved in 10%. The immediate-early-response 3 (IER3) gene, which is located on chromosome 6p21, encodes for a glycoprotein that plays a role in the regulation of apoptosis and cell cycle progression. Recently, it was shown that IER3 gene aberrations frequently occur in adult MDS patients, which are not restricted to patients with chromosome 6 aberrations and that low IER3 expression was associated with a worse outcome. Therefore, we investigated the frequency and prognostic impact of IER3 expression in childhood MDS.

Methods:
IER3 mRNA expression was determined by quantitative real-time PCR in 58 childhood MDS patients of which 17 carried a chromosome 6 aberration, and in normal bone marrow (n=8). In addition, methylation-specific-PCR (MSP) was performed to investigate the methylation status of the promoter region of the IER3 gene, as a plausible cause for the downregulation of IER3.

Results:
Median IER3 mRNA expression was 0.9% in MDS (range 0.01–73.3% relative to GAPDH expression) and 3.3% in normal bone marrow (range 0.81–85.5% relative to GAPDH expression) (p=0.05). A more than 4-fold decrease in IER3 expression below the mean of healthy controls was found in 74% (43/58) of the childhood MDS patients. There was no difference in IER3 mRNA expression between MDS patients with or without chromosome 6 aberrations (MWU p= 0.89). Also, no difference in IER3 mRNA expression was found between the different WHO-subtypes or between primary versus secondary MDS. Three patients with a chromosome 6p21 rearrangements in the IER3 region based on genomic profiling (array-CGH) showed expression-levels in the range of normal bone marrow. Low IER3 mRNA expression was associated with adverse outcome in childhood MDS patients (Cox regression analysis estimated hazard ratio 0.73, p=0.027, 95% CI-interval 0.55–0.97). The low IER3 expression appeared not to be due to hypermethylation of its promoter region.

Conclusion:
IER3 expression is low in childhood MDS patients with and without chromosome 6 aberrations and this low expression is associated with poor outcome. However this seems to be due to therapy related mortality, rather than by the increased risk of relapse. The IER3 downregulation is not regulated by hypermethylation of the IER3 promoter region.

Disclosures:
Hasle: Pfizer: Research Funding.
Frequent Clonal Evolution in Multiple Myeloma,
Authors: Hwang Sang Mee , Choi Jungeun , Yim Sunhee , Kim Tae Young , See Chaja , Kim Miyoung , Yoon Sung-Soo , Lee Dong Soon 
Published: October 2019

Abstract
Abstract 3919

Background:
Multiple myeloma is a clonal bone marrow disease characterized by the neoplastic transformation of differentiated B cells. Various complex cytogenetic and molecular genetic aberrations are present that are important for prognostication and follow up investigation. We investigated the clonal evolution of multiple myeloma patients at relapse or at progression compared from the diagnosis by conventional cytogenetics, fluorescence in situ hybridization (FISH) and cytoplasmic immunoglobulin fluroscence in situ hybridization (cIg FISH). Methods: 35 patients diagnosed as multiple myeloma by bone marrow examination from January 2003 to March 2011 were included. Conventional cytogenetics were performed in all patients at diagnosis and at relapse or progression. FISH was performed in 24 patients with available specimen for at least 3 items including −13/del(13q), p53 deletion/del(17p), 1q21 gain, p16 deletion, IgH rearrangement, t(4;14) and t(14;16). The FISH results were confirmed with cytoplasmic immunoglobulin FISH specifically staining plasma cells. Results: Forty-nine percent of the patients had relapsed or progressed with additional clonal evolutions and they were detected by conventional cytogenetics. Numerical abnormalities were more frequent than structural abnormalities and structural abnormalities involving chromosome 1 was frequent. Thirty-five percent had developed −13/13q loss which is considered a poor prognostic factor. cIg-FISH found additional aberrations in 20% of the patients such as RB1 deletion, del(17p) and t(14;16). Conclusion: Conventional cytogenetics and cIG-FISH are both necessary in relapsed patient since clonal evolutions develop in many patients which may only be detected by one method. Full evaluation of cIg-FISH including non-poor prognostic factors may be considered since new clones evolve that can be a candidate of follow-up marker and since prognostic factors can change as treatment modality changes.

Disclosures:
No relevant conflicts of interest to declare.