bluuebunny/crossref_metadata_2025_split huggingface dataset:
SUPER- BEAM (SB): Incorporation of Bortezomib, Thalidomide, Dexamethasone, Cisplatin and Rapamycin Into the BEAM Regimen for Multiple Myeloma (MM).
Authors: Waheed Sarah , Alsayed Yazan , Nair Bijay , Szymonifka Jackie , Shaughnessy John D , van Rhee Frits , Anaissie Elias , Barlogie Bart 
Published: October 2019

Abstract
Abstract 3421
Poster Board III-309

Introduction
While the prognosis of patients with MM has been drastically improved with the introduction of novel agents into the treatment armamentarium, relapse management remains a difficult task, especially in the post-transplant and high-risk MM setting, as defined by the presence of cytogenetic abnormalities (CA) and gene expression profiling (GEP).

Patients and Methods
We have explored the efficacy and safety of SB in 95 patients with MM. The regimen comprised BCNU at 300mg/m2 on day 1, etoposide 200mg/m2 on days 1-4; cytarabine 400mg/m2 on days 1-5; melphalan 140mg/m2 on day 5 plus: bortezomib 1.0-1.3mg/m2 on days 1+4, thalidomide 100-200mg on days 1-5, dexamethasone 20-40mg days 1-5, cisplatin 10-12.5mg/m2/d by continuous infusion on days 1-5, rapamycin 3mg on day 1 and 1mg on days 2-5; followed by autotransplant (AT) on day 6.

Results
Patient characteristics included age >=65, 19%; LDH>ULN, 43%; CA, 67%; GEP high-risk, 44%; GEP MF, 15%; GEP delTP53, 22%; prior AT, 75% including 46% with 2AT and 12% with 3 AT. CR and near-CR status was documented in 50%; TRM occurred within 100 days in 6%. Three-year estimates of overall survival (OS) and event-free survival (EFS) were 34% and 18%; OS/EFS were superior: (a) without CA – 60%/50% versus 15%/5% with CA (p=0.003/0.0005); (b) with GEP low-risk – 55%/20% versus 10%/15% with high-risk MM (p=0.009/0.01); (c) with GEP Hyperdiploidy and Low Bone disease molecular subgroups – 70%/35% versus 20%/10% in the remainder (p=0,001/0.002); and (d) absence of progression prior to SB – 52%/35% versus 16%/5% for the remainder (p=0.002/0.0006). Univariately significant adverse variables for OS and EFS included low albumin, B2M>=3.5mg/L, CA, GEP high-risk and relapse just prior to SB, of which B2M, CA and pre-SB survived on multivariate analysis for the 78 patients with all variables; among the 57 with GEP data, OS was inferior with GEP high-risk MM (HR=3.55, p=0.007) whereas EFS was inferior with high LDH (HR=3.44, p=0.004), CA (HR=2.79, p=0.02) and pre-SB relapse (HR=2.94, p=0.035).

Conclusions
We conclude that SB is a safe salvage regimen that was well-tolerated for the majority in the outpatient setting. Although beneficial to patients lacking CA and GEP high-risk status, the poor outcome also with SB in the presence of these adverse features emphasize the urgent need to discover agents/strategies effective in this setting.

Disclosures
van Rhee: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Long Term Results of BL22 (CAT-3888) in Multiply Relapsed Hairy Cell Leukemia.
Authors: Kreitman Robert J , Wilson Wyndham H , Stetler-Stevenson Maryalice , Noel Pierre , FitzGerald David J. , Pastan Ira 
Published: October 2019

Abstract
Abstract 3442
Poster Board III-330
BL22 is a 63 kDa anti-CD22 recombinant immunotoxin containing truncated Pseudomonas exotoxin and variable domains from an anti-CD22 antibody. Patients with multiply relapsed/refractory hairy cell leukemia received BL22 and achieved 19 (61%) complete remissions (CRs) and 6 (19%) partial responses (PRs) in phase I testing, and 17 (47%) CRs plus 9 (25%) PRs in phase II testing (n=36), for overall response rates (ORR) of 72-81%. The average dose/cycle was the same for phase I and II (29 vs 33 ug/Kg x3). The dose for phase II was 40 ug/Kg x3 initially and 30 ug/Kg x3 for retreatment, but retreatment was held if patients had hematologic remission (HR, neutrophils ≥ 1500/mm3, Hgb ≥ 11 g/dL, and platelets ≥ 100,000/mm3) after cycle 1. Disease-free survival (DFS, CR duration) for phase II has not yet been reached at a median of 32 (range 4-62) months, with 12 (71%) of 17 CRs still ongoing. Considering all 36 CRs from phase I and II testing, median DFS was 33 (3-112) months with 15 (42%) of 36 CRs ongoing. Patients in CR usually underwent bone marrow biopsy every 6 months for 2 years and yearly thereafter, and after relapsing usually remained in HR. In fact, the median HR duration of these patients has not yet been reached at 42 (range 4-112) months, with 24 (67%) of the 36 patients remaining in HR or CR. Outcomes were better for those with pre-BL22 spleens measuring ≤ 200 mm in height than those with either prior splenectomy or spleens > 200 mm, in terms of CR (68% vs 34%, p=0.007), ORR 95% vs 48%, p=0.000003), and DFS (median 69+ vs 27 mo, p=0.002). In contrast, CR rates or DFS was not related to whether patients had <1 (n=28) or >1 (n=8) years of response to their last course of purine analog (p=0.5-0.75). Of 69 patients who received BL22, 8 (12%) had a completely reversible hemolytic uremic syndrome (HUS) and all maintained normal renal function after a median 80 (9-112) months of follow-up. We conclude that BL22 is highly active producing durable remissions in chemoresistant HCL, particularly in patients with limited disease burden. Testing is underway with a high-affinity version of BL22, called HA22 (CAT-8015).

Disclosures
Kreitman: NIH: Patents & Royalties. Off Label Use: BL22 is a recombinant immunotoxin which targets CD22+ cells. FitzGerald:NIH: Patents & Royalties. Pastan:NIH: Patents & Royalties.
A Study of Aberrant DNA Methylation in Refractory and Relapsed Childhood Acute Lymphoblastic Leukaemia.
Authors: Kapatai Georgia , Nyangoma Stephen O , Kearns Pamela 
Published: October 2019

Abstract
Abstract 3456
Poster Board III-344
Refractory and relapsed Acute Lymphoblastic Leukaemia (ALL) raise difficult clinical challenges and represent a significant cause of death in childhood and adolescence. This study examines epigenetic changes in relapsed paediatric ALL to increase our understanding of the mechanisms of treatment failure in these patients. Aberrant DNA methylation, a frequent phenomenon in paediatric ALL, has been identified as an independent factor of poor prognosis. In this study, using a CGI microarray consisting of 12K clones representing 5411 unique chromosomal sequences spread throughout the genome, we analysed a cohort of 22 childhood B-precursor ALL patient samples, 11 diagnosis samples and 11 relapse samples (unmatched) from patients who experienced a hematologic relapse, and developed genome-wide methylation profiles of leukaemic cells, at diagnosis and relapse. Comparison of these profiles identified 227 genes with statistically significant methylation changes – increase and decrease of methylation levels - between the two patient groups. The methylation status and the methylation change of 5 genes (ECRG4, CDH5, IRX3, FOXD3 and ERBB4) were independently verified, using pyrosequencing, in 6 ALL patients, 3 diagnosis and 3 relapse samples. The relationship between methylation and expression of one of these genes (ECRG4) was examined in ALL cell lines (CEMC1 and Jurkat) before and after 5-Aza-2'-deoxycytidine treatment. More genes are currently under investigation. Methylation studies on the repetitive element LINE-1 showed a significant increase in methylation of repetitive sequences in relapse samples (mean 79% vs. 89%, respectively; p=0.003, Mann Whitney test). Chromosomal mapping of the 227 genes revealed significant clustering of differentially methylated targets in chromosomes 11, 13 and 15, chromosomal locations that were previously found to be associated with ALL prognosis. Functional gene relation analysis revealed a connection between 11 genes (FOXD3, HPGD, NR4A2, CAST, TBRG4, XRCC6, NAB2, SEZL6, CDH13, NR2F1, SP1) that show increased methylation in relapse ALL and NR3C1, the gene coding for glucocorticoid receptor. Currently we are investigating the role of methylation in glucocorticoid resistance in ALL cell lines. Our data indicate an underlying epigenetic mechanism responsible for the chemoresistance observed in relapsed paediatric ALL patients.

Disclosures
No relevant conflicts of interest to declare.
Prospective Evaluation of An Agvhd-Specific Proteomic Pattern in More Than 340 Patients.
Authors: Mischak-Weissinger Eva M. , Holler Ernst , Schleuning Michael , Beutel Gernot , Greinix Hildegard , Dickinson Anne M , Ferrara James LM , Buchholz Stefanie , Krons Annika , Kontsendorn Julia , Hahn Norbert , Zander Axel R. , Kolb Hans-Jochem , Metzger Jochen , Ganser Arnold 
Published: October 2019

Abstract
Abstract 347
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for many hematologic malignancies or hematopoietic dysfunction syndromes, but the application is still limited due to major complications, such as severe graft versus host disease (GvHD) and infectious complications. Diagnosis GvHD is based on clinical features and biopsies, a non invasive, unbiased laboratory test does not exist.
To date the proteomic pattern specific for aGvHD was evaluated blindly on 961 samples collected from 345 patients undergoing allo-HSCT at MHH and 7 additional clinics, including the University of Michigan. The majority of the patients included were transplanted for hematological malignancies (n=329), 16 for hematopoietic failure syndromes, mainly severe aplastic anemia. Conditioning regimens included dose reduced conditioning regimens (FLAMSA and ClaraC for the majority of the patients of MHH), as well as standard conditioning regimens (TBI+Cy or Busulfan+Cy) for about 35% of the patients. GvHD-prophylaxis was cyclosporine A (CSA) and mycophenolate (MMF) or CSA metothrexate (MTX) as appropriate. In addition, about 80% percent of the patients received ATG (antithymocyte globulin) prior to HSCT.
A peptide pattern of 31 peptides - either absent/decreased (15) or present /increased (16) - was previously published (Weissinger et al. 2007). Prospective and blinded evaluation of the patients included in this diagnostic analysis for early recognition of patients at risk for aGvHD development revealed the correct classification of patients developing aGvHD about 7 days prior to the development of clinical symptoms for aGVHD with a sensitivity 76% and specificity of about 85% (fig.1). Additional data obtained from patients transplanted until September 2009 will be reported. Based on these data a pre-emptive therapy multicenter trial, administering steroids upon positivity of the proteomic pattern has been initiated now in 10 German centers, testing the efficacy of the pre-emptive therapy on incidence and severity of aGvHD and a possible benefit on overall survival of the patients.

Disclosures:
Krons: mosaiques-diagnostics GmbH: Employment. Metzger:mosaiques-diagnostics GmbH: Employment.
Changes in Platelet Activation Associated with Hypertensive Disorders of Pregnancy.
Authors: Bouchard Beth A. , Schonberg Adrienne , Badger Gary J. , Bernstein Ira M. 
Published: October 2019

Abstract
Abstract 3504
Poster Board III-441
Pre-eclampsia is associated with increased rates of platelet clearance, changes in platelet function, and platelet activation. The goal of the current study was to assess changes in basal levels of platelet activation in individuals with pregnancies with hypertensive complications, and to compare those levels to individuals with uncomplicated pregnancies. In this study, three indices of platelet activation, platelet CD63 expression (% CD63), monocyte/platelet aggregate (% MP) formation, and neutrophil/platelet aggregate formation (% GP) were measured in whole blood by flow cytometry using specific, fluorescently-labeled monoclonal antibodies in 20 nulliparous women of reproductive age who subsequently conceived singleton pregnancies. Subjects were re-examined in early (11 - 16 wks) and late pregnancy (31 - 34 wks), as well as ∼15 months postpartum. Three of these women were diagnosed with hypertensive complications (1 gestational hypertension with intrauterine growth restriction, 2 pre-eclampsia), and delivered at term. However, all subjects were normotensive at all study points. The data are expressed as the mean ± SEM. P < 0.05 is considered significant. Subjects with uncomplicated pregnancies were 29.4 ± 0.77 years old with a BMI of 23.6 ± 0.83 kg/m2 at the time of the pre-pregnancy studies. Subjects with pregnancies with hypertensive complications were 32.0 ± 1.5 years old with a BMI of 21.3 ± 0.88 kg/m2 at the time of the pre-pregnancy studies. No differences in the platelet activation markers, % CD63 and % GP, were observed in this study. In contrast, a strong trend for increased % MP formation in pre-pregnancy measurements in those women destined to develop hypertensive complications of pregnancy was observed (p=0.062): Women with pregnancies with hypertensive complications had substantially more % MP formation (20.9 ± 10.3%) than women with uncomplicated pregnancies (7.1 ± 4.2%). In individuals with uncomplicated pregnancies, an increase in the % MP formation over pregnancy was observed over time, and this platelet activation marker remains elevated (20.2 ± 4.4%, p=0.015) in postpartum measurements when compared to pre-pregnancy values. A markedly different pattern was observed in women with pregnancies with hypertensive complications with postpartum values below the pre-pregnancy values (5.3 ± 12.2% vs. 20.9 ± 10.3%). These combined observations suggest that hypertensive complications of pregnancy are associated with alterations in the pattern of platelet activation in pregnancy and postpartum.

Disclosures:
No relevant conflicts of interest to declare.
Decitabine Increase Platelet Count by Two Mechanisms.
Authors: Wang Jianhui , Li Zongdong 
Published: October 2019

Abstract
Abstract 3507
Poster Board III-444
Thrombocytopenia is frequently associated with the myelodysplastic syndromes (MDS). 5-aza-2'-deoxycytidine (Decitabine) has been used to treat MDS with an approximately 20% response rate in thrombocytopenia. In this study, we have investigated the effect of Decitabine on platelet count in mouse. We report here that enhanced platelet release and maturation of megakaryocyte are two mechanisms involved in Decitabine induced elevation of platelet count. We first noted that a 30% of platelet count increase was found in the Balb/c mice 12 hours after the injection of Dectiabine at a clinically relevant dose (15 mg/m2) suggesting an instant platelet release from spleen or from megkaryocyte of bone marrow. The effect of Decitabine on megakaryocyte maturation was studied in in vitro differentiation of mouse bone marrow cells and megakaryoblastic cell line L8057. Decitabine (2.5 mm) is able to induce L8057 cells to differentiate into a megakaryocyte like polyploidy cells with positive marker of acetylcholinesterase and αIIb integrin. High expression of αIIb integrin was also found in the primary bone marrow cells cultured with both thrombopoietin and Decitabine as compared to thrombopoietin alone. The demethylation-induced transcription of GP6 has been reported in thrombopoietin induced megakaryocyte differentiation. Since Decitabine is a DNA demethylation reagent, we have investigated the GP6 expression in Decitabine treated L8057 cells and have found upregualtion of GP6 expression. Although the role of DNA demethylation in megkaryoctye differentiation still needs to be verified, our current data support that Decitabine is able to drive magakaryocyte maturation.

Disclosures:
No relevant conflicts of interest to declare.
A New Immunodeficient Mouse Strain, NOD/SCID IL2Rγ−/− SGM3, Promotes Enhanced Human Hematopoietic Cell Xenografts with a Robust T Cell Component.
Authors: Wunderlich Mark , Chou Fu-Sheng , Mizukawa Benjamin , Link Kevin A , Mulloy James C. 
Published: October 2019

Abstract
Abstract 3524
Poster Board III-461
Several strains of immunodeficient mice have been employed in the effort to model both normal and aberrant growth and differentiation of human hematopoietic cells in vivo. Despite numerous successes in this field, room remains for improvement. For example, robust models of in vivo differentiation and expansion of human erythroid and T cells are lacking or challenging at best. With the goal to further improve in vivo human hematopoietic cell study, we have crossed the NOD/SCID IL2Rγ knockout mice (NSG) with the NOD/SCID-SGM3 mice (NS-SGM; transgenic expression of human cytokines SCF, GM-CSF, and IL-3) to create a new strain of immunodeficient mice (NSG-SGM3). Uncultured umbilical cord blood CD34+ cells (UCB) were used to initiate xenografts in these three strains as well as NOD/SCID (NS) mice for comparison. Although xenografts with high human composition can be set up in NS mice, the graft, which is B-lymphoid biased without any measurable T cell component, tends to fade over time. In comparison, NSG mice offer longer sustained engraftment with a predominantly B-lymphoid bias and an inconsistent minor T cell component that is absent in NS mice. These mice also display increased levels of human cells in the periphery, allowing for easier measurement of the graft. Similar to NS grafts, NS-SGM3 grafts are initiated at high levels of chimerism, decrease significantly over time, lack T cells, and have a relatively low peripheral involvement. However, the graft consists of a more balanced myeloid/lymphoid distribution. The NSG-SGM3 combines some of the useful properties of the parent strains. Grafts remain at high, sustained levels through 16 weeks while maintaining a fairly balanced myeloid/lymphoid contribution. Chimerism in the NSG-SGM3 mice is readily detectable in the periphery as well as the BM. Remarkably, as early as 8 weeks post-transplant, we observed consistently high human T cell engraftment and expansion far superior to what we observed in NSG mice in parallel experiments using the same UCB samples. Flow cytometric analysis revealed the presence of numerous T cell sub-populations, suggesting significant recapitulation of human T cell development and function in NSG-SGM3 mice. Although it remains unclear as to why the unique combination of SGM3 cytokine expression and IL2Rγ knockout promotes enhanced human T cell engraftment and expansion, this mouse presents an improved opportunity to examine human T cell development and function in a xenograft setting as well as modeling T cell associated diseases including HIV infection, GVHD, and T cell leukemia.

Disclosures:
No relevant conflicts of interest to declare.
Survival Advantage with Hypomethylating Agents In Patients with Higher Risk Myelodysplastic Syndrome
Authors: Park Young-Hoon , Lee Je-Hwan , Lee Kyoo Hyung , Lee Jung-Hee , Kim Dae-Young , Kim Sung-Doo , Lim Sung-Nam , Choi Yunsuk , Seol Miee , Lee Young-Shin , Kang Young-A , Jeon Mijin 
Published: October 2019

Abstract
Abstract 1859

Background:
Two hypomethylating agents, azacitidine and decitabine, are active in myelodysplastic syndrome (MDS) and both drugs have been approved for the treatment of MDS in Korea. In this retrospective analysis, we tried to analyze the effects of hypomethylating agents on the clinical outcomes of the patients with MDS.

Methods:
A total of 385 patients, who were diagnosed as MDS at the Asan Medical Center between July 1992 and March 2010, were included in this study. We divided the patients into three treatment groups such as hypomethylating therapy (HMT, n=92), intensive chemotherapy (IC, n=15), and supportive care (including low-dose cytarabine and immunosuppressive treatment, SC, n=278). Primary end points of this study were overall survival (OS) and progression-free survival (PFS). PFS was defined as time from diagnosis to AML progression or death. All survival data were censored at the time of hematopoietic cell transplantation (HCT) to eliminate the influence of HCT on survivals. The difference of survivals was compared using time updated Cox model because times from diagnosis of MDS to treatment (HMT or IC) were various.

Results:
Baseline clinico-laboratory features were not significantly different between 3 treatment groups (HMT vs. IC vs. SC) in regard to sex, age, WHO subtype, and IPSS risk category. Among 83 patients in the HMT group, 39 (47.0%) attained any response to HMT including complete response, partial response, marrow complete response, and hematologic improvement. Survival data were the followings: OS, HMT vs. IC vs. SC, median 62.5 vs. 16.7 vs. 21.0 months; PFS, median 37.7 vs. 13.8 vs. 17.8 months. Multivariate analyses by stratified time updated Cox model showed that hazard ratio (HR) of HMT compared to SC was 1.029 (95% CI, 0.670–1.582, P=0.895) for OS and 0.539 (95% CI, 0.362–0.803, P=0.002) for PFS. When we performed subgroup analyses in lower risk disease (IPSS Low/Intermediate-1) and higher risk disease (IPSS Intermediate-2/High), the effects of HMT on survivals were different by the risk stratification of MDS. In lower risk MDS, there were no survival benefits of HMT compared to SC (OS, median 53.9 vs. 39.8 months, HR 1.570, P=0.108; PFS, median 37.7 vs. 52.5 months, HR 0.880, P=0.633), whereas both OS and PFS were significantly longer in HMT compared to SC (OS, median 137.9 vs. 5.9 months, HR 0.289, P=0.043; PFS, median 80.2 vs. 0.9 months, HR 0.154, P<0.001).

Conclusion:
Our data suggested that hypomethylating therapy could improve the survivals (OS and PFS) of the patients with higher risk MDS.

Disclosures:
No relevant conflicts of interest to declare.
PI3K/AKT Pathway as a Potential Therapeutic Target In Myelodysplastic Syndrome
Authors: Rezende Denise C , Pacheco Lorena Zaida , Pelloso Luis Arthur F. , Chauffaille Maria L. , Silva Marçal C.A , Kimura Elisa , Casaes-Rodrigues Rafael L , Segreto Helena , Yamamoto Mihoko , Kerbauy Daniella Marcia Maranhao Bahia 
Published: October 2019

Abstract
Abstract 1871

Introduction:
PI3K/AKT pathway is involved in cell growth, proliferation and apoptosis. A key downstream effector is the phosphorylated serine-threonine Akt (p-AKT). Constitutive activation of PI3K/AKT has been observed in solid tumours and leukemic cells. Inhibition of PI3K/AKT activity, results in apoptosis in cell lines (CL) after treatment with different compounds, e.g. deguelin, a natural product from the leguminous Mundulea sericea, with antitumour effects. Aims: To evaluate PI3K/AKT activation in MDS patients and its therapeutic potential in MDS.

Methods:
PI3K/AKT activation was evaluated by flow cytometry (FC) using an alexa-fluor 488-antibody Ser 473 p-AKT (Cell Signalling Technology). A triple immunostaining procedure using CD45-PerCP and CD34-PE was used for p-AKT expression in CD34+ primary samples. The p-AKT activity was determined using Kolmogorov-Smirnov test (D). CD34+ cells from healthy donors and Jurkat cells were used as negative and positive controls respectively. Apoptosis (determined by Annexin V and PI/7AAD) and cell cycle arrest (using RNAse and PI) were determined following treatments with LY294002 (50uM), and deguelin (100-500nM) in P-39 myeloid leukemia cell line, with constitutive PI3K/AKT activation. Apoptosis was determined in bone marrow mononuclear cells and CD34+ cells from MDS patients with the same treatments. To evaluate in vivo activity of deguelin, we used a xenotransplant model. Briefly, NODSCID mice were injected intrafemurally with P-39 CL and 12 days post transplant a three week-course of treatment, every other day, was started (deguelin 4mg/Kg, n=3 vs vehicle, n=3).

Results:
P-39 CL showed constitutive PI3K/AKT activation with levels significantly higher than in CD34+cells from controls (median±SD= 0.73.

Disclosures:
No relevant conflicts of interest to declare.