bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extramedullary Relapse of Acute Adult Leukemia Following Allogeneic Stem Cell Transplantation:10 Cases Analysis.
Authors: Shi Jimin , Luo Yi , Tan Yamin , Zhu Xiaoli , He Jingsong , Zheng Weiyan , Xie Wanzhuo , Li Li , Ye Xiujin , Zhang Jie , Cai Zhen , Lin Maofang , Huang He 
Published: October 2019

Abstract
Abstract 4513

Background:
Up to date, the knowledge concerning the predisposing factors, pathogenesis and mechanisms of isolated extramedullary relapse (EMR) of acute leuekmia (AL) has not been well elucidated.

Method:
We retrospectively analyzed 215 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) at our center from 1998 to 2006. All of them were adult AL patients (110 acute myeloid leukemia (AML), 102 acute lymphocytic leukemia (ALL) and 3 acute mixed lineage leukemia). 10 cases (4.7%) experienced relapse of extramedullary sites. Among these 10 patients, there were four male and six female patients with a median age of 25 years (range, 22–38 years). Six patients were AML and four patients were ALL. The median interval from diagnosis to transplantation was 9 months (range, 6–15 months). Five patients had cytogenetics or molecular abnormalities. All the patients were in first CR. All the donors were HLA-identical matched (5 siblings and 5 unrelated donor). Conditioning regimen included BU and CY without total body irradiation (TBI). Graft-versus-host disease (GVHD) prophylaxis is consisted of cyclosporin A, a short-term methotrexate and mycophenolate mofetil.

Result:
Ten patients experienced isolated EMR at a median of 10 months (range, 3–28months) after allo-HSCT. Sites of EMR varied widely and included CNS (leptomeninges, brain, retro-orbital tissue and paraspinal tissue), skin, bone, pelvis and breasts. Five patients experienced two or more sites of EMR. The most frequently involved in relapse sites were CNS (4 patients) and skin (3 patients). Three patients subsequently developed bone marrow relapse, two patients in 2 and 3 months after the initial EMR and the third patient in 3 months after the second onset of EMR. The remaining seven patients did not develop bone marrow involvement at a follow-up ranged from 3 to 8 months after the initial EMR. Three patients received donor lymphocytes infusion (DLI) combined with chemotherapy and (or) irradiation, two patients achieved CR and remain free of disease for 25 and 32 months after transplant whereas one died due to the second EMR and the following marrow relapse. Two patients received local surgery in combination with radiotherapy or chemotherapy and both remain free of disease for 7 and 18 months post transplant. Among five patients who were only treated with local irradiation or chemotherapy or supportive care, four died from progressive disease.

Conclusion:
The prognosis of EMR is generally considered to be unfavorable. An intensified regimen combined of local interventions with systemic chemotherapy may be benefit for patients.

Disclosures:
No relevant conflicts of interest to declare.
The Value of Donor Lymphocyte Infusions In Unstable Mixed Chimerism In Patients with Beta Thalassemia.
Authors: Karasu Gülsün Tezcan , Ye¸silipek Akif , Karaüzüm Sibel , Uygun Vedat , Akcan Mediha , Manguoğlu Esra , Küpesiz Alphan , Hazar Volkan 
Published: October 2019

Abstract
Abstract 4521
The only curative option for ß talasemia remains allogeneic hematopoietic stem cell transplantation (HSCT) to correct the genetic defect and provide a normal hemoglobin level in the recipient. Engraftment of donor derived cells is necessary for a success of transplantation. However, it has been shown that complete donor hematopoesis is not essential for sustained engraftment in thalassemia. Donor and recipient cells may coexist and produce a functional graft commonly referred to as donor/recipient mixed chimerism (MC) even with a low amount of engrafted donor cells. We documented our experience in a cohort of 19 beta thalassemia patients receiving DLI (donor lymphocyte infusions) following 21 transplantations with unstable mixed chimerism (MC). Seven patients received DLI with the indication of having more than 25% residual host cells (RHC) (MClevel3(residual host cells>25%)) early after transplantation and assigned as early-DLI group. Four patients although had MClevel3 in the early period, received deferred DLI and assigned as late-DLI group. The difference between these two groups, in respect to preserving functional graft, was not found statistically significant. However the chimerism kinetics of these early and late-DLI groups were also different and a slower decline in percentage of donor cells were observed in patients preserving grafts. Ten patients received DLI in the later period and although a significant increase in percentage of donor cells was not detected, increase in hemoglobin levels was provided. The infusions were safe with acceptable risk for GVHD. We believe that patients with more than 25% of RHC within two months early intervention with DLI seems feasible. Deferring DLI to a later period especially if the decrease in percentage of donor cells is so prompt, seems less effective. In the later period, we propose to consider the hemoglobin level as the main determinative factor for DLI application rather than the percentage of donor cells in line with expectance of better long-term tolerance. A better understanding of the mechanisms underlying the occurrence of persistent MC and strategies for induction and maintenance of tolerance will provide better interventions and outcomes for these patients.

Disclosures:
No relevant conflicts of interest to declare.
Successful Haploidentical Stemcell Transplantation In a Patient with Fanconi Anemia and AML.
Authors: Duerken Matthias , Schneider Henriette , Soerensen Jan , Bader Peter 
Published: October 2019

Abstract
Abstract 4586
Allogeneic hematopoetic transplantation is the only curative treatment in patients with fanconi anemia indicated as soon transfusion dependency occurs and a matched family or unrelated donor is available. Overall survival for matched or nearly (5/6) matched unrelated donor transplantation improved since the introduction of fludarabine-based conditioning regimens from 30% to 53%. Transplantation after malignant transformation, in heavily pretransfused patients or from alternative donors is associated with a dismal outcome. We report the case of a 7 year old girl with fanconi anemia who developed AML-M4 (monosomy 7 and gain on chromosome 3) with 24% peripheral blasts during donor search for HCT. Remission was acchieved with a mild chemotherapeutic regimen consisting of a single dose of intravenous (300mg/m2) and intrathecal (40mg) cytarabine and daily oral thioguanine (cumulative dose: 930mg/m2). 4 weeks after diagnosis of AML, the girl was transferred for allogeneic PBSCT (CD3/19 depleted) from an unrelated mismatched (7/10) donor. Conditioning regimen consisted of Fludarabine, Busulfex, ATG and OKT-3. Unfortunately, mixed chimerism was observed and on day +21 graft rejection was diagnosed. The patient underwent a second PBSCT from the same donor after conditioning with Fludarabine, Alemtuzumab and Cyclophosphamide and 12 days later received a stem-cell-boost due to poor hematological regeneration. Prolonged aplasia under treatment with G-CSF was suspicious for non-engraftment. The indication for a third PBSCT with her haploidentical father as donor was set. Conditioning in the aplastic patient with elevated autologous T-Lymphocytes consisted of ATG only for 3 days. Full engraftment was achieved on day +11. CMV-reactivation was effectively treated with a combination therapy of valganciclovir and foscavir. One year after the third PBSCT, the patient is in continuing morphologic remission with normal Cytogenetics and complete donor chimerism. Mild Graft vs. Host Disease (Grade I, Skin) dissolved after short term therapy with Prednison. Still she suffers under minor restrictions in her every day life. We demonstrate here the case of a CMV-positive patient with fanconi anemia and AML, polytransfused (27 red-cell-packs and 94 platelet-transfusions) who survived mismatched PBSCT of her CMV-positive father after two failed PBSCT from an alternative 7/10-mismatched donor. To our knowledge this is the first patient with fanconi anemia and AML, successfully transplanted from an haploidentical donor.

Disclosures:
No relevant conflicts of interest to declare.
ICOS Gene Polymorphisms In B-Cell Chronic Lymphocytic Leukemia In a Polish Population.
Authors: Frydecka Irena , Karabon Lidia , Jedynak Anna , Tomkiewicz Anna , Pawlak Edyta , Wolowiec Dariusz , Kielbinski Marek , Kuliczkowski Kazimierz , Woszczyk Dariusz , Wrobel Tomasz 
Published: October 2019

Abstract
Abstract 4614

Introduction:
There is strong evidence that altered immunological function entails an increased risk of B-cell chronic lymphocytic leukemia (B-CLL). The main mechanism of an antitumor response depends on T-cell activation. Unlike the constitutively expressed CD28, inducible costimulatory molecule (ICOS) is expressed on the T-cell surface after activation. ICOS enhances all the basic T-cell responses to a foreign antigen, namely proliferation, secretion of lymphokines, the up-regulation of molecules that mediate cell-cell interaction, and effective help for antibody secretion by B cells. ICOS is essential for both efficient interaction between T and B cells and normal antibody responses to T cell-dependent antigens. It does not up-regulate the production of interleukin-2, but superinduces the synthesis of interleukin-10. Our previous results indicated a role of ICOS gene as a susceptibility locus to B-CLL. Therefore an extended study was undertaken to evaluate the association between four ICOS polymorphisms (which were recently described as functional ones) and susceptibility to B-CLL in a Polish population.

Methods:
A case-control study of 296 individuals including 146 B-CLL patients was conducted on four polymorphisms in the ICOS gene. Genotyping of the polymorphisms ICOSISV1+173T>C (rs10932029), ICOSc.1624C>T (rs10932037), ICOSc.2373G>C (rs4675379), and ICOSc.602A>C (rs10183087) was done using allelic discrimination methods with the TaqManÒ SNP Genotyping Assay.

Results:
There were no statistically significant differences in the allele, genotype, and haplotype distributions between B-CLL patients and healthy controls for any of the investigated polymorphic markers in the ICOS gene. However, we noted that patients carrying genotype ISV1+173T>C [TT], ICOSc.602A>C [AA], ICOSc.1624C>T [CC], and ICOSc.2373G>C [GG] have a decreased frequency of progression to a higher Rai stage during 60-month follow-up (21.35 vs. 40.8%, p=0.013) compared with other individuals.

Conclusion:
This study showed that the investigated polymorphisms do not modulate the risk of B-CLL in the Polish population, but are associated with disease dynamics in particular with the time to Rai stage progression.

Disclosures:
No relevant conflicts of interest to declare.
Cyclin D1 mRNA Expression In CLL: a Pilot Study.
Authors: Mocikova Heidi , Pekova Sona , Zejskova Lenka , Spacek Martin , Kozak Tomas 
Published: October 2019

Abstract
Abstract 4619

Background.
Expression of cyclin D1 demonstrated by immunohistochemistry is seen in 95% of mantle cell lymphomas and in other lymphoproliferative diseases including 10% of chronic lymphocytic leukemias (CLL). This study analyzed the impact of cyclin D1 positivity on time to treatment (TTT) and overall survival (OS) measured by RT PCR in newly diagnosed CLL patients and correlation with reported prognostic factors.

Patients and methods.
Level of cyclin D1 (quantitative real-time RT-PCR with a specific TaqMan flurescent hybridization probe) mRNA expression was analysed in 72 samples (57 peripheral blood and 15 bone marrow) from patients with newly diagnosed CLL. Cyclin D1 expression (cut-off according to ROC curve >3 over the threshold expression in healthy donors) was reported as positive. Fisher's exact test was used to analyze the relationship of cyclin D1 positivity and prognostic factors: del17p, del11q, unmutated IgVH, trisomy 12, ZAP 70 and CD38 positivity, elevated B2microglobulin, elevated LDH and lymphocyte doubling time (LDT) <6 months. The comparison of time to treatment (TTT) and prognostic factors with cyclin D1 positivity was calculated via Spearman correlation coefficient. Survival curves were calculated by Kaplan-Meier survival analysis and comparison between subgroups was performed by the log-rank test.

Results.
Cyclin D1 was positive in 29 (40%) CLL patients. Although cyclin D1 was not statistically significant for TTT (P=0,145), a trend was observed, suggesting a negative prognostic impact of cyclin D1 overexpression in CLL. Following variables correlated significantly with TTT: del17p (P=0.037), del11q (P=0.003), unmutated IgVH (P=0.004), trisomy 12(P=0.024), positive CD38 (P=0.014), elevated B2microglobulin (P<0.001), elevated LDH (P<0.001) and LDT <6 months (P<0.001). Del 17p, del 11q, trisomy 12 and elevated B2microglobulin were independent factors for TTT in the multivariate analysis. None of these factors were significant for overall survival due to the short follow-up.

Conclusion.
Cyclin D1 measured by RT-PCR from peripheral blood or bone marrow has no statistically singificant impact on TTT or OS, though a trend pointing to cyclin D1 overexpression in CLL as a negative prognostic marker can be suggested. This data should be confirmed on a larger cohort of patients with a longer follow-up.

Disclosures:
No relevant conflicts of interest to declare.
Left Atrium Enlargement Is An Independent Predictor of Overall Mortality In Patients with Cardiac AL Amyloidosis.
Authors: Mohty Dania , Pibarot Philippe , Darodes Nicole , Tanguy Benedict , Lavergne David , Echahidi Najmeddine , Virot Patrice , Bordessoule Dominique , Jaccard Arnaud 
Published: October 2019

Abstract
Abstract 4621

Background:
Primary systemic amyloidosis (AL) is a severe plasma cell disorder characterized by amyloid fibrils extracellular deposition in different organs. Myocardial involvement is frequent and has major impact on prognosis. Echocardiography (TTE) is the most common test performed when cardiac involvement is suspected. We hypothesized that a simple measurement of left atrium enlargement (LA) by TTE may provide an important risk marker for this disease.

Methods and results:
Between 1997 and 2010, 114 patients were diagnosed with systemic AL. Sixty one patients of the cohort (54%) had cardiac involvement on the basis of standard criteria defined as: mean LV wall thickness >12mm with no other cardiac causes. They had first TTE within 16 days of diagnosis. Patients were mainly treated with conventional chemotherapy (M-Dex) or with new agents for refractory or relapsing patients We retrospectively collected demographic baseline characteristics along with biological and echo data of these patients. Mean age was 61±11 years; 60% were male; 19% had hypertension. Mean left ventricular ejection fraction and mean LV wall thickness were respectively 58±13% and 15±3 mm. Mean follow up time was 2.1±2 years. None had significant valvular heart disease. LA enlargement was defined by M mode as > 40 mm in male and > 36 mm in female. Patients with enlarged LA had significantly more hypertension and lower ejection fraction and more hypertrophied LV walls (All P< 0.05). At 3 years, survival rate was markedly reduced in patients with enlarged LA vs. those with normal LA: 34±9% vs.75 ±9% (P =0.02). By multivariate analysis, after adjusting for age, gender, and presence of hypertension, LA enlargement remained an independent predictor of overall mortality at 3 years (HR=2.88; CI (1.12-8.84); P=0.03).

Conclusion:
In patients with systemic AL amyloidosis and cardiac involvement, LA enlargement, a surrogate marker of diastolic dysfunction and elevated LV filling pressure, is a powerful independent predictor of long-term mortality. Therefore LA enlargement may help to enhance risk stratification in patients presenting with this disease.

Disclosures:
No relevant conflicts of interest to declare.
Differential Gene Expression Involved In Angiogenesis, Metabolism, Cell Proliferation and Self-Renewal and Pluripotency In Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)
Authors: Falantes Jose F , Calderón Cristina , Trujillo Pablo , Martin-Antonio Beatriz , González Jose , Urbano Alvaro , Carmona Magdalena , Espigado Ildefonso 
Published: October 2019

Abstract
Abstract 4646

Background
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal disorders characterized by clinical and prognostic heterogeneity, mainly explained by different genetic abnormalities among other factors. The role of some key genes involved in disease pathogenesis in both entities remain unclear.

Methods and patients
Study objective was to analyse differences in gene expression related to angiogenesis, metabolism and cell proliferation, self-renewal and pluripotency in patients (pts) with MDS and AML. Thirty-three bone marrow (BM) samples at diagnosis were analysed and distributed in 4 different groups: control group (n=8), low-risk MDS (LR-MDS:<10% BM blasts; n=15), high-risk MDS (HR-MDS:>10% BM blasts; n=4) and AML (n=6). Total RNA was isolated from BM samples. Genes analysed were: vascular endothelial growth factor (VEGF) for angiogenesis, MYC, macrophage migration inhibitory factor (MIF) and glycogen synthase (GYS) for metabolism and cell-proliferation and Oct4 as transcription factor required to maintain an undifferentiated state for self-renewal and pluripotency. Gene expression was quantified by qRT-PCR in triplicate using ß-actin gene as control. SPSS software (v.16) and Mann-Whitney U-test were applied for statistical analysis (P value ≤.05 was considered significant in all cases).

Results
After analysis, only mRNA levels of VEGF and MYC showed significant difference between LR-MDS and the control group. However, higher expression of all genes were observed in HR-MDS vs LR-MDS (p≤.05) as shown in table 1. When compared HR-MDS to AML, no difference was observed in VEGF, MYC, MIF and GYS, but significant difference was noticed in mRNA expression of Oct4 in AML samples (p=.032) vs HR-MDS. Globally, gene expression in MDS (pts with LR and HR-MDS) was significant lower than in AML pts in all genes studied as expected.

Conclusions
Increased expression of VEGF, cMYC, MIF, GYS and OCT4 in HR-MDS vs LR-MDS and in AML vs MDS (global) suggests that these factors may play a relevant role in pathogenesis of both entities. These results point towards a different biological behaviour in less proliferative disease respect advanced stages and AML in different cellular pathways involved in disease progression. They might also justify clinical heterogeneity among patients with MDS and in patients with AML vs MDS as a sole group, and also being responsible for different response to treatment options. Analysis of protein expression is ongoing.

Disclosures:
No relevant conflicts of interest to declare.
Identification of JAK1 Mutation In 40 Cases of Adult Acute T Lymphoblastic Leukemia
Authors: Sun Aining , Wang Wenjuan , Chen Guanghua , Depei Wu , Chen Suning , Chang Huirong , Ding Zixuan 
Published: October 2019

Abstract
Abstract 4652

Objective
This study was purposed to analyze the mutations of JAK1 in bone marrow cells from adult patients with newly-diagnosed T cell acute lymphoblastic leukemia (T-ALL).

Methods
The entire coding sequence of JAK1 in bone marrow mononuclear cells (MNCs) from 40 adult T cell ALL patients were screened by polymerase chain reaction (PCR) and direct sequencing, then the clinical features of JAK1 mutation positive patients were analyzed.

Results
JAK1 mutations were identified in 5%(2/40) patients, one is point mutation, the other is insertion mutation, resulting in changes in amino acid sequences, and the two types of mutations are different from those mutations found before.

Conclusion
The JAK1 mutations were found in about 5% newly-diagnosed T cell acute lymphoblastic leukemia, which was lower than those report abroad.

Disclosures:
No relevant conflicts of interest to declare.
Preclinical Safety of Baxter's Recombinant Factor IX
Authors: Dietrich Barbara , Kubik Susan , Auer Wilfried , Wuersch Kuno , Reipert Birgit , Horling Frank , Wolfsegger Martin , Ehrlich Hartmut J. , Scheiflinger Friedrich , Schwarz Hans Peter , Muchitsch Eva-Maria 
Published: October 2019

Abstract
Abstract 4654
Baxter has developed a rFIX product which is produced by a genetically engineered Chinese hamster ovary (CHO) cell line in a cell culture medium free from any animal or human proteins. The objective of this preclinical study-program was to evaluate the safety of Baxter's rFIX in different species.
The preclinical program included studies on established models of general safety pharmacology (conscious, telemetered cynomolgus monkey), thrombogenicity (rabbit, Wessler test), single and repeated dose toxicity (mouse, rat, cynomolgus monkey), local tolerance (rabbit), and comparative immunogenicity (mouse, rat, cynomolgus monkey). Commercially available licensed rFIX and pdFIX served as active reference items.
Thrombogenicity studies showed no thrombogenic potential of Baxter's rFIX. General safety pharmacology revealed no adverse effects on clinical signs, cardiovascular or respiratory variables. Single dose toxicity studies in mice, administered at doses of up to 7500 IU/kg BW, and repeated administration of Baxter's rFIX in rats and cynomolgus monkeys, administered doses of up to 750 IU/kg, confirmed the safety of the new product. Furthermore, Baxter's rFIX was well tolerated at the injection site after intravenous injection. No differences in immunogenicity between Baxter's rFIX and the reference items were revealed by comparative immunology studies.
This good safety profile of Baxter's rFIX was the basis for proceeding with human trials, which have recently been initiated.

Disclosures:
Dietrich: Baxter Innovations GmbH: Employment. Kubik:Baxter Innovations GmbH: Employment. Auer:Baxter Innovations GmbH: Employment. Wuersch:Baxter Innovations GmbH: Employment. Reipert:Baxter Innovations GmbH: Employment. Horling:Baxter Innovations GmbH: Employment. Wolfsegger:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Schwarz:Baxter Innovations GmbH: Employment. Muchitsch:Baxter Innovations GmbH: Employment.
The cytokines of helper T cells in Patients with immune Thrombocytopenic Purpura
Authors: Li Feng , Wu Boting , Zhan Yanxia , Cheng Yunfeng 
Published: October 2019

Abstract
Abstract 4663
Immune thrombocytopenic purpura (ITP) is traditionally considered an auto-antibody mediated disease. Recently the role of T cell immunity in ITP has been recognized and discussed by various researchers. In order to investigate changes in T cell subgrouping of ITP patients, we enrolled 20 previously untreated ITP patients (8 males, 12 females) with a median age of 41 (range: 20 to 81) and 20 normal controls. After standard dose of prednisone treatments (1mg·kg-1·d-1), 12 patients achieved complete remission and 7 partial remission. Using real-time RT-PCR methods, we measured the expression of 7 T cell associated genes including T-bet, IFN-γ, GATA-3, TGF-β, Foxp3, IL-2, IL-4 in PBMC of ITP patients before and after treatment and of normal controls. The results showed that T-bet, IFN-γ and IL-2 were significantly over-expressed in ITP patients (p<0.001), which represented a Th1 up-regulation. After treatment, T-bet, IFN-γ, IL-2 and IL-4 were markedly down-regulated, while Foxp3 were up-regulated (p<0.05). Interestingly, TGF-β showed a different pattern between old and young patients. It was down-regulated (p<0.05) among patients younger than 60, while up-regulated in older patients. In conclusion, we found significant change of T cell associated gene expression in ITP patients. And standard dose of prednisone treatment could effectively tune T cell subgroups to a suppressive pattern.

Disclosures:
No relevant conflicts of interest to declare.