bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiometabolic Risks Among Survivors of Childhood Hematologic Malignancies.
Authors: Mulrooney Daniel A. , Kelly Aaron , Baker K. Scott , Steffen Lyn , Lunsford-Lee Jill , Petryk Anna , Sinaiko Alan R. , Dengel Donald R. , Perkins Joanna , Messinger Yoav H. , Zhou Xia , Steinberger Julia
Published: October 2019

Abstract 4113

Survival rates for childhood hematologic malignancies continue to improve. Research suggests these individuals are at increased risk for late adverse cardiovascular outcomes. This analysis includes children (n=101) who survived ≥ 5-yrs following diagnosis of acute lymphoblastic leukemia (ALL) (n=78), acute myeloid leukemia (AML) (n=5), and non-Hodgkin lymphoma (NHL) (n=18), compared to their frequency matched healthy siblings (n=123). Anthropometric measurements, blood pressure (BP), fasting glucose, insulin, and lipids were collected; insulin resistance was assessed by euglycemic hyperinsulinemic clamp, adjusted for lean body mass (low Mlbm represents insulin resistance); carotid artery stiffness (distensibility and compliance – low levels represent increased stiffness), adjusted for lumen diameter, was assessed by ultrasound. Least squares means and standard errors, adjusted for age, gender, pubertal development, and body mass index (BMI) were compared. Survivors (63.4% male) mean age at diagnosis was 10.3 yrs (5.7-15.8) and 15.0 yrs (9.9-17.9) at evaluation; siblings (56.1% male) were 13.6 yrs (9.0-18.0) at evaluation. Among survivors, 88 (87.1%) received chemotherapy only and 13 (12.9%) chemotherapy and cranial radiation. Metabolic syndrome (MS) (modified criteria for children) was present in 8 (7.9%) survivors vs. 6 (4.9%) siblings (p=0.35). Nevertheless, 25 (24.8 %) survivors had two or more MS components compared to 17 (13.8 %) siblings (p=0.04). There were no differences between cases and siblings on measures of adiposity (BMI, waist circumference, % body fat, visceral fat), BP, fasting glucose, insulin, and lipids. However, survivors were significantly more insulin resistant and had stiffer carotid arteries compared to controls (Table). Despite similar levels of adiposity, survivors of childhood hematologic malignancies demonstrate signs of insulin resistance and increased vascular stiffness at a young age compared to healthy controls. These findings highlight: 1) the heightened cardiovascular risk profile among children who survived hematologic malignancies and 2) that the typical components of the MS may not be sufficiently sensitive measures of risk in this young population.

Survivors (n = 101) Siblings (n = 123) (p) LS means (SE) LS means (SE) Body mass index (BMI) (kg/m2) 21.3 (0.5) 21.2 (0.5) 0.8 Visceral fat (cm3) 22.8 (1.0) 22.3 (1.0) 0.7 Insulin resistance [Mlbm (mg/kg/min)] 12.6 (0.5) 14.2 (0.5) 0.007 Carotid artery distensibility (%) 13.5 (0.4) 14.9 (0.4) 0.004 Carotid artery compliance (mm2/mmHg) 0.16 (0.004) 0.17 (0.004) 0.008

Disclosures:

No relevant conflicts of interest to declare.
Clinical Manifestation of 1000 Leukemias.
Authors: Racil Zdenek , Mayer Jiri , Brejcha Martin , Cetkovsky Petr , Prochazkova Jirina , Zounar Rene
Published: October 2019

Abstract 4134

Background

New available diagnostic methods could specify the diagnosis of leukemias and new drugs can improve survival of pts. with malignancy. However till today clinical manifestation continues to be the key point in diagnostic procedure of these diseases and time from the first symptoms to define diagnosis and to start of anticancer treatment is often critical for pt's. prognosis.

Methods

Documentation of 1007 consecutive pts. referred to 3 hematological centers in Czech Republic with diagnosis of the 6 most frequent leukemias between 2004-3/2009 was analyzed. Special consideration was addressed to clinical and laboratory findings and pt's. complaints before defining the diagnosis in hematological center.

Results

In 1007 pts. – 439 (44%) females/ 568 (56%) males – diagnosis of leukemia was established [ALL – 106 (11%), AML - 369 (37%), APL - 74 (7%), HCL - 41 (4%), CML - 123 (12%), CLL - 294 (29%)]. Median age at time of diagnosis was 60 years (ALL - 47, AML - 62, APL - 46.5, HCL - 59, CML - 55, CLL – 66).

Leukemia was diagnosed in 599 (59%) after first symptoms occurred and pt. visited doctor and in 408 (41%) cases accidentally. However, this accidental diagnosis occurred only in 24% pts. with acute leukemia (ALL, AML, APL) and vice-versa in 60% of pts. with chronic leukemias.

The frequency of first symptoms described by pts. shows Table 1.

The first doctor visited by patient and describing abnormality was general practitioner in 48.5%, internist in 21.8%, hematologist in 7.8% and other in 22.4%.

Median time from the first symptoms to define diagnoses was 17 days (ALL – 24, AML – 20, APL – 14, CLL – 16, CML 14, HCL – 31); median time from the first medical examination to define diagnosis was 8 days (ALL – 9, AML – 7, APL – 6, CLL – 12, CML - 6, HCL – 20) and finally the median time from the first examination by hematologist to referring pt. to hematological center was 3 days (ALL – 1, AML – 2, APL – 1, CLL – 32, CML - 8, HCL – 18).

Decision procedure of the first visited doctor was stated as inadequate in 5.5% of pts. – especially in pts with AML (9.4%). Late diagnosis influenced character of treatment and pt's prognosis in 1.5% and 1.6% of pts. respectively – mostly in pts. with acute leukemias (2.9% and 2.8%).

Conclusion

Our analysis showed that the time from the first symptoms until define diagnosis is surprisingly long although pts. with acute leukemia are very often symptomatic at the time of diagnosis. Moreover in these patients with acute leukemias (especially with AML) the diagnostic process was most frequently found as a less adequate and this could influenced the pt's prognosis.

Disclosures:

No relevant conflicts of interest to declare.
Effect of Thalidomide and Arsenic Trioxide On the Release of Tumor Necrosis Factor – α (TNF-α) and Vascular Endothelial Growth Factor (VEGF) From the KG-1a Human Acute Myelogenous Leukemia Cell Line.
Authors: Girgis Erian , Mahoney John , Khalil Rafaat , Soliman Magdi
Published: October 2019

Abstract 4165

Although the exact mechanism of action of thalidomide is still unknown, it has been suggested that it may affect TNF-α in addition to its possible anti-angiogenic and immunomodulatory properties. Studies conducted in our lab have indicated that thalidomide cytotoxicity in KG-1a human acute myelogenous leukemia cell line was enhanced by combining it with arsenic trioxide. So, the current investigation was conducted in order to evaluate the effect of thalidomide either alone or in combination with arsenic trioxide on the release of TNF-α and VEGF from this cell line in an attempt to clarify its possible cytotoxic mechanism. Human acute myelogenous leukemia cell line KG-1a (obtained from American Type Culture Collection, ATCC) grown in complete medium containing Iscove's modified Dulbecco's medium and fetal bovine albumin were used in this study. The cells were cultured for 48 hours in a 12 well-culture plates in duplicates at a concentration of 2×106 cells/ml in the presence or absence of thalidomide (5 mg/L) [Tocris bioscience, Ellisville, Mo] and or arsenic trioxide (4 μM) [Sigma-Aldrich, Inc., St. Louis, MO]. Cells were harvested by centrifugation and the levels of TNF-α and VEGF in the supernatant were determined by ELISA using the Quantikine TNF-α and VEGF kits respectively (R&D Systems, Minneapolis, MN). Results obtained indicate that the levels of TNF-α in the supernatant of KG-1a cell cultures incubated with both thalidomide and arsenic trioxide, whether alone or in combination were statistically lower than those observed in the supernatant of control cells (2.89 pg/ml in thalidomide treated cells supernatant, 5.07 pg/ml in arsenic trioxide treated cells supernatant and 4.15 pg/ml in case of the combined treatment with thalidomide and arsenic trioxide versus 16.88 pg/ml in the supernatant of control cells, p<0.05). However, the levels of VEGF in the supernatant of thalidomide treated cells were statistically higher than those in the supernatant of control cells (69.61 pg/ml versus 11.48 pg/ml, p< 0.001). Of note, that arsenic trioxide whether alone or in combination with thalidomide did not produce any statistically significant difference in the levels of VEGF as compared to control or thalidomide treated cell supernatant. These findings clearly indicate that both thalidomide and arsenic trioxide inhibition of TNF-α production by KG-1a cells may play an important role in their cytotoxic effect. However the increase in VEGF levels in the supernatants of thalidomide treated KG-1a cells may reflect a compensatory mechanism of cells which have survived thalidomide cytotoxicity (Supported by NIH grant RR03020).

Disclosures:

No relevant conflicts of interest to declare.
Prolonged Administration of Defibrotide Is Non-Immunogenic in Rats and Dogs.
Authors: Fareed Jawed , Hoppensteadt Debra , Cunanan Josephine , Jeske Walter , Adiguzal Cafer , Zhu He , Echart Cinara , Iacobelli Massimo
Published: October 2019

Abstract 4180

Introduction

Polyelectrolytes such as heparins and sulfated glycosaminoglycans are capable of interacting with endogenous proteins resulting in the generation of neoepitopes leading to the formation of antibodies such as the anti-heparin platelet factor 4 antibodies. Defibrotide represents a polyanionic, DNA derived antithrombotic/antiischemic drug which is currently used in the management of various blood and vascular disorders. Although defibrotide does not have the same protein binding profile as heparins, it mediates various cellular and plasmatic responses to produce its pharmacologic effects. The purpose of this study is to determine if the long term administration of defibrotide results in the generation of any antigenic responses in rats and dogs.

Methods

Individual groups of rats (n=24) and dogs (n=30) were administered intravenously with varying dosages of Defibrotide (0-4800 mg/kg/day in rats and 0-1600 mg/kg/day in dogs) for a 3 month period of time. At the end blood samples were drawn from each group and the collected sera were tested for the presence of anti-defibrotide, antiphospholipid and anti-heparin PF4 (HIT antibodies) using modified ELISA methods which utilized specific secondary antibodies (IgG-rat/dog conjugated to alkaline phosphatase) for the rat and dog plasmas. Blood samples collected from normal rats and dogs constituted the control group (n=30-40).

Results

Neither the rats nor the dogs treated with Defibrotide exhibited any generation of anti-defibrotide, HIT and antiphospholipid antibodies in all groups of animals tested. There was no significant difference (p>0.05) between the control and defibrotide treated animals. The average circulating levels of defibrotide were dose dependent.

Conclusion

Prolonged administration of defibrotide to rats and dogs did not result in the production of antibodies to the drug product. Moreover, there was no evidence for the generation of HIT and antiphospholipid antibodies in these studies. Therefore, unlike heparins, defibrotide administration to animals does not lead to the generation of antibodies.

Disclosures:

Echart: Gentium: Employment. Iacobelli:Gentium: Employment.
Systematic Evaluation of Coagulation Factors as Targets for Anti-Thrombotic Therapy Using Antisense Technology.
Authors: Crosby Jeff , Gao Dacao , Zhao Chenguang , Bhattacharjee Gourab , May Chris , Zhang Hong , MacLeod Robert , Monia Brett P.
Published: October 2019

Abstract 4181

Human clinical efficacy has been demonstrated with antisense oligonucleotides (ASOs) in several disease indications, including dyslipidemia, cancer, diabetes and multiple sclerosis. Second generation ASOs show potent pharmacology in many tissues, with liver being one of the most sensitive to ASO action. As the liver is responsible for production of many of the factors involved in blood coagulation we systematically designed and evaluated ASOs selective for several members of the coagulation cascade. ASOs targeting coagulation cascade members of both the intrinsic and extrinsic pathway produced highly specific target knockdown in liver. An overall aim of this study was to evaluate the contribution of the various factors to the coagulation process as well as to assess their relative risk/benefit relationships. The “risk” component was determined by bleeding tendency as measured by blood volume loss following tail nick, and the “benefit” component was determined by antithrombotic effect following ferric chloride induced thrombosis in the inferior vena cava. We have previously reported the activity of FVII and FXI ASOs in a ferric chloride mouse model without increased bleeding risk. Here we identify additional promising new antithrombotic targets. FII and FIX ASOs were able to reduce thrombosis, but inhibition of these targets had deleterious effects on the bleeding tendency. The ASO effects on PT and aPTT will be presented. The approach used in this study will be used to further characterize targets for antithrombotic potential and determine their ability to be combined with antiplatelet therapies. In addition to the characterization of antithrombotic targets, these ASOs will be evaluated and developed as potent, selective and potentially safer human antithrombotic therapeutics.

Disclosures:

Crosby: Isis Pharmaceuticals, Inc.: Employment. Gao:Isis Pharmaceuticals, Inc.: Employment. Zhao:Isis Pharmaceuticals, Inc.: Employment. Bhattacharjee:Isis Pharmaceuticals, Inc.: Employment. May:Isis Pharmaceuticals, Inc.: Employment. Zhang:Isis Pharmaceuticals, Inc.: Consultancy. MacLeod:Isis Pharmaceuticals: Employment. Monia:Isis Pharmaceuticals, Inc.: Employment.
Autologous Blood Donation for Apheresis of Peripheral Blood Hematopoietic Stem Cell in Low-Body Weight Children with Type 1 Diabetes.
Authors: LI CP , Zhou Rong-Fu , Zhou M. , Shao XY , Zhang QiGuo , Ouyang Jian
Published: October 2019

Abstract 4194

Backgroud

Autologous peripheral blood stem cells transplantation is widely used in treatment of malignant blood diseases, solid tumors and autoimmune diseases recently. Before apheresis, we filled the pipelines of Baxter CS-3000PLUS blood cell separator with the autologous blood instead of irradiated allogenetic blood.

Objective

The study is aimed to explore the safety and clinic efficacy of autologous blood donation for apheresis of stem cell in low body weight pediatric patients with type 1 diabetes.

Method:

There were three pediatric patients with type 1 diabetes in our hospital between August 2007 and December 2007. These patients included 2 male and 1 female with age of 5, 9, 9 respectively. Their weight was 15,18 and 23.5 kilograms respectively. Their blood test indexes were HB>120g/L,HCT>34%. On the 14th day before apheresis, 100ml autologous blood was collected and preserved in 4°C. Mobilization program was CTX 2g/m2 for 2 days and G-CSF 5∼10 μg/kg/d on the 5th day of before apheresis. Apheresis was initiated when WBC>5.0×109/L. SVSCH and SVCC were installed to blood cell separator at first. Before apheresis, we filled the pipelines of blood cell separator with the autologous blood instead of irradiated allogenetic blood.

Result

On the 9th day after the autologous blood donation, RBC ? AHB and HCT went back to the original level. In the process of apheresis.,every vital sign including blood pressure and heart rate was normal during apheresis. Hypotension or hyperthermia did not appear. The amount of CD34+ cell reached to 1.28-3.05×106/kg.

Conclusion

It is concluded that autologous blood donation is a safe and an effective method to avoid allogenetic blood transfusion for apheresis of stem cell in low body weight pediatric patients.

Disclosures:

No relevant conflicts of interest to declare.
Congenital Factor XIII Deficiency as Cause for Intracraneal Hemorrhage.
Authors: Dasi Maria Angeles , Argiles Bienvenida , Cid Ana R , Carreras M. Carmen , Aznar J. Antonio , Santos Maria Teresa , Valles Juana , Peinador Magdalena
Published: October 2019

Abstract 4208

Severe congenital factor XIII (FXIII) deficiency is an autosomal recessive disease of with a low prevalence in the general population (3-5 cases per million), associated with generally severe hemorrhagic diathesis, where the presence of intracraneal hemorrhage (ICH) is much higher than in other coagulopathologies such as hemophilia A or B. However, the basic coagulation tests are normal, which could delay the diagnosis.

We present three cases of severe congenital FXIII deficiency (not diagnosed when referred to our center) with severe hemorrhagic pathology. These patients had normal basic coagulation tests and did not have a family bleeding history. The table show the results.

Table Patient 1 Patient 2 Patient 3 Date of birth 1959 1978 2006 Sex Female Female Female Age at diagnosis 15 years old 12 years old 18 months old Cause of patient remission Ankle hemarthrosis Seizures Subdural hematoma Subdural hematoma Prior hemorrhagic history -umbilical cord bleeding-frontal hematoma requiring surgical management at 12 months-bleeding with dentition -umbilical cord bleeding-hematoma in buttock requiring RBC transfusion for anemia.-hemarthrosis in both knees -umbilical cord bleeding-growing cephalohematoma until 3rd week of life-hematoma by venipuncture lasting 2-3 weeks at 6 months.-delayed healing-Subdural hematoma after minor trauma 3 days prior. basic coagulation tests (PT, APTT, TT, fibrinogen) Normal Normal Normal Level of functional FXIII <1% < 5 % < 5 % Initial treatment Plasma Plasma FXIII concentrate Prophylaxis -Plasma: 2 Units every 6 weeks -FXIII concentrate every 4 weeks (since 1994) FXIII concentrate every 4 weeks FXIII concentrate every 3 weeks Evolution Major ICH at 30 years old. (had suspended prophylactic treatment in1989) Favorable evolution without consequences. Favorable evolution without consequences.

COMMENTS

Congenital Factor XIII deficiency, although infrequent, should be included in the differential diagnosis of hemorrhagic processes with normal coagulation tests, especially if triggered spontaneously or in a disproportionate manner (in quantity and/or duration). Bleeding of the umbilical cord in the first days or weeks after birth is characteristic of this deficiency (present in 80% of cases). The prophylactic administration of Factor XIII is fundamental due to the frequency of intracranial hemorrhaging.

Disclosures:

No relevant conflicts of interest to declare.
Clinical Implications of Clonal Cytogenetic Abnormalities of Aquired Aplastic Anemia.
Authors: Kim Sung Hyun , Lee Ji Hyun , Kwon Kyung A. , Lee Suee , Oh Sung Yong , Kwon Hyuk-Chan , Han Jin-Yeong , Song Moo-Kon , Chung Joo-Seop , Lee Sang-Min , Joo Young-Don , Lee Ho Sup , Kim Yang Soo , Kim Hyo Jin
Published: October 2019

Abstract 4217

Background

Cytogenetic abnormalities (CA) have been reported infrequently in patients with otherwise typical aplastic anemia (AA). The relevance of CA in AA to the prognosis of AA and the evolution to the hematologic malignancies is controversial.

Design and Methods

One hundred and twenty-nine adult AA patients from four centers located in Busan, South Korea, who had successful cytogenetics at initial diagnosis were retrospectively analyzed.

Results

.The median follow-up duration of the overall patients was 46.8months. The ratio of severe AA to non-severe AA was 59:41. The patients were classified into 5 groups according to the CA and progression to the hematologic malignancies. Among the patients with normal cytogenetics at initial diagnosis, 117 remained AA with normal cytogenetics (Group 1). Six patients (4.7%) had CA at initial diagnosis (Group 2). The CA showed trisomy 8 in two cases and trisomy 11, deletion of Y chromosome, t(2;9), and t(22;?) in each case. One with trisomy 11 later developed monosomy 1. None of the Group 2 evolved to acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Two patients with normal cytogenetics at initial diagnosis later developed monosomy 4, and monosomy 7, respectively, with persistent AA (Group 3). Group 3 patients were treated only with intermittent transfusion but spontaneously recovered from cytopenia and are still alive without transfusion requirement. Among the AA with normal cytogenetics at initial diagnosis, four patients (3.2%) progressed to AML or MDS; two remained normal cytogenetics (Group 4), and two patients obtained structural CA (Group 5) at follow-up, respectively.

Conclusion

The majority of the AA patients had normal cytogenetics at initial diagnosis. Non-severe AA patients may have CA. AA patients with CA at initial diagnosis or at follow-up are not at greater risk of evolution to the hematologic malignancies, and have no significant difference in survival. Prospective studies and more patients are needed to establish the clinical relevance of CA.

Disclosures:

No relevant conflicts of interest to declare.
Evaluation of Stem Cell Concentrate Prepared From Bone Marrow Aspirate Using the Res-QTM system.
Authors: Kumar Vijay , Chapman John R
Published: October 2019

Abstract 4232

BACKGROUND

The Res-Q System is a point of care device intended for the preparation of cell concentrates from bone marrow by centrifugation. Stem cell concentrates from bone marrow aspirate (BMA) were prepared in less than 15 minutes. The bone marrow concentrate was collected in the device funnel and extracted in a harvesting syringe. The cellular components of samples were analyzed pre- and post processing.

STUDY DESIGN

For this study 4 anticoagulated bone marrows were processed. All samples were evaluated for cell recovery, hematocrit, total nucleated cells (TNC), mononuclear cells (MNC), CD34+ cells, cell viability and colony forming units before and after Res-Q60 processing. The Res Q processed post samples were cultured and cells characterized by flow cytometry using cell surface markers.

RESULTS

The Res-Q60 process achieved MNC fraction volumes of 6.7 ± 0.1 ml with a final average hematocrit of 17± 0.6%. The post-processing recovery of CD34+ cells was 90 ±12.7%, of MNC was 85 ± 4% and of TNC was 64 ± 13%. No change in cell viability was observed using the Res-Q60 device. Res-Q derived cell concentrate cultured in mesenchymal stem cells basal media followed by immunophenotyping measured by flow cytometry were ≥ 95% positive for CD73, CD90 and CD105. The same cells lack (≤ 5%) expression of CD31 and CD34.

CONCLUSIONS

In conclusion, Res-Q60 system provides a new simple method for preparation of cell concentrates from bone marrow at the point of care.

Disclosures:

Kumar: Thermogenesis Corp.: Employment. Chapman:Thermogenesis Corp.: Employment.
Molecular Characterization of a Novel Chromosomal Translocation t(12;14)(q23;q11.2) in T-Lymphoblastic Lymphoma Between the T Cell Receptor Delta Deleting Elements (TRDREC and TRAJ61) and the Hypothetical Gene C12orf42.
Authors: Przybylski Grzegorz K , Dittmann Kathleen , Grabarczyk Piotr , Dölken Gottfried , Busemann Christoph , Gesk Stefan , Harder Lana , Landmann Eva , Siebert Reiner , Schmidt Christian A.
Published: October 2019

Abstract 4239

Chromosomal aberrations have diagnostic, prognostic and therapeutic consequences in haematological malignancies. By combining fine-tiling comparative genomic hybridization (FT-CGH) and ligation-mediated PCR (LM-PCR) we established a fast and robust approach to precisely characterize chromosomal breakpoints. Using this approach we characterized at the molecular level novel chromosomal translocation t(12;14)(q23;q11.2) in T-lymphoblastic lymphoma occurring during the deletional rearrangement of the T cell receptor delta gene (TRD). Normally, this transient rearrangement is a pivotal step in T cell differentiation towards the alpha/beta versus the gamma/delta lineage and generates the T cell receptor excision circles (TREC), which are quantitated to determine the proliferative history of T cells. We found that the rearrangement disrupted the hypothetical gene C12orf42 and brought the Achaete-scute complex homolog 1 (ASCL1) gene into proximity to the TRA enhancer, which is encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors and is overexpressed in medullary thyroid cancer and small cell lung cancer.

Disclosures:

No relevant conflicts of interest to declare.
Clinical Significance of Circulating Ki-67 Protein and Caspase-3 Activity Levels in Chronic Myeloid Leukemia.
Authors: Bruey Jean-Marie , Kantarjian Hagop M. , Estrov Zeev , Ma Wanlong , Yeh Chen-Hsiung , Sferruzza Anthony , Albitar Maher
Published: October 2019

Abstract 4249

Ki-67 and caspase-3 are widely accepted as proliferation and apoptosis markers. We recently reported that Ki-67 can be detected as a circulating protein (cKi-67) in the plasma of patients with acute lymphoblastic leukemia (ALL), and that higher levels correlated with more aggressive disease. Here we investigated the levels of cKi-67 in patients with chronic myeloid leukemia (CML). We also evaluated the level of apoptosis in CML as determined by plasma levels of caspase-3 activity. The study included 127 CML patients: 81 in chronic phase and 46 in accelerated phase/blast crisis. cKi-67 levels were determined with an electro-chemiluminescence-based immunoassay. Apoptosis was determined by measuring caspase-3 activity (DEVD) in the plasma using a standard enzymatic fluorogenic assay. Patients with CML had significantly (P<0.0001) higher levels of cKi-67 and caspase-3 activity than normal control (n = 96). However, median (range) cKi-67 levels did not differ significantly between CML patients in chronic phase (523 [73-5857] ng/mL) and those in accelerated/blast crisis phase (710 [100-3530] ng/mL), nor did caspase-3 activity: 12.2 (6.1-29.1) pmol/min the chronic phase group and 12.2 (range=6.6-17.9) pmol/min in the accelerated/blast crisis group. The median of cKi-67 and caspase-3 in the healthy control group was 353.06 and 8.19, respectively and range 35.76-2830.65 ng/ul and 4.54-34.30 pmol/min, respectively. Neither cKi-67 level nor caspase-3 activity correlated with white cell count or blast count in the chronic phase or in the accelerated/blast crisis phase. There was no correlation between cKi-67 or caspase-3 levels and response to imatinib therapy. However, patients in the chronic phase with high levels of cKi-67 (>354 ng/mL) had significantly longer survival than did those with lower levels (P=0.003); cKi-67 levels were not associated with outcome in accelerated/blast phase CML. Caspase-3 activity did not correlate with outcome in chronic or accelerated/blast phase patients. In conclusion, cell proliferation and apoptosis as determined by plasma cKi-67 level and caspase-3 activity are elevated in CML, but higher levels of cKi-67 unexpectedly correlated with longer survival in chronic phase CML. Although the cause for this is unknown, it is possible that higher levels of cKi-67 reflect that more stem cells are in cell cycle, and this may make them more susceptible to therapy.

Disclosures:

No relevant conflicts of interest to declare.
Soluble IL2R (CD25), IL10 and PDL1 May Control T Cell Activation in Chronic Myeloid Leukemia.
Authors: Christiansson Lisa , Lindqvist Camilla , Tötterman Thomas H , Simonsson Bengt , Olsson-Strömberg Ulla , Loskog Angelica
Published: October 2019

Abstract 4252

Cancer patients are known to have an impaired anti-tumor immune response because of various immune escape mechanisms exerted by the tumor cells. These mechanisms involve release of soluble molecules and expression of membrane-bound proteins inhibiting different arms of the anti-tumor immune responses. The immune escape mechanisms seen in cancer patients complicate the use of immunotherapy, such as tumor vaccines and adoptive T cell transfer. The aim of our study was to investigate the presence of IL10, soluble IL2R (sIL2R; CD25) and programmed death receptor ligand 1 (PDL1) in patients with chronic myeloid leukemia (CML) and to study their role as T cell inhibitors. IL10, sIL2R and PDL1 are all known immune inhibitory molecules. IL10 is a secreted molecule that has various suppressive effects on many different immune cells. sIL2R binds IL2 efficiently and may thereby prevent the binding of IL2 to IL2R on T cells, an interaction that is necessary for proliferation and maintenance of tumor-specific T cells. PDL1-expressing tumor cells can bind programmed death receptor 1 (PD1) on T cells. This interaction can induce apoptosis in the T cells. In this study, we used cytometric bead array, ELISA and multicolor flow cytometry to screen CML patients and healthy controls for the presence of IL10, sIL2R and PDL1 in blood. Further, Alamar Blue TM assay and IFNγ detection by flow cytometry were used to investigate T cell proliferation and activation in the presence of the inhibitors. We found that the levels of IL10 and sIL2R were increased in CML patient plasma compared to the levels in healthy control subjects. The level of sIL2R in a subgroup of patients was four-fold higher than the mean level of healthy controls. Patient T cells stimulated with various strong T cell stimuli including CML-specific peptides failed to respond to stimuli as measured by flow cytometric detection of the cytotoxic T cell activation marker IFNγ, indicating that these T cells might be anergic. In vitro studies on T cells from healthy donors showed that both IL10 and sIL2R have the ability to inhibit T cell proliferation. Half of the CML patients had a PDL1 expression on the CD34 cell population raging from 1-36%. PDL1 may, hence, be involved in T cell control in CML. Taken together, our results show that T cells from CML patients fail to respond to stimuli and that these T cells may be controlled by the high levels of IL10, sIL2R and PDL1 seen in the patients. Screening for these inhibitors may aid selection of patients considered for immunotherapy.

Disclosures:

Simonsson: Novartis: Consultancy, Honoraria, Research Funding, Sponsor; BMS: Consultancy, Honoraria, Research Funding, Sponsor; SCHERING-PLOUGH: Sponsor. Olsson-Strömberg:BMS: Honoraria.
Long-Term Follow-up of Patients with Chronic Myeloid Leukemia Having Received Autologous Stem Cell Transplantation.
Authors: Hackanson Bjorn W. , Waller Cornelius F
Published: October 2019

Abstract 4268

Before the introduction of imatinib mesylate, the median survival of chronic myeloid leukemia (CML) patients was approximately 60 months and the standard treatment with interferon-alpha (IFN-α) resulted in major cytogenetic responses of 20-25 %. As an alternative treatment approach at that time, intensive chemotherapy followed by autologous hematopoietic stem cell transplantation (autoHSCT) was investigated with the rational of debulking disease burden and mobilisation and transplantation of Philadelphia chromosome-negative (Ph-) stem cells. In the era of tyrosine kinase inhibitors (TKIs) as state-of-the-art therapy for CML, the concept of autoHSCT has attracted only little interest and long-term follow-up and outcome data after autoHSCT in CML patients is scarce.

In this long-term analysis, we report on 21 CML patients, mobilized in early chronic phase (ECP) and transplanted with largely Ph- grafts, who received interferon alpha (IFNα) as maintenance. Imatinib mesylate was given upon cytogenetic relapse or disease progression after IFN-α. The 10-year survival was 61% and 11 patients (52%) were alive at a median follow-up of 12.5 years (range 0.3 - 13.8) with 8 patients in complete hematologic remission (CHR) and 3 of 8 in major molecular remission (MMR). While all patients in MMR and 2 of 5 patients in CHR received imatinib, it is noteworthy that three patients remaining in CHR only received IFN-α maintenance after autoHSCT.

With the limitations of a small patient population, this is the longest follow-up analysis demonstrating that autoHSCT in CML is very efficient to debulk the disease and able to induce major and sustained molecular responses in the majority of patients with substantial long-term survival rates.

Disclosures:

Waller: Hospira UK Ltd: Consultancy.
Detection of BCR-ABL Mutations in Patients with Chronic Myeloid Leukemia Treated with Imatinib. Experience of One Centre.
Authors: Gutierrez J. Valentin Garcia , Odriozola Jesùs , Lopez Javier , Herrera Pilar , Calbacho Maria , Jimenez-Rolando Marta , Tenorio Maria , Chinea Anabelle , Garcia-Laraña Jose
Published: October 2019

Abstract 4280

Introduction

Imatinib (Imatinib) offers outstanding results in the treatment of chronic phase of chronic myeloid leukaemia (CML). However, there are still some patients who do not achieve an optimal response. There are several possible mechanisms both for primary refractoriness and for acquired resistance, but very often the blame falls in the appearance of ABL-kinase-domain (KD) mutations. Different mutations are related to variable degrees of resistance, ranging from the extreme refractoriness of the mutation T315I down to some which appear to have no clinical significance.

Aims

To define the clinical characteristics and outcome of patients treated in our centre, in which ABL-kinase-domain mutations through direct DNA sequencing have been analysed.

Results

In 24 of a total 86 patients, KD mutations were looked for. Screening for mutations was undertaken for one of three reasons: at diagnosis in 6 patients, suboptimal response (Leukemia-Net criteria) in 10 cases and Treatment-Failure (LN criteria) in 8 cases. Median time from diagnosis to ABL mutation detection was 38 months. No risk factors at diagnosis for the appearance of KD mutations have been found. Of the 7 mutations, 5 cases corresponded to treatment failures and 2 to patients in so-called suboptimal responses. One patient, after achieving a complete response to Imatinib, developed a T315I KD mutation and died due to blastic crisis despite having received second generation TKI. Another patient in failure (mutation G250E) achieved a molecular response with dasatinib. No mutations were found in 6 patients checked before treatment, but one of these developed a mutation G250E after 18 months, along with the criteria of a suboptimal response and achieved a mayor molecular response with dasatinib.

Conclusions

KD mutations are found in a proportion of patients in the situation of suboptimal response or failure to IM, more frequently in the latter in our experience, but the clinical significance of some of them is still unclear. On the contrary, DNA sequencing for screening at the moment of diagnosis offers little relevance in chronic phase CML.

Disclosures:

No relevant conflicts of interest to declare.
Anti-CD25 instead of ATG for the Conditioning of HLA-Mismtched Hematopoietic Stem Cell Transplantation.
Authors: Wang Jun , Meng Qingxiang , Guo Nailan
Published: October 2019

Abstract 4315

Purpose

To analysis the effect of Anti-CD25 instead of ATG for the conditioning of HLA-mismatched hematopoietic stem cell transplantation (HSCT).

Methods

21 cases underwent HLA-mismatched HSCT in our hospital from Mar. 2006 to May 2009. Diagnosis included ANLL(n=9)(2 in CR,7 in Relapse)?ALL(n=2), AHL(n=2), CML(n=4), MDS (n=2) and SAA (n=1), HLA Typing : All patients receive transplants from HLA-mismatched related donors. Among whom, 1,2 and 3 antigen mismatched were 11,8 and 2 cases respectively. Conditioning regimen consisted of modified BU/CY (n=12), BU/CY (n=6), FLU/BU (n=2) and CY/ATG for SAA(n=1). In addition, ATG(Thymoglobuline, 5-7.5mg/Kg, iv, divided into three days, -8∼-6d) was given for 8 patients. Anti-CD25 was given for 13 patients, including Daclizumab (50mg/d, -1?,03?,+4?,+11d) for 7 patients and Basiliximab (20mg/d, -1?,02?,+2?,+7d) for 6 patients. GVHD prophylaxis consisted of CSA and short course of MTX. In addition, MMF was given in all patients at the dosage 1.0 g/d for one month. The donors were given granulocyte colony-stimulating factor (G-CSF) at a dosage of 5 μg/Kg.d subcutaneously for 5 days, bone marrow was collected on day 3, peripheral blood stem cells were collected at day 4 and 5.

Results

Engraftment was obtained in all 21 patients, the median time to WBC >0.5×109/L and BPC>20×109/L in ATG and Anti-CD25 group were 14, 13d and 13, 12d, respectively (p>0.05), I∼II aGVHD accurred in 3 cases(37.5%) in ATG group and 5 cases(23.1%) in Anti-CD25 group,III∼IV aGVHD was observed in 1 case (12.5%) in ATG group and 2 cases (15.3%) in Anti-CD25 group. cGVHD was evaluable in 14 patients who survived after day +100, Extensive cGVHD developed in 1 (20%) of 5 patients in ATG group, and in 4 (44%) of 9 patients in Anti-CD25 group. Daclizumab and Basiliximab were not cause any infusion-related toxicity. Up to now, 13 patients survived in complete remission follow up 3-59 months, 4 cases (50%) died (3 in TRM and 1 in relapse) in ATG group, 4 cases (30.7%) died (1 in TRM and 3 in relapse) in Anti-CD25 group.

Conclusion

The replacement of ATG with Anti-CD25 seems to be more safety and effective for the conditioning of HLA –mismatched HSCT.

Disclosures:

No relevant conflicts of interest to declare.
Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Haematological Lymphoid Malignancies: Long Term Follow-up in a Single Centre Series.
Authors: Benakli Malek , Ahmed nacer Redhouane , Talbi Amina , Belhadj Rachida , Mehdid Farih , Rahmoune Nadia , Harieche Farida , Abderahmani Soumeya , Saidani Keltoum , Akhrouf Sabrina , Boumansour Faiza , Zerhouni Fatiha , Hamladji Rose-Marie
Published: October 2019

Abstract 4326

Background

Patients (pts) with recurrent and refractory haematological lymphoid malignancy (HLM) have a very limited survival expectance. RIC allo-SCT has been proposed as a strategy for retaining the graft versus malignancy effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 32 pts treated by RIC allo-SCT.

Patients and methods

Between April 2001 and November 2007, 32 pts with HLM underwent RIC allo-SCT with an HLA-identical sibling donor. Fifteen pts with multiple myeloma, 7 pts with Non-Hodgkin lymphoma, 6 pts with Chronic lymphoid leukaemia, 3 pts with Hodgkin lymphoma and 1 pt with Waldenstrom disease. At time of allo-SCT, 10 pts were in complete remission (3 received prior autologous transplant) and 22 in refractory/progressive disease (6 received prior autologous transplant). Median age was 38 years (range, 28-60) and the sex-ratio (M/F) 2,2. Median time from diagnosis to RIC allo-SCT was 18 (range,6-76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 6,2.106/kg (range, 1.9-13,6).

Results

Neutropenia occurred in all pts (100%) and the median duration of aplasia was 9 (range, 5-16) days. Only 10 pts (31 %) required red blood cells transfusions and 23 pts (71 %) needed platelets transfusions. Acute GVHD was observed in 15 cases (47 %) including 10 cases of grade II-IV. Fifteen pts (75 %) had chronic GVHD, of whom 9 with an extensive form. Four pts (12 %) had CMV reactivation at a median time 60 (range, 52-80) days after transplantation. Six pts (18 %) had late onset relapse at a median time of 13 (range, 4-45) months. TRM was 43 % at one year after RIC allo-SCT. With a median follow-up of 60 (range 18-97) months, 12 pts (37,5 %) are still alive in complete remission with full donor chimerism. Twenty pts (62,5 %) have died (5 early severe infections, 10 GVHD, 3 after relapse, one myocardial infarction, and one accident). Overall and progression-free survivals at 8 years are 31 % and 30 % respectively.

Conclusion

This study, after a large follow-up, suggests that RIC allo-SCT is a potential therapy for refractory or progressive HLM. However, TRM is still high likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions.

Disclosures:

No relevant conflicts of interest to declare.
Sirolimus for Graft-Versus-Host-Diseases Prophylaxis in Non-Myeloablative Matched Related Transplantation: Safety and Efficacy.
Authors: Zheng Hong , Carraher Michelle , Schaefer Eric , Talamo Giampaolo , Ehmann W. Christopher , Rybka Witold , Claxton David F.
Published: October 2019

Abstract 4329

The use of sirolimus (rapamycin) as an immunosuppressive agent after allogeneic hematopoietic transplantation is appealing given its antitumor and tolerance-inducing properties. Its safety and efficacy have been studied but are not completely understood in this patient population. We have compared GVHD prophylaxis with sirolimus together with early withdrawal of concomitant tacrolimus to standard tacrolimus in 49 patients receiving non-myeloablative transplant from matched related donors. All patients received identical conditioning with Cyclophosphamide 1g/m2 days –7 and –6 and Fludarabine 25mg/m2 days –7 through –3. Twenty-three patients received standard GVHD prophylaxis with methotrexate and tacrolimus. Twenty-six patients received methotrexate, sirolimus, with tacrolimus tapering over 15 days beginning day 20 or 30. Overall survival (OS) was similar in sirolimus and no sirolimus groups (median 526 vs 723 days, p=0.77). Similarly progression-free survival (PFS) was comparable (median 300 vs 382days p=0.78). Full chimerism was achieved in 73% patients received sirolimus vs. 58%patients received no sirolimus by day 100 (p=0.46). Chimerism was similar in the two groups at all time points examined. Toxicities including microangiopathy (MA), hypertriglyceremia and nephrotoxicity were analyzed. In patients receiving sirolimus MA developed in 2/26(8%) vs. in 1/23(4%) patients receiving no sirolimus (p=0.28). Creatinine >3mg/dl was seen in 6/26 (23%) patients receiving sirolimus vs. 6/23 (26%) patients receiving no sirolimus (p=0.47). In contrast the incidence of hypertriglyceremia (>500mg/dl) was significantly higher in the sirolimus group (10/26, 38% vs 2/23, 9% p<0.01). Hypertriglyceremia was however easily treated with anti-lipid agents, and no patient developed significant pancreatitis or other complications. The incidence of grade II-IV acute Graft versus host disease (GVHD) was modestly higher in the sirolimus (9/26, 35%) vs no sirolimus group (2/23, 9%), (p=0.0418). This acute GVHD occurred late at 60-100 days, more than 2 weeks after discontinuation of tacrolimus. Chronic GVHD was similar between patients receiving sirolimus and no sirolimus (15/26, 58%, vs. 9/23, 39%; p=0.25), as was transplant related mortality (3/26, 12%, vs. 4/23, 17%; p=0.69). Although sample size is limited, our data suggest that replacing tacrolimus early with continued sirolimus may be associated with modest increases in aGVHD. In our patients there is however little to suggest a negative impact on survival and engraftment. Other toxicities of sirolimus are minimal. Whether the early substitution of sirolimus for tacrolimus post transplant yields improved tumor control must await results of larger studies in specific tumor types.

Disclosures:

Off Label Use: Sirolimus for GVHD prophyllaxis.
Long Term Results of High-Dose Melphalan and Autologous Stem Cell Transplantation in Non-Amyloid Monoclonal Immunoglobulin Deposition Disorders.
Authors: Girnius Saulius , Seldin David C. , Quillen Karen , Finn Kathleen T. , Andrea Nancy T. , Sloan John Mark , Sanchorawala Vaishali
Published: October 2019

Abstract 4356

Monoclonal Immunoglobulin Deposition Disorder (MIDD) is a plasma cell dyscrasia in which whole immunoglobulins or heavy or light chain subunits form non-fibrillar deposits in various tissues, causing organ dysfunction. Several studies have previously reported that high dose melphalan and autologous stem cell transplantation (HDM/SCT) is safe and effective at achieving a complete hematologic response in this disease, but long term data is sparse. Hematological complete response is defined as normalization of serum free light chain ratio and concentration, bone marrow exam with less than 5% plasma cells, and absence of monoclonal gammopathy in serum and urine by immunofixation electrophoresis. Between 2003 and 2008, ten patients with MIDD were treated with HDM/SCT at a dose of 200mg/m2 (n=6) or 100-140 mg/m2 (n=4) depending upon age and clinical status and were assessed for hematologic responses and improvements in organ function at 3-6 and 12 months, and annually thereafter. The median age was 45 years (range, 34 to 70); all but one patient were male. Six patients had kappa clonal predominance and four patients had lambda clonal predominance. All ten patients had renal involvement, two were on dialysis and one had undergone a renal transplant. Two patients also had extrarenal manifestations with cardiac involvement. The median creatinine clearance was 26 mL/min (range 20 to 100) and the median 24 hour urine total protein excretion was 4,037 mg (range, 458 to 15,632). Peripheral blood stem cells were collected after GCSF mobilization and a median of 6.9 ×106 CD34cells/kg were collected. There was no treatment related mortality within 100 days of SCT. One patient developed end stage renal disease during the peri-transplant period. Of the seven patients who have had follow-up of at least a year, five (71%) achieved a complete hematological response (CR) and two (29%) had a partial hematological response. One patient died six months after HDM/SCT due to progressive disease. Clinical and organ responses were also evident after HDM/SCT in 5 out of 7 patients. The median creatinine clearance was 42 mL/min (range, 38-55) and the median 24 hour urine total protein excretion was 179 mg (range, 150 to 349) at 2 years after treatment. Of the five patients with hematologic CR, 3 (60%) have relapsed at a median of 3 years (range, 2-3). Two of the 5 patients continue to have hematologic CRs at four and six years after HDM/SCT. In summary, HDM/SCT in MIDD often results in hematological CRs, as well as an improvement in renal function. However, the 5-year relapse rate is high. This group of patients may benefit from maintenance anti-plasma cell therapy.

Disclosures:

No relevant conflicts of interest to declare.
Absolute Lymphocyte Count Assessed During Routine Follow-up Is a Risk Factor for Relapse Post-Autologous Peripheral Blood Hematopoietic Stem Cell Transplantation in Patients with Diffuse Large B-Cell Lymphoma.
Authors: Porrata Luis , Inwards David J , Ansell Stephen M , Micallef Ivana , Johnston Patrick L , Hogan William , Markovic Svetomir
Published: October 2019

Abstract 4359

Routine serial chimerism analysis after allogeneic stem cell transplantation (Allo-SCT) has been used as a risk factor for post-Allo-SCT cancer relapse. In non-Hodgkin lymphoma (NHL) patients treated with autologous peripheral blood hematopoietic stem cell transplantation (APHSCT), a specific predictor during routine follow-up that could be used to ascertain risk for post-APHSCT relapse has not been identified. Thus, we set out to investigate if absolute lymphocyte count (ALC) measured at post APHSCT follow-up could serve as a marker of post-APHSCT NHL relapse. ALC was obtained at the time of confirmed relapse at follow-up and at last no evidence of relapse follow-up. From 1993 until 2005, 269 patients treated with APHSCT for diffuse large B-cell lymphoma (DLBCL), were included in this study. Patients at last follow-up with no relapse (N=137) had a higher ALC compared with those with confirmed relapsed at follow-up post-APHSCT (N= 132) [median ALC x 109/L of 1.66 (range: 0.13-3.69) vs 0.71 (range: 0.03-4.75), p <0.0001, respectively]. ALC at follow-up was a strong predictor for relapse with an area under the curve (AUC) = 0.86 (p<0.0001). An ALC of 1.0 × 109/L was identified as the optimal cut-off point. An ALC < 1.0 × 109/L at the time of confirmed relapse had a positive predictive value of 89% and a positive likelihood ratio of 8.4 to predict relapse post-APHSCT. Patients with an ALC ≥ 1.0 × 109/L (N = 147) had a cumulative incidence of relapse of 19% versus 92% for patients with an ALC < 1.0 × 109/L (N = 122) (p<0.0001) at follow-up post-APHSCT. This study suggests that ALC at follow-up can be used as a marker to assess risk of DLBCL relapse during routine follow-up after APHSCT.

Disclosures:

No relevant conflicts of interest to declare.