bluuebunny/crossref_metadata_2025_split huggingface dataset:
Determinants of Persisting Thrombocytopenia In Patients with Type 1 Gaucher Disease Treated with Alglucerase/Imiglucerase for 4–5 Years
Authors: Cappellini Maria D. , Belmatoug Nadia , Cole Alex , Dahl Stephan vom , Deegan Patrick , Goldblatt Jack , Rosenbloom Barry E. , Tylki-Szymañska Anna , Weinreb Neal J. , Zimran Ari , Hollak Carla 
Published: October 2019

Abstract
Abstract 4719

Introduction:
Thrombocytopenia in type 1 Gaucher disease (GD) may result in surgical, obstetrical and spontaneous bleeding. Treatment with alglucerase/imiglucerase generally results in rapid improvement in platelet count but, in rare cases, the platelet response to therapy is slow or lacking. The factors underlying persisting thrombocytopenia despite treatment are poorly understood.

Aim:
To identify patient characteristics associated with (and potentially predictive of) persisting thrombocytopenia despite therapy by retrospective analysis of ICGG Gaucher Registry data.

Methods:
1,016 type 1 GD patients with an intact spleen, date of diagnosis and therapy initiation, no treatment breaks 4–5 years after therapy initiation, and known platelet counts, were classified into four groups by last platelet count 4–5 years after therapy initiation: >120 × 109/l (n = 772); >100 to <120 × 109/l (n = 94); >80 to <100 × 109/l (n = 80); and <80 × 109/l (n = 70, of which 20 had <60 × 109/platelets/l). Patients were characterized by demographics, BMI; platelet count; anemia; biomarkers; hepatomegaly; splenomegaly; and skeletal assessments at baseline (therapy initiation) and after 4–5 years of therapy. Initial enzyme dose and cumulative average dose were noted. Possible associations with persisting thrombocytopenia were tested using a multivariate analysis calculating odds ratios adjusted for age at diagnosis and therapy initiation, genotype, sex, year of diagnosis, and year of therapy initiation.

Results:
Of the 1,016 patients in this study, 20 (2%) had platelet counts <60 × 109/platelets/l after 4–5 years of therapy. These patients all had severe splenomegaly at baseline. Associations between persisting thrombocytopenia were found between baseline low platelet count (<80 × 109/l), splenomegaly and anemia (p <0.0001). After 4–5 years, persisting thrombocytopenia was associated with anemia (p <0.0001), reduced WBC (p = 0.049), splenomegaly (p <0.0001), hepatomegaly (p = 0.006), bone pain (p = 0.035) and cumulative enzyme dose (dose range 18.6–55.5 U/kg/2weeks; doses <25th percentile: p = 0.043). Too few data prevented reliable analysis of other bone parameters and biomarkers.

Discussion and conclusion:
Persisting thrombocytopenia despite therapy is rare (2% of patients with platelets <60 × 109/l). The strong association between splenomegaly, anemia and thrombocytopenia at therapy initiation and persisting thrombocytopenia after 4–5 years of treatment suggests that in a minority of cases extensive spleen involvement, possibly with fibrosis, may be predictive of thrombocytopenia that is refractory to treatment. Findings underline the importance of initiating treatment before irreversible complications have developed.

Disclosures:
Cole: Genzyme Corp: Employment.
Value of Survival Gains In Chronic Myelogenous Leukemia
Authors: Yin Wesley , Penrod John R , Maclean Ross , Humphrey Jeffrey , Bahceci Erkut , Lakdawalla Darius 
Published: October 2019

Abstract
Abstract 4736

Background:
Tyrosine Kinase Inhibitors (TKI) are the first line therapies for patients with chronic myelogenous leukemia (CML). The value of survival gains to patients associated with TKI treatment—in aggregate or relative to the cost of treatment—is unknown.

Methods:
Multivariate Cox proportional hazard models are used to construct real-world, community-based estimates of survival improvements in CML associated with the introduction of first-line TKI therapy, controlling for characteristics of patients which may independently affect survival. We then employ an economic framework following Becker, Philipson and Soares (2005) to calculate social value of infra-marginal improvements in survival gains due to treatment with TKIs. Finally, the value of community-based improvements in CML survival from treatment by newer TKIs used in second line is estimated by combining community-based survival data for first-line TKIs, along with clinical data on health improvements for CML patients receiving a TKI in second line.

Results:
Introduction of first-line TKIs in 2001 is associated with a real-world decrease in the all-cause mortality hazard rate of 0.183 (p < 0.01) for CML patients. A decrease of this magnitude is associated with an increase in life expectancy from 60 to 110 months for treated CML patients with median survival length in 2001. We estimate that patients place an annual value of $110,000 on first-line treatment with TKIs. This implies that for all patients in present and future CML cohorts, the present social value of first-line TKI therapy is $88bn. The present value of costs is estimated to be $8bn, suggesting that more than 90% of social value of TKIs in first line therapy is retained by patients. In second-line CML therapy, use of newer TKI agents is estimated to have created $47bn in social value, of which roughly 88% is retained by patients. This estimated value of the newer TKIs does not incorporate possible benefits in first-line therapy.

Conclusions:
In total, the TKI class in first and second-line theray has created over $135bn in social value. Approximately 90% of this value is retained by patients; approximately 10% is recouped by manufacturers. These estimates suggest that at current price levels, the vast majority of value created by new therapies in CML is appropriated by patients. In addition, since our estimates of survival community-based improvements are somewhat smaller than those contained in clinical trial estimates, this suggests the potential value of addressing real-world obstacles to efficacy, such as poor adherence.

Disclosures:
Yin: Precision Health Economics: Consultancy. Penrod:Bristol-Myers Squibb: Employment. Maclean:Bristol-Myers Squibb: Employment. Humphrey:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Lakdawalla:Bristol-Myers Squibb: Consultancy; Precision Health Economics: Equity Ownership.
Adolescent and Young Adult (AYA) Cancer Survivorship Curriculum In a University Setting
Authors: Wood William , Wright Sarah , Stephens Anne , Santacroce Sheila , Blatt Julie , Shea Thomas C. 
Published: October 2019

Abstract
Abstract 4749

Background:
That pediatric, adolescent and young adult cancers have become compatible with long term survivorship in the majority of cases has meant a growing emphasis on an understanding of the late effects of treatment. Among the barriers to successful health self-management in the context of transition of care from pediatricians to internists is the challenge of finding adult health care providers in the community who are comfortable caring for patients in this age group. We have developed a curriculum relating to different aspects of AYA survivorship for oncology and primary health care trainees who may come across AYA cancer survivors in the course of usual practice. Focus groups were used to refine the modules before the current application.

Aim:
To improve provider knowledge of AYA survivorship issues and management in a university setting.

Methods:
Using a combination of review articles, original research, and published guidelines for cancer survivorship, 8 teaching modules (power point presentations of 8–15 slides each) were developed: health care self-management; bone health; cardiac late effects; fertility late effects; neurocognitive late effects; psychosocial late effects; pulmonary late effects; and second malignancies. Modules were refined with the use of provider focus groups. These recently have been made available to trainees at UNC: (pediatrics [P], medicine-pediatrics [MP], medicine [M], medical hematology oncology [MHO], pediatric hematology oncology [PHO], and nurse practitioner students [NP]) in hard copy and on departmental websites. Computerized pre- and post-tests were developed for each module to assess content acquisition and will be required of the ~6 trainees/month rotating through the Survivors Clinics or on inpatient or outpatient services. At the end of each module, participants also are being asked, using a 3 point scale (agree [3], neutral [2], disagree [1]) if they feel the sessions gave them increased confidence in following AYA survivors. Participants also will be given the opportunity to critique the modules.

Results:
Preliminary results will not be available until December. However, enthusiasm among the target audience during the first 2 months of this program has been strong.

Conclusion:
Short teaching modules can be developed to engage trainees in AYA late effects issues. Ongoing work is being done to assess the effectiveness and usefulness of the modules for providers at UNC who care for adolescent and young adult cancer survivors. We anticipate that this approach will be expanded to our outreach practices. Parallel modules are in development for AYA survivors and their families. *With support from a 2009 ASH Alternative Training Pathway Grant, T. Shea, PI.

Disclosures:
No relevant conflicts of interest to declare.
Hepatitis B Surface Antigen Seropositivity and Low Body Weight Are Correlated with Asymptomatic Neutropenia In the Thai Population
Authors: Lawasut Panisinee , Nakorn Thanyaphong Na , Rojnuckarin Ponlapat , Intragumtornchai Tanin 
Published: October 2019

Abstract
Abstract 4751

Background
The etiology of asymptomatic neutropenia is unknown. We have conducted a community-based study to determine predisposing factors for asymptomatic neutropenia in the Thai population.

Method
Blood specimens and self-report questionnaires (filled out with assistance from medical personnel) were collected from individuals in Bangkok and 4 surrounding provinces. Asymptomatic neutropenia was defined by an absolute neutrophil count of less than 1.5 × 109/liter, in the absence of any symptoms or known risk factors. Patients with a history of malignancy were excluded. Subjects that met this criterion for neutropenia were examined for the presence of anti-HIV and anti-hepatitis C virus (HCV) antibodies, hepatitis B surface antigen (HBsAg), antinuclear antibody (ANA), rheumatoid factor (RF), thyroid dysfunction, reduced serum ferritin, and reduced serum vitamin B12 and folate; this panel of laboratory tests was also done on control subjects (4 controls for every 1 neutropenic case – see below), which were picked at random from the normal population and were matched for age, sex, site of survey, and underlying disease. Odd ratios (OR) were then computed for significant risk factors.

Results
Overall, 7,180 individuals were included; 28 had neutropenia (0.39%, 95% CI 0.25–0.53). Based on answers to the questionnaire, the only factor correlating with neutropenia was low body weight (body mass index < 18.5 kg/m2, p = 0.015); age, sex, site and period of survey, underlying disease, medications, herbal ingestion, food supplement, radiation exposure, family history of hematologic disease, alcohol consumption, history of drug abuse or exposure to chemical substance had no significant association with neutropenia. Additional tests on 25 of the neutropenic cases revealed positive findings for HBsAg (20%), anti-HCV antibody (12%), ANA (16%), RF (4%), hypothyroidism (4%), hyperthyroidism (14%) and hypoferritinemia (24%); none showed anti-HIV positivity, or low levels of serum vitamin B12 and folate. Of the 100 normal controls, 4% showed seropositive for HBsAg. HBsAg positivity was thus the significant risk factor associated with neutropenia (OR 6.0, 95%CI 1.48–24.34, p = 0.012).

Conclusion
HBsAg seropositivity is strongly associated with asymptomatic neutropenia in the Thai population. Low body weight is also correlated with the disorder, perhaps as a result of subtle nutritional deficiencies. Possible mechanisms that underlie neutropenia are currently being explored.

Disclosures:
No relevant conflicts of interest to declare.
Assessing the Experience of Living with Chronic Myeloid Leukemia (CML) From the Patient's Perspective: Results of a Patient Survey
Authors: Victor Timothy W , Hirji Ishan , Hicks Ian , Chapnick Jonathan , Davis Catherine , Bahceci Erkut 
Published: October 2019

Abstract
Abstract 4755

Background:
While clinical outcomes among CML patients have shown great improvement with the development of TKIs, few studies have been conducted to assess the impact of CML and CML treatment from the perspective of CML patients. Information on CML treatment adherence and impact on quality of life (QoL) has been captured in the context of clinical trials with QoL being measured using generic measures. Very little is known about patient experience of CML and CML treatment in the real-world setting.

Objective:
To assess the impact of CML and CML treatment on daily productivity, quality of life and treatment adherence, from the patientâ|CE™s perspective.

Method:
In a pilot survey, twenty patients diagnosed with CML described their experiences in single 45 minute interviews conducted via telephone. Eligible patients included adults (>18 years) diagnosed with chronic phase CML and either currently on oral treatment for their CML or on drug holiday. Questions included in the pilot survey addressed overall treatment satisfaction, ease/burden of daily treatments and impact of treatment on daily activities. A preliminary analysis of 16 patients included in the pilot study was conducted.

Results:
Mean patient age was 52.9 years (SD = 12.6), 56.3% were male, averaged 3.1 years since diagnosis (SD = 3.1). Patientsâ|CE™ satisfaction with their oral CML treatment was high (mean 9.3 on a scale of 1 – 10, where 1 = not at all satisfied and 10 = very satisfied, SD = 1.3) among the 14 patients who provided a score. Perception of having a favorable response to treatment was also high (14/16). While patients reported good adherence to their treatment regimens, 9/16 patients mentioned missing doses of their CML treatment. Constitutional symptoms of treatment were reported as a daily occurrence by 50% of patients (8/16).

Conclusion:
In this pilot survey of the CML patientâ|CE™s perspective, high patient satisfaction with oral CML treatments was primarily attributable to a high overall response to treatment. Willingness to adapt to certain aspects of CML treatment was high given that treatment was perceived as being life-saving. Understanding factors which could minimize the impact on daily activities is important as new treatment options become available. Results from this pilot survey will inform the content of a self-administered questionnaire to include an expanded cohort of CML patients (n=300) within the US and Europe.

Disclosures:
Victor: Bristol-Myers Squibb Company: Research Funding. Hirji:Bristol Myers-Squibb: Employment. Hicks:Bristol-Myers Squibb Company: Research Funding. Chapnick:Bristol-Myers Squibb Company: Research Funding. Davis:Bristol Myers-Squibb: Employment.
Metformin Selectively Suppressed the Proliferation of AML Stem Cells through Increased Phosphorylation of AMP-Activated Protein Kinase
Authors: Shin Myung-Geun , Eom Ha-Young , Kim Hye-Ran , Shin Jong-Hee , Suh Soon-Pal , Ryang Dong-Wook 
Published: October 2019

Abstract
Abstract 4771

Background:
Leukemic stem cell (LSC) has been accused to play a pivotal role in pathogenesis of hematological malignancy such as acute myeloblastic leukemia (AML). AML stem cell (ASC) is known as CD34+CD38– leukemic cell population. Yet, despite their critical importance, much remains to be learned about selectively targeting ASC. Recently metformin selectively targets breast cancer stem cells, and acts together with chemotherapy to block tumor growth. Thus, the current study investigated whether metformin selectively inhibits AML cells and AML stem cells directly or indirectly.

Materials and Methods:
ASC showing CD34+CD38– phenotype were selectively sorted from primary bulk AML cells and KG-1 AML cell lines using single cell sorter (BD FACS Aria cell sorter, BD Biosciences, USA). ASC from primary AML samples and cell lines were cultured in serum media with each 100 ng/mL of stem cell factor, Flt-3, thrombopoietin and G-CSF. Metformin (1,1-dimethylbiguanide hydrochloride) and idarubicin (IDA) were dissolved and diluted with high purity distilled water in various concentrations (0.1 mmol/L to 30 mmol/L). Morphological change, cell count, viability and apoptosis using annexin V flowcytometry were checked after treatment of metformin and IDA. Phosphorylation of AMPK was assayed by western blotting and mitochondrial membrane potential was measured using MitoTracker green dye.

Results:
The frequency and proportion of ASC varied according to FAB subtypes. The mean proportion of ASC from AML M2, M4 and M3 showed 25.1±22.5% (mean±SD), 15.1±16.6% and 6.5±3.3%, respectively. The mean proportion of ASC from KG-1 cell lines was 78.6±6.2%. Total cell count of ASC was gradually decreased after treatment of metformin in dose-time dependent manner. Overall viability of AML cell lines and ASC disclosed significant decrease after treatment of metformin. The proportion of apoptosis was increased in time and dose dependent manner after 24-hr treatment of metformin. Mitochondrial membrane potentials were increased after metformin exposure at dose dependent manner. Moreover, when combined with lower concentration of IDA, more profound selective killing effect on AML cell lines and ASC was observed. Western blot analysis showed that the treatment of AML cell lines and ASC with 30 mmol/L of metformin resulting in the increased phosphorylation of AMP-activated protein kinase (AMPK) at approximately 1.5-fold over total AMPK.

Conclusion:
Metformin selectively kills AML cells as well as AML stem cells, and acts together with chemotherapeutic drugs to eradicate leukemic cells and their stem cells.

Disclosures:
No relevant conflicts of interest to declare.
Microarray Analysis of CD34+CXCR4+ and CD34+CXCR4- Cells Reveals Two Distinct Hematopoietic Stem/Progenitor Populations
Authors: Donahue Robert E , Jin Ping , Tian Yu , Allen Robyn S , Bonifacino Aylin , Stroncek David 
Published: October 2019

Abstract
Abstract 4798
Although CD34+ cells represent a small population of phenotypically defined cells within the bone marrow and peripheral blood circulation, they remain a very heterogeneous population of cells which contain hematopoietic stem/progenitor cells. CXC Chemokine Receptor 4 (CXCR4) is an α-chemokine receptor specific for stromal-derived-factor-1 (SDF-1 also called CXCL12) and is found on CD34+ cells. Plerixafor (also known as Mozobil® or AMD3100) is currently used as a mobilizing agent for CD34+ cells by interfering with the binding of CXCR4 to SDF-1. To explore differences between CD34+CXCR4+ and CD34+CXCR4- populations, gene and microRNA signatures were determined using microarray analysis. Three healthy human donors were cytokine mobilized with G-CSF, peripheral blood mononuclear cells were collected by apheresis, and CD34+ cells were immunoselected using the Miltenyi CliniMACS® system and cryopreserved. These cells were then thawed and allowed to sit overnight at 37°C in X-Vivo-10. The following day the cells were stained and sorted on a BD FACSAria III® cell sorter. All three individuals CD34+CXCR4+ and CD34+CXCR4- fell within two rather restrictive populations based on forward and side scatter gating with CD34+CXCR4+ cells routinely being smaller in size than the CD34+CXCR4- populations (Figure 1). Total RNA was isolated from the sorted cells and amplified to cRNA. Control cRNA was labeled with Cy3 dye and experimental cRNA was labeled with Cy5 dye and co-hybridized to a custom-made 17.5K cDNA (UniGene cluster) microarray. Using unsupervised and supervised Eisen's hierarchical clustering and Array Class Comparison analysis relationships were determined. Hierarchical cluster analysis demonstrated that the CD34+CXCR4+ and CD34+CXCR4- had different gene expression patterns (Figure 2). Ingenuity Pathway Analysis revealed that genes up-regulated in the CD34+CXCR4+ population were related to TREM-1 signaling (innate immunity), dendritic cell maturation, NFAT-regulation of the immune response, and T-cell receptor and NK cell signaling. In contrast, the CD34+CXCR4- population expressed more primitive genes such as those related to IGF-1, ERK/MAPK, IL-3, and Nitric Oxide signaling as well as transcription factors such as N-myc and HOX-A9. MicroRNA profiling of the CD34+CXCR4- population also express the miR-17-92 polycistron cluster (miR17, 18a, 19a, 19b, 20a, 92) (Figure 3). These results are consistent with the CD34+CXCR4- population being more primitive than the CD34+CXCR4+ population. It is interesting to speculate whether the CD34+CXCR4+ population includes a progenitor for T cell and innate immune responses while progenitors for hematopoietic stem cells and adaptive immune responses are within the CD34+CXCR4- populations.

Disclosures:
No relevant conflicts of interest to declare.
Analysis of Calcium Profile and Bone Mineral Density in Patients with Sickle Cell Disease
Authors: Gonçalves Lucila Macedo , Cancado Rodolfo , Petry Tarissa Beatrice Zanata , Melo Murilo Rezende , Salles João Eduardo , Scalissi Nilza Maria , Chiattone Carlos 
Published: October 2019

Abstract
Abstract 4810

Introduction:
Sickle Cell Disease (SCD) is a genetic disorder where the red blood cells assume an abnormal, rigid, sickle shape, causing tissue hypoxia with subsequent increase of osteoclastic activity, originating osteopenia and osteoporosis. The prevalence of the osteoporosis in the SCD can vary from 25 a 50%, affecting more commonly the children. There are few data regarding the prevalence of bone mineral low density in adults. Our objective was to analyse the calcium profile and bone mineral density (BMD) of pacients with SCD and describe the prevalence of osteopenia in this group.

Material and Methods:
We have studied 49 patients with SCD analysing the serum and 24 hours urinary calcium, serum ferritin, LDH, parathyroid hormone (PTH) and BMD in the lombar vertebrae and proximal femoral.

Results:
From the 49 patients, 21(42.9%) were males and 28(57.1%) females, mean age of 27 years old (16-51 yr), 55.1% (27) of the patients presented osteopenia and 26.5% (13) osteoporosis, considering lombar vertebrae BMD. Only 18.4% (9) had normal BMD. Mean ± DP PTH was 85.3 ± 79.32 and mean ± DP serum calcium of 8.9 ± 0.44. Mean ± DP LDH was 970.8 ± 492.36 and we have observed significant correlation between this variable and low BMD (p<0.02).

Conclusion:
The prevalence of osteopenia and osteoporosis was extremely high (81.6%) in the studied patitents. The secondary hyperparatireoidism was present in many patients and we did not find hypoparathyroidism. The hemolysis appears as a factor that contributes for the low BMD.

Disclosures:
No relevant conflicts of interest to declare.