bluuebunny/crossref_metadata_2025 huggingface dataset:
Thrombophilia Effect On Periprocedural Thromboembolism and Bleeding in Chronically Anticoagulated Patients
Authors: Wysokinska Ewa M. , McBane Robert D , Wysokinski Waldemar E , Slusser Joshua , Hodge David O , Heit John A
Published: October 2019

Abstract 3404

Background:

Appropriate periprocedural management of the chronically-anticoagulated patient with an inherited or acquired thrombophilia is uncertain.

Objective:

To estimate the 3-month cumulative incidence of thromboembolism (TE) and major bleeding and test thrombophilia as a potential predictor of these outcomes among chronically-anticoagulated patients undergoing a procedure.

Methods:

2182 consecutive patients referred to the Mayo Thrombophilia Center for standardized peri-procedural anticoagulation management were followed for TE, major bleeding and survival. The three-month cumulative incidence rates for TE, major bleeding and death were estimated by Kaplan-Meier analyses. For each chronic anticoagulation indication, we tested “strong” thrombophilia (antithrombin, protein C or protein S deficiency, homozygous or combined heterozygous Factor V Leiden or prothrombin G20210A), ”weak” thrombophilia (heterozygous Factor V Leiden or prothrombin G20210A), lupus anticoagulant/antiphospholipid antibodies and bridging heparin as potential predictors of TE and major bleeding using Cox proportional hazards modeling.

Results:

Patients with thrombophilia tended to be younger with a slight female predominance. Compared to no thrombophilia, thrombophilia patients (n=202; 143 bridged with heparin) had similar rates of venous (0% vs. 0.5%; p=0.34) and arterial (0.5% vs. 0.5%; p=0.94) thromboembolism, major bleeding (2.0% vs. 2.0%; p=0.97) and mortality (1.5% vs. 2.2%; p=0.52). Among thrombophilia patients, the TE and major bleeding rates were similar for strong (n=29) or weak thrombophilia (n=99), or lupus anticoagulant/antiphospholipid antibodies (n=74). Similarly, among thrombophilia patients, bridging heparin did not affect the rates of major bleeding (2.1% vs. 1.7%; p=0.85) or TE (0.7% vs. 0%, p=0.52).

Conclusions:

Inherited or acquired thrombophilia does not appear to impact the rates of TE, major bleeding or mortality after temporary interruption of chronic anticoagulation for an invasive procedure.

Disclosures:

No relevant conflicts of interest to declare.
Cluster Analysis Followed by Network Meta-Analysis to Compare Efficacy and Safety of Dabigatran, Rivaroxaban and Apixaban After Elective Total Knee and Hip Replacement Surgery
Authors: Harenberg Job , Marx Svetlana , Zolfaghari Shabnam , Weiss Christel , Wehling Martin , Schulze Astrid , Dahl Ola E
Published: October 2019

Abstract 3409

The new oral anticoagulant (NOAC) regimens (dabigatran 150mg od (D150) and 220mg od (D220), rivaroxaban 10mg od (R10), and apixaban 2.5mg bid (A5) have shown equivalent or superior efficacy and safety vs enoxaparin regimens for prevention of venous thromboembolism (VTE) following elective total knee (TKR) or hip replacement (THR) surgery. Due to a lack of head to head trials a network meta-analysis (NMA) may give information on a comparison between NOACs.

Studies comparing a NOAC with low-molecular-weight heparin for prevention of VTE following TKR and THR were included into the following set of analyses. First, a cluster analysis was performed to identify homogenous groups. Second, only homogeneous studies regarding each endpoint (VTE and VTE related death, major bleeding, and mortality) were included into a meta-analysis for each NOAC regimen. The odds ratio (OR) and 95% confidence interval (CI) were calculated for each NOAC program versus the comparator. Third, these OR and 95% CI were used for the NMA comparing the 4 treatment regimens.

First, cluster analysis identified duration of treatment (10+5 and 32+5 days) as the only measure for obtaining homogeneity of trials for every NOAC on every endpoint at 10+5 and 32+5 days (p>0.05) except for A5 and VTE over 10+5 days (analysis not performed). Third, the results of the NMA of the OR and 95% CI of the 4 NOAC regimens over 10+5 days were: D150 and D220 not different on any endpoint; D150 and D220 inferior to R10 for VTE (p<0.01, p<0.001); A5 trend for less major bleeding than R10 (p=0.0546); no differences for the other indirect comparisons. Results for 32+5 days were: D150 and D220 not different on any endpoint; D150 and D220 inferior to R10 VTE (p<0.001, p=0.0015) and to A5 for VTE (p<0.001, p<0001); R10 and A5 not different on VTE. Comparisons of major bleeding and mortality were not different.

The lack of a standard definition of VTE and bleeding outcomes between and sometimes within the studies of the NOACs substantially reduce the number of homogenous studies for inclusion into the present NMA using cluster analysis. The differences may help doctors and patients to decide the optimal treatment regimen for individual patient groups.

Disclosures:

No relevant conflicts of interest to declare.
BCOR Is Involved in Myeloid Cell Growth Control by Regulating Hox Genes
Authors: Cao Qi , Gery Sigal , Shojaee Seyedmehdi , Gearhart Micah , Bardwell Vivian , Muschen Markus , Koeffler H. Phillip
Published: October 2019

Abstract 3445

BCOR interacts with Polycomb group (PcG) proteins to form a PRC1-like transcriptional repressive complex. BCOR is an essential developmental regulator: hemizygous mutation of BCOR in males causes gestational lethality, and heterozygous mutation in females causes the X-linked developmental disorder Oculofaciocardiodental syndrome (OFCD). Studies in humans, cell lines and mice indicate that BCOR plays key roles in the regulation of early embryonic development, mesenchymal stem cell function and hematopoiesis. Recently, recurrent somatic BCOR mutations have been reported in retinoblastoma, medulloblastoma and acute myelogenous leukaemia (AML) suggesting BCOR functions as a tumor suppressor protein. The goal of the current study was to begin elucidating the function of BCOR in normal hematopoiesis and in hematopoietic transformation. To examine this in the mouse we transduced bone marrow (BM) from mice harboring a conditional Bcor deletion allele (BcorFl/Y) with lentivirus expressing CRE. FACS analysis showed that with CRE, 83% of Bcor-/Y (Bcor KO) BM cells kept in IL3, IL6 and stem cell factor (SCF) were CD34+ compared to 95% of non-induced BcorFl/Y (Bcor WT) BM cells. Moreover, following G-CSF treatment, Bcor KO BM cells showed a much higher incidence of cell differentiation (40.5%) compared to Bcor WT cells (5.4%) as shown by CD11b/Gr-1 FACS analysis. Surprisingly, Bcor KO BM cells also showed significantly higher proliferation rates in liquid culture and methycellulose colony assays. To identify BCOR downstream target genes, we compared the gene expression profiles between Bcor KO and WT BM cells. Real-time-PCR of individual Hox genes confirmed the upregulation of HoxA5, HoxA7 and HoxA9 in Bcor KO BM cells, which are known to increase self-renewal of immature hematopoietic cells. In addition, ChIP analysis showed specific binding of BCOR to HoxA7 promoter. In conclusion, our results from mouse experiments suggest that BCOR is involved in maintaining the CD34+ stem cell state and loss of BCOR leads to enhanced myeloid cell differentiation and proliferation possibly by regulating Hox genes. In addition, we examined BCOR expression levels in a large panel of human leukemic cell lines; high level BCOR mRNA and protein were detected in most cell lines. Notably, 2 cell lines, U937 and HL60, had low levels of BCOR mRNA and no detectable BCOR protein. Treatment of both cell lines with the differentiation inducers ATRA, Vitamin D3 or DMSO lead to a mark induction in BCOR expression both at the mRNA and protein level, suggesting that BCOR may be involved in myeloid cell differentiation. Further investigation should shed more light on the roles BCOR that plays in normal hematopoiesis and whether BCOR loss later in hematopoiesis could result in a differentiation block.

Disclosures:

No relevant conflicts of interest to declare.
Overexpression of Sharp-1 in MLL-AF6-Positive Acute Myeloid Leukemia
Authors: Kawasaki Akira , Taneja Reshma , Delwel Ruud , Tenen Daniel G.
Published: October 2019

Abstract 3493

Patients with acute myeloid leukemia (AML) carry various chromosomal translocations and/or mutations. Although t(6;11)(q27;q23) is observed in only less than 0.5 % of adult AML patients, this translocation is reported to be one of the independent poor prognostic factors in AML. This translocation induces expression of MLL-AF6 fusion protein, but the precise mechanism of leukemogenesis by MLL-AF6 has not yet been elucidated compared to other MLL fusion proteins. During the analysis of gene expression profiling of >500 AML patients registered in Erasmus University Medical Center in Rotterdam, we happened to find that all of five patients carrying t(6;11) translocation exhibited overexpression of Sharp-1/Dec2, which is involved in the circadian rhythm. AML cell lines carrying this translocation, ML-2 and CTS, also showed more than 10-fold upregulation of Sharp-1 expression. Knockdown of MLL-AF6 expression to 10 % in ML-2 cells by shRNA suppressed expression of Sharp-1 to less than 1 % through the change in the methylation status of histone H3 lysine residues in the Sharp-1 gene promoter region confirmed by chromatin immunoprecipitation. In addition, this knockdown induced growth suppression of ML-2 cells to 40–50 %. Proliferation of ML-2 cells was also suppressed by the knockdown of Sharp-1. Growth suppression of ML-2 cells is neither due to increased apoptosis nor increased differentiation, but due to increased number of cells undergoing cellular senescence together with the upregulation of p21. Furthermore, exogenous expression of Sharp-1 in murine bone marrow cells induced the proliferation of myeloid cells with the reduction of lymphoid cells in the bone marrow transplantation model. These results suggested that Sharp-1 plays a crucial role in the pathogenesis of AML with t(6;11)(q27;q23) and that targeting of Sharp-1 in leukemic stem cells would be a novel therapy for this poor outcome AML.

Disclosures:

No relevant conflicts of interest to declare.
Bcr-Abl Represses IRF8 Gene Transcription in a Stat5-Dependent Manner
Authors: Hjort Elizabeth , Huang Weiqi , Eklund Elizabeth A.
Published: October 2019

Abstract 3497

The interferon consensus sequence binding protein is a member of the interferon regulatory factor family of transcription factors (referred to as Icsbp or Irf8). The first described functions for Icsbp involved regulation of phagocyte and B-cell effector genes, including genes encoding components of the phagocyte NADPH-oxidase, Toll-like receptors and interleukin receptors. However, subsequent studies in murine models and human disease indicated that Icsbp also functions as a myeloid leukemia suppressor. For example, decreased Icsbp expression is found in chronic myeloid leukemia (CML) in association with uncontrolled disease, drug resistance and progression to blast crisis (BC). Decreased Icsbp expression is also found in the bone marrow of subjects with some subtypes of acute myeloid leukemia (AML). Consistent with this clinical correlative data, IRF8−/− mice exhibit a myeloproliferative neoplasm that is similar to CML and progresses to BC over time. However, the mechanism for decreased Icsbp expression in leukemia is not known, although preliminary studies indicate that DNA-methylation of the IRF8 locus is not altered. Therefore, in these studies, we investigate the effects of Bcr-abl on IRF8 transcription. This is clinically relevant, because previous studies in our laboratory identified a set of Icsbp-target-genes that contribute to the pathogenesis of CML. We find that Bcr-abl decreases expression of Icsbp mRNA and protein in a kinase dependent manner. Since it is unlikely that Bcr-abl directly binds to the promoter to regulate gene transcription, we hypothesized that Bcr-abl regulates IRF8 through an intermediary transcription factor. In this study, we determine that Stat5 negatively regulates IRF8 transcription through a proximal promoter cis-element. We also find that Stat5 repression activity is necessary for Bcr-abl dependent regulation of IRF8. Bcr-abl is known to phosphorylate and activate Stat5 in CML. In our studies, we find that Stat5 protein (but not mRNA) is also increased in Bcr-abl+ cells. Stat5 is a known substrate for calpain; a serine protease. We previously demonstrated that Icsbp regulates calpain protease activity through repression of the gene encoding Gas2; an endogenous calpain inhibitor. Consistent with this, our current studies demonstrate that Stat5 protein stability is increased in Bcr-abl+ cells in an Icsbp/Gas2/calpain-dependent manner. These results identify novel mechanisms by which Bcr-abl-kinase activity controls a positive feedback loop that leads to decreased Icsbp expression and stabilization of Stat5 protein. These studies suggest that targeting Gas2/calpain might be a novel therapeutic approach to CML.

Disclosures:

No relevant conflicts of interest to declare.
Curcumin Potentiates Antitumor Activity of Imatinib Via Inhibition of the AKT/mTOR Signaling Pathway and Down-Regulation of Bcr-Abl Gene in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
Authors: Gong Yuping , Guo Yong , Niu Ting
Published: October 2019

Abstract 3559

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is triggered by constitutively activated BCR-ABL and SRC family tyrosine kinases. They interact each other, then activate downstream growth-signaling pathways including Raf/MEK/ERK,Akt/mTOR and STAT5 pathways. The BCR-ABL tyrosine kinase inhibitor imatinib is the standard treatment for Ph+ leukemia. However, response rate of Ph+ ALL to imatinib is low, relapse is frequent and quick. Studies have documented the potential anti-tumor activities of curcumin, a yellow colored polyphenol from the perennial herb Curcuma longa. However, whether curcumin can be used in the therapy for Ph+ALL remains obscure. Here, we reported that curcumin induced autophagic cell death by activating RAF/MEK/ERK pathway in early stage of the 24-hour exposure course, later induced apoptosis by inhibiting AKT/mTOR, ABL/STAT5 signalings, down-regulating expression of bcr/abl gene and Bcl2 anti-apoptosis protein, and up-regulating the expression of pro-apoptosis protein BAX in Ph+ALL cell line SUP-B15. Furthermore, we found curcumin exerted synergetic anti-leukemia effect with imatinib by inhibiting imatinib-mediated up-regulation of the activation of AKT/mTOR signaling and down-regulating expression of bcr/abl gene. It is worth noting that curcumin provide advantages over dexmethasone as to synergetic anti-leukemia effect with imatinib because dexmethasone improved the imatinib-mediated up-regulation of the activation of AKT/mTOR/P70S6 signaling. In primary samples from Ph+ALL patients, curcumin inhibit growth signaling not only in newly-diagnosised patient but also in imatinib-resistant patient. Moreover, curcumin effectively exhibited anti-leukemia efficacy and synergetic anti-leukemia effect with imatinib in Ph+ALL mouse models. These results demonstrate that curcumin may be a promising agent for the treatment of patients with Ph+ ALL, and curcumin might be particularly effective when used with current induction regimens consisting of imatinib with or without chemotherapy for treating Ph+ ALL. [Grant Support:National Natural Science Foundation of China (No.30770912), Foundation of the Science & Technology Department of Sichuan Province (No.2008SZ0017)].

Disclosures:

No relevant conflicts of interest to declare.
Sustained Long-Term MMR to a Reduced Dose of Imatinib in Chronic-Phase CML: A Pilot Study of SLC22A1 Gene Polymorphisms
Authors: Lee Se Ryeon , Lee Seok Young , Kim Dae Sik , Park Yong , Sung Hwa Jung , Choi Chul Won , Ahn Jae Sook , Yang Deok-Hwan , Kim Byung Soo
Published: October 2019

Abstract 4449

Background:

Recently, The efficacy of reduced dose of imatinib for the patients with small BSA was reported by our group and Japanese group. Also, therapeutic drug monitoring to maintain a plasma threshold level of about 1,000ng/ml would be beneficial during imatinib therapy in practical setting. But, we sometimes see a discrepancy between imatinib trough level and clinical efficacy. Observed inter-patient pharmacokinetic variability may be due to patients' genetics.

Method:

We investigated a panel of 9 polymorphisms in 4 genes (ABCG2, SLC22A1, ABCB1, CYP3A5), potentially associated with the pharmacogenetics of imatinib in a subset of 7 patients with sustained MMR. The DNAs from peripheral blood samples were genotyped. Imatinib trough levels were tested between 21 and 27 hours from the last dose of imatinib.

Result:

All patients were reduced dose to 300mg/day within six months after starting imatinib therapy with 400mg/day. The main reasons for dose reduction were severe neutropenia or thrombocytopenia (≥ grade 3) (62.9%). They couldn't increase a standard imatnib dose due to severe adverse effect. Although relatively small BSA (mean BSA; 1.53), 4 of seven patients showed lower imatinib trough level than 1,000ng/ml. After median follow-up period of 66.2 months (18.4∼150.7), all patients have sustained MMR. Allele frequencies of rs683369, rs2282143, rs628031and rs2282143 polymorphisms of SLC22A1 gene were 0%, 78.5% and 8.3%, respectively. Interethnic differences in the genotype and allele frequencies of SLC22A1 gene polymorphism were observed when compared with other previous major populations. The SNPs rs2282143, T allele and rs628031, G allele were more common in Asians (5.5–16.8% and 76.2–81%) and African Americans (8.2% and 73.5%) than in Caucasians (0–2% and 57.4–60%).

Conclusion:

In our pilot study, we found interethnic differences in the genotype and allele frequencies of SLC22A1 gene in spite of very small cases. These findings might be explained a discrepancy between imatinib trough level and clinical efficacy in practical setting with reduced dose and further studies with larger scale will be needed to clarify the effect of these results.

Disclosures:

No relevant conflicts of interest to declare.
Parameters That Contribute to Hearing Loss in Cml Patients
Authors: Benneh Amma A. , Olayemi Edeghonghon , Baidoo Kenneth , Adjei David Nana
Published: October 2019

Abstract 4455

Background:

Chronic Myeloid leukaemia (CML) is a clonal disease that results from an acquired genetic change in a pluripotential haemopoietic stem cell. Hearing loss is a rare complication of CML. The most probable cause of the hearing loss in CML has been attributed to hyperleukostasis rather than leukaemic infiltration as seen in other leukaemias. This supported by the fact that hearing loss can be reversed in some patients if leukapheresis is done early.

Patients and Methods:

This retrospective study was conducted at the Korle-Bu Teaching Hospital, Accra, Ghana. Study included adult patients diagnosed with (CML) over a five year period from January 2007 to December 2011 who presented with hearing loss. Seven of them presented with hearing loss. Diagnosis of CML was made by a bone marrow aspirate and confirmed with Fluorescence in situ hybridization (FISH) analysis for Philadelphia chromosome. Medical records of cases were analyzed for their demographic characteristics and clinical features. Haemoglobin levels, total white cell count at presentation and platelet count were also obtained from their full blood counts. Correlation between hearing loss and parameters such as age, sex, total white cell count at presentation, level of haemoglobin, platelet count and results of FISH analysis on presentation were analysed and level of significance obtained using Pearson's correlation.

Results:

Eight-three patients were diagnosed with CML over the period and 8.4% (7) presented with hearing loss. Six of the patients were males and there was one female. Significant level of significance was found between hearing loss and white cell count (p=0.043), haemoglobin level (p=0.024), sokal score (p=0.001) and results of FISH at diagnosis (p=0.039). Level of significance was 5%.

Conclusion:

There was significant correlation between hearing loss and parameters such as white cell count at presentation, haemoglobin level, sokal score and results of FISH at diagnosis in this study. These factors played a role towardsthe loss of hearing of these CML patients in the study.

Disclosures:

Baidoo: GSK: Speakers Bureau.
Conjunctival Biopsy to Guide Treatment of Chronic Ocular Gvhd
Authors: Patel Pritesh R. , Ghandi Sonal , Sonawane Snehal , Tibrewal Sapna , Jassim Saumad , Gaitonde Sujata , Saraf Santosh L , Jain Sandeep , Rondelli Damiano
Published: October 2019

Abstract 4491

The treatment of chronic ocular graft-versus-host disease (GVHD) is empirical, mainly due to the lack of knowledge of its pathogenesis. The goals of this study were to describe the histopathologic and immunophenotypic characteristics of conjunctival biopsies from patients with chronic ocular GVHD and to determine whether these findings can guide immunomodulation or palliative management strategies of GVHD associated dry eye disease.

A conjuctival biopsy was obtained in eleven patients who previously received an allogeneic hematopoietic stem cell transplant (HSCT) and presented with chronic GVHD and dry eye symptoms. Hematoxylin and eosin (H&E) and immunohistochemical staining of conjunctival biopsies were analyzed for presence of inflammatory cells (B and T cells), fibrosis, and apoptosis. All conjunctival biopsies showed the presence of keratosis and parakeratosis and 7/11 (64%) biopsies had evidence of conjunctival epithelial apoptosis. Immunohistochemistry demonstrated the presence of inflammatory cells in 72% (8/11). These cells were predominantly CD3+ T lymphocytes (54%), with a CD4:CD8 cell ratio of 1:1.7. No biopsies showed B cells. Fibrosis was noted in 54% of biopsies (6/11). Conjunctival apoptosis detected by caspase-3 antibody staining showed significant moderate positive correlation with goblet cell loss (r=0.6, p=0.04). Presence of inflammatory cells showed a stronger correlation with conjunctival apoptosis as compared with fibrosis (r=0.38 and 0.26 respectively), however both correlations were not significant (p<0.05).

A standard dry eye treatment regimen in chronic ocular GVHD remains to be determined, thus examining the histopathologic features may help guide a more focused management strategy. In this study conjunctival apoptosis was associated with significant goblet cell loss and it more frequently accompanied inflammation as compared to fibrosis. Aggressive topical immunomodulation may reduce inflammation and goblet cell loss in patients with conjunctival biopsies positive for apoptosis.

Disclosures:

No relevant conflicts of interest to declare.
Comparative Outcomes of Reduced-Intensity and Myeloablative Conditioning in Unrelated Cord Blood Transplantation for Adult Standard-Risk Hematological Diseases
Authors: Nishida Aya , Ota Hikari , Ishiwata Kazuya , Tsuji Masanori , Yamamoto Hisashi , Asano-Mori Yuki , Yamamoto Go , Uchida Naoyuki , Izutsu Koji , Wake Atsushi , Yoneyama Akiko , Makino Shigeyoshi , Taniguchi Shuichi
Published: October 2019

Abstract 4498

Background:

Unrelated cord blood transplantation (uCBT) using reduced-intensity conditioning (RIC) is increasingly used for older and medically unfit patients. Data on the efficiency of hematopoietic stem cell transplantation (HCT) after RIC in younger and standard-risk patients are limited relative to myeloablative conditioning (MAC).

Objective and method:

To compare the outocomes of RIC to MAC in uCBT for adult patients with standard-risk hematological diseases, we retrospectively reviewed medical records of 57 standard risk hematological disease patients who underwent first uCBT at Toranomon Hospital from Jan. 2005 to December.2011. The definition of standard risk disease is severe aplastic anemia (SAA), myelodysplastic syndrome (MDS) in RA, RARS, and RCMD, acute myeloid or lymphoid leukemia (AML, ALL) in complete remission (CR) 1 or 2, chronic myeloid leukemia (CML) in chronic phase, malignant lymphoma (ML) and adult T-cell leukemia (ATL) in CR. RIC and MAC are defined according to previously reported criteria.

Result:

The median age of the studied patients was 55 years (range; 26–70). Twenty nine of patients received RIC and 28 MAC. Eleven patients of SAA, 7 MDS, 17 AML, 12 ALL, 5 CML, 2 ML, and 3 ATL were included in this study. Median follow-up days of survivors was 299 (11–2522). Cumulative incidence of neutrophil engraftment was 89.2% and the median days of engraftment is 20 days (11–51). Cumulative incidence of grade 2 to 4 acute graft versus host disease (aGVHD) was 42.9%. The 5-year disease-free and overall survival (DFS and OS) rates were 49.1% and 42.6%, respectively. The 5-years OS was comparable between MAC and RIC (RIC= 52.1% versus MAC= 44.2%; P=0.90). The 5-years OS of the elderly patients >54 years (n=27, 47%) were significantly lower than that in the younger patients (n=30, 53%) (35.1% versus 63.7%; P=0.042). The 5-years transplant-related mortality (TRM) was comparable between MAC and RIC (RIC= 35.0% versus MAC= 28.6%; P=0.56). The relapse rate was also comparable in two groups (RIC=11.9% versus MAC=33.6%; P=0.2)

Conclusion:

This study showed that uCBT with RIC for standard risk disease patients with median age of 55 years old had the similar results as MAC regimens in the 5-years OS, DFS, TRM and relapse rate.

Disclosures:

No relevant conflicts of interest to declare.
A Novel Conditioning Regimen Improves Outcomes in b-Thalassemia Major Patients Using Unrelated Donor Peripheral Blood Stem Cell Transplantation
Authors: Chunfu Li , Huayin Liu , Liu Qifa
Published: October 2019

Abstract 4514

We used a novel NF-08-TM transplant protocol in 100 consecutive patients with β-thalassemia major (TM), including 66 with allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated donors (UD) with well-matched human leukocyte antigens (HLAs) and 34 with hematopoietic stem cell transplantation (HSCT) from matched sibling donors (MSD). The median age at transplantation was 6.5 yo (range: 0.6–15 yo), and the ratio of male to female patients was 68:32. The median follow-up time was 24 months (range: 12–39 months). The 3-year overall survival (OS) and TM-free survival (TFS) were 92.4% and 90.9% in the UD-PBSCT group and 88.2% and 82.4% in the MSD-HSCT group. The cumulative incidences of graft rejection (GR) and grade II–IV acute graft-versus-host disease (aGVHD) were 1.5% and 10.6%, respectively, in the UD-PBSCT group and 6.1% and 5.9%, respectively, in the MSD-HSCT group. The cumulative incidence of transplant-related mortality (TRM) was 7.6% in the UD-PBSCT group and 11.8% in the MSD-HSCT group. In conclusion, UD-PBSCTs using the well-tolerated NF-08-TM protocol show similar results to MSD-HSCTs and can be used to treat b thalassemia patients in the absence of MSD.

Disclosures:

No relevant conflicts of interest to declare.
Abolished Daily Expression Patterns of SIRT1, SIRT2, and SIRT5 in Human Chronic Myeloid Leukemia
Authors: Yang Ming-Yu , Lin Pai-Mei , Hsu Jui-Feng , Yang Wen-Chi , Liu Yi-Chang , Hsiao Hui-Hua , Chang Chao-Sung , Hsu Cheng-Ming , Lin Sheng-Fung
Published: October 2019

Abstract 4613

Circadian rhythms regulate various functions of human body and disruption of circadian rhythm has been associated with cancer development and tumor progression. Circadian clock genes use transcriptional-translational feedback loops to control circadian rhythms. Many transcriptional regulators are histone acetyltransferases (HAT) or histone deacetylases (HDAC). As clock function and integration of inputs rely on transcriptional regulation, it is possible that chromatin is remodeled during circadian cycles and in response to signals that regulate the clock. SIRT1 (sirtuin 1) is a HDAC that has recently been identified as a crucial modulator of the circadian clock machinery. To date, at least 7 SIRT genes (SIRT1–7) have been identified. In our previous report we have demonstrated the daily expression patterns of PER1, PER2, PER3, CRY1, CRY2, and CKIe in peripheral blood (PB) of healthy individuals were abolished in chronic myeloid leukemia (CML) patients and partial recoveries of daily patterns were observed in CML patients with complete cytogenetic response (CCyR) and major molecular response (MMR) post-imatinib treatment [J Biol Rhythms 2011]. In this study we further investigated the expression profiles of the 7 SIRT genes (SIRT1–7) in PB total leukocytes from 49 CML and 22 healthy volunteers. Collection of PB was carried out at four time points: 2000 h, 0200 h, 0800 h, and 1400 h, respectively. In PB total leukocytes of healthy individuals, the daily pattern of SIRT1 (p < 0.01) and SIRT5 (p < 0.05) expression level peaked at 0200 h, and SIRT2 (p < 0.01) peaked at 0800 h. Daily pattern expression of these 3 genes was abolished in newly diagnosed pre-imatinib mesylate treated and blast crisis-phase CML patients. Partial daily patterns of gene expression recoveries were observed in CML patients with CCyR and MMR. In some serial monitored individual patients, the recoveries of oscillations of SIRT1, 2, and 5 genes expression accompanied with the disappearance of BCR-ABL transcripts were also noted. The expression of SIRT3, 6, and 7 did not show a time-dependent variation among the healthy and CML patients. SIRT4 expression was undetectable both in the healthy and CML patients. Updated in vitro study results of the regulation of SIRT1, 2, and 5 genes on circadian clock genes expression will be presented at the meeting.

Disclosures:

No relevant conflicts of interest to declare.
Descriptive Evaluation of Age-Related Differences in Clinical Manifestation and Treatment of Von Willebrand's Disease in an Open-Label, Prospective, Non-Interventional Study (wilate®-SET)
Authors: Hegener Oliver , Scharrer Inge , Feddern Jennifer , V Wolfgang A. Miesbach , Von Depka Mario , Kadar Janos
Published: October 2019

Abstract 4630

Efficacy, tolerability and dosing of a VWF/FVIII concentrate may differ in paediatric, adults, and elderly patients. It is therefore reasonable to collect and evaluate clinical data of patients from different age groups and to look into differences in treatment and reason for treatment with VWF/FVIII concentrate. A cohort of 120 patients suffering from all types of von Willebrand's disease (VWD) from an on-going German post-marketing surveillance study was analysed for age-related differences in treatment with a high-purity, double virus inactivated VWF/FVIII concentrate (wilate®).

Results:

Thirteen children up to 12 years of age and 14 patients being 65 or older were treated for prophylaxis, haemorrhages or peri-operatively. Obvious deviations were found in general condition, bleeding locations and types of surgeries for the elderly patients. Further, the data provide evidence of age group-related differences regarding reason for administration (see table 1) and dosages administered. The efficacy and tolerability of wilate®treatment in children and elderly was as high as in the total group.

Conclusion:

Young or old age seem to have an impact on clinical requirements of VWD. However, larger cohorts are required to confirm these first findings of the non-interventional study “Wilate SET”.

Disclosures:

Hegener: Octapharma AG: Employment. Feddern:Octapharma: Employment.
Donor CMV Status Influence On the Outcome of Allogeneic Stem Cell Transplantation (HSCT); A Study by the Infectious Diseases Working Party (IDWP) of the EBMT
Authors: Ljungman Per T. , Brand Ronald , De La Camara Rafael , Cordonnier Catherine , Einsele Hermann , Styczynski Jan , Ward Katherine N. , Cesaro Simone
Published: October 2019

Abstract 465

A previous study from the IDWP of the EBMT showed that CMV seropositive patients undergoing unrelated donor HSCT had increased NRM and decreased survival if they were grafted from a CMV seronegative donor. This finding has been controversial and we therefore decided to revisit the question with a larger number of patients and including new factors such as conditioning intensity.

Patients were selected from the EBMT database who had received an allogeneic HSCT from 1992 – 2008 and for whom both the donor and recipient CMV status were known. Patients receiving cord blood grafts were excluded. 54660 patients were identified and included in the study; 32320 seropositive and 22340 seronegative patients. The different donor categories (sibling, mis-matched family, unrelated) were analyzed separately. Cox multivariate models were fitted to estimate the effect of donor serological status (positive versus negative) on outcome both in CMV seropositive and CMV seronegative patients adjusted for year of HSCT, donor and patient gender, recipient age, stem cell source, diagnosis, use of alemtuzumab or ATG, country, and conditioning intensity (RIC vs. MAC).

Seronegative patients receiving grafts from seropositive unrelated donors had an decreased overall survival (OS; HR 1.13; p<.01); relapse free survival (RFS; HR 1.10; <p<.01) and increased non-relapse mortality (NRM; HR 1.13; p<;.01) while no significant effect was seen on relapse incidence (RI; HR 1.06). There were no significant effects in patients receiving HLA-identical or mis-matched family donors. Seropositive patients receiving grafts from seropositive unrelated donors had improved OS (HR 0.91; p<.01), RFS (HR 0.94; p<.05), and decreased NRM (HR 0.87; p<.01) if they had received MAC. No effect of donor serostatus was seen in patients receiving unrelated donor grafts after RIC. No effect of donor status was seen on RI. There were no significant effects in patients receiving HLA-identical or mis-matched family donors. Based on the recent study of Elmaagacli et al showing a decreased relapse risk in patients transplanted for AML of early CMV replication, a separate analysis regarding RI was performed only in AML patients in first CR. However, no effect of donor serostatus on RI was found in either seropositive or seronegative patients.

In this analysis we confirm the negative effect on OS, RFS, and NRM if a CMV seropositive unrelated donor is selected for a CMV seronegative patient. It therefore remains important to select a seronegative donor when the patient is seronegative. For a CMV seropositive patient our data support the choice of a CMV seropositive donor if the patient is planned to receive a myeloablative conditioning regimen.

Disclosures:

No relevant conflicts of interest to declare.
Acquired Glanzmann's Thrombasthenia Associated with Hodgkin Lymphoma: Rapid Reversal of Functional Platelet Defect with Chemotherapy Despite Persistence of a Glycoprotein Iib/Iiia Auto-Antibody
Authors: Raman Vinod , Quillen Karen , Sloan John Mark
Published: October 2019

Abstract 4656

Background:

Acquired Glanzmann's Thrombasthenia (GT) is a rare hemorrhagic disorder characterized by the impairment of platelet function caused by inhibition of GpIIb/IIIa signaling, often by an autoantibody. This disorder has been associated with lymphoproliferative and autoimmune disease.

Case:

A previously healthy 44 year old male presents with severe spontaneous nasal, gingival, and gastrointestinal bleeding with mildly elevated INR and aPTT and normal platelet count in the setting of newly diagnosed stage IVB classical Hodgkin lymphoma, Nodular Sclerosis type.

At presentation, platelet aggregation studies showed no aggregation with ADP, epinepherine, and arachidonic acid, with preserved ristocetin aggregation. An anti-platelet antibody was detected. Bone marrow aspiration showed megakaryocytes that were increased in number with occasional atypical forms. Patient was started on ABVD chemotherapy for Hodgkin lymphoma with immediate resolution of bleeding diathesis. Repeat platelet aggregation after cycle 2 of ABVD showed normalization of platelet aggregation. Despite the clinical resolution of bleeding tendency and functional platelet defect, a persistent anti-platelet antibody directed against GPIIb/IIIa receptor was detected.

Conclusion:

Acquired Glanzmann thrombasthenia is a rare disorder of hemostasis associated with lymphoma and autoimmune conditions. The prompt reversal of the functional defect with chemotherapy in this patient, as well as the persistence of the GpIIb/IIIa antibody, suggest that there may be additional additional lymphoma-specific factors that modify the effect of the autoantibody.

Disclosures:

No relevant conflicts of interest to declare.
Superior Immunomodulatory Effects of Cultured Mast Cells: Potent Strategy for Treatment of Gvhd
Authors: Araki Raita , Maeba Hideaki , Kuroda Rie , Fujiki Toshihiro , Mase Shintaro , Koizumi Shoichi , Yachie Akihiro , Nishimura Ryosei
Published: October 2019

Abstract 4684

Mast cells have long been known as effector cells in the various IgE-mediated allergic responses. However, recent studies demonstrated that mast cells play various roles in immune reactions in coordination with other immune cells. That is, mast cells exert pro-inflammatory or anti-inflammatory effects depending on the situation. In addition, mast cells have association with tumor development. In allogeneic hematopoietic stem cell transplantation (HSCT), only a few have reported that the numbers of mast cells were correlated with the severity of acute GVHD in the skin. However, exact role of mast cells in GVHD remains unclear. With the purpose of potential application of mast cells in a clinical HSCT for GVHD, mixed lymphocyte reaction (MLR) was performed to clarify whether mast cells impaired the alloreaction or not. To generate bone marrow derived cultured mast cells (BMCMCs), BM cells from mice were incubated in complete RPMI containing IL-3 for 6 weeks. As shown in the figure, we showed that MLR was strongly inhibited when BMCMCs from the stimulator strain were added to the coculture (Stimulator (S): DCs obtained from C57BL/6, Responder (R): splenocytes from Balb/c, BMCMCs from C57BL/6). Next, when BMCMCs from the responder strain were added to the coculture, MLR was also suppressed (S: DCs obtained from C57BL/6, R: splenocytes from Balb/c, BMCMCs from Balb/c).

In conclusion, mast cells suppressed lymphocyte proliferation induced by allo-DCs in an MHC-independent manner. Just like mesenchymal stem cells, cell therapy utilizing cultured mast cells may reduce GVHD severity.

Disclosures:

No relevant conflicts of interest to declare.
Post-Marketing Safety Experience with Edoxaban in Japan for Thromboprophylaxis Following Major Orthopedic Surgery
Authors: Kuroda Yasufumi , Hotoda Hitoshi , Nishikawa Yasuhiro , Nishiwaki Akinori
Published: October 2019

Abstract 4697

Background

Edoxaban, an oral, selective, direct factor Xa inhibitor, is approved in Japan as a once-daily dose (15 mg or 30 mg tablets) for the prevention of venous thromboembolism (VTE) following major orthopedic surgery, including total knee arthroplasty, total hip arthroplasty, and hip fracture surgery. Currently, edoxaban is in phase 3 clinical development for the prevention of stroke and systemic embolic events in patients with atrial fibrillation as well as treatment and prevention of recurrence of VTE. This report describes the adverse drug reactions (ADRs) that were spontaneously reported during early post-marketing phase vigilance (EPPV) since the July 2011 commercial launch in Japan.

Methods

EPPV was conducted for the initial 6 months from launch: July 19, 2011, to January 18, 2012. All ADRs that were spontaneously reported, were collected and analyzed.

Results

The estimated exposure was approximately 20,000 patients. A total of 67 ADRs were reported in 56 patients, of which 15 (in 14 patients) were serious. The mean age of the patients was 74.1 years, mean weight was 59.4 kg, and approximately 70% of the patients were female. The majority of ADRs were bleeding events (51 ADRs in 42 patients), and serious ADRs included cerebral hemorrhage (n=1), gastric hemorrhage (n=1), gastric ulcer hemorrhage (n=1), and surgical site hemorrhage (n=12). Most of these ADRs occurred within the first week of treatment and there were no fatalities. The majority of non-serious adverse events associated with bleeding that occurred in more than one patient included subcutaneous hemorrhage (n=9), wound hemorrhage (n=5), post-procedural hematoma (n=4), anemia (n=4), and hemarthrosis (n=3). Other non-serious adverse events occurring in more than one patient included abnormal hepatic function (n=4) and diarrhea (n=2).

Conclusions

Preliminary data from EPPV for the first 6 months of commercial use of edoxaban did not identify any unforeseen safety signals. This evidence confirms the known safety profile of edoxaban—that edoxaban has been shown to be well tolerated.

Disclosures:

Kuroda: Daiichi Sankyo Pharma Development: Employment. Hotoda:Daiichi Sankyo Co., Ltd.: Employment. Nishikawa:Daiichi Sankyo Co., Ltd.: Employment. Nishiwaki:Daiichi Sankyo Co., Ltd.: Employment.
The Cost of Pediatric Unrelated Donor Transplantation
Authors: Barros Daniele Porto , Seber Adriana , Domingues Fernando , Antunes Luciana , Araujo Valeria , Felix Olga , Ibanez Adriane , Zecchin Victor , Gouveia Roseane , Ginani Valeria Cortez , Petrilli Antonio Sérgio , Vergueiro Carmen
Published: October 2019

Abstract 4711

Allogeneic unrelated hematopoietic stem cell transplants (HSCT) are complex procedures that need adequate hospital infrastructure, a competent team, high-cost procedures and medications. Most transplants that are performed in Brazil are paid by the government. The national health system reimburses the hospital U$ 35,801.00 as a flat rate. The government has recently increased this amount by 60% but there are not national studies to use to evaluate the appropriateness of this amount.

The objective of this study was to retrospectively evaluate the cost of ten consecutive unrelated donor HSCT performed in our institution.

Methods:

The project was approved by our IRB (CEP-UNIFESP #1875/11) and granted waiver to request consent. The costs were evaluated from the first appointment until one year after transplant or death divided as 1) pre-HSCT, 2) conditioning therapy, 3) from the day of transplant until first discharge, 4) until D+100, 5) until D+180, and 6) until D+360. The costs included medications, supplies, blood transfusions, laboratory, imaging and the cost of the ward. Housing and out-of pocket costs or loss of income were not evaluated. Patients were evaluated according to the Pediatric EBMT score (1–3).

Results:

Ten consecutive children 2–14 years of age underwent unrelated donor HSCT from June, 2010 to May, 2011. Diagnoses were ALL (4). AML (3), lymphoma (2), and aplastic anemia (1). Three patients had early disease and others were in advanced phases of the diseases. Eight were CMV positive. Five had marrow and five cord blood transplants. The median time was 3.7 years from diagnosis to transplant and 80 days from referral to transplant. The patients remained in the unit for a median of 80 days (21–50). Median time to engraftment was D+22 (12–56) and six had complications and needed Intensive Care support. Of the 10 children, seven were discharged but three relapsed; overall survival is 50%. The median total cost during the first year was U$112,130.00 (mean U$ 174,000.00) – 44% of that spent within the first 100 days post HSCT. The first admission had a median total cost of U$ 60,700.00 (13,580 – 157,840). Total costs were approximately 40% higher than the direct cost. The highest costs were blood products and medications. No relationship was found between cost and age, gender, graft source of Pediatric EBMT-score.

Conclusion:

Unrelated-donor HSCT are expensive procedures and the government only partially reimburses its cost. Even with the 60% increase in reimbursement there will be a deficit in more than half of the procedures. We are working to increase this amount paid in patients who have complications and will have to continue to find alternative resources to finance the transplants.

Disclosures:

No relevant conflicts of interest to declare.
Decreased Apoptosis in Bone Marrow of Pediatric Patients After HLA-Identical Stem Cell Transplantation for African Sickle Cell Anemia
Authors: Isgrò Antonella , Marziali Marco , Sodani Pietro , Gaziev Javid , Fraboni Daniela , Paciaroni Katia , Simone Maria Domenica , De Angelis Gioia , Alfieri Cecilia , Gallucci Cristiano , Roveda Andrea , Torelli Fabio , Cardarelli Luisa , Ribersani Michela , Lucarelli Guido
Published: October 2019

Abstract 4751

Background.

In thalassemia patients ineffective erythropoiesis appears to be caused by accelerated apoptosis, in turn caused primarily by deposition of a-globin chains in erythroid precursors. The bone marrow is the main site of the erythroid cell death. The occurrence of apoptosis at the polychromatophilic stage coincides with the stage where intensive hemoglobinization occurs and could be explained by the increase in a-globin production and precipitation. The mechanism of BM apoptosis is also observed in sickle cell anemia (SCA), but is reduced. We report our experience concerning 12 geno-identical hematopoietic stem cell transplantation (HSCT) for SCA-patients, to analyse the effect of transplant on “normalization” of intramedullary apoptosis.

Patients and Methods.

Twelve patients with a median age of 12 years (range, 2–16), affected by sickle cell anemia (SCA), received hematopoietic stem cell transplantations from HLA-identical, related donors following a myeloablative conditioning regimen. We studied Fas (CD95+) and caspases-3 expression on erythroblast subpopulation. Using both CD71 and FSC parameters, we obtain 3 principal populations, which we labelled A, B, C erythroblasts (Ery. A, Ery. B, Ery. C). Ery A (CD71high FSChigh) are basophilic, Ery. B (CD71high FSClow) are late basophilic and polychromatic, whereas Ery. C (CD71low FSClow) are orthochromatic erythroblasts and reticulocytes.

Results.

We observed an expansion of Ery A, Ery B and Ery C population at baseline, probably as an essential process needed to maintain a constant red cell production in SCA patients (42.4% Ery A; 24.7% Ery B; 35.6% Ery C). After BM transplant decreased levels was observed especially on Ery A and Ery B populations (12.9% Ery A; 7% Ery B; 35% Ery C). After BM transplant Fas expression was reduced in all 3 erythroid population, but significantly on more immature Ery A (17% vs 3.5% CD95+ on Ery A; 32.2 vs 24.4 on Ery B; 5% vs 3.3% on Ery C). This observation may suggest that Fas, expressed by early erythroblasts in vivo, might contribute to the cell death of erythroid precursors in bone marrow, but this was corrected after HSCT. In addition, only after transplant we observed an initial increase of caspases 3 on more mature Ery C population (2.3% at baseline vs. 15.3% after transplant), as observed during later steps of “normal” cell maturation.

Conclusion.

After HSCT in SCA we observed a “normalization” of erythroid populations, in parallel with decreased intramedullary apoptosis rate, suggesting normal erythroid maturation in ex-SCA patients.

Disclosures:

No relevant conflicts of interest to declare.