bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Interleukin-15 Superagonist (IL-15 SA) Combined with Donor Lymphocyte Infusion (DLI) Significantly Enhances Graft-Versus-Tumor Activity after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Bailey Cavan , Panis Michelle M , Buyukgoz Cihangir , Budak-Alpdogan Tulin , Flomenberg Neal , Alpdogan Onder 
Published: October 2019

Abstract
Donor lymphocyte infusion (DLI) has been successfully used clinically to augment the graft-versus-tumor (GVT) effect following hematopoietic stem cell transplantation (HSCT) in relapsed patients. However, improvements can still be made in enhancing anti-tumor activity, reducing graft-versus-host disease (GVHD) and decreasing complications from opportunistic infections. Our studies present clear evidence of increased tumor clearance via cytokine therapy in combination with DLI as a way to “boost” the infused cells function. Interleukin-15 (IL-15) is a potent cytokine that increases CD8+ T and NK cells number and function in normal mice and recipients of stem cell transplantation. Despite this, obstacles remain for use of IL-15 therapeutically, specifically its low potency and short in vivo half-life. To overcome this, a new IL-15 superagonist (IL-15 SA-(ALT-803)) has been developed with a longer half-life and increased potency.
Administration of IL-15 SA to recipients of CFSE labeled T cells increases proliferation of CD8+T cells and IFN-γ and TNF-α secretion from CD8+T cells. We developed a murine DLI model by titrating the dose of infused T cells in a parent-F1 model, and then combined IL-15 SA administration with DLI in murine recipients of allogeneic HSCT. In this model, lethally irradiated CB6F1 (H2Kb/d) mice were transplanted with T- cell depleted bone marrow cells from C57BL6 mice (H2Kb). All recipients of HSCT were also co-injected A20 B-cell lymphoma cells transfected with a luciferase-producing gene, which allows bioluminescent imaging and tracking of tumor progress in vivo. Mice receiving DLI (2.5 X 105 T cells) with IL-15 SA injections given at 1μg/mouse on days 17 and 24 post-BMT show less tumor burden and increased overall survival (p = 0.04) and decreased tumor growth (p = 0.02) (Figure 1). The IL-15 SA treated group had a significantly less weight loss than the control group (p = 0.007). No GVHD symptoms were noted via weekly clinical scoring, highlighting both the efficacy and overall safety of the IL-15 SA therapy. Furthermore, we evaluated T- cell exhaustion markers on CD8+ T cells in surviving mice. We found increased programmed death-1 (PD-1) expression on T cells even when the tumor burden is cleared. Treatment with IL-15 SA reduced PD-1 expression on donor CD8+ T-cells in mice surviving more than 120 days post-transplant.
We conclude that IL-15 SA enhances CD8+ T cell function by increasing cytokine secretion and proliferation of T cells whereas could also prevent T cell exhaustion. We suggest that IL-15 SA is a long-waited lymphoid growth factor and has the potential to use in combination with DLI for the treatment of recurrent disease after HSCT.

Disclosures
No relevant conflicts of interest to declare.
FLT Imaging Reveals Kinetics and Biology of Engraftment after Myeloablative HSCT
Authors: Williams Kirsten M , Holter Chakrabarty Jennifer L. , Lindenberg Liza , Adler Steve , Gea-Banacloche Juan , Blacklock-Schuver Bazetta , Hakim Frances T. , Hickstein Dennis D. , Kochenderfer James N , Wilder Jennifer , Chinn Tracey , Kurdziel Karen , Steinberg Seth M. , Khuu Hanh , Lin Frank I , Fowler Daniel H. , Halverson David , Avila Daniele N. , Selby George , Taylor Tiffani N. , Mann Jennifer , Hsu Jennifer , Epstein Robert B. , Anderson Stacy L , Chuong Nguyen , Havlicek Joseph , Li Shibo , Pham Tom , Kraus Teresa , Vesely Sara K. , Pavletic Steven Z. , Bollard Catherine M. , Choyke Peter , Gress Ronald E 
Published: October 2019

Abstract

Bone marrow failure is associated with high morbidity and mortality after hematopoietic stem cell transplantation (HSCT) due to complications associated with prolonged neutropenia. Using the positron emission tomography (PET) imaging probe, 3’-deoxy-3 18F-fluorothymidine (18FLT), we illustrate HSC homing very early after myeloablative HSCT in adults in vivo. In our prospective trial, NCT01338987, we imaged 14 patients undergoing myeloablative transplantation with Cytoxan and total body irradiation and evaluated corresponding uptake of radiotracer 18FLT in osseous structures throughout the bone marrow compartment following full myeloblation, early engraftment, and hematopoietic reconstitution. 18FLT was safe and did not delay engraftment. Objective increases in 18FLT uptake measured by standardized uptake value (SUV) revealed evidence of stem cell homing to medullary bone marrow sites within 5 days of donor cell infusion. In patients without relapse (n=11), mean thoracic spine SUV was greater among patients with rapid (<21 days) as compared to slow engraftment (≥21 days). Using SUV, we could differentiate full ablation (SUV of 0.65) from early engraftment at day +5-6 (SUV 1.1, p <0.05). 18FLTsignal increases revealed a consistent pattern of marrow recovery that recapitulated fetal ontogeny, claiming sites of hematopoiesis that are normally dormant in adults. These findings were substantiated with in vitro cellular recovery data. 18FLT SUV could also predict marrow recovery after secondary graft failure without additional HSC infusion. In summary, our data show that 18FLT reveals homing, kinetics, and biology of hematopoietic engraftment in adults in vivo.18FLT could predict engraftment very early after HSCT and could be of value to predict primary or secondary graft failure in high risk populations, such as recipients of cord blood transplantation or haplo-identical transplantation.

Disclosures
No relevant conflicts of interest to declare.
Ethnic Disparities in Survival of Chronic Myeloid Leukemia
Authors: Ghimire Krishna B , Shah Binay K. 
Published: October 2019

Introduction:
Development of tyrosine kinase inhibitors has led to significant improvement in survival of chronic myeloid leukemia (CML) patients. We conducted this study to evaluate any ethnic disparity in CML survival.
Methods:
We analyzed surveillance, Epidemiology, and End Results, SEER 18 registry to compare 1 and 3 years relative survival rates of CML patients diagnosed between 2001- 2008 by ethnicity - Caucasian, African American (AA), Others (O). We analyzed survival rates by age (≤65, >65), and time periods: (2001-2004) and (2005-2008). We used SEER*Stat software to calculate Z value.
Results:
There were 6,306 CML patients during (2001-2008); 3,111 during (2001-2004) and 3,195 during (2005-2008). The 1-year relative survival rates among Caucasians (n=6,306), AA (n=790), and Others (n=532) were 80.0±0.5%, 83.8 ±1.4%, and 84.0±1.7% [Z value 2.43 (AA vs Caucasian), 2.15 (O vs Caucasian)] respectively. The 3 years RS rates were 65.6±0.7%, 70.2±1.8%, and 70.9 ±2.1% respectively with Z value 2.49 (AA vs Caucasian) and 2.42 (Caucasian vs O).
Among younger patients (age ≤65 years, n=4,245) Caucasians had better RS compared to AA (83.1±0.7% vs 78.7±1.8%, Z value 2.24) at 3 years. There was no difference survival at 1and 3 years in older patients (age >65 years, n= 3,383).
The survival rates of patients diagnosed during 2001-2004 were similar for all ethnic groups. Among patients diagnosed during 2005-2008, survival rates were significantly higher for AA versus Caucasians (1 year RS 86.6±1.8% vs 81.3±0.7%, Z value 2.45, and 3 year RS 73.8±2.4% vs 68.3±0.9%, Z value 2.20). Others also had better RS compared to Caucasians (87.1±2.1% vs 81.3±0.7%, Z value 2.22) at 1 year.
There was no racial disparity in survival rates when analyzed by age (≤65 and >65) and sex at 1 and 3 years during 2001-2004 and 2005-2008.
Conclusions:
Our study showed that there is ethnic disparity in CML survival. Among CML patients diagnosed during 2005-2008, AA and Other races had superior survival rates compared to Caucasians.

Disclosures
No relevant conflicts of interest to declare.
Prognostic Understanding, Quality of Life, and Mood in Patients Undergoing Hematopoietic Stem Cell Transplantation
Authors: El-Jawahri Areej , Traeger Lara , Kuzmuk Kailyn , Eusebio Justin , Vandusen Harry , Shin Jennifer , Gallagher Emily , Greer Joseph , Pirl William , Jackson Vicki , Ballen Karen K. , Spitzer Thomas R. , Graubert Timothy A. , McAfee Steven L. , Dey Bimalangshu R. , Chen Yi-Bin , Temel Jennifer S. 
Published: October 2019

Abstract
Background: In advanced cancers, patients' prognostic perceptions influence their medical decisions. However, little is known about how patients with hematologic malignancies undergoing hematopoietic stem cell transplantation (HCT) and their family caregivers (FC) understand their prognosis. We examined prognostic understanding in these patients and their FC during hospitalization for HCT and its relationship with quality of life (QOL) and mood.
Methods: We conducted a longitudinal study of patients hospitalized for HCT and their FC. At baseline (6 days pre-HCT), we used a 10-item questionnaire to measure patients' and FC information preferences and perception of prognosis. We also asked oncologists to estimate the patients' prognosis. At day-6, day+1, day+8 of HCT, we assessed QOL (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT)), and mood (Hospital Anxiety and Depression Scale). We evaluated the relationship between participants' prognostic understanding and their QOL and mood during hospitalization for HCT using multivariable linear mixed models.
Results: We enrolled 97% of consecutively eligible patients undergoing autologous (n=30), myeloablative (n=30) or reduced intensity (n=30) allogeneic HCT. Most patients (80/90, 88.9%) and FC (41/47, 87.1%) believed that it is extremely or very important to know about prognosis. However, the majority of patients (66/85, 77.6%) and FC (33/46, 71.7%) reported an inaccurate and more optimistic perception of the patients' prognosis compared to the oncologist (P < 0.0001) [Figure 1]. Patients with an accurate understanding of their prognosis reported worse QOL (F = 4.3, P = 0.03) and a higher rate of depression (F = 4.4, P = 0.04) with worsening depressive symptoms over time (F = 4.13, P = 0.006) compared to patients with an inaccurate prognostic perception.
Conclusions: The majority of patients and FC reported inaccurate and more optimistic perception of prognosis compared with the oncologist. Patients with an accurate perception of their prognosis had lower QOL, higher rates of depression, and worsening depression symptoms during hospitalization for HCT. Interventions are needed to improve prognostic understanding, while providing them with the psychosocial support they need to cope with this difficult information.
Figure 1: Patients', Family Caregivers', and Oncologists' Prognostic Perception Figure 1:. Patients', Family Caregivers', and Oncologists' Prognostic Perception

Disclosures
Off Label Use: Sorafenib for FLT3-ITD AML.
Development of Quality Metrics to Evaluate Pediatric Hematologic Oncology Care in the Outpatient Setting
Authors: Teichman Jennifer R , Gupta Sumit , Punnett Angela 
Published: October 2019

Abstract
Introduction:
Systems to quantify and incentivize quality of care (QoC) have been developed in multiple healthcare settings. In pediatric oncology, lists of QoC metrics or recommendations have been procured through consensus methodologies such as the Delphi process. To date, no QoC metrics have been developed for outpatient pediatric oncology.
Objectives:
The aim of this study was to develop a list of QoC metrics for the leukeumia-lymphoma (LL) clinic at the Hospital for Sick Children in Toronto, using a consensus process that could be adapted to other clinic settings.
Methods:
A modified Delphi process following the American Society of Clinical Oncology (ASCO) guidelines was used to generate consensus on a list of QoC metrics (Loblaw et al., 2012). A Medline-Ovid search was conducted for quality indicators, metrics and recommendations relevant to pediatric oncology. Results were screened for (a) system-level metrics that could be translated to a clinic level and (b) clinic-level recommendations that could be converted to measurable quantities. Additional metrics outside the literature search were considered. A provisional list was compiled and circulated electronically to local stakeholders, including medical and nursing staff (n=10). Stakeholders ranked each metric on a 5-point Likert scale based on importance and feasibility of measurement (round 1). Stakeholders provided feedback on the metrics and suggested additional metrics. Median, interquartile range and full ranges were calculated for each metric. A metric was considered to reach consensus if the percent of respondents ranking within two consecutive scores was ≥70%. Results and comments from round 1 were re-circulated to stakeholders in personalized reports. This allowed each stakeholder to compare his or her previous scores with overall scores for each metric. Stakeholders were asked to re-rank each metric (round 2).
Results:
The literature search yielded 2 relevant publications from which a provisional list of 27 metrics was generated. Metrics were grouped into 7 categories (Table 1). In round 1, 19/27 (70%) metrics reached consensus. Stakeholders’ comments resulted in 4 new metrics and edits to 8 original metrics. All metrics were included in round 2 for a total of 31. Twenty-four of 31 (77%) metrics reached consensus after round 2 (Table 1). Thirteen were chosen for the final list based on highest consensus scores, highest interquartile and full ranges, and minimizing redundancy.
Conclusion:
This study demonstrates the feasibility of using a modified Delphi process to generate QoC metrics for a pediatric hematology oncology clinic, and provides a model other clinics may employ for local use. The final metrics will be used to evaluate the quality of care in the LL clinic, and to identify areas for improvement in clinic function.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Non-Coding RNAs Transcribed from ERV-9 LTR Retrotransposons Regulate Erythropoiesis
Authors: Hu Tianxiang , Pi Wenhu , Tuan Dorothy 
Published: October 2019

Abstract
Long noncoding RNAs (lncRNAs) regulate diverse cellular processes in development, differentiation and malignancy. In human cells, over 80% of the lncRNAs contain retrotransposon sequences transcribed from Alu, L1 and LTR retrotransposons, which comprise ~40% of the human genome. The functional significance of the retrotransposon lncRNAs is largely unknown. The human genome contains ~4000 copies of the ERV-9 LTR retrotransposon, which exhibits strong enhancer activity and initiates synthesis of ERV-9 lncRNAs in erythroid progenitor cells. Recently, we discovered that depletion of the ERV-9 lncRNAs in human erythroid progenitor cells cultured ex vivo from peripheral blood CD34+ cells inhibited ex vivo erythropoiesis. Whole genome RNA sequencing (RNA-seq) found that depletion of ERV-9 lncRNAs significantly suppressed transcription of 608 genes including ~50 key erythroid genes. We hypothesize that the ERV-9 lncRNAs together with the ERV-9 LTR act in cis to regulate transcription of these key erythroid genes and other genes to set up a transcriptional network that promotes erythropoiesis.
In the human b-globin gene locus, we showed previously that the ERV-9 LTR retrotransposon performs a beneficial biological function: The ERV-9 LTR enhancer binds NF-Y and GATA-1 and -2 to assemble an LTR-pol II transcription complex, which transcribes long, noncoding RNAs (lncRNAs) from the LTR R-U5 regions through the downstream locus control region (LCR) and intergenic DNAs to reach and activate transcription of b-globin gene 70 kb away. In this tracking and transcription (T&T) mechanism of long-range LTR enhancer function, the ERV-9 lncRNAs could be merely by-products of the tracking and transcribing process of the LTR complex without any functional significance. However, we found recently that depletion of the ERV-9 lncRNAs suppressed transcription of the entire human globin gene locus, diminished occupancies of NF-Y, GATA-1 and -2 and pol II at the ERV-9 LTR and reduced the looping frequency of the ERV-9 LTR with the globin gene locus in erythroid progenitor cells. Thus, the ERV-9 lncRNAs acted in cis to facilitate assembly of the LTR-pol II complex and modulate long-range LTR enhancer function in transcriptional activation of b-globin gene. Genome-wide, whether the ERV-9 lncRNAs transcribed from other gene loci perform similar biological function is under investigation.

Disclosures
No relevant conflicts of interest to declare.
Elevated Red Cell Reduced Glutathione Is a Novel Biomarker of Diamond-Blackfan Anemia
Authors: Utsugisawa Taiju , Uchiyama Toshitaka , Ogura Hiromi , Aoki Takako , Hamaguchi Isao , Ishiguro Akira , Ohara Akira , Kojima Seiji , Ohga Shouichi , Ito Etsuro , Kanno Hitoshi 
Published: October 2019

Abstract
Diamond-Blackfan anemia (DBA) is a rare congenital red cell aplasia characterized by congenital anomalies and predisposition to cancer. Recent observation disclosed that heterogeneous mutations in ribosomal protein (RP) genes are present in approximately 50% of patients, suggesting that diagnosis should be made by clinical phenotypes such as age, hematological findings or positive family history. Although elevated activity of red cell adenosine deaminase (eADA) has been utilized as a useful biomarker for differential diagnosis of DBA, approximately 20% of DBA patients are eADA-negative. Recent observations suggested that ribosomal haploinsufficiency increases oxidative stress, leading to p53 gene activation and premature death of erythroid cells. We hypothesized that reduced glutathione (GSH), an essential antioxidant of erythroid cells, might be upregulated in red cells of DBA subjects. In order to test this hypothesis, we examined red cell GSH as well as eADA of 22 patients in 18 DBA families, in whom we had identified gene mutations in RPS19, RPL5, RPL11, RPS10, RPS17 or RPS35a. All except one DBA patients showed elevated GSH (>88.6 mg/dl RBC, M+SD), whereas 17 out of 22 patients exhibited elevated eADA (>2.31 IU/g Hb, M+3SD). We also examined 14 unaffected members of the DBA families, with 1 out of 14 subjects showing elevated GSH and none showing elevated eADA. We performed linear discriminant analysis between DBA and non-DBA subjects with both eADA and GSH using the Support Vector Machine (SVM) from 36 subjects, and successfully obtained a formula to discriminate DBA from unaffected subjects: 0.937*eADA+0.0702*GSH-7.9044 >0. By using this formula, all DBA examined can be diagnosed and unaffected family members can be excluded. Since approximately 50% of clinically diagnosed DBA cases have no causative RP gene mutations, the combined assessment of eADA and GSH might be quite useful for biochemical diagnosis of DBA.

Disclosures
No relevant conflicts of interest to declare.
An Unsuspected Dyserythropoiesis in Gaucher Disease
Authors: Reihani Niloofar , Arlet Jean-Benoît , Billette de Villemeur Thierry , Belmatoug Nadia , Colin Yves , Hermine Olivier , Le Van Kim Caroline , Franco Mélanie 
Published: October 2019

Abstract
Introduction: Gaucher disease (GD) is a lysosomal storage disorder, impairing glucosylceramide catabolism. GlcCer-laden macrophages transform into Gaucher cells and are responsible for the major GD symptoms (tissue infiltration, organomegaly, bone lesion). However, other signs of the disease such as anemia, spleen and bone infarcts might involve red blood cells (RBC). Despite the lysosomal characteristic of GD and the evidence of the central rdole of macrophages, our recent findings pointed out unexpected RBC abnormalities (Franco et al, Blood. 2013;121:546-555). These findings uncovered an overlooked aspect in GD showing that GD RBC exhibit abnormal rheological, morphological and membrane adhesion properties. Thus, RBC could be considered as culprit for ischemic events in GD. In this study, we analyzed the erythroid differentiation in GD to address the etiology of red cell abnormal behavior. We induced in vitro erythropoiesis from circulating GD patient progenitors.
Methods: After purification of CD34+ cells from peripheral blood of Gaucher patients (n=20) or controls (CTL), erythroid progenitors were expanded in the absence of erythropoietin (EPO) and differentiated in a second step with erythropoietin. GD and CTL CD34- cells were differentiated into macrophages by addition of M-CSF in the culture medium. To determine the effect of CTL and GD macrophages on normal erythropoiesis, in vitro generated macrophages were co-cultured with CTL erythroid progenitors in the presence of EPO. Proliferation of progenitors as well as erythroid differentiation were examined by flow cytometry and cytology.
Results: Our preliminary results showed: (i) a dramatic decrease in proliferation of progenitors in the first step of expansion (**p <0.005), (ii) an accelerated erythroid maturation as evaluated by the percentage of cells expressing and non-expressing Glycophorin A and C-Kit, respectively (**p <0.005), (iii) an absence of effect of Gaucher macrophages co-culture on normal erythroid terminal maturation, and (iv) a correlation between the acceleration level of maturation and the degree of anemia in GD patients as determined by hemoglobin level (**p<0.005).
Conclusion: We evidenced an unexpected dyserythropoiesis characterized by accelerated erythroid differentiation in GD. The observed dyserythropoiesis is independent of macrophage defects and is intrinsic to the GD erythroid lineage. These studies by helping to understand the role of erythroid cells in the pathophysiology of GD as well as the mechanism of anemia should prove useful for the development of additive therapies to alleviate debilitating clinical complications of this morbid disease such as osteonecrosis and splenomegaly.

Disclosures
Le Van Kim: SHIRE: Research Funding.