bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expansion of Lymphocytes for Cell-Based Therapeutics
Authors: Heslop Helen E. 
Published: October 2019

Abstract
Abstract SCI-48
Adoptive transfer of T cells can lead to targeted and long-lived anti-tumor or anti-infective activity and can also modulate alloreactivity. T cell therapies have been used in both autologous and allogeneic settings. Donor-derived cytotoxic specific T lymphocytes (CTLs) have already proved highly effective in preventing or treating viral infections and Epstein-Barr virus (EBV) lymphomas developing after allogeneic hemopoietic stem cell transplant while T cells expanded ex vivo with CD3/28 beads have enhanced immune reconstitution after autologous stem cell transplantation. Clinical responses have also been observed following T cell therapy in patients with melanoma, lymphoma or nasopharyngeal cancer. Although successes have been obtained, these studies have also provided insights into the requirements for more effective cellular immunotherapy, which may be obtained by genetic modification of T cells. Approaches under evaluation in the clinic include transfer of artificial T cell receptors to target tumor cells, transfer of genes to render T cells resistant to tumor evasion mechanisms and transfer of a suicide gene that can be activated should adverse effects occur to allow the cell to be destroyed on exposure to a specific signal. The suicide gene strategy using the herpes simplex viral thymidine kinase (Tk) gene allows ablation of infused donor T cells if they induce graft-versus-host disease after allogeneic HSCT and has reached phase III clinical trial. In all these adoptive T cell immunotherapy strategies, broader application is limited by suboptimal persistence of transferred T cells, and by the complexity of current manufacturing techniques. Current research focuses on defining the optimum type of cell for transfer and the ex vivo selection and expansion procedures that favor long term persistence, since broader applicability will require ex vivo expanded T cells to show clinical activity and to have robust manufacturing processes and a clinical distribution paradigm. Strategies for simplifying and accelerating manufacture of T cell products have included the use of artificial antigen presenting cells expressing co-stimulatory ligands to provide a rapid source of antigen and optimized costimulation; bioreactors to grow cells in a closed system; and cytokine combinations to optimize cell growth and survival. Integration of these multiple approaches will be required to determine the best cell type and culture conditions for generating T cells for subsequent adoptive transfer into a complex immune network.

Disclosures:
Off Label Use: T cell products in studies conducted under INDs.
Prognostic Import of French-American-British (FAB) System As Embedded in 2008 Revision of World Health Organization Classification of AML: Review of SWOG Data
Authors: Newell Laura F , Othus Megan , Walter Roland B. , Petersdorf Stephen H. , Chauncey Thomas , Anderson Jeanne E. , Godwin John E. , Kopecky Kenneth J. , Appelbaum Frederick R. , Estey Elihu H. 
Published: October 2019

Abstract
Abstract 1446

Background:
After many years of use, the French-American-British (FAB) system for classification of AML has been replaced by that of the World Health Organization (WHO), as revised in 2008 (Blood 2009;114: 937–51). While unlike FAB, WHO uses genetic and clinical information to specify AML subtypes, the FAB system remains embedded in the WHO category of “AML not otherwise specified” (NOS). Here we ask whether the subdivision by FAB of AML NOS is of prognostic significance.

Methods:
FAB data were available on 970 newly-diagnosed patients treated on various SWOG protocols from 1986 to 2009. The protocols generally called for 3+7 type induction therapy. Exclusion of patients with recurrent genetic abnormalities, therapy-related AML (T-AML), or AML with myelodysplasia related changes (MDS-AML), as stipulated in WHO 2008 (NPM1 and CEBPA mutation status was unavailable), left 447 with AML NOS whose FAB type was recorded. We used multivariate analyses adjusting for age, sex, cytogenetic risk (SWOG criteria), pretreatment performance status, blood counts, and marrow blasts, to assess whether FAB was independently associated with outcome in these 447 patients and used areas under the receiver operator characteristic curve (AUC) to quantify the predictive ability of FAB, with AUC of 1.0 indicating perfect prediction and an AUC of 0.5 equivalent to a coin flip.

Results:
The 447 patients had median age of 58 years, CR rate 56% and median survival 17.2 months. Given the association between T-AML or MDS-AML and FAB types M6 or M7 (p=0.02 in this dataset), only 2% of the 447 patients were M6 or M7; 8% were M0, 27% M1, 26% M2, 25% M4, and 12% M5 (we excluded patients with M3). CR rates were 47% M0, 56% M1, 53% M2, 54% M4, 72% M5, and 45% M6 or M7. Survival probability was longest with M6/M7 followed by M5. The multivariate analyses showed the following for the effect of FAB (considered as M0, M1, M2, M4, M6/M7):
Results were similar regardless of whether we considered FAB as above or grouped as M0, M1/M2, M4/M5, M6/M7. In particular, FAB was not associated with any outcome and its removal from more complete adjusted models had little effect on the models' predictive ability.

Conclusion:
These results question the utility of the FAB system as embedded in WHO 2008.

Disclosures:
No relevant conflicts of interest to declare.
Hematopoietic Cell Transplantation – Specific Comorbidity Index As An Instrument to Predict Survival in Patients Admitted to Intensive Care Unit Early After Allogeneic Transplantation
Authors: Bayraktar Ulas D. , Shpall Elizabeth J , Liu Ping , Ciurea Stefan O , De Lima Marcos , Rondon Gabriela , Price Kristen J , Champlin Richard , Nates Joseph L 
Published: October 2019

Abstract
Abstract 147

Background:
Hematopoietic cell transplantation – specific comorbidity index (HCT-CI) based on pre-transplant comorbidities was shown to be predictive of survival and non-relapse mortality in patients undergoing allogeneic stem cell transplantation (ASCT). We assessed HCT-CI as a predictive instrument for survival in patients admitted to intensive care unit (ICU) early after ASCT.

Methods:
Patients older than 18 who were admitted to ICU between the preparative regimen initiation and post-transplant day 100 were included. Demographics, pre-transplant comorbidities, disease characteristics, transplant data, dates of transplantation, ICU admission, and last follow-up were gathered from institutional registries. Reason for ICU transfer, date and survival status at the time of hospital discharge were gathered from individual medical records. HCT-CI scores were calculated as previously described by Sorror et al. Patients who were transferred to a hospice and died within 7 days of the transfer were considered to have died in the hospital for the purpose of current analyses.

Results:
Of 3039 patients who underwent ASCT between June 2001 and December 2011 at MD Anderson Cancer Center, 377 patients (12%) were transferred to ICU within 100 days of the transplant. Disease and transplant characteristics of the patients are demonstrated in the Table. The most common reasons for ICU transfer were respiratory failure (n=230), septic shock (n=44), altered mental status (n=33), hemorrhage (excluding intracranial, n=28), and arrhythmias (n=20). Median age was 53 years with a range of 19–80. The most common pre-transplant comorbidities were pulmonary in 302 (80%) and cardiac in 73 patients (19%). Overall 240 patients (64%) died in the hospital. A comprehensive logistic regression model demonstrated HCT-CI score ≥3 to be associated with a higher risk of death in the hospital (Table). Patients with myeloproliferative diseases and those admitted to ICU during the preparative regimen had less risk of dying in the hospital while those who received ablative regimens had an increased risk. One-year overall survival (OS) rates were 22%, 16%, 16%, and 10% among patients with HCT-CI scores of 0–1, 2, 3, and ≥4, respectively. A Cox proportional hazards model demonstrated HCT-CI score of ≥4 to be a poor prognostic factor on OS (HR: 1.72, 95% CI: 1.21–2.44). The only other significant prognostic factor on OS was the age.

Conclusion:
Overall prognosis in patients who are transferred to ICU within 100 days of ASCT is poor. HCT-CI score could aid clinicians to identify the worst-to-perform patients within this population.

Disclosures:
No relevant conflicts of interest to declare.
The SirT1 Inhibitor Tenovin-6 Induces Monocytic Differentiation in APL Cells
Authors: Sunami Yoshitaka , Araki Marito , Morishita Soji , Hironaka Yumi , Edahiro Yoko , Komatsu Norio , Ohsaka Akimichi 
Published: October 2019

Abstract
Abstract 1542
Tenovin-6, an inhibitor for nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase Sirtuins, shows cytotoxicity to cancerous cells and thus recognized as a potential therapeutic compound for cancer treatment (Lain S., et al. (2008) Cancer Cell. 13,454–63). Since there is limited information for the cytotoxic property of this compound for hematopetic malignancies, we treated an APL (acute promyelocytic leukemia) cell line NB4 with Tenovin-6. As expected, Annexin V assay revealed that Tenovin-6 induced apoptosis in NB4 cells. However, to our surprise, at modest concentration, Tenovin did not induce cell death, rather inhibited NB4 cell proliferation and altered cell morphology. The fluorescence-activated cell sorting (FACS) analysis revealed that tenovin-6-treated NB4 cells are positive for CD11b and CD36 with decreased level of CD13 and CD33. Moreover, tenovin-6-treated NB4 cells presented nitroblue tetrazolium reduction capacity, suggesting that tenovin-6 induced monocytic differentiation in NB4 cells.
To assess how Tenovin-6 induces cellular differentiation in NB4 cells, we investigated downstream target of Sirtuins. Although Tenovin-6 reportedly promotes acetylation of p53 by inhibiting SirT1, a founder of Sirtuin family proteins, the acetylation status of p53 is unchanged at the concentration where we observed differentiation. This suggests that Tenovin-6 induces NB4 differentiation through inhibiting other Sirtuin family proteins. These findings demonstrate a potential of Tenovin-6 as a differentiation-inducing reagent in APL cells.

Disclosures:
No relevant conflicts of interest to declare.
Therapeutic Comparision of Surgical Resection Followed by R-CHOP and R-CHOP Alone for Primary Localized Intestinal Diffuse Large B Cell Lymphoma
Authors: Lee Ho Sup , Park Lee Chun , Lee Eun Mi , Shin Seong Hoon , Ye Byeong Jin , Oh Sung Yong , Song Moo-kon , Lee Sang Min , Lee Won-Sik , Kang Byung Woog , Chang Myung Hee , Cho Seok-Goo , Yahng Seung-Ah , Yoon Sung-Soo , Kwon Ji-Hyun , Kim Yang Soo 
Published: October 2019

Abstract
Abstract 1627
Abstract

Background:
Gastrointestinal tract is the most commonly involved extranodal site and is represented 10–15% of all non-Hodgkin¡&hibar;s lymphoma (NHL) cases and 30–40% of all extranodal sites. In this retrospective studies, the purpose is finding appropriate treatment strategy according to comparing the efficacy of treatment in patients with primary intestinal diffuse large B cell lymphoma (DLBL) undergoing surgery followed chemotherapy or chemotherapy alone.

Method:
Seventy six patients were newly diagnosed with DLBL and received chemotherapy between March 2004 and June 2011. Primary intestinal lymphoma which had predominant intestinal lesions was diagnosed by specialized hemato-oncologist. All patients were treated with rituximab combined cyclophosphamide, adriamycin, vincristine, and prednisolone (R-CHOP). Patients were divided into two groups. One included patients who were undertaken surgery followed by R-CHOP (surgery group). The other included patients who were undertaken R-CHOP alone (CT group).

Results:
The characteristics of the patients were as follows: the median age was 56.5 years (range 15–85 years) with a female-to-male ratio of 45: 31. Patients characteristics had no significant difference between two groups. The estimated 3 years progrression free survival rates (PFS) and overall survival rates (OS) of surgery and CT group were 92.2% and 74.8%, (p=0.009) and 94.2% and 80.7%, (p=0.049) respectively. In univariate analysis, PFS and OS were estimated in Lugano stage I, II1 and II2, IIE (p=0.006 and p=0.036), Low, Low-intermediate, and high-intermediate risk (p=0.004 and p=0.000), and surgery and CT alone, (p=0.009 and p=0.049), respectively. In multivariate analysis, there was no independent predictive factors for survival.

Conclusion:
Patients treated with surgery followed by R-CHOP were seemed to have higher survival rate than R-CHOP alone although there was no significant differences for survival rate. There was no significant prognostic factors for survival but there were possible prognostic factors such as Lugano stage, IPI risk, and treatment modality for PFS and OS.
Figure. The superior survival rates were shown in surgery group than those in R-CHOP chemotherapy group.

Disclosures:
No relevant conflicts of interest to declare.
Treatment with a Bortezomib-Containing Regimen Is Associated with Better Therapeutic Outcomes in Patients with Waldenstrom's Macroglobulinemia Who Have Familial Disease Predisposition
Authors: Treon Steven P , Hunter Zachary , Hanzis Christina , Tripsas Christina , Ioakimidis Leukothea , Patterson Christopher , Manning Robert , Sheehy Patricia , Turnbull Barry 
Published: October 2019

Abstract
Abstract 1643
We examined the impact of familial predisposition on treatment outcome in 135 Waldenstrom's macroglobulinaemia (WM) patients, 26.7% of whom had first or second degree relative(s) with a B-cell lymphoproliferative disorder. All patients were rituximab-naïve and received a rituximab-containing regimen. There were no significant differences in baseline characteristics between cohorts. Overall (93.9% vs. 75.0%; p=0.029) and CR/VGPR (23.2% vs. 16.7%; p<0.0001) responses, time to progression (45.5 vs. 21 months; p=0.015), and to next therapy (50.0 vs. 33.0 months; p=0.024) favored sporadic patients. By multivariate analysis, familial predisposition was an independent marker for disease progression (Hazard ratio 0.554). We next assessed whether the type of treatment used impacted therapeutic outcome in patients with familial WM. Overall, major and CR/VGPR responses were better among patients with familial but not sporadic WM who received a bortezomib versus non-bortezomib containing regimen (Figure 1). A longer TTP was also observed for familial but not sporadic WM patients who received a bortezomib versus non-bortezomib containing regimen. For patients with familial disease, the median TTP was estimated at >33 versus 20.6 months for bortezomib and non-bortezomib containing therapy, respectively (p=0.08). For sporadic WM patients, the median TTP was estimated at >35 versus 45.5 months for bortezomib and non-bortezomib containing therapy, respectively (p=0.68). The findings of this study convey that familial disease predisposition is an important determinant of response, TTP and TTNT in patients with WM. Treatment with a bortezomib-containing regimen is associated with better therapeutic outcomes in patients with WM who have familial disease predisposition, and may be revealing of signaling pathways that are present in familial patients and amenable to select targeting by proteasome inhibition.Figure 1.Overall, major, and VGPR/CR responses for 135 WM patients with sporadic (A) or familial (B) disease who received either bortezomib or a non-bortezomib containing regimen. *p=0.05; and **p=0.0006 among familial WM patients who received bortezomib versus non-bortezomib containing therapy.Figure 1. Overall, major, and VGPR/CR responses for 135 WM patients with sporadic (A) or familial (B) disease who received either bortezomib or a non-bortezomib containing regimen. *p=0.05; and **p=0.0006 among familial WM patients who received bortezomib versus non-bortezomib containing therapy.

Disclosures:
No relevant conflicts of interest to declare.
MicroRNA-130a Targets ATG2B, AGO4 and DICER1, Inhibits Autophagy and Induces Cell Death in Chronic Lymphocytic Leukemia
Authors: Kovaleva Valentina , Mora Rodrigo , Stilgenbauer Stephan , Lichter Peter , Seiffert Martina 
Published: October 2019

Abstract
Abstract 1768
B-cell chronic lymphocytic leukemia (CLL) is characterized by deregulated expression of microRNAs (miRNAs). These post-transcriptional regulators of gene expression play a crucial role in controlling multiple cellular processes. By microarray analysis and quantitative RT-PCR we observed significantly lower levels of miR-126, miR-130a, miR-143, miR-181a and miR-326 in primary CLL cells compared to normal B cells. Transfection of synthetic miR-130a or miR-143 induced a significant reduction in cell viability of both primary CLL cells and the CLL cell line MEC-1. As autophagy is connected to cancer cell survival and resistance to apoptosis, we investigated the effect of these two miRNAs on autophagy by following the specific autophagosome marker LC3 (microtubule-associated protein 1 light chain 3). Therefore, we generated MEC-1 cells stably expressing GFP-tagged LC3 and analyzed autophagosome formation by using an imaging flow cytometer quantifying GFP-positive dots. These experiments revealed that autophagy is induced in these cells upon starvation, and that introduction of miR-130a, but not miR-143, resulted in a reduction of autophagosome formation (see Figure). These findings were verified by LC3 Western blot analysis, and extended to primary CLL cells, showing for the first time that autophagy is an active process in these cells and that miR-130a inhibits autophagy in primary CLL cells as well. To further elucidate the molecular mechanism of miR-130a-mediated CLL cell survival and autophagy, we aimed at identifying putative target genes of this miRNA and identified ATG2B, an autophagy-related gene, as well as DICER1 and AGO4, two components of the miRNA processing machinery, as direct target genes of miR-130a in CLL cells. The relevance and role of these three novel target genes in miR-130a-regulated cell death/cell survival programs is under current investigation.
Figure: Analysis of autophagy using MEC-1 cell line stably expressing GFP-tagged LC3 protein. Green dots representing autophagosomes were quantified in MEC-1/GFP-LC3 cells under starvation by imaging flow cytometry (Image Stream, Amnis). Transfection with synthetic miR-130a reduced the autophagic flux in these cells compared to scrambled negative control miRNA (NC). Figure:. Analysis of autophagy using MEC-1 cell line stably expressing GFP-tagged LC3 protein. Green dots representing autophagosomes were quantified in MEC-1/GFP-LC3 cells under starvation by imaging flow cytometry (Image Stream, Amnis). Transfection with synthetic miR-130a reduced the autophagic flux in these cells compared to scrambled negative control miRNA (NC).

Disclosures:
No relevant conflicts of interest to declare.
Long-Term Outcome of B-CLL Patients Treated in a Prospective Trial Evaluating Combination of Oral Fludarabine and Cyclophosphamide As Frontline Therapy
Authors: Guièze Romain , Tournilhac Olivier , Maloum Karim , Leprêtre Stéphane , Haioun Corinne , Feugier Pierre , Delmer Alain , Leporrier Michel , Cazin Bruno 
Published: October 2019

Abstract
Abstract 1795

Introduction.
The combination of fludarabine and cyclophosphamide (FC) has become the core combination of modern frontline chemotherapy for fit and young B-CLL patients (pts). Recently the association with rituximab to FC (IV administration) has been shown to increase the response and extend both progression free survival (PFS) and overall survival (OS) in untreated pts (Hallek et al., Lancet 2010). So far few data are available concerning the very long term outcome of pts treated by FC containing regimen. Methods. We previously reported a prospective phase II trial (Cazin et al., BJH 2008) of the oral combination of FC over 5 days in 75 patients with untreated B-CLL and less than 66 years old. The study was conducted between October 1999 and February 2001. Briefly, oral FC then demonstrated high efficacy with overall response rate (ORR) and complete response (CR) rate of 80% and 53% respectively despite the absence of rituximab in this regimen. We here propose to examine 10-year end points of progression-free survival (PFS), overall survival (OS), impact of genomic features, and risk of therapy-related myeloid neoplasm (t-MN) by updating survival data of all the pts incuded in this trial. Results. With a median follow-up of 10.7 years, the median 10-year OS was 51.7%. Responders presented better 10-year OS than non-responders (57% vs. 38%, p=0.031) but quality of response (CR vs. PR) did not significantly impact 10-year OS. A major prognostic impact of IGVH mutational status could be observed since 10-year OS was 81% for mutated patients vs. 44% for unmutated pts (p=0.012). The median 10-year PFS was 30% and clearly influenced by the mutational status (50% if mutated profile vs. 12% if unmutated profile, p=0.02). However there is no trend of a plateau and even long term responding patients still relapse with time. Finally, only one patient developed t-MN but 9 others presented solid neoplasms. Conclusion. Long-term follow-up of B-CLL patients prospectively treated in a phase II clinical trial demonstrates extended OS and PFS with oral FC without high risk of t-MN.

Disclosures:
No relevant conflicts of interest to declare.