bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment Patterns and Outcomes in Elderly Patients with Multiple Myeloma,
Authors: Bang Soo-Mee , Kyle Robert A , Lee Jae Hoon , Dispenzieri Angela , Larson Dirk , Colby Colin L. , Rajkumar S. Vincent , Kumar Shaji 
Published: October 2019

Abstract
Abstract 3980

Background:
Nearly half of patients with multiple myeloma (MM) are over 70 years at the time of diagnosis. While the survival of patients with myeloma has improved in the last decade, several studies have suggested no significant change for the elderly patients. These patients often have other comorbidities and are less likely to tolerate standard treatment approaches. We retrospectively studied the treatment patterns, outcomes, and prognostic factors in patients over 75 years of age.

PATIENTS AND METHODS:
We identified 212 patients who were older than 75 years from among 1545 patients seen at the Mayo Clinic within 90 days of diagnosis during 1999 to 2008. We only included 139 patients in whom complete treatment details were available.

RESULTS:
The median age was 80 years (range: 76–94) with 20 (14%) patients older than 85 years; 79 (57%) were male. Thirty-five patients (25%) had a history or coexistence of one or more malignancies. Chromosome analysis and FISH were performed in 65% and 22% respectively. Abnormal cytogenetics were seen in 30 (33%) of the 90 tested patients. The median survival of the 139 elderly patients was 27 months (95% CI: 20∼35) compared to 62 months (56∼68) for 1,290 patients ≤ 75 years of age seen during the same period. Sixty-nine (50%) patients received one or more novel agents (thalidomide, lenalidomide, pomalidomide, bortezomib) and showed longer median survival (40 months vs 13 months) compared with those not receiving these agents (p=0.0008). Age over 85, initial poor performance score > 1, thrombocytopenia, elevated serum LDH or beta2-microglobulin, response more than stable disease to first therapy resulted in inferior survival. Among them, only performance status had the persistent significance in multivariate analysis.

CONCLUSION:
Older patients receiving newer therapies appear to have a better outcome, which is still lagging behind the younger patients. A poor performance score at diagnosis predicts for eventual poor outcome.

Disclosures:
No relevant conflicts of interest to declare.
Family History of Venous Thromboembolism As a Risk Factor for Thrombosis in Multiple Myeloma Patients: A Population-Based Study,
Authors: Kristinsson Sigurdur Y , Goldin Lynn , Turesson Ingemar , Bjorkholm Magnus , Landgren Ola 
Published: October 2019

Abstract
Abstract 3987

Background:
Patients with multiple myeloma are at an increased risk of venous thromboembolism (VTE), especially when treated with thalidomide and lenalidomide. The etiology of this is largely unknown, but probably involves both genetic and environmental factors. Family history of VTE is a known risk factor for VTE in the general population, including known inherited thrombophilic abnormalities. The influence of a family history of VTE as a potential risk factor for VTE in multiple myeloma patients is unknown. To expand our knowledge on this topic, we conducted a large population-based study based on all multiple myeloma patients diagnosed in Sweden 1958–2004.

Patients and Methods:
We assessed the impact of family history of VTE as a risk factor for VTE among 21,067 multiple myeloma patients and 83,094 matched controls. Data on multiple myeloma patients was gathered from the Swedish Cancer Registry, information on first-degree relatives from the national Multigenerational Registry, and occurrence of VTE from the nationwide Patient Registry. We calculated odds ratios (OR) and 95% confidence intervals (CI) using chi-square.

Results:
Of the 21,067 multiple myeloma patients included in the study (54% males, median age at diagnosis 71 years), 66% had an identifiable first-degree relative. VTE was diagnosed in 1,429 multiple myeloma patients, and 921 had a family history of VTE. Compared to multiple myeloma patients without a family history of VTE, multiple myeloma patients with a family history of VTE had a 2.2-fold (95% CI 1.8–2.7; p<0.001) higher risk of VTE. Among 4,986 controls that were diagnosed with VTE, 316 had a family history of VTE. Controls with a family history of VTE had a 1.5-fold (95% CI 1.3–1.7; p<0.001) increased risk of VTE compared to controls without a family history of VTE. The difference of the impact of family history of VTE on the risk of VTE in multiple myeloma patients versus controls was significant.

Summary and Conclusions:
In this large population-based study including more than 20,000 multiple myeloma patients, we found family history of VTE to have a larger impact on VTE risk in multiple myeloma than in matched controls. Our findings confirm that genetic factors contribute to thrombophilia in multiple myeloma and may have therapeutic implications regarding thromboprophylaxis and treatment.

Disclosures:
No relevant conflicts of interest to declare.
In Vitro Generation of Influenza-Virus Specific T Cells for Adoptive Immunotherapy,
Authors: Gaundar Shiva , Blyth Emily , Clancy Leighton , Simms Renee , Gottlieb David 
Published: October 2019

Abstract
Abstract 4040
Influenza viruses cause fatal respiratory infections in stem cell transplant patients. Specific T cells provide long-lived adaptive immunity to influenza and the potential for generating such cells for clinical use was investigated. The inactivated influenza vaccine (Fluvax, CSL Australia) was used as the antigen source. Only reagents and culture media approved for clinical manufacture were used. Monocyte-derived dendritic cells (MoDC) pulsed with Fluvax were used to stimulate autologous PBMC at a responder to stimulator ratio of 10:1. On Day 7, a second stimulation was performed. 20U/ml IL-2 was added from Day 7 and 50U/ml IL-2 from Day 14 onwards. Media exchanges were performed as required using fresh medium containing IL-2.
Over 21 days of culture, a mean fold increase of 26.3 in cell number was observed (n=7). Cultures were mainly T cells (mean 92.9%) with effector and central memory phenotypes. CD4 cells dominated (mean 78.1%) with a lower percentage of CD8 cells (mean 14.9%). Following expansion, CD154 was expressed on 8.1% of CD4 cells (<1% in unstimulated cells). Both CD4 (mean 26.3%) and CD8 (mean 3.2%) cells produced one or more of the Th1 cytokines IFNg, TNFa and/or IL-2 when restimulated with Fluvax antigen pulsed MoDC. Most responding CD4 cells produced all three cytokines simultaneously, while CD8 cells primarily produced IFNg alone. A mean of 11.1% CD4 and 9.1% of CD8 cells mobilized CD107 on the cell surface when restimulated with Fluvax. Th1 cytokines were produced in response to stimulation with antigens derived from individual H1N1, H3N2 and Brisbane virus strains by the CD4 subset in all of 6 cases and CD8 subset in 2 of 6 cases. In addition, both CD4 and CD8 cells proliferated on restimulation with Fluvax or antigen from H1N1, H3N2 or Brisbane strains.
In conclusion, we demonstrate a clinically applicable method that yields high numbers of highly reactive T cells specific for influenza viruses including the H1N1 strain. Cells express a phenotype of activated antigen specific cells capable of B cell helper function. We propose that reconstructing host immunity through adoptive transfer of donor derived influenza virus specific T cells possibly combined with early post-transplant influenza vaccination will reduce the frequency of influenza-related deaths in the period of severe immune suppression that follows allogeneic stem cell transplant.

Disclosures:
Off Label Use: Use of influenza vaccine for in vitro cell generation.
Simultaneous Isolation and Enrichment of Multi Specific and Multi Functional T-Cells Populations for Treatment of Patients Undergoing Allogeneic Hematopoetic Stem Cell Transplantation,
Authors: Kruse Meike , Bonig Halvard , Kapp Markus , Germeroth Lothar , Einsele Hermann , Grigoleit Götz Ulrich 
Published: October 2019

Abstract
Abstract 4056
Allogeneic hematopoetic stem cell transplantation (aHSCT) is a treatment option for a variety of diseases in particular heamatological malignancies. Due to an ongoing immunosuppression to prevent graft versus host reaction (GvHD), disease relapses as well as viral infections are major causes of morbidity and mortality after aHSCT.
T cell responses against different tumor-associated and tumor-specific antigens could be detected not only in patients with malignant diseases but also in healthy donors. We investigated the selection of MART-1 (Melanoma Antigen Recognized by T-cells), Proteinase 3 and WT-1 (Wilms Tumor- Antigen) specific T cells from the blood of healthy donors as basis for a tumor-specific T cell transfer in the context of aHSCT.
With a newly established protocol, based on streptamer selection, we isolated simultaneously multi-functional and multi-specific T-cell populations. We selected tumor-antigen-specific CTL′s (Cytotoxic T- Lymphocytes) mentioned above and also antiviral T-cells namely against CMV, EBV and AdV from a single blood donation. In this simultaneous selection with up to 7 different epitopes in one step, even the tumor specific T cells, which are known to be rarely detected among healthy donors, could be enriched to an amount sufficient for a direct T cell transfer.
Purity achieved after selection was at least 82% and up to 98,87%, which minimizes the risk for GvHD after clinical application. The possibility to transfer these selected CTL`s to patients after stem cell transplantation improves the graft versus tumor effect as well as the anti infective T cell immunity without a relevant risk for GvHD.
Furthermore, the selected multi specific T cell populations could be expanded in vitro without loss of specificity and include different phenotypes such as central memory and memory effector cells, which may provide long lasting immunity.
Moreover, starting with a leukapheresis, we successfully transferred our selection protocol in a closed system according to current good manufacturing practice (cGMP) requirements, which allows clinical application in the future. With that, it opens new perspectives in cellular immunotherapy against malignancies and viral infection for patients after aHSCT.

Disclosures:
No relevant conflicts of interest to declare.
What Predicts High Risk Acute Gvhd At Diagnosis?: Identification of Those At Highest Risk by a Novel Acute Gvhd Risk Score,
Authors: MacMillan Margaret L. , Defor Todd E. , Weisdorf Daniel J. 
Published: October 2019

Abstract
Abstract 4062
To define high risk acute graft-versus-host disease (GVHD) at its onset, we examined the initial GVHD stage and grade of 864 patients at the University of Minnesota who received uniform therapy with prednisone 60 mg/m2/d. We compared the prognostic utility of the Minnesota (MN) (modified from Consensus) versus Center for International Blood and Marrow Transplant Research (CIBMTR) GVHD organ stage-derived grading systems. As neither GVHD grading system optimally predicted outcomes, a novel acute GVHD risk score was devised by combining the MN and CIBMTR systems. Using multiple regression analysis, we could dichotomize patients into (high risk, HR, n=86) acute GVHD with initial grade IIIC, IID or IVD who were significantly less likely to respond to steroid therapy by day 28 than patients with standard risk (SR, initial grade IA-IIIB, n=778) GVHD (Univariate complete response [CR]+ partial response [PR] at day 28: HR 43% [95% CI 33–53%] vs. SR 68% [95% CI 65–71%], p <.001; Multivariate HR Relative Risk [RR] of overall response [CR+PR], 0.3, 95% CI, 0.2–0.5, p<.001). The probability of treatment-related mortality (TRM) at 2 years was significantly higher in patients with HR than SR acute GVHD (51% [95% CI 40–62%] vs. 38% [95% CI 35–41%], p <.01) (figure).
In multivariate analysis, patients with HR acute GVHD had a 2 fold increase risk of TRM (RR, 2.0, 95% CI, 1.4–2.8, p<.001) and similarly higher 2 year mortality (RR, 1.5, 95% CI, 1.1–2.1, p=.004). Using this novel acute GVHD Risk Score, we can identify initially HR GVHD as either skin stage 4, lower gastrointestinal (GI) stage 3+, liver stage 3+, or skin stage 3 and lower GI or liver stage 2+ GVHD. Patients with HR acute GVHD at onset have a poor prognosis, require alternative initial therapy and should be the focus of novel therapeutic trials.

Disclosures:
Weisdorf: Genzyme: Consultancy, Research Funding.
Umbilical Cord-Derived Mesenchymal Stem Cells for Treatment of Steroid-Resistant Severe Acute Graft-Versus-Host Disease
Authors: Chen Guanghua , Yang Ting , Fu Chengcheng , Miao Miao , Jin Zhengming , Tang XiaoWen , Han Yue , He Guangsheng , Zhang Xuhui , Ma Xiao , Chen Feng , Hu Xiaohui , Xue Shengli , Wang Ying , Qiu Huiying , Sun Aining , Depei Wu 
Published: October 2019

Abstract
Abstract 4536

Objective
To evaluate the safety profile and efficacy of umbilical cord-derived mesenchymal stem cell infusion in patients with steroid-resistant, severe, acute graft-versus-host disease (aGVHD).

Methods
A total of 19 patients with steroid-resistant severe aGVHD received mesenchymal stem cell infusion treatment. We analyzed the treatment response, transplantation-related mortality, events associated with infusion and relapse rate.

Results
Two patients with grade II, 5 patients with grade III and 12 patients with grade ‡W aGVHD received a total of 58 infusions of mesenchymal stem cell. The mean total dose of mesenchymal stem cell was 2.13×106 (range 0.6–7.2×106) cells per kg bodyweight. 7 patients received one infusion, 2 patients received two infusions, and 10 patients received three or more infusions. 11 patients had a complete response and 4 had a partial response and 4 had no response. No patients had side-effects during or immediately after infusions of mesenchymal stem cell and no ectopic tissue was detected to date. 11 patients survived and 8 died, 4 for aGVHD, 1 for infection and 2 for aGVHD with concomitant infection and 1 for underlying leukemia relapse. The cell viability of freshly prepared mesenchymal stem cell is 93% (92%-95%) by trypan blue staining. The cell viability of controlled-rate freezed and thawed cells mesenchymal stem cell is 72% (70%-74%).

Conclusion
Infusion of umbilical cord-derived mesenchymal stem cell expanded in vitro is an effective therapy for patients with steroid-resistant, severe aGVHD without negative impact on relapse. Freshly prepared mesenchymal stem cells are superior to freezed and thawed cells in terms of cell viability.

Disclosures:
No relevant conflicts of interest to declare.
VITAMIN D Insufficiency Affects Time to FIRST TREATMENT (TFT) In EARLY CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)
Authors: Molica Stefano , Digiesi Giovanna , Antenucci Anna , Levato Luciano , Mirabelli Rosanna , Gentile Massimo , Giannarelli Diana , Sperduti Isabella , Morabito Fortunato , Conte Laura 
Published: October 2019

Abstract
Abstract 4601
Recent data suggest that vitamin D insufficiency is related to inferior prognosis in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). We evaluated whether 25(OH)D serum levels affect time to first treatment (TFT), a disease-specific end point, in 130 previously untreated CLL patients with early disease (i.e., Binet stage A). Measurement of 25(OH)D was conducted by means of a direct, competitive chemiluminescence immunoassay using the DiaSorin LIAISON 25(OH)D TOTAL assay (DiaSorin, Inc., Stillwater, Minnesota). Levels of 25(OH)D did not reflect Rai substages (P=0.27), Beta2-microglobulin (P=0.52), absolute lymphocyte count (P=0.21), FISH chromosome abnormalities (P=0.11), mutational status of IgVH (P=0.43), ZAP-70- (P=0.53) or CD38-expression (P=0.82).Overall, 42 patients (31.8%) had severe vitamin D insufficiency (< 10 ng/mL), 66 (50%) had mild to moderate insufficiency (10–24 ng/mL), and 24 (18.1%) had 25(OH)D levels within the optimal range(25–80 ng/mL), with no relationship between the month of sample collection and 25(OH)D level (P=0.188). A patient stratification according to these 3 groups led to significant difference in terms of TFT, with vitamin D insufficient patients having the shortest TFT (P=0.02). With respect to continuous 25(OH)D levels and clinical outcome, TFT was shorter as 25(OH)D decreased until a value of 13.5 ng/mL at which point the association of 25(OH)D and TFT remained constant. As a matter of fact, the 25(OH)D value of 13.5 ng/mL identified two patients subsets with different TFT risk (HR=1.91; 95%CI=1.06–3.44;P=0.03). In multivariate analysis the variable entering the model at a significant level were mutational status of IgVH (P<0.0001), serum thymidine kinase ((P=0.02) and absolute lymphocyte count (P=0.03). Thus confirming the Mayo clinic experience, our data provide further evidence that 25(OH)D levels may be an important host factor influencing TFT of Binet stage A patients. Since the effect of 25(OH)D insufficiency may be may be relevant in this subset of patients who are generally observed for years before starting therapy future trials should address the role of vitamin D therapy in delaying disease-progression.

Disclosures:
No relevant conflicts of interest to declare.
Analysis of Mantle Cell Lymphoma Patients Reveals Novel Regulatory Circuits Involving MicroRNAs and Their Targets
Authors: Kulvait Vojtech , Pospisil Vit , Vargova Karin , Trneny Marek , Klener Pavel , Stopka Tomas 
Published: October 2019

Abstract
Abstract 4624
Mantle cell lymphoma (MCL) represents B-cell lymphoma derived from the mantle zone that surrounds normal germinal center follicles. Pathophysiology of this hardly curable disease involves t(11,14)(q13,q32) translocation which leads to upregulation of Cyclin D1(CCND1). Recently, microRNAs were demonstrated to significantly modify MCL pathogenesis (Jian-Jun Zhao et al. 2010) and therapy responsiveness (Jiang et al. 2010). In order to broaden our knowledge of regulatory pathways in MCL we searched for differentially expressed microRNAs and their differentially expressed mRNA targets between MCL samples and control samples. Samples consist of magnetically separated B cells derived from peripheral blood. We used 1) Microarray mRNA hybridization [Affymetrix Human Genome U133 Plus 2.0 Array, N(MCL)=5, N(control)=5] and 2) microRNA profiling [TaqMan® Array Human MicroRNA Card A v2.0 technology, N(MCL)=5, N(control)=5] followed by statistical analysis [limma (Smyth 2005)]. Differentially regulated targets of the deregulated microRNAs were selected from the databases involving both predicted (Betel et al. 2007) or confirmed (Hsu et al. 2010) target mRNAs. Among the most significant upregulated microRNAs (exceeding 10 fold) are miR-9, miR-124 and miR-183. We have found that upregulated miR-9 has confirmed downregulated target gene PRDM1 (PR domain zinc finger protein 1) which plays a role in B cell maturation (Turner et al. 1994) and may act as a tumor suppressor (Pasqualucci et al. 2006). Upregulation of miR-9 and downregulation of its targets was recently demonstrated in Burkitt lymphoma (Onnis A et al. 2010) and Hodgkin lymphoma (Nie K et al. 2008). Two additional upregulated microRNAs, miR-124 and miR-183, yet not associated with lymphomas, have downregulated target gene Integrin beta-1 (CD29) which regulates survival (Fukumori et al. 2003). Among most significant downregulated microRNAs is miR-101 (FC=-7). Downregulated microRNA miR-101 has known oncogene N-Myc (MYCN) as upregulated confirmed target and DNA (cytosine-5)-methyltransferase 3A (DNMT3A) as upregulated target. Overexpression of a well known hematopoietic oncogene MYCN and epigenetic repressor DNMT3A may represent additional pathogenesis-related factors in MCL. Our data support importance of the candidate mechanisms involving microRNAs and their target programs in pathogenesis of MCL. They are currently extended on a larger patient cohort by analyzing expression and functional significance of the candidate microRNAs. (Grants: NT10310-3/2009, MPO FR-TI2/509, NPVII 2B06077, MSM 0021620806, LC 06044, SVV-2011-262507).

Disclosures:
No relevant conflicts of interest to declare.
Analysis of Methylation Status of ZAR1, GATA4, CDH22, SOX3, SLC16A5, PFN2, EHD3 and TBPL1 in Hematological Malignancies
Authors: Kobayashi Yujin , Hatta Yoshihiro , Takeuchi Jin , Fujiwara Kyoko , Shinojima Yui , Kawashima Hiroyuki , Igarashi Jun , Nagase Hiroki 
Published: October 2019

Abstract
Abstract 4631

Background:
DNA cytosine methylation in CpG dinucleotides is an important epigenetic event and critical for the control of gene expression, and appears to play a crucial role in tumorgenesis in hematologic malignancies. To identify novel tumor-specific differentially methylated regions in human leukemia/lymphoma, we performed methylation analysis of new target lesions in hematological malignancies.

Methods:
The aberrant methylation at 8 new candidate human homologous genomic regions (ZAR1, GATA4, CDH22, SOX3, SLC16A5, PFN2, EHD3 and TBPL1), where hypermethyloation status was identified through a mouse-skin cancer model study by the RLSG method, were analysed with quantitative DNA methylation analysis using the Sequenom MassARRAY system. 8 human leukemia/lymphoma cell lines (HL-60, KG-1, Jurkat, MOLT-4, NALM-6, K562, Ramos, and Raji), and bone marrow or peripheral blood samples from 20 patients with leukemia before treatment were obtained for samples (10 in AML, 4 in Ph- ALL, 2 in Ph+ ALL, 2 in CML-CP, 1 in CML-BC, and 1 in CLL). Normal lymphocyte cells from four healthy individuals were used as normal controls. Each data were assigned as hypermethylaion when the average methylation levels of the entire target regions were more than 50%.

Results:
In ZAR1, SLC16A5 and EHD3, hypermethylation level was seen in all leukemia/lymphoma cell lines. GATA4, CDH22 and SOX3 showed hypermethylaion in all tumor cell lines except for AML cell line KG-1. PFN2 showed hypermethylation in all cell lines except for KG-1, T-ALL cell line Jurkat and MOLT-4. No aberrant methylation among tumor and normal cells was observed in TBPL1. Interestingly, DNA methylation patterns of ZAR1, GATA4, CDH22, and SOX3 were different between the clinical specimens of AML and ALL. Hypermethylation of those genes were frequently observed in ALL samples but less in AML. The Mann-Whitney U-test showed that the differences were significant in all ZAR1, GATA4, CDH22, and SOX3 (p < 0.01, respectively). DNA samples from CML-CP patients showed no abnormal methylation patterns in all genes. DNA from T-CLL patient showed hypermethylation only in EHD3. No abnormal methylation pattern was observed in SLC16A5 and PFN2 in clinical specimens. None of the normal control samples showed aberrant methylation in any genes.

Conclusion:
We identified regions aberrantly methylated with high frequency among the new candidate genes in leukemia and lymphoma, and demonstrated a distinct methylation pattern between tumors and normal lymphocytes. Aberrant DNA methylation of ZAR1, GATA4, CDH22 and SOX3 may be associated to differentiation to lymphoid populations of leukemia.

Disclosures:
No relevant conflicts of interest to declare.