bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic Impact of Pretransplant Transfusion Amount on Outcome After Allogeneic Stem Cell Transplantation In Adult Patients with Severe Aplastic Anemia
Authors: Lee Sung-Eun , Lee Jong-Wook , Yahng Seung-Ah , Cho Byung-Sik , Eom Ki-Seong , Kim Yoo-Jin , Kim Heeje , Min Chang-Ki , Lee Seok , Cho Seok-Goo , Kim Dong-Wook , Min Woo-Sung , Park Chong-Won 
Published: October 2019

Abstract
Abstract 3503

Background:
Aplastic anemia (AA) is a life-threatening bone marrow failure disorder. Therefore, many patients with AA require blood transfusions as supportive management. Regular transfusions of packed red cell (PRC) lead to the development of iron overload, which is known to increase the risk of complications after stem cell transplantation (SCT). However, the prognostic impact of pretransplant transfusion history of PRC on outcome in AA has not been completely analyzed. We investigated the impact of pretransplant transfusion amount of PRC on outcome after allogeneic SCT in severe AA (SAA).

Methods:
221 adult patients with SAA who underwent allogeneic SCT between January 1995 and August 2007 who had not received optimal iron chelating therapy were selected for retrospective analysis.

Results:
221 patients were divided into two groups according to the mean amount of pretransplant transfusion (32 PRC units): receiving less than 32 PRC units (n=164), >32 PRC units (n=57) before SCT. The median follow-up duration of survivors after SCT was 47.9 (39.5-56.2) months in ≤32 PRC units of transfusion group and 42.8 (39.7-45.9) months in >32 PRC units of transfusion group. Primary engraftment was achieved in all, but 13 patients (9/164 patient, 5.5% in the ≤32 PRC units of transfusion group, 4/57 patients, 7% in the >32 PRC units of transfusion group, P=0.745) developed secondary graft failure. Acute GVHD (grade II-IV) developed in 27.4% in ≤32 PRC units of transfusion group and 42.1% in >32 PRC units of transfusion group (P=0.04), and extensive type of chronic GVHD occurred in 20.7% and 26.3% among evaluable patients, respectively. In the comparison between two groups, higher pretransplant transfusion group has significantly increased risk of transplant-related mortality (TRM) (<32 PRC units of transfusion: 8.2% vs >32 PRC units of transfusion: 25.2%, P=<0.000), and lower overall survival (OS) (91.8% vs 75.2%, P=0.001) than those with lesser transfusion history. Multivariate analysis revealed that higher pretransplant PRC amount [HR (95% CI) 3.09 (1.44-6.63), P=0.004] and donor type (related vs unrelated) [HR 2.41 (95% CI) (1.10-5.27), P=0.028] were independent prognostic factor for affecting OS.

Conclusion:
These results indicate that higher pre-transplant transfusion history of PRC was associated with increased TRM and decreased OS, and it has shown to have a negative impact on outcome after SCT in SAA.

Disclosures:
No relevant conflicts of interest to declare.
Transplant Conditioning Regimens and Outcomes After Allogeneic Hematopoietic Cell Transplantation (HCT) In Children and Adolescents with Acute Lymphoblastic Leukemia (ALL)
Authors: Tracey James , Zhang Mei-Jie , Sobocinski Kathleen A , Thiel Elizabeth L. , Eckrich Michael J. , Pasquini Marcelo C , Saber Wael , Weisdorf Daniel J. , Horowitz Mary M. , Eapen Mary 
Published: October 2019

Abstract
Abstract 3506
Recurrent disease is the most important cause of treatment failure after HCT. Total body irradiation (TBI)-containing conditioning regimens are associated with fewer relapses and longer leukemia-free survival (LFS) in children and adolescents with ALL. While TBI <13 Gy + cyclophosphamide (Cy) is considered standard, attempts to lower relapse rates have led to addition of a second chemotherapeutic agent (etoposide) or higher dose TBI (≥13 Gy) with or without addition of etoposide. TBI dosing (<13 Gy vs. ≥13 Gy) or the addition of etoposide to TBI + Cy regimen has not been examined in children. We report on 765 patients aged <18 years, who received either an HLA-matched sibling (n=160) or an unrelated donor (URD, n=605) HCT between 1998 and 2007. Seventy percent of patients were in 2nd complete remission (CR), 20% were in 3rd CR, and the remaining 10%, in relapse at HCT. The median age of the study population is 9 years and the median follow-up of surviving patients is 4 years. Transplant outcomes were examined in four treatment groups: 1) TBI <13 Gy + Cy (n=304), 2) TBI <13 Gy + Cy + etoposide (n=108), 3) TBI ≥13 Gy + Cy (n=327), and 4) TBI ≥13 Gy + Cy + etoposide (n=26). Ninety-six percent of patients in the TBI <13 Gy group received 12 Gy and 4%, 10 Gy. Irradiation doses in the TBI ≥13 Gy group were 13.2 Gy (24%), 13.5 Gy (41%) and 14 Gy (35%). Patient and disease characteristics (performance score, disease status, NCI-risk score, duration of first remission and cytogenetic risk) were similar among the treatment groups. The 3-year probabilities (95% confidence interval) of treatment-related mortality (TRM), relapse, and LFS in the four treatment groups are shown in the Table below. Neither higher dose TBI (≥13 Gy) nor the addition of etoposide regardless of TBI dose was associated with lower risks of leukemia recurrence or longer LFS after HCT. In the absence of an advantage for leukemia control, further intensification of the conditioning regimen TBI <13 Gy + Cy is not recommended.
TRM Relapse LFS 1) TBI dose <13 Gy + Cy 25 (21–31)% 30 (24–35)% 45 (39–51)% 2) TBI dose <13 Gy + Cy + etoposide 29 (21–38)% 26 (18–34)% 45 (35–54)% 3) TBI dose ≥13 Gy + Cy 23 (19–28)% 33 (28–39)% 43 (38–49)% 4) TBI dose ≥13 Gy + Cy + etoposide 35 (17–52)% 31 (15–69)% 35 (17–52)%

Disclosures:
No relevant conflicts of interest to declare.
Trend towards Improved Day 100 and 2-Year Survival After SCT for AL Amyloidosis: Outcomes Before and After 2006
Authors: Gertz Morie Abraham , Lacy Martha , Dispenzieri Angela , Kumar Shaji , Buadi Francis , Dingli David , Leung Nelson , Hogan William J , Hayman Suzanne R. 
Published: October 2019

Abstract
Abstract 3554

Introduction:
The role of SCT in the management of Ig light chain (AL) amyloidosis remains undefined.

Patients:
We report 422 patients (Table 1) who received SCT for AL amyloidosis to compare outcomes of patients treated before January 2006 with those of patients treated from January 2006 until December 1, 2009.

Results:
Day 100 all-cause mortality decreased over this time period from 12% to 7% (P=.09) figure 1. Survival at 2 years increased from 78% to 82%. Figure 2 The major determinants of early mortality (before day 100) were the presence of cardiac involvement with amyloid and increased levels of cardiac biomarkers, lower serum albumin, higher serum creatinine, and a higher number of organs involved. (Table 2) On multivariate survival analysis, higher levels of serum troponin T and N-terminal pro–brain natriuretic peptide were the only predictors of early mortality after SCT.

Conclusion:
Improved supportive care and refined patient selection has improved the safety margin for patients undergoing SCT; short-term mortality showed a more than 40% decrease after 2005. Recognition of this decrease in mortality is important for physicians caring for these patients as they weigh the pros and cons of SCT vs novel agent-based treatment in management of amyloidosis.

Disclosures:
Gertz: Celgene: Honoraria; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.
Impact of the Presence of An Internal Tandem Duplicate of FlT3 Receptor (ITD) on the Outcome of Adult Patients with Acute Myelocytic Leukemia (AML) Autografted In First Remission (CR1)Norbert-Claude Gorin, Myriam Labopin, Jordi Esteve, and Mohamad Mohty, on Behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)
Authors: Gorin Norbert C. , Labopin Myriam , Esteve Jordi , Mohty Mohamad 
Published: October 2019

Abstract
Abstract 3556
The prognosis of patients with AML harbouring the FlT3 ITD is known to be poor in patients treated with chemotherapy only. However it remains uncertain whether it also has an impact on outcome following high dose intensification and autologous stem cell transplantation (ASCT).We adressed the question using the EBMT data base. Information on the presence or the absence of FlT3ITD was available in 134 adult patients with AML who were autografted in CR1 in the period of January 1999 to December 2009. 76 patients (42 with normal karyotypes) were ITD negative and 58 (36 with normal karyotypes) were ITD positive. 90% of the patients received peripheral blood as a source of stem cells. The follow up was 30 mo (1-139).Patients ITD positive were older than patients ITD negative (52.8 vs 47.4 years; p=0.009)and their White cell counts at diagnosis were higher (52 vs 10.9 109/l; p<0.0001).For the 134 patients, the 3 year leukemia free survival (LFS) was 42 ± 5%, the relapse incidence (RI) 53 ± 4% and the non relapse mortality (NRM) 6 ±3%.Patients positive for Flt3ITD had a 3 year LFS of 34±7% vs 46±6% in those with no ITD (p=0.12), and a RI of 62±7% vs 45±6% (p=0.051). In Patients with ITD, age was the only significant poor risk factor with a LFS of 20 ± 9% in those older than 53 years (median) vs 46±10% in those younger. Further studies are needed with a larger patient population to draw valuable conclusions. However, these results suggest that while ASCT is of little benefit to older patients, it remains valuable in younger patients with AML harbouring the FlT3ITD, in whom the outcome does not differ from the ITD negative population.

Disclosures:
Mohty: Genzyme: Consultancy, Honoraria, None, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria; Janssen Cilag: Consultancy, Honoraria; Celgene: Honoraria.
High Dose Therapy with Autologous Stem Cell Transplantation Vs Standard Dose Chemotherapy In Multiple Myeloma: A Meta-Analysis
Authors: Faußner Florian , Pfirrmann Markus , Dempke Wolfram 
Published: October 2019

Abstract
Abstract 3559

Introduction.
Myeloablative high dose chemotherapy (HDT) followed by single autologous stem cell transplantation is currently the standard treatment for patients younger than 65 years in newly diagnosed multiple myeloma (MM). Several randomized controlled trials (RCTs) comparing HDT with standard dose therapy (SDT) have shown some benefit in overall survival (OS) and progression free survival (PFS), whereas other RCTs did not confirm this finding. Koreth et al. (2007) performed a metaanalysis summarizing the existing data of the RCTs including 2,411 patients. These authors found a significant superiority for HDT in PFS but not in OS. Since a number of new studies have been published recently, we attempted to re-analyze the current data in terms of the endpoints OS and PFS.

Methods.
We searched PubMed, Embase, abstracts of former ASH meetings and ClinicalTrials.gov as well as bibliographies of included trials and recent reviews from september 2009 until may, 20th 2010. Amongst the 3,484 results in this search we identified 10 RCTs comparing HDT with SDT on an intent-to-treat-basis. Treatment characeristics and outcomes of OS and PFS were calculated using R. Furthermore, we tested for statistical heterogenity, publication bias and performed subgroup analyses.

Results.
9 RCTs including 2,600 patients were fully analyzed. Patients undergoing HDT with stem cell transplantation did have significant PFS benefit (Hazard Ratio 0.73; 95% conficence intervall 0.56–0.95; P=0.02) but not OS benefit (HR 0.90; 95% CI 0.74–1.10; P=0.32) compared to patients undergoing SDT. Additional data from ongoing clinical trials are expected, thus updated results at the meeting including 10 RCTs with about 3,400 patients will be presented.

Conclusion.
Although there is only a trend to OS benefit with HDT, it is currently still the first line treatment. Additional data from ongoing clinical trials and new studies using novel agents like thalidomide, lenalidomide and bortezomib are egerly warrented to finally evaluate the role of HDT in the treatment management of patients with newly diagnosed MM.

Disclosures:
No relevant conflicts of interest to declare.
Characteristic Proinflammatory Serum Cytokine Profiles In Patients with B-Cell Chronic Lymphocytic Leukemia
Authors: Harding James J. , Yeh Raymond , Nikhamin Yan , Frattini Mark , Lamanna Nicole , Jurcic Joseph G , Heaney Mark , Brentjens Renier 
Published: October 2019

Abstract
Abstract 3595

Background:
Cytokines are posited to play a critical regulatory role on the survival of the B-cell neoplastic clone in Chronic Lymphocytic Leukemia (CLL). AIM: The primary goals of this study were 1) to define additional relevant cytokines, growth factors and chemokines in CLL pathophysiology and 2) to correlate abnormal cytokine levels with disease stage, relevant hematological data and multiple prognostic factors. METHODS: A novel bead-based protein array system was employed to simultaneously measure 38 proinflammatory cytokines in the sera of CLL patients (N=116) and healthy age and sex matched controls (N=30). These results were correlated with Rai stage, β2-microglobulin level, LDH, CD38 expression and cytogenetic abnormalities. RESULTS: We first confirmed previous observations that TNFα, IL-1α, IL-1RA, IL-10, sIL-2Rα, VEGF and sCD40 ligand are significantly elevated in patients with CLL as compared with healthy controls. Expanding on the current literature, we demonstrated perturbations in an additional 15 serum cytokines in affected individuals. Compared to healthy controls, CLL patients had an increase in serum levels of IL-3 (p=0.002), IL-7 (p=0.008), INF-2α (p<0.0001), MCP-1 (p<0.0001), MIP-1β (p=0.002), MDC (p<0.0001), Fractakine (p<0.0001), EGF (p<0.0001), FGF-2 (p<0.0001), GRO (p<0.0001), Eotaxin (p<0.0001) and FLT-3 ligand (p<0.0001). Patients with CLL also exhibited significantly lower levels of INF-γ (p<0.01), IL-6 (p<0.005) and IL-8 (p<0.002) when compared to healthy individuals. Advanced Rai stage and high risk chromosomal abnormalities (del 11q and del 17p) strongly correlated with higher serum levels of TNFα, soluble IL-2Rα, IL-10, MCP-1, MIP-1α, MIP-1β and IP-10. Finally, serum levels of TNFα, MIP-1α and MIP-1β correlated with other adverse prognostic markers, including total white blood cell count, serum β2-microglobulin and LDH levels as well as CD38 expression. CONCLUSION: We have demonstrated numerous previously unrecognized cytokine abnormalities in patients with CLL and described a unique cytokine signature associated with advanced disease. Supported by the current understanding of cytokine biology and CLL pathophysiology, our observations suggest an important regulatory role for hematopoietic cytokines, such as IL-3 and IL-7, in promulgating survival of the aberrant B-cell clone. Likewise, the profoundly high levels of chemokines (i.e. MCP-1, MIP-1α, MIP-1β, IP-10) and their association with high risk prognostic factors argue for their role in sustaining the neoplastic microenvironment. Finally, the altered levels of IL-10, IL-6 and INF-γ observed in patients with CLL likely contribute to the immunosuppressive phenotype of the disease state.

Disclosures:
No relevant conflicts of interest to declare.
T Cells From CLL Patients Recognize Spontaneously Peptides Derived of the Receptor Tyrosine Kinase Ror1
Authors: -Farsangi Mohammad Hojjat , Daneshmanesh Amir Hossein , Jeddi-Tehrani Mahmood , Osterborg Anders , Shokri Fazel , Mellstedt Håkan , Rabbani Hodjattallah 
Published: October 2019

Abstract
Abstract 3603

Background:
The receptor tyrosine kinase Ror1 is a tumor-associated molecule over-expressed in chronic lymphocytic leukemia (CLL) and a variety of other malignancies with potential implication for targeted immunotherapy. Little is known about the functional role of Ror1 in the leucomogenesis of CLL. Aims: To assess spontaneous T cell response against Ror1 in CLL patients.

Methods:
Autologous T cell response against Ror1 was studied in 9 CLL patients and 6 healthy subjects expressing the HLA-A2 allele. Four synthetic 9-mer HLA-A2 restricted peptides selected from different parts of the Ror1 molecule were loaded on dendritic cells and co-cultured with enriched autologous T cells. T cell response was determined by enumeration of the frequency of IFN-γ, IL-5 and IL-17A secreting T cells by ELISPOT. Cell proliferation was determined by 3H-thymidine incorporation.

Results:
Our results demonstrated a significantly higher frequencies of IFN-γ producing T cells (p<0.05-0.0001) and to a lesser extent IL-17A secreting autologous T cells (p<0.05) in response to Ror1 peptides in CLL patients compared to healthy controls. No IL-5 secreting T cells were noted. The frequency of IFN-γ secreting T cells was significantly higher in non-progressive as compared to progressive CLL patients (P<0.05). No differences were observed between patients with mutated and unmutated immunoglobulin heavy chain variable region (IGHV) genes.

Conclusion:
Ror1 may spontaneously induce mainly a type 1 T cell response in CLL patients, particularly in those with non-progressive disease as compared to progressive disease. Ror1 may be an immunodominant antigen in CLL which, has also been suggested by Fakuda et al. PNAS, 105, 3047, 2008. Active immunotherapy using Ror1 as a target might be an interesting approach to test in the clinic.

Disclosures:
No relevant conflicts of interest to declare.
Epigenetic Silencing of Bcl-2, C/Ebpa and p14ARF by the AML1/ETO Oncoprotein Contributing to Growth Arrest and Differentiation Blockage
Authors: Zhuang Wen-yue , Chen Zi-Xing 
Published: October 2019

Abstract
Abstract 3617
The t(8; 21) is one of the most frequent chromosomal translocations associated with acute leukemia. The AML1(RUNX1)-ETO(MTG8) fusion transcription factor generated by the t (8; 21) translocation is believed to deregulate the expression of genes that are crucial for normal differentiation and proliferation of hematopoietic progenitors, resulting in acute myelogenous leukemia by recruiting co-repressor complexes to DNA. To investigate the role of AML1-ETO in leukemogenesis, we transfected the cloned AML1-ETO cDNA with plasmid and expressed the AML1-ETO protein in U937 myelomonocytic leukemia cells. Interestingly, we found dichotomous phenomena in these transfected leukemic cells, i.e. growth arrest versus differentiation block (detailed data?). The AML1-ETO transfected U937cells were growing significantly slower than that of empty vector-transfected cells and nontransfected cells (P<0.01). As the surface markers for myeloid differentiation, the expression of CD11b and CD14 measured by flow cytometry demonstrated that the percentage of CD11b+ cell was 4.1%-7.0% in U937-A/E1-4 cells, which was significantly lower(P<0.01) than those in U937-Mock cells (11.4%) and U937-WT cells (11.0%). Moreover, the expression of CD14 antigen was decreased by 1.5–2-fold as compared with the control cells. By focusing on the anti-apoptotic gene (Bcl-2), a key transcription factor (C/EBPA) which regulates granulocytic differentiation and a tumor suppressor gene (p14ARF), we found that AML1-ETO- expressing cell subclones displayed low levels of these three genes in comparison with the non-transfected U937 (P<0.001). In primary bone marrow cells of acute myeloid leukemia containing t(8;21)/AML1-ETO, levels of Bcl-2, C/EBPA and p14ARF mRNA were markedly lower (P<0.001) when compared with other acute myeloid leukemias lacking this translocation (n=10). Chromatin immunoprecipitation assays (ChIP) demonstrated that Bcl-2, C/EBPA and p14ARF were among the direct transcriptional regulating targets of AML1-ETO. The universal binding of AML1-ETO to genomic DNA resulted in MeCP2 recruitment (P<0.01), reduction of histone H3 (P<0.0 1) or histone H4(P<0.01) acetylation and increased tri-methylation on histone H3 lysine 9 (P<0.01)as well as histone H3 lysine 27 (P<0.01), indicating that AML1-ETO induced heterochromatic silencing of Bcl-2, C/EBPA and p14ARF. These results suggested that the aberrant transcription factor AML1-ETO epigenetically silences the function of Bcl-2, C/EBPA and p14ARF gene by inducing repressed chromatin configurations at their promoters through histone modification. Considering that apoptosis-enhancing effect of AML1-ETO would not be favorable to the leukemogenesis, it must be compensated by some other effects to permit its leukemogenic potential.

Disclosures:
No relevant conflicts of interest to declare.
The Transcriptional Network Governed by Interferon Regulatory Factor (IRF8) In Germinal Center B Cell Lymphomas.
Authors: Shin Dong-Mi , Lee Chang-Hoon , Morse Herbert 
Published: October 2019

Abstract
Abstract 3638
The transcription factor IRF8, is highly expressed in germinal center (GC) centroblastic B cells and diffuse large B cell lymphomas (DLBCL). IRF8 is known to play roles in GC formation as well as in early B cell fate commitment, functioning both as a transcriptional activator and repressor; however, the transcriptional network regulated by IRF8 has not been elucidated yet. To identify direct targets of IRF8 on a genome-wide scale, we used ChIP-chip and expression profiling to study human and mouse lymphoma cell lines of GC origin – human Ly1, Odh1 and Val and mouse NFS201, NFS202, and NFS205. The IRF8-negative human multiple myeloma cell line, MMS1, and mouse plasmacytoma cell line, MPC11, were used as negative controls. For the human lines, 271 IRF8 target genes with common binding sites in all three cell lines, but not in negative cell line, were highly enriched for genes involved in innate immunity and adaptive immunity. Two well-established IRF8 target motifs- GAAANNGAAA and GGAANNGAAA - were significantly enriched in promoters of these genes compared to sequences 1kb upstream. Studies of the mouse lines identified 871 IRF8 targets with the lowest number found in NFS205. NFS205 expressed little PU.1, a common partner of IRF8 in DNA binding. PU.1 ChIP-chip analyses of the mouse lines allowed us to classify IRF8 targets into those that are PU.1-associated and PU.1-independent. Analyses of expression profiling of siIRF8-treated cells were used to identify transcriptionally active IRF8 targets. Gene Set Enrichment Analysis (GSEA) revealed significantly high enrichment of IRF8 ChIP targets as well as significant enrichment of genes involved in hematopoietic development. Finally 52 IRF8 targets common to human and mouse GC neoplasms were identified and characterized as contributing to antigen presentation, BCR and CD40 signaling, and interferon signaling, which can contribute differentially to the normal GC reaction and B cells transformation. These results define the contribution of IRF8 to the transcriptional network in GC B cells and provide new insights into the workings of the GC reaction in health and disease.
This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases.

Disclosures:
No relevant conflicts of interest to declare.