bluuebunny/crossref_metadata_2025_split huggingface dataset:
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
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
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
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
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
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
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
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
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
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
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.