bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Critical Population Analysis of 57, 500 US Multiple Myeloma Patients: Impact of Race, Age, and Decade of Treatment on Overall Survival
Authors: Kaya Hakan , Martincic Danko , Jawed Irfan , Peressini Ben , Elaimy Ameer L , Lee Christopher M 
Published: October 2019

Abstract
Abstract 2948

Background:
Recent clinical observations and published reports have suggested that there has been a significant improvement in overall survival (OS) in patients with multiple myeloma (MM) during the last decade. Previous studies have also suggested that OS was superior in younger MM patients. A large population analysis studying the impact of different races on overall survival is lacking. For this reason, we aimed to study OS differences among patients of different races. We also hypothesized that OS had already improved from the 1970s to 2000s in all MM patients due to other factors, as well as the availability of novel agents. Methods: For the years from 1973 to 2008, data on 57, 574 MM patients were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program of the US National Cancer Institute. Statistical analysis evaluating patient population baseline characteristics (race, age) and year of diagnosis were performed by using univariate and multivariate Cox regression models for the OS endpoint. Results: The mean patient age at diagnosis was determined to be 68 (median = 69) years. Mean survival was determined to be 33 months (median = 21). Asian/Pacific Islander race was associated with an improved OS, HR 0.94 (CI 0.92–0.96, P <0.001). Multivariate hazard ratio analysis did not reveal any statistically significant differences in OS between patients in the white and black race (P =0.687). Younger age (age <65) was associated with improved OS when compared with patients aged 65–75 or patients aged >75 (both P <0.001). Recent treatment decades (1983–1992, 1993–2003, and 2004–2008) were associated with improved OS on multivariate analysis with HR 0.90 (CI 0.90–0.91, P <0.001), HR 0.79 (CI 0.78–0.79, P <0.001), and HR 0.71 (CI 0.69–0.74, P <0.001), respectively. Conclusions: As the largest population analysis to date, this study revealed a statistically significant improvement in OS for patients belonging to Asian/Pacific Islander race groups. In addition, MM patients from all subgroups who were treated in more recent decades, even before the availability of novel agents, exhibited superior OS. This may be due to advances in supportive care and/or earlier diagnosis, as well as an increased use of hematopoietic stem cell transplantation. With the availability of novel agents during the last decade, OS has significantly improved. Our study shows that older MM patients continued to have decreased levels OS even after the availability of novel agents. Future studies are needed to evaluate the effectiveness of novel agents in various age subpopulations.

Disclosures:
No relevant conflicts of interest to declare.
The TGF- β Family Member Growth Differentiation Factor 15 (GDF15) Regulates the Self-Renewal of Multiple Myeloma Cancer Stem Cells
Authors: Tanno Toshihiko , Merchant Akil , Agarwal Jasmin R. , Wang Qiuju , Matsui William 
Published: October 2019

Abstract
Abstract 2954
Multiple myeloma (MM) cancer stem cells (CSCs) possess both enhanced tumorigenic potential and relative drug resistance suggesting they play a major role in disease relapse and progression. Therefore, a better understanding of the processes regulating MM CSCs may lead to the development of novel therapies that prevent tumor regrowth and improve long-term outcomes. Normal stem cells are tightly regulated by factors within the local microenvironment that include both soluble factors and direct contact with accessory cells. However, external factors regulating MM CSCs have not been identified. Recent studies have demonstrated that stromal cells in the MM bone marrow microenvironment secrete growth differentiation factor 15 (GDF15), a member of the TGF-b family. We initially studied the role of this cytokine in the pathogenesis of MM by examining circulating GDF15 levels in MM patients. Compared to healthy volunteers, we found that median GDF15 levels were significantly increased in MM patients (821 vs. 390 pg/ml; n=16; p<0.05) and increased with disease stage (Stage II=585 pg/ml, Stage III=1, 004 pg/ml). To examine the functional effects of GDF15 on MM cells, we cultured human MM cell lines (NCI-H929, RPMI 8226) with recombinant GDF15 and found that it induced the expansion of isolated CD138neg MM CSCs in a dose-dependent manner but had little impact on the growth of CD138+ plasma cells (Fig). Furthermore, GDF15 enhanced clonogenic myeloma growth as evidenced by increased colony formation that was maintained during serial replating, a surrogate for self-renewal. This effect appeared to be GDF15 specific since it could be blocked using anti-GDF15 antibody. Similarly, GDF15 treatment increased the in vitro clonogenic growth of MM CSCs from primary clinical bone marrow specimens. We also investigated the down-stream cellular pathways potentially mediating the effects of GDF15 and found that it activates the AKT signaling pathway known to improve the self-renewal of embryonic (ES) and normal hematopoietic stem cells. GDF15 also induced expression of the SOX2 transcription factor known to be upregulated in CD138neg MM CSCs. Since SOX2 is required for the self-renewal of ES cells and the generation of induced pluripotent stem (iPS) cells, its induction by GDF15 may also increase the self-renewal of MM CSCs. GDF15 is the first soluble factor identified that regulates MM CSCs, and its effects are mediated by the activation of highly conserved self-renewal programs.

Disclosures:
No relevant conflicts of interest to declare.
Poor Mobilization of CD34+ Stem Cells Predicts Inferior Relapse and Survival Outcomes After Autologous Stem Cell Transplantation for Multiple Myeloma
Authors: Lazaryan Aleksandr , Duong Hien , Rybicki Lisa , Reu Frederic J. , Dean Robert , Sobecks Ronald , Tench Shawnda , Copelan Edward A. , Kalaycio Matt , Bolwell Brian J. 
Published: October 2019

Abstract
Abstract 3000
Autologous stem cell transplantation (ASCT) remains the standard upfront therapy of younger patients with multiple myeloma (MM). Identifying a prognostic threshold amount of mobilized CD34+ hematopoietic stem cells (SC) may become an important modifiable parameter in the era of novel stem cell mobilization strategies. While poor mobilization of CD34+ cells has been shown to cause delays in hematopoietic recovery, the data on long-term clinical outcomes of patients with inferior CD34+ SC collection (‘under mobilizers’) are limited. We analyzed prospectively collected data on 239 adult patients with MM who underwent ASCT at our institution from 01/1996 to 12/2009. Fifty-one patients (21.3%) who collected less than 4 × 106/kg CD34+ SC were classified as ‘under mobilizers’ and were compared to the rest of the study population (n=188) who collected ≥ 4 × 106/kg CD34+ SC. Even though under mobilizers were slightly older (median 59 vs. 54 years, p =0.01), had longer time from diagnosis to ASCT (11 vs. 8 months, p =0.05), and required more days of leukapheresis (5 vs. 3 days, p <0.001), they did not differ from the other group according to the number of prior treatment regimens, mobilization method (only 2 patients received plerixafor), performance status, or disease remission status at transplant (all p >0.2). Median time-to-recovery for both neutrophils (11 vs. 10 days, p <0.001) and platelets (13 vs. 12 days, p <0.001) was delayed among under mobilizers. Under mobilizers had worse relapse-free survival (RFS) (hazard ratio [HR]=1.49, 95% CI, 1.03–2.16, p =0.03) and non-relapse mortality (NRM) (HR=3.59, 95% CI, 1.51–8.56, p <0.01) in multivariable Cox proportional hazards analysis. Even though the association between poor CD34+ SC collection and inferior overall survival did not reach statistical significance (HR=1.42, 95% CI, 0.94–2.16, p =0.1), under mobilizers were found to have significantly higher rates of 100-day post-transplant mortality (p =0.02). We conclude that in the context of ASCT for MM, failure to collect ≥ 4 × 106/kg CD34+ SC is independently associated with worse RFS and NRM.

Disclosures:
No relevant conflicts of interest to declare.
Mesenchymal Stem Cells As a Treatment for Steroid-Resistant Acute Graft Versus Host Disease (aGVHD); A Multicenter Phase I/II Study
Authors: Ozawa Yukiyasu , Goto Tatsunori , Ohashi Kazuteru , Murata Makoto , Eto Tetsuya , Kobayashi Naoki , Taniguchi Shuichi , Imamura Masahiro , Ando Kiyoshi , Kato Shunichi , Mori Takehiko , Teshima Takanori , Mori Masaki , Muroi Kazuo , Miyamura Koichi , Ozawa Keiya 
Published: October 2019

Abstract
Abstract 3042

Introduction:
Allogeneic hematopoietic stem cell (HSC) transplantation is an effective therapy for a number of diseases. However, severe graft versus host disease (GVHD) remains a life-threatening complication after allogeneic stem cell transplantation, and it is very difficult to treat steroid-resistant GVHD. Mesenchymal stem cells (MSCs) have a homing activity to inflammatory sites and modulate immune response via PGE2 and so on, suggesting that MSCs might be effective for refractory aGVHD. Recently, clinical studies have suggested that MSC infusion can also reduce the severity of GVHD. We report here the results of our multicenter phase I/II study of MSCs for treatment of steroid-resistant aGVHD.

Methods:
Patients with steroid-resistant, grade II-IV, aGVHD were treated with MSCs derived from bone marrow of healthy volunteers and expanded in vitro (JR-031). MSCs were administered twice a week for 4 weeks. All patients received 2 × 106 cells/kg of MSCs for each infusion. Patients with PR after 4 weeks were given continued weekly MSCs infusion for an additional 4 weeks.

Results:
From January 2009 to November 2010, 14 patients were treated. The median age was 52 years old (range: 4–62), Male (n=5) and Female (n=9). Nine patients were diagnosed as grade II aGVHD, 5 patients were diagnosed as grade III and no patients were diagnosed as grade IV aGVHD. Thirteen of 14 patients (92.9%) responded to MSCs, achieving CR (n=8) or PR (n=5) 4 weeks after treatment. Eleven patients (78.6%) survived 24 weeks after treatment. Seven patients showed severe adverse effects including thrombocytopenia, neutropenia and hepatic dysfunction, however, no patients had severe infections which was shown by existing salvage therapy for aGVHD.

Conclusion:
The prognosis of steroid-resistant aGVHD was poor, and the most effective salvage therapy remains to be clarified. In this study, we showed that in vitro expanded MSCs, JR-031, might be a safe and effective salvage therapy for patients with steroid-resistant aGVHD.

Disclosures:
Kato: Research Grant for Tissue Engineering (H17-014) and a Research Grant for Allergic Disease and Immunology (H20-015) from the Japnese Ministry of Health, Labor and Welfare.: Research Funding.
Treatment of Steroid Resistant Grade II to IV Acute Gvhd by Infusion of Mesenchymal Stroma Cells Expanded with Human Plasma and Platelet Lysate - a Phase I/II Study
Authors: Boome Liane CJ te , Lindemans Caroline A , Slaper-Cortenbach Ineke , Rozemuller Henk , Petersen Eefke J , Boelens Jaap Jan , Bierings Marc , Wulffraat Nico , Kuball Jurgen 
Published: October 2019

Abstract
Abstract 3046
Introduction For numerous malignant and non-malignant hematological diseases allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy. However, a major complication is the acute graft versus host disease (aGVHD), which is life-threatening and substantially reduces efficacy of HSCT. In particular, the outcome for patients with severe steroid-resistant aGVHD is very poor. Therefore, it remains important to search for new therapeutic strategies for the treatment of aGVHD.
Objective Feasibility of the generation mesenchymal stroma cells (MSCs) expanded with human plasma and platelet lysate (hPPL) was tested as well as the feasibility and safety of the application of MSCs in patients with steroid-refractory extensive aGVHD.
Method In an open-label, non-randomized prospective phase I/II study MSCs were extracted from the bone marrow of healthy volunteers, expanded with human plasma and platelet lysate (hPPL), and stored. Patients with steroid-refractory extensive aGVHD were treated with ∼2×106/kg MSC. Response rate, transplantation-related deaths, and other adverse events were assessed for up to 12 months after the last infusion of the cells.
Results Between January 2009 and December 2010, 18 patients were treated, 5 children and 13 adults, median age was 32.5 years (range 1.3–65.9). Organ involvement of the aGVHD was 67% skin, 83% gastro-intestinal and 28% liver. Overall grade was II for 4 (22%), III for 13 (72%), and IV for 1(6%) patients. 1 patient received one infusion, all other patients received two or more infusions. No patient had side-effects during or immediately after infusions of the MSC. Median follow-up was 5.5 months (range 0.33–12). Complete overall response was observed in 11 (61%) patients after a median of 65 days (range 10–184 days). The overall survival was significant better (p <0.001) compared to non-responders. Of the 11 patients who reached a CR, 8 relapsed median 59 days (1–244) after reaching CR. Three children with subsequently limited cGVHD, allo immune lung and auto-immune cytopenia and 5 adults with all relapse GVHD of the gut, median 98 days (35–302 days). However, GVHD of the gut was then sensitive for the treatment with steroids. Overall, 7 patients died, 4 due to progression of aGVHD, 1 patient due to abdominal bleeding and 2 due to sepsis.
Conclusion Generation and infusion of MSCs in steroid-resistant aGVHD grade II- IV is a feasible, safe and very effective. In addition, also patients who initially responded to MSCs but develop later a relapse of aGVHD during tapering or cessation of immunosuppressive drugs become again sensitive to the treatment with steroids.

Disclosures:
No relevant conflicts of interest to declare.
HLA DR15 Antigen Status Does Not Impact Graft-Versus-Host Disease or Disease-Free Survival in HLA-Matched Sibling Transplantation for Hematologic Malignancies
Authors: Battiwalla Minoo , Ellis Kristin , Pavletic Steven Z. , Akpek Gorgun , Hematti Peiman , Klumpp Thomas R , Maziarz Richard T. , Savani Bipin N. , Aljurf Mahmoud , Cairo Mitchell S. , Drobyski William R. , George Biju , Hahn Theresa , Khera Nandita , Litzow Mark R. , Loren Alison W. , Saber Wael , Arora Mukta , Urbano-Ispizua Alvaro , Cutler Corey S. , Flowers Mary E.D. , Spellman Stephen 
Published: October 2019

Abstract
Abstract 3094
The HLA class II DRB1 antigen DR15 is an important immunobiologic marker in immune mediated marrow failure states. DR15 has also been reported in small studies to be associated with favorable outcomes (reduction in acute GVHD and reduced relapse resulting in improved overall survival) after allogeneic hematopoietic cell transplant. To elucidate the impact of DR15 on major transplant outcomes, we conducted a retrospective study of 2, 891 recipients of first marrow or mobilized peripheral blood stem cell transplantation for the treatment of acute myeloid leukemia (n=1038), acute lymphoblastic leukemia (n=700), chronic myeloid leukemia (n=948), or myelodysplastic syndrome (n=205) between 1990–2008 and reported to the CIBMTR registry. Selection was confined to HLA-identical sibling transplantation to avoid HLA-disparity as a driving force for observed differences. All patients received conventional myeloablative conditioning, T-replete grafts and cyclosporine plus methotrexate- based GVHD prophylaxis. DNA-based HLA typing allowed categorization of 732 (25.3%) patients as positive and 2159 (74.7%) patients as negative for DRB1*15 :01 or *15 :02 (DR15). There were no significant differences in baseline characteristics between the HLA DR15-positive and -negative groups. In univariate analysis, HLA-DR15 status had no impact on neutrophil engraftment, acute graft-versus-host disease (GvHD) II-IV or III-IV, chronic GVHD, treatment related mortality, relapse, disease-free survival or overall survival. Confining the univariate analysis to myeloid malignancies did not alter these findings. Multivariate analysis models were constructed with DR15 status forced into the models in all steps of model building and the final model regardless of its statistical significance. Other variables tested included: donor/recipient age, CMV status, disease, disease stage, graft source, Karnofsky score, race and year of transplant. Variables that attained a p-value ≤0.05 were held in the final multivariate models. In multivariate analysis, DR15 status showed no significant difference in the primary outcomes of acute GVHD II-IV or III-IV, chronic GVHD, overall survival, or relapse. In conclusion, DR15 status had no impact on major HLA-matched sibling donor hematopoietic cell transplantation outcomes in this large and homogenous cohort of leukemia and MDS patients.

Disclosures:
No relevant conflicts of interest to declare.
Liver Specific Delivery of siRNA Targeting EGLN Prolyl Hydroxylases Activates Hepatic Erythropoietin Production and Stimulates Erythropoiesis,
Authors: Querbes William , Bogorad Roman , Moslehi Javid , Akinc Akin , Wong Jamie , Zurenko Chris , Qin June , Hettinger Julia , Kuchimanchi Satya , Charisse Klaus , Sah Dinah WY , Fitzgerald Kevin , Kotelianski Victor , Kaelin William G. 
Published: October 2019

Abstract
Abstract 3161
Anemia in chronic kidney disease patients due to impaired renal production of erythropoietin (EPO) and insufficient erythropoiesis is a significant public health problem. One approach to compensate for the low EPO levels in patients with impaired kidney function would be to stimulate the levels of EPO production from non-renal sources. It is well known that during fetal development the liver serves as the primary producer of EPO until the kidney becomes the dominant source after birth. Negative regulation of EPO production is mediated by the EGLN family of prolyl hydroxylases (PHDs1-3) that play an important role in oxygen sensing by targeting the transcription factor hypoxia inducible factor (HIF) for degradation via the proteasome. HIF stabilization and activity is required to mediate EPO gene transcription. Previously it has been shown that liver specific conditional knockout of all three PHDs is required to activate HIF and induce EPO production in liver (Minamishima et al. Science 2010). Here we show that simultaneous siRNA mediated knockdown of all 3 PHD genes in mouse liver using lipid nanoparticles (LNPs) can induce hepatic EPO mRNA activation, elevation of serum EPO levels and stimulation of erythropoiesis. We extend these data by examining siRNA knockdown of different combinations of the 3 PHD genes and demonstrate that PHD2 is the dominant PHD gene regulating hepatic EPO production. In addition, due to the specificity of the LNP delivery system we show that the HIF activation and increase in EPO mRNA occurs specifically in liver. Increases in serum EPO and hematocrit were durable for two weeks and one month after a single intravenous dose of LNP siRNA. Furthermore, PHD siRNA silencing in a 5/6 nephrectomy model successfully elevates hemoglobin levels and corrects anemia. In conclusion, targeting of EGLN prolyl hydroxylase genes with siRNA therapeutics has potential in the treatment of anemia associated with chronic kidney disease and provides liver-specific target gene regulation.

Disclosures:
Querbes: Alnylam Pharmaceuticals: Employment. Bogorad:Alnylam Pharmaceuticals: Research Funding. Moslehi:Alnylam Pharmaceuticals: Honoraria. Akinc:Alnylam Pharmaceuticals: Employment. Wong:Alnylam Pharmaceuticals: Employment. Zurenko:Alnylam Pharmaceuticals: Employment. Qin:Alnylam Pharmaceuticals: Employment. Hettinger:Alnylam Pharmaceuticals, Inc.: Employment. Kuchimanchi:Alnylam Pharmaceuticals: Employment. Charisse:Alnylam Pharmaceuticals: Employment. Sah:Alnylam Pharmaceuticals, Inc.: Employment. Fitzgerald:Alnylam Pharmaceuticals: Employment. Kotelianski:Alnylam Pharmaceuticals: Employment. Kaelin:Fibrogen: Consultancy, Equity Ownership.
Identification of MicroRNAs Associated with Erythropoiesis Through Deep Sequencing of Red Blood Cells,
Authors: Doss Jennifer F , Jima Dereje , An Xiuli , Dave Sandeep S. , Chi Jen-Tsan Ashley 
Published: October 2019

Abstract
Abstract 3164
We have recently found that human mature red blood cells (RBCs), though lacking large RNAs, possess a diverse and abundant set of microRNAs (miRNAs). MiRNAs are a class of small RNAs that inhibit translation and/or promote degradation of target mRNAs. Red blood cells are an ideal model for small RNA identification due to the relatively low amount of contaminating mRNA, tRNA, and rRNA fragments.
We performed deep sequencing of small RNAs in human RBCs to provide an unbiased set of both known and novel microRNAs, and to gain insight into the process of erythropoiesis. Small RNA libraries were applied to the Illumina GAII deep sequencing platform from both HbAA and HbSS individuals, as microRNAs have also been shown to be genetic determinants of sickle cell phenotypes (Sangokoya 2010). A modified version of the probabilistic modeling algorithm, miRDeep (Friedländer 2008), was used to identify several novel and known microRNAs. Genomic loci that overlapped with miRNAs described in miRBase were identified as known miRNAs. The remaining genomic loci were identified as encoding candidate novel miRNAs. Collectively, we identified 253 predicted miRNA precursor loci from the two samples. 226 miRNA precursor loci annotated in miRBase were identified as known miRNAs, whereas the remaining 27 precursor loci were identified as candidate novel miRNAs. In addition to miRNAs, we identified other small RNAs that did not pass miRDeep criteria. One of the most abundant sequences consisted of a distinct fragment of Ro-associated Y4 RNA (hY4). Y RNAs are involved in chromosomal DNA replication and cell proliferation, and specifically, RNAs hY1 and hY4 have been shown to be present in mature human erythrocytes (O'Brien 1990).
In addition, we also identified the relative expression of both novel and known microRNAs during erythropoiesis using both human and mouse erythroid differentiation models. We are currently investigating the relevant targets and regulatory functions of these microRNAs during erythropoiesis, as well as experimental validation of authentic microRNA fuction of novel microRNAs. This global analysis will enhance our understanding of events dictating red cell maintenance and development.

Disclosures:
No relevant conflicts of interest to declare.