bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted-Capture Sequencing Is a Useful Method for MRD Markers Screening in KMT2A (MLL) Rearranged Leukemia
Authors: Sanada Masashi , Yamada Tomomi , Iijima-Yamashita Yuka , Nishijima Dai , Kanamori Takashi , Tomizawa Daisuke , Hori Toshinori , Horibe Keizo 
Published: November 2019

Immunoglobulin (Ig)/T-cell receptor (TCR) gene rearrangement-based molecular minimum residual disease (MRD) monitoring has become one of the most powerful prognostic indicators for patients with acute lymphoblastic leukemia (ALL). Infant ALL has a poor prognosis and requires therapeutic development based on accurate MRD assessment. However, there are some difficulties associated with the highly sensitive detection of MRD based on Ig/TCR gene rearrangements in infant ALL cases, compared to other B-ALL cases, because of the immature Ig/TCR gene rearrangement patterns and their oligoclonality. Since KMT2A(MLL) gene rearrangements are identified in infant ALL at a high frequency, the use of KMT2A rearranged sequences is an alternative method for MRD detection in KMT2A rearranged ALL cases. However, identifying the genomic breakpoints in KMT2A rearrangements by conventional methods is laborious and difficult in routine practice. To detect molecular MRD markers in infant ALL cases, we designed capture probes covering the coding and recognition signal sequences of the V, D, and J genes of the Ig/TCR loci and common genomic breakpoints in KMT2A, AFF1 (AF4), MLLT3 (AF9), MLLT1 (ENL), MLLT10 (AF10), and ELL. 88 infant ALL cases from the JPLSG MLL-10 study, including 73 cases with KMT2A rearrangements, were analyzed by high-throughput target-capture sequencing on the Illumina platform. The sequenced data were analyzed with the Ig/TCR recombination analysis tool Vidjil and the Genomon pipeline for detection of KMT2A rearrangements.
Although 40% of cases in this study were marker-negative in the conventional marker screening analysis, clonal Ig/TCR targets for MRD measurements were identified in more than 80% of the cases by target-capture sequencing. Ig / TCR rearrangements detected in infant ALL were unique and related to age at diagnosis and type of KMT2A rearragement. KMT2A-rearranged cases showed a significantly higher frequency of incomplete rearrangements of IGH and TCRD compared to KMT2A-negative infant ALL cases.　The target-capture method also showed an increased sensitivity of Ig/TCR-based MRD measurements even in cases where MRD measurement was possible.　Genomic breakpoints of KMT2A rearrangements were detected in 80% of KMT2A-rearranged cases, in which KMT2A was most frequently rearranged with AFF1, followed by MLLT1, MLLT3, and MLLT10. Other rare fusion partners of the KMT2A gene were also captured by probes for KMT2A sequences. The determined patient-specific genomic breakpoint sequences could be used for monitoring the MRD of KMT2A-rearranged cases. Thus, target-capture sequencing is an easy and useful method for screening MRD markers in infant leukemia cases.

Disclosures
No relevant conflicts of interest to declare.
Role of Thrombopoietin in Stimulating Megakaryopoiesis of ITP Patients Via Rescuing Vascular Niche
Authors: Jiao Yingying , Zeng Xiaoyuan , Li Zongpeng , Chong Beng H , Zhang Yujiao , Ye Jieyu 
Published: November 2019

Background: Previous studies have shown that the vascular niche was damaged in patients with immune thrombocytopenia (ITP). It is mainly manifested that the migration and tube-formation ability of bone marrow endothelial progenitor cells (BM-EPCs) were significantly reduced. Endothelial cells as an important part of the vascular niche play an important role in regulation of megakaryocytes and platelet hematopoiesis. Our previous studies suggested that thrombopoietin (TPO) has a protective effect on human endothelial cells. This study aim to investigate whether TPO has a protective effect in EPCs of ITP patients and to explore its mechanism.
Methods: BM-EPCs were isolated from ITP patients, and divided into two groups: TPO-treated group and TPO-free (control group). CCK8 was used to explore whether TPO has proliferative effect on BM-EPCs. BM-EPCs was identified by flow cytometry with co-expression of mouse anti-humanCD133, mouse anti-human CD34 and mouse anti-human vascular endothelial growth factor receptor (CD309) monoclonal antibodies. Moreover, the number of EPCs was evaluated with DiL-Ac-LDL uptake and FITC-UEA -I binding assay. Furthermore, the function of BM-EPCs was studied by using tube-formation and migration experiments.
Results: The ITP patient-derived EPCs in TPO-treated group exhibited longer fusiform and elliptical shape after 5 days and cobblestone-like morphology after 7-10 days. The result of CCK-8 showed TPO could promote the proliferation of EPCs and the optional drug concentration is 100 ng/ml. Much higher expression of CD34/CD133/CD309 in TPO-treated group was detected by flow cytometry. The number of cells with immunofluorescence double staining in TPO group was significantly higher than of control group (n=4, p<0.05). The tube formation (n=5, p<0.05) and migration capacity (n=5, p<0.05) were significantly enhanced in TPO-treated group.
Conclusion: Our studies indicates that TPO may exert megakaryopoiesis effect in ITP patients via protection of BM-EPCs. This may provide a supplemental explanation of how recombinant TPO and TPO receptor antagonist acts on ITP treatment.
Keywords: thrombopoietin; vascular niche; endothelial progenitor cell, megakaryopoiesis; endothelial cell

Disclosures
No relevant conflicts of interest to declare.
Clinico-Pathological Profiles of Obese Patients with Chronic Myeloid Leukemia (CML) and Their Response to Therapies (TKIs)
Authors: Yassin Mohamed A , Abdulla Mohammad Abdul-Jaber , Abbas Feryal , Chandra Prem , Nashwan Abdulqadir Jeprel , Ghasoub Rola S , Kassem Nancy , Al Sabbagh Ahmad , Nawaz Zafar , Akiki Susanna Jane 
Published: November 2019

Background and Objectives:
Cancer patients in Qatar are managed in a standardized manner through a single center guided by the National Cancer Framework. Most cancer medication-dosing is based on weight and height (body surface area), however in CML, tyrosine kinase inhibitors (TKIs) dosing is fixed. Obesity, defined by a BMI of 30 or more, presents a risk to health yet to the best of our knowledge, there have been no large studies on obesity and response to TKI therapy in CML. The aim of this study was to explore the clinical characteristics of obese and non-obese CML patients, and compare their response to standard dose TKI therapy.
Methods:
A retrospective analysis was performed of 123 patients treated for CML in chronic phase at NCCCR over a 23-year period, 69 obese (BMI > 30) vs. 54 with normal BMI = 18.5 - 24.99 (controls). Comparisons were made of characteristics at diagnosis including: gender, age, ethnicity, CBC parameters, spleen size, Sokal score, bone marrow findings, TKI prescribed, together with response assessment using ELN guidelines.
Results:
Mean age at diagnosis was lower in obese patients compared with control group (39.0 vs 42.2). Obese patients had lower WBC count and higher Hgb at diagnosis (mean WBC 153.9 vs. 193.0; mean Hgb 11.4 vs. 10.3). A higher proportion of obesity group was females (31/69) compared to control group (14/54). Spleen size and Sokal scores were lower in obesity group (17.1 vs. 18.3 and 0.81 vs. 0.91 respectively). More obese patients received Imatinib (40 vs. 12 in control group) compared with other TKIs (21 vs. 37 in control group). Few patients in obesity group had to switch to an alternative TKI (13 vs. 20 in control group). Compared to control group more obese patients achieved a major molecular response (MMR defined as BCR-ABL/ABL (IS) value below 0.1%) (47 of 60 vs. 22 of 42; p = 0.011).
Conclusions:
The data suggests differences in clinical characteristics and response to treatment between obese and non obese patients that warrants further investigation. Obese patients with CML were younger at diagnosis, had better response to treatment and were less likely to need switch TKI due to failure of treatment.
Table

Disclosures
No relevant conflicts of interest to declare.
Microbial-Derived Metabolites Drive Protective Type-I Interferon Responses in Models of Gut Epithelial Damage and Limit Graft-Versus-Host Disease
Authors: Thiele Orberg Erik , Göttert Sascha , Poeck Hendrik 
Published: November 2019

Background: Graft-versus-host disease (GVHD) is a dreaded complication after stem-cell transplantation (SCT). Standard treatment relies on immunosuppressants but is associated with an increased risk of infection and relapse. Up 50% of patients develop steroid-refractory GVHD, with dismal impact on SCT outcomes.
New studies in mice suggest that induction of type-I interferon (IFN-I) signalling or activation of IFN-I inducing pathways such as cGAS/STING or RIG-I/MAVS can promote gut barrier integrity and limit GVHD. However, the endogenous ligands that drive this "protective" IFN-I response are poorly defined. Recent data in mice and humans suggest that microbial-derived metabolites such as small-chain fatty acids or indoles can decrease GHVD mortality. Here, we describe IFN-I inducing metabolites that improve outcomes in mouse models of gut epithelial damage and acute GVHD via a mechanism dependent on STING signalling.
Methods: To investigate which cell types mediate protection and how, we generated intestinal organoids and antigen presenting cells (APC) from bone marrow of WT or genetically deficient mice (MAVS-/-, STING-/-, IFNAR-/-) under steady state conditions versus chemotherapy, total body irradiation and after allogeneic SCT in the presence or absence of microbial metabolites. Analysis was performed by microscopy, immunoblotting, qPCR, ELISA and flow cytometry. Outcomes of gut-injured mice were assessed by clinical scoring, histopathology, flow cytometry and organoid recovery.
Results: Metabolite treatment promoted regeneration of intestinal organoids as assayed by organoid numbers as well as proliferation. These effects were dependent on IFN-I and STING signalling. In addition, we found activated pro-inflammatory NFkB signalling and decreased apoptosis as evidenced by reduced caspase-3 cleavage. In APCs, IFN-I responses were enhanced in the presence of metabolites including increased IFN-β production and upregulation of IFN stimulated genes. Metabolite-treated mice showed improved recovery of intestinal stem cells following gut injury by chemotherapy and irradiation and increased survival in acute GVHD.
Conclusions: Our findings uncover a mechanism by which microbial metabolites amplify IFN-I signals, promote tissue regeneration and thereby prevent allo-activation and GVHD. We show for the first time that these IFN-I inducing metabolites are protective in diverse models of gut damage -- from chemotherapy and radiation to immune-mediated damage -- via a STING-dependent mechanism. Perhaps the poor prognosis of GVHD patients exhibiting a loss of microbiota diversity can be explained in part by an absence of "protective" metabolites able to amplify critical IFN signals. We are currently studying whether metabolite levels correlate with severity and outcome of GVHD in humans.
Figure

Disclosures
No relevant conflicts of interest to declare.
Changes in Platelet Utilization Via Implementation of Transfusion Guidelines in a Large Health System Hospital
Authors: Bowers Reid Christian , Thompson Michael A. , Van Dreser Julie , Sanchez Federico Augusto 
Published: November 2019

Background: As part of system wide implementation of Patient Blood Management (PBM), transfusion guidelines were implemented at St. Luke's Medical Center, Advocate Aurora Health in Milwaukee, WI.
Methods: Beginning in 2015 Aurora Health Care made a platelet (PLT) count of ≤10K the standard threshold below which PLT transfusion is considered appropriate. Additionally, transfusing PLTs as single donor units with a PLT count between each unit was made standard. Education was provided to clinicians on the new standard including best practice advice in the transfusion ordering workflow. Data was gathered on institutional PLT use and individual clinician PLT ordering practices. Further education was provided based on the extent to which data showed conformity to the new standard.
Results: During PBM implementation 2015-2018 despite an initial decline there was a modest overall increase in institutional PLT usage from 2515 to 2933 units. The percentage of transfusions ordered with PLT ≤10K rose from 21.6% to 31.9%. The percentage of transfusions ordered as single donor units increased from 82.5% to 91.5%. See Graph/Table 1 & 2 for further analysis of individual practitioner PLT ordering. See Table 3 for reporting period volume data.
Conclusions: Implementation of PLT transfusion guidelines was associated with an initial annual reduction in PLT usage, but annual PLT utilization did go up overall during the reporting period. Individual clinician transfusion practices overall conformed more with guidelines at the end of the reporting period than at the beginning. Changes in treatment guidelines for acute promyelocytic leukemia, i.e. target PLT >50K, during the reporting period may account for a rebound in PLT usage and a decrease in the percentage of transfusions ordered with PLT ≤10K in the later vs. the earlier years of the reporting period. By contrast transfusions continued a positive trend toward being given as single donor units even in the later years of the reporting period.

Disclosures
Thompson: Doximity: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Lynx Bio: Research Funding; BMS: Research Funding; VIA Oncology: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties: Myeloma reviewer; AbbVie: Research Funding.
Is It Time to Take MRD More Seriously? Relationship between MRD, Functional Cure and Life Expectancy Among Patients with Ph- B Cell Precursor ALL (BCP-ALL)
Authors: Shao Qiujun , Tiwana Simran , Despiegel Nicholas , Dirnberger Franziska 
Published: November 2019

Background: Although BCP-ALL patients can achieve complete remission (CR) after induction chemotherapy, about 40% of them have residual leukemia cells in the bone marrow which is called minimal residual disease (MRD). Complete MRD response is defined as lack of MRD with an assay sensitivity of &gt;= 10-4, which, if sustained for more than five years, may be regarded as a functional cure for ALL. On the contrary, presence of MRD is a signal of high risk of relapse leading to poor health outcomes. Blinatumomab is the only drug approved for BCP-ALL patients with MRD based on the results from BLAST, a single-arm phase 2 study conducted to assess the efficacy and safety of blinatumomab in adult BCP-ALL patients in CR with MRD. Currently, there is limited evidence on the relationship between MRD response and functional cure in ALL and life years gained.
Objectives: The objective of this study was to assess the relationship between complete MRD response after blinatumomab treatment and 1) functional cure; 2) life years and quality adjusted life years (QALYs) gained among BCP-ALL patients with MRD.
Methods: The relationship between MRD response, and clinical outcomes was analyzed using an existing cost-effectiveness analysis (CEA) based on combined decision tree and Markov cohort model over a lifetime horizon (50 years). The model includes survival conditional on treatment and MRD status for time to stem transplant, relapse and death. In the CEA, blinatumomab was compared to standard of care (SOC, defined as conventional maintenance chemotherapy). Clinical probabilities were derived primarily from blinatumomab clinical trial data and a non-interventional cohort study (used as a historical control). Life years gained were adjusted for quality based on utility values from trial EQ-5D scores. An annual discount rate of 3.5% was applied to estimate future outcomes.
Results: In the base case, the complete MRD response rate was 83.6%, and blinatumomab yielded more life years gained (8.26 vs. 5.68) and more QALYs (6.56 vs. 4.44) compared with SOC. The proportion of patients achieving a functional cure was 43.59% in blinatumomab group vs. 26.78% in the SOC group. Clinical response varied with variations in MRD response rate at 75%, 78%, 80%, 85%. Specifically, when the complete MRD response rate increased from 75% to 85%, the total life years gained in the blinatumomab group increased by 0.51, QALYS increased by 0.42, and the proportion of patients cured increased by 3.05%.
Conclusion: Achieving complete MRD response is associated with longer life expectancy, higher probability of being cured, and more QALYs among patients with BCP-ALL and MRD.

Disclosures
Shao: Amgen: Employment. Tiwana:Amgen: Employment, Equity Ownership. Despiegel:Amgen: Employment, Equity Ownership. Dirnberger:Amgen: Employment, Equity Ownership.
Safety Analysis of Five Randomized Controlled Studies of Daratumumab in Patients with Multiple Myeloma
Authors: Al Hadidi Samer , Kamble Rammurti , Miller-Chism Courtney Nicole , Mims Martha P. 
Published: November 2019

ABSTRACT
BACKGROUND
Daratumumab is an anti-CD38 monoclonal antibody that is used more frequently in patients with Multiple Myeloma (MM). Multiple studies have demonstrated the efficacy and safety of daratumumab for relapsed/refractory MM and primary treatment for transplant eligible and ineligible patients.
METHODS
We conducted an integrated safety analysis to characterize the frequency, severity, natural history, and outcomes of adverse events (AEs) with daratumumab versus comparators. Data were pooled from 5 completed phase III randomized controlled studies that had included 1798 daratumumab-treated and 1797 comparator-treated patients with MM as a first line in both transplant eligible and transplant ineligible and for relapsed/refractory disease(Table.1). Safety analyses included reporting of AEs using crude and exposure-adjusted incidence rates.
RESULTS
The median follow up duration is 16.84 months (range: 7.4-28 months) for both daratumumab-treated and comparator-treated patients. Discontinuation for any reason occurred less often with daratumumab (22% vs. 33.9%) though discontinuation because of AEs occurred at similar rates (25% vs.26%) as well as deaths due to AEs occurred at similar rates (2.25% vs. 1.84%). When adjusted to exposure, neutropenia, lymphopenia, diarrhea, fatigue, dyspnea, pneumonia and hypertension were the only common grade 3 AEs more often reported with daratumumab than with the comparators(Table.2). The prevalence of common grade 3/4 AEs with daratumumab were <7% apart from neutropenia, lymphopenia and pneumonia (45.9 vs. 32.3, 13 vs. 7.5, and 10.6 vs.7.2)(Table 3). Grade 3/4 daratumumab infusion related reactions happened in 3.8%
CONCLUSIONS
These results from an integrated analysis support a favorable benefit/risk profile of daratumumab in patients with MM.

Disclosures
No relevant conflicts of interest to declare.
Hepatosplenic T Cell Lymphoma Case Report Presented with Hemphagocytosis Lymphohistiocytosis
Authors: Abu Haleeqa Mohamed , Alshehi Fatemah , Alghamrawi Gannat , Richard Lois 
Published: November 2019

We are reporting a challenging case 37-year-old Pakistani male patient with Hepatosplenic T-Cell lymphoma (HSTCL) which is a rare aggressive form of Peripheral T-Cell lymphoma that is characterized by primary extra nodal disease with malignant T-cell proliferation in the liver, spleen, and bone marrow. He presented initially with nonspecific symptoms of generalized fatigue & vague abdominal pain . He was found to have hepatosplenomegaly (with liver & splenic lesions), derranged liver enzymes. He refused investigation and lost follow up.
He came back 3 months after in a bad condition with fever, abdominal pain & he deteriorated very rapidly. The diagnosis was challenging as he required an extensive investigations that ultimately showed the characteristic clinical, histopathologic, and cytogenetic features of hepatosplenic T-cell lymphoma with HLH presentation.
Patient had multiorgan failure,coagulopathy, shock(hepatic/renal/septic) and started on vasopressors, Ferritin was high >16000, Secondary Hemophagocytic Lymphohistiocytosis (HLH) was made at this point & patient was started on dexamethasone as per HLH protocol 2004 to reduce the tumor burden, and the plan was to start CHOP after 2 days, if patient condition allowed.
Bone marrow biopsy showed: hypercellular Bone marrow massively infiltrated by neoplastic mature T-lineage population with overall morphologic & phenotypic characteristics consistent with T cell lymphoma.
Flow cytometry was done from peripheral blood as bone marrow aspiration revealed dry tap.it showed presence of approximately 30-40% circulating lymphoma cells with aberrant mature T-cell phenotype, CD3+, TCRgd+, CD56+, CD8+/CD4-, and CD5-. The overall morphology and immunophenotypic features were consistent with hepatosplenic T-cell lymphoma (WHO classification updated 4th edition,2016).
patient received full CHOP. All through patient was steadily worsening and unfortunately passed away.
HSTCL is a rare and challenging diagnosis and presentation can be dramatic like this case with HLH. T cell lymphoma can present with HLH and treatment
Figure

Disclosures
No relevant conflicts of interest to declare.
Platelet Function Disorder Is More Common Than Von Willebrand Disease in Women with Inherited Bleeding Disorders: Report from a Public Sector University in Pakistan
Authors: Hossain Nazli , Shamsi Tahir S. , Naz Arshi , Abbas Sidra , Khan Nazeer 
Published: November 2019

Abstract
Introduction: Inherited bleeding disorders are an important cause of menorrhagia.
Aim: To determine the prevalence of inherited bleeding disorders in women with menorrhagia in the absence of systemic and pelvic pathologies.
Methods: The study period was from March 2013 to September 2018. It was carried out at the Department of Obstetrics & Gynecology, Unit II, Dow Medical College and Ruth Pfau KM Civil Hospital in Karachi. The laboratory investigations were carried out partly at Dow Diagnostic Research Laboratory and mainly at the National Institute of Blood Disease & Bone Marrow Transplant. Included in the study were young girls and women who presented with menorrhagia at menarche or in the later years of reproduction, with normal bimanual pelvic examination and pelvic ultrasound results.
Results: Approximately 200 women with a mean menstrual cycle duration of 9.3+ 3.5 days were included. The mean age of the included patients was 32 years. Married women's partners were cousins in 50% of the women, while unmarried girls' parents were cousins in all cases. Platelet aggregation defect was presented in 33 (16.6%) women, von Willebrand disease in 26 (13.1%) women, factor IX deficiency in 20 (10%) women, combined defects in 29 (14.6%) women, and factor VII and VIII deficiencies in 4 and 11 (2%, 5.5%) women, respectively. Isolated defect with ADP, epinephrine, and collagen were decreased in 35 (17.6%), 41 (20%), and 33 (16%) women, respectively.
Conclusion: Inherited bleeding disorders were a common cause of menorrhagia in our population. Consanguinity was frequently seen in these subjects. Except for some forms of VWD, all other disorders have an autosomal recessive inheritance pattern. After excluding gynecological and medical causes, a work up for inherited bleeding disorders should be advised.
Keywords: menorrhagia, platelet function disorder, inherited bleeding disorders, Pakistan.

Disclosures
No relevant conflicts of interest to declare.