bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gemtuzumab Ozogamicin After Allogeneic Stem Cell Transplantation for Acute Leukemia
Authors: Kobayashi Takeshi , Shingai Naoki , Ikegawa Shuntaro , Takahashi Yukie , Aoki Jun , Yoshioka Kosuke , Mori Jinichi , Yasunaga Megumi , Umezawa Yoshio , Oshikawa Gaku , Doki Noriko , Kakihana Kazuhiko , Ohashi Kazuteru , Sakamaki Hisashi 
Published: October 2019

Abstract
Abstract 1970

Abstract
Controversy abounds that anti-CD33 immunoconjugate, genutuzumab ozogamicin (GO) is really effective or not as a treatment for relapsed acute myeloid leukemia (AML). Consequently, GO is now commercially available in Japan, but not in USA or Europe. In this study, we have retrospectively analyzed the clinical impact of GO therapy as salvage or maintenance setting after allogeneic hematopoietic stem cell transplantation (allo-HSCT).
During last 5 years, GO was given to 19 patients with AML as salvage therapy for disease recurrence (n = 15 patients) or maintenance therapy (n = 4 patients) after allo-HSCT in our institution. Clinical characteristics of these 19 patients are summarized (see Table): Median age was 44 years (range, 21–70 years). GO was basically administered at a dose of 3 mg/m2. The median cycle of GO therapy was 3 cycles (range, 1–12 cycles) and 3 cycles (range, 1–4 cycles) as salvage and maintenance therapy, respectively. GO was administered at a median of 205 days after allo-HSCT (range, 38–3,111 days) in the setting of salvage therapy, while as maintenance therapy, patients with high risk AML received GO as early as 29 days after allo-HSCT (range, 24–71 days).
Two of 15 patients with recurrent disease achieved complete remission and 4 patients showed partial response (>50% decrease of bone marrow blast percentage). Thus, a total of 6 patients (40%) exhibited initial response to GO. However, 5 patients of them developed irreversible hepatic veno-occulusive disease (VOD) and eventually died at median of 146 days after GO therapy (range, 9–206 days). In view of 4 patients with maintenance therapy, 1 patient have faced to the subsequent disease relapse but no patients developed severe adverse effects including hepatic VOD and all patients are currently alive, albeit short follow-up. This small study demonstrates that GO offers an alternative tool for rescuing relapsed AML after allo-HSCT, but increases the risk of developing life-threatening hepatic VOD. Thus, further clarification is needed regarding which patients to treat with GO and at what dose of GO.

Disclosures:
No relevant conflicts of interest to declare.
Haploidentical Allogeneic Hematopoietic Stem Cell Transplantation Using the Donors with the HLA-B*5801-TNFα -308A Haplotype Produced Higher Frequency of Untoward Effects in Acute Lymphocytic Leukemia Patients
Authors: Yang Liyun , Chen Yan , Zhu Sainan , Bu Dingfang , Wang Lixiang , Jiao Xiaojie , Lu Xuechun , Liu Hongxing , Zhu Ping 
Published: October 2019

Abstract
Abstract 2002
In this study, we investigated the clinical characteristics of acute lymphoblastic leukemia (ALL) patients using sibling donors with HLA-B*5801-TNFα-308A haplotype (B5801-TNF2) for haploidentical or identical hematopoietic stem cell transplantation (HSCT). A total of 136 B-ALL cases and 29 T/NK-ALL cases were recruited. DNA samples from the patients and their siblings were assayed for genotyping of HLA and TNFα at -308 (rs1800629). B5801-TNF2 haplotype in donors was determined by analyzing TNFα -308 and HLA-B genotypes in patients and their family members. Outcomes within 2 years including overall mortality and non-relapse mortality, disease course and complications within 100 days were compared among patients using related donors with HLA-B*5801-TNFα-308A haplotype for haploidentical HSCT (B5801-TNF2+HID group), those using related donor without HLA-B*5801-TNFα-308A haplotype for haploidentical HSCT (B5801-TNF2-HID group), and those using related sibling either B5801-TNF2+ or B5801-TNF2- haplotype for identical HSCT (SID group). In the 165 sibling donors after HSCT, 35 were found to carry HLA-B*5801-TNFα-308A haplotype. There were 21 cases in B5801-TNF2+HID group, 100 cases in B5801-TNF2-HID group, and 44 cases in SID group. Compared patients in B5801-TNF2-HID and SID groups, patients in B5801-TNF2+HID group had higher overall mortality (adjusted P=0.039) and non-relapse mortality within 2 years (adjusted P=0.001), delayed platelet engraftment (adjusted P<0.0001), higher incidences of severe acute graft-versus-host disease (P=0.007), severe late onset hemorrhagic cystitis (P=0.002), blood stream infection (P=0.017), and invasive fungal disease (P=0.004) within 100 days. Therefore, sibling donors carrying HLA-B*5801-TNFα-308A haplotype for haploidentical HSCT caused higher mortality rate and higher frequency of severe complications in ALL recipients.

Keywords:
HLA-B*5801-TNFα-308A haplotype; acute lymphoblastic leukemia; allogeneic haploidentical hematopoietic stem cell transplantation; allogeneic identical hematopoietic stem cell transplantation

Disclosures:
No relevant conflicts of interest to declare.
Outcome of Stem Cell Transplantation in Adults with Acute Myelogenous Leukemia and Normal Cytogenetics (NC-AML) According to Presence of FLT-3 Internal Tandem Duplication (FLT-3ITD) At the Time of Diagnosis
Authors: Berman Ellin , Jakubowski Ann A , Maloy Molly , Jurcic Joseph G. , Jhanwar Suresh C. , Hedvat Cyrus V. , Giralt Sergio , Papadopoulos Esperanza B. 
Published: October 2019

Abstract
Abstract 2038

Background:
Cytogenetic abnormalities in leukemic blasts at time of diagnosis are the most important prognostic factors in acute myelogenous leukemia (AML). However, approximately 50% of patients (pts) with AML have normal cytogenetics (NC-AML). Within this population, the presence of somatic mutations further refines the prognosis. Mutations such as the internal tandem duplication of FLT-3 (FLT-3 ITD), and mutations in NPM1 and IDH1 have been all been shown to have significant prognostic value in determining response to chemotherapy and overall survival (OS). FLT-3 ITD is present in approximately 30% of pts with NC-AML and is considered the most significant predictor of poor prognosis following chemotherapy. However, it is not clear whether the presence of FLT-3 ITD influences the outcome of patients who undergo hematopoietic stem cell transplant (HSCT). We therefore performed a retrospective analysis of all adult patients with NC-AML and FLT-3 ITD present at time of diagnosis who underwent HSCT at MSKCC between 2007 and 2012.

Methods:
A total of 196 pts with AML underwent HSCT during this period. For this analysis, we excluded 112 pts with abnormal cytogenetics, 5 pts who had no cytogenetic testing performed, and 27 pts with normal cytogenetics who did not have molecular analysis performed.

Results:
A total of 52 pts with normal cytogenetics had molecular testing done; of these, 35 were FLT-3 negative (67%) and 17 were FLT-3 positive (33%). Characteristics of the 2 groups are shown below:

Conclusion:
Both groups had similar clinical and transplant characteristics, relapse rates, and OS (p=NS in all categories). We conclude that in this relatively small group of pts (1) HSCT appears to overcome the negative prognostic effect of FLT-3 ITD and (2) use of a T cell depleted graft does not influence transplant outcomes. A larger cooperative group analysis will be needed to confirm these findings.

Disclosures:
No relevant conflicts of interest to declare.
The Erythropoiesis Stimulating Agent Omontys/Peginesatide up-Modulates Erythroid Progenitor Formation, and Cell Surface Erythropoietin Receptor Levels.
Authors: Verma Rakesh , Green Jennifer M , Leu Karen , Mortensen Richard B , Young Peter R. , Schatz Peter J , Wojchowski Don M. 
Published: October 2019

Abstract
Abstract 2089
Peginesatide is a peptide-based erythropoietin receptor (EPOR) agonist with recent FDA approval for treating the anemia of chronic kidney disease among adult dialysis patients. Although peginesatide exhibits a 47.9h half-life when given IV in dialysis patients, it is administered once-monthly. Taken together, this predicts that additional functional properties contribute to peginesatide's durable erythropoiesis stimulating activity. Here we report on three such properties. During ex vivo murine bone marrow erythroid development, compared directly to rHuEPO, peginesatide first enhanced KitposCD71pos progenitor cell expansion (including KitposCD71lowCD36posCD13pos erythromyelo- progenitors). Second, peginesatide exhibited a 1300 minute EPOR residence time vs. 77 minutes for rHuEPO. Third, the culture of EPO-dependent human UT7epo cells in peginesatide led to substantial EPOR up-modulation, as well as an apparent lessening of the processing of mature EPOR's. Furthermore, in studies that compared peginesatide vs. rHuEPO effects on the erythroid development of human bone marrow-derived CD34pos progenitors, the following differences were observed. At days 6–10 of culture, peginesatide gave rise to increased frequencies (up to 200% as compared to rHuEPO) of KitposCD71pos co-positive erythroid progenitors. At early stages (d2-d4), cell-surface EPOR levels also were elevated among progenitors expanded in peginesatide. When levels of CD13posCD36pos co-positive cells were analyzed, frequencies of these erythromyelo-progenitors also were heightened up to three-fold. Analyses of cultures at later time-points (eg, d10 of culture) indicated that peginesatide and rHuEPO supported the formation of GPAhigh erythroblasts at similarly high frequencies. In addition, cytospin analyses revealed morphological distinctions for multicellular proerythroblast complexes formed in peginesatide. Peginesatide's persistent erythropoietic activity allowing for once-monthly dosing therefore is likely to involve novel effects on erythromyelo-progenitor recruitment, and increased EPOR cell surface expression including apparent increases in relative levels of full-length EPOR forms.

Disclosures:
Green: Affymax, Inc.: Employment. Leu:Affymax, Inc.: Employment. Mortensen:Affymax, Inc.: Employment. Young:Affymax, Inc.: Prior employment Other. Schatz:Affymax, Inc.: Employment. Wojchowski:Affymax, Inc.: Membership on an entity's Board of Directors or advisory committees.
Hydroxyurea up-Regulates Voltage-Dependent Anion Channels in Human Sickle Cell Erythrocytes.
Authors: Park Nick , Diaz Daniel , Nakagawa Peggy , Puthenveetil Geetha , Gershon Paul , Nugent Diane J 
Published: October 2019

Abstract
Abstract 2119

Background:
Hydroxyurea (HU) is clinically effective in reducing the frequency of pain crises in adults and children with sickle cell disease (SCD). In addition to increased fetal hemoglobin production, HU is known to induce macrocytosis in sickle cell erythrocytes and prolong red cell survival. However, the precise mechanism by which HU produces its varied effects is unknown. Isoelectric focusing has been applied to characterize changes in the red cell membrane following exposure to HU, but this technique has limitations in its ability to identify differences in specific membrane proteins. Mass spectrometry (MS) provides another proteomic approach in analyzing red cell proteins in SCD.

Methods:
Red blood cells were obtained from patients with SCD on HU therapy. After multiple wash and lysis steps, ghost membranes were obtained following ultracentrifugation. The membrane samples were then analyzed via tandem mass spectrometry and western immunoblot assay.

Results:
In comparison to a normal control, patients with SCD on HU therapy were found to have significantly elevated levels of voltage-dependent anion channels (VDAC) by MS, using a false discovery rate of less than five percent. The application of a stringent threshold initially identified 346 protein candidates. Out of these 346 proteins, 125 contained multiple peptides which all passed quantitation data filters according to quality parameters. Within the set of 125 proteins, 4 proteins were significantly up-regulated (up to 50-fold) in patients with SCD on HU therapy. VDAC2 and VDAC3 are members of the eukaryotic mitochondrial porin family which form channels through the mitochondrial outer membrane allowing diffusion of small hydrophilic molecules. VDAC1 can be found in both the mitochondrial outer membrane and the plasma membrane, where it is involved in cell volume regulation and apoptosis.

Conclusions:
Up-regulation of VDAC proteins may play an important role in altering the intracellular osmotic composition of the sickle cell erythrocyte resulting in decreased sickling and improved red cell survival in patients with SCD on HU therapy.

Disclosures:
No relevant conflicts of interest to declare.
Correlations Between Pancreatic Iron Burden and Heart Iron Overload and Function by MRI in a Large Cohort of Thalassemia Major Patients.
Authors: Meloni Antonella , Restaino Gennaro , Missere Massimiliano , Positano Vincenzo , Romano Nicola , Serra Giuseppe , Biguzzi Rino , De Franceschi Lucia , Favilli Brunella , Sallustio Giuseppina , Lombardi Massimo , Pepe Alessia 
Published: October 2019

Abstract
Abstract 2123

Background.
The leading cause of death in thalassemia major patients remains the heart failure, but impairment of the endocrine and exocrine function of the pancreas is a common complication. Multiecho T2* Magnetic Resonance Imaging (MRI) is a well established technique for heart and liver iron overload assessment. Little is known about the relationship between myocardial iron burden and cardiac function with pancreatic siderosis.
Aim of our study was to investigate using quantitative MRI the correlation between heart iron overload and function with pancreatic siderosis in thalassemia major patients.

Methods.
We studied 147 thalassemia major patients (233 males, mean age 31±9 years) consecutively enrolled in the Myocardial Iron Overload in Thalassemia network where MRI (1.5 T) was performed using standardized and validated procedures. Myocardial iron overload was measured by T2* multislice multiecho technique. Biventricular function parameters were quantitatively evaluated by cine images. Pancreatic iron burden was measured using a T2* gradient-echo multiecho sequence. The images were analyzed using a previously validated, custom-written software (HIPPO-MIOT IFC-CNR®).

Results.
Significant positive correlations of the global pancreas T2* values were demonstrated for global heart T2* values (r=0.355, P<0.0001; Figure 1), number of segments with normal T2* (r=0.389, P<0.0001) and T2* values in the mid-ventricular septum (r=0.323, P<0.0001). Of the 136 patients with pancreatic iron overload, 45 (33.1%) had a pathological global heart T2* value. No patients without pancreatic iron overload had cardiac iron overload. A normal global pancreas T2* value showed a negative predictive value of 100% for cardiac iron.
Pancreatic T2* values were positively related with left ventricular (r=0.21, P=0.028; Figure 2A) and right ventricular (r=0.23, P=0.015; Figure 2B) ejection fractions. No significant correlation was found between pancreatic T2* values and biventricular volumes.

Conclusions.
Pancreatic iron overload is positively correlated to myocardial iron overload and negatively correlated to bi-ventricular systolic function.

Disclosures:
No relevant conflicts of interest to declare.
Induced Pluripotent Stem Cells From a Patient with Reticular Dysgenesis Recapitulate Defective Myelopoiesis in-Vitro: A Disease Model to Enhance Our Understanding of a Rare Disease.
Authors: Weinacht Katja G. , Felgentreff Kerstin , Devine Alex , Schambach Axel , Al-herz Waleed , Notarangelo Luigi Daniele 
Published: October 2019

Abstract
Abstract 2142
Reticular dysgenesis (RD) is one of the most severe forms of combined immunodeficiency characterized by severe congenital neutropenia (SCN) and impaired lymphocyte development. Origin of the neutropenia is thought to be an early differentiation arrest at the promyelocte stage. Recently the disease has been mapped to mutations in the gene encoding for Adenylate Kinase 2 (AK2). Adenylate kinase 2 is a phosphokinase implicated in mitochondrial energy homeostasis. The exact mechanism, however, how a defect in this ubiquitously expressed enzyme selectively manifests in defective granulopoiesis and lymphopoiesis remains poorly understood. A significant obstacle to the study of rare diseases like Reticular Dysgenesis has been the inadequacy of animal models and limited availability of patient specimens.
We have successfully generated induced pluripotent stem cells (iPSCs) from a patient with Reticular Dysgenesis and proven genetic defect in Adenylate Kinase 2 (AK2). Myeloid precursors derived from the AK2-deficient iPSCs morphologically mimic the myeloid maturation arrest seen in the bone marrow of patients with this condition (Figure 1). We are currently using this in-vitro model as a platform to study the mechanisms underlying the maturation arrest on a cellular and molecular level.

Summary: Here we report a pluripotent stem cell (iPSC)-based disease model for Reticular Dysgenesis. This model does not only accurately recapitulate the myeloid disease phenotype observed in vivo but enables us to study previously unknown disease pathology. This is an example how iPSC technology enhances our understanding of a rare disease that has thus far been limited by the availability of study material.

Disclosures:
No relevant conflicts of interest to declare.
An ω-6 Fatty Acid, Dgla, Prevents Platelet Activation and Thrombosis in Vivo.
Authors: Yeung Jennifer , Ikei Kenneth , Vesci Joanne , Holman Theodore R , Holinstat Michael 
Published: October 2019

Abstract
Abstract 2169
Platelets play a pivotal role in thrombotic events leading to clot formation and clot stability in vivo. Uncontrolled signaling events in the platelet can result in unwanted thrombosis, which may eventually lead to the development of myocardial infarction or stroke. Previously, we have shown that ex vivo treatment of human platelets with the ω-6 fatty acid dihomo-γ-linolenic acid (DGLA) or its eicosanoid derived from 12-LOX oxidation, 12-hydroxyeicosatrienoic acid (12(S)-HETrE), inhibits PAR and collagen-induced platelet aggregation, clot retraction, and GPIIbIIIa activation. Since early studies have shown dietary supplementation of fatty acids increase fatty acid incorporation into the platelet lipid membrane (Barre, DE Lipids 1992; 27(5): 315–320; Marry, MJ Prostaglandins Leukot Essent Fatty Acids 1997; 56(3):223–223), we postulated that altering fatty acid composition in the platelet through dietary supplementation in vivo may be a viable approach to inhibiting platelet function. Therefore, a longitudinal study of wild-type mice on normal chow compared to mice supplemented with high (.5 g/kg) or low (.13 g/kg) DGLA diets was conducted. Each set of mice (7–8 mice) was given the designated diet for a period of 1, 2, or 3 months. At each time point, tail bleeding times and ex vivo platelet function in PRP were performed. Tail bleeding times from mice on the high DGLA diet were significantly prolonged by more than 15 minutes. Further, a smaller but statistically significant delay in clotting time was observed in mice on the low DGLA diet compared with control mice. Additionally, ex vivo aggregation response to collagen (1 μg/mL to 20 μg/mL) and PAR4-AP (50 μM to 500 μM) in platelets from mice on the high DGLA diet showed significant shifts to the right in their ability to induce platelet aggregation compared with control mice suggesting these mice were protected against thrombosis. JON/A and P-selectin binding to the PRP of high and low DGLA were also significantly attenuated in response to PAR4-AP. This study, which evaluated the in vivo and ex vivo effects of DGLA on regulation of platelet reactivity, supports DGLA as a potent, endogenous anti-thrombotic agent. Understanding the mechanistic details by which DGLA protects against thrombosis and maintains hemostasis through its COX-1 and 12-LOX-dependent bioactive metabolites will help to identify the potential viability of this target for anti-platelet intervention.

Disclosures:
No relevant conflicts of interest to declare.
Protective Role of ADAMTS13 for Myocardium in Mouse Model of Experimental Myocardial Infarction.
Authors: Doi Masaaki , Matsui Hideto , Takeda Yukiji , Saito Yoshihiko , Takeda Maiko , Matsunari Yasunori , Nishio Kenji , Shima Midori , Banno Fumiaki , Akiyama Masashi , Kokame Koichi , Miyata Toshiyuki , Sugimoto Mitsuhiko 
Published: October 2019

Abstract
Abstract 2175
The metalloprotease ADAMTS13 regulates the size of von Willebrand factor (VWF) multimers, controlling excessive VWF functions and preventing thrombotic occlusion of microvasculature. We previously reported that ADAMTS13 deficiency aggravated the extent of brain ischemic stroke in a mouse model of middle cerebral arterial occlusion, suggesting the relevant role of ADAMTS13 in the pathophysiology of brain stroke (Fujioka, et al. Blood, 2010; 115: 1650). These results raised the possibility that the functional regulation of VWF by ADAMTS13 could also play a role in coronary ischemic events such as myocardial infarction. To address this issue, we have used a mouse model of experimental myocardial infarction. The left anterior descending coronary artery in mice was ligated at 2 mm downstream from the origin under thoracotomy with ventilator-assisted respiration, and the cardiac function was evaluated with M-mode echocardiography after 7 days of operation. We compared 20 wild-type (WT) mice and 20 Adamts13 −/− (KO) mice, all of which were 12–14 weeks of age, healthy and fertile. Significantly (p < 0.01) decreased ejection fraction (EF; 44.0±6.7%) and increased left ventricular end-diastolic diameter (LVDd; 4.68±0.69 mm) of KO mice, as compared to WT (EF; 62.7±13.0% and LVDd; 3.77±0.56 mm, respectively), revealed that cardiac functions were apparently more impaired in KO mice. In addition, these reduced cardiac functions observed in KO mice were improved to an extent comparable to those of WT mice by the bolus injection of recombinant human ADAMTS13 (rhADAM; 3 μg/mouse, n=20) just after the operation (KO mice + rhADAM, EF; 58.2.±9.9% and LVDd; 3.16±0.52 mm). Consistent with echocardiography data, histological studies demonstrated the significantly (p < 0.01) higher infarct ratio in myocardium of KO mice (WT; 37.3±18.4%, KO; 59.1±16.3%, KO + rhADAM; 33.7±24.4%). Our results indicate that ADAMTS13, as seen in the case of brain ischemic stroke, plays a protective role for myocardium in coronary artery ischemia, improving myocardial functions and the severity of heart failure. Proper functional regulation of VWF-dependent thrombotic or inflammatory responses by ADAMTS13 could reduce thrombotic occlusion of microvasculature including leukocyte plugging, contributing to better local microcirculation which is crucial for tissue or organ functions.

Disclosures:
No relevant conflicts of interest to declare.