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ASH News Daily
http://www.hematology.org/Annual-Meeting/AND.aspx

Nov 7th, 2018 - ASH News Daily is the official print publication of the ASH annual meeting. View an archive of recent ASH News Daily publications

ASH 2018 coming attractions look at the big picture
https://www.mdedge.com/hematologynews/article/189383/aggressive-lymphomas/ash-2018-coming-attractions-look-big-picture

Nov 21st, 2018 - Big trials, big results in malignant and nonmalignant hematologic disorders are on the program at the 2018 ASH annual meeting.

What's Hot at This Year's ASH Meeting?
https://www.medscape.com/viewarticle/905521

Nov 23rd, 2018 - The premier event in hematology is celebrating its diamond anniversary. This will be the 60th annual meeting of the American Society of Hematology (ASH). It will be returning to the city of San Diego, California, and will run from November 30 to December 4.

Every Patient Tells a Story: Using Narrative Medicine to Cure Disease
https://www.ashclinicalnews.org/on-location/every-patient-tells-story-using-narrative-medicine-cure-disease/

Nov 21st, 2018 - As part of the Education Program at the 2018 ASH annual meeting, three physician-writers will offer their take on the intersection of storytelling, writing, and medicine – asking why doctors should care about the narrative, how the patient narrative informs treatment decisions, and how writing can be a tool for advocacy and change.

ASH-a-Palooza: Trainee Day. Reimagined
https://www.ashclinicalnews.org/on-location/ash-palooza-trainee-day-reimagined/

Nov 21st, 2018 - The “Trainee Day” that attendees may know from past annual meetings has been reimagined as ASH-a-Palooza – a new educational experience that will offer a relaxed, open learning environment for trainees in a festival-like setting with multiple opportunities for micro-learning. During breaks between sessions at Petco Park, trainees can enjoy ballpark-style food and are invited to visit informatio...

For the Love of the Lab: Interview with John E. Dick, PhD
https://www.ashclinicalnews.org/on-location/love-lab-interview-john-e-dick-phd/

Nov 21st, 2018 - John E. Dick, PhD, recipient of the 2018 Mentor Award in basic science, tells us about his career in the lab – from working at “the mecca of stem-cell research” to learning how to foster creativity in his own lab

Platelet Biogenesis in the Lung Circulation
http://www.bloodjournal.org/content/132/Suppl_1/SCI-22

Nov 21st, 2018 - Platelets are indispensable in hemostasis, thrombosis, and immune responses. In humans, billions of platelets are produced each day from megakaryocytes, however the mechanisms of mature platelet production are incompletely understood. Megakaryocytes are produced in the bone marrow and have been visualized to communicate with the bone marrow sinusoids to release proplatelet fragments. Megakaryoc...

Overall Survival of HIV-Positive Patients with HLH
http://www.bloodjournal.org/content/132/Suppl_1/4957

Nov 21st, 2018 - Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare but life-threatening disorder affecting the interplay between natural killer cells, macrophages, and cytotoxic lymphocytes. In HLH, persistent macrophage activation results from dysregulated cytokines produced from T-lymphocytes. The disease can be primary (due to a genetic defect) or secondary (triggered by another disease proces...

Hemophagocytic Lymphohistiocytosis in Early Infancy- Pitfall of Differentiation between Hereditary and Infectious Reasons
http://www.bloodjournal.org/content/132/Suppl_1/4961

Nov 21st, 2018 - Hemophagocytic Lymphohistiocytosis (HLH) is characterized by pathologic immune activation which occurs either as a familial disorder or as an acquired condition. The diagnosis of HLH requires the presence of five out of nine criteria: fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis in bone marrow, hyperferritinemia, low or absent natural killer cell...

IL-6 As a Potential Cell Released Marker of Prostate Cancer Cell Death
http://www.bloodjournal.org/content/132/Suppl_1/4964

Nov 21st, 2018 - Introduction: Interleukin 6 (IL-6) is proinflammatory cytokine which is produced by cell when Nod-like receptors (NLRs) are activated. Increased production of IL-6 was shown to promote tumor growth and metastasis.Therefore, it could be suggested that activation of NLRs could support malignancy. PC-3, prostate tumor derived cells, was shown to produce IL-6; however, little is known about the rol...

5-Azacytidine Induces NOXA and PUMA Expression to Prime AML Cells for Venetoclax-Mediated Apoptosis
http://www.bloodjournal.org/content/132/Suppl_1/2644

Nov 21st, 2018 - Acute myeloid leukemia (AML) is a clonal hematologic malignancy characterized by genomic heterogeneity and epigenetic changes, including aberrant DNA hypermethylation. Phase-Ib clinical data in relapsed/refractory AML patients indicate that combining venetoclax with the hypomethylating agents (HMAs) 5-azacitidine (5-Aza) or decitabine results in an overall response (OR) of 62% (DiNardo et al. 2...

A 36-Dimensional Cytometry by Time of Flight (CyTOF) Analysis of De Novo Acute Myeloid Leukemia (AML) Patients Eligible for Intensive Chemotherapy
http://www.bloodjournal.org/content/132/Suppl_1/1502

Nov 21st, 2018 - Introduction Chemotherapy induced clonal selection and development are major contributors to disease relapse and resistance to therapy in AML. An immediate response to chemotherapy in intracellular signalling networks can be detected within minutes in vivo. (Irish J. et al 2004) We hypothesize that by analyzing the immediate intracellular chemotherapy response we might reveal which cancer clone...

A Feasibility and Safety Study of CD19 and CD22 Chimeric Antigen Receptors-Modified T Cell Cocktail for Therapy of B Cell Acute Lymphoblastic Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/277

Nov 21st, 2018 - Introduction: Chimeric antigen receptor (CAR) T cell therapy targeting CD19 has recently demonstrated high success but also shown limitations regarding their toxicity and development of CD19negative variants. Here we reported results from a phase I study designed to determine the safety of the CD19 CAR-T and CD22 CAR-T cocktail and the feasibility of making enough quantities to treat patients w...

A Genome-Wide CRISPR Screen Implicates MYC Dysregulation in TCF3-PBX1 B-ALL
http://www.bloodjournal.org/content/132/Suppl_1/3915

Nov 21st, 2018 - Introduction: Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer, of which, precursor B-cell ALL (B-ALL) accounts for approximately 80% of diagnoses. B-ALL is a heterogeneous disease, with patients characterised and risk stratified according to their cytogenetic profile. TCF3-PBX1 B-ALL was associated with a poor prognosis, but on current therapies outcome has greatly impr...

A Long-Term Retrospective Analysis of Arsenic-Containing Triple-Agents Treatment for Acute Promyelocytic Leukemia (APL) in a Cohort from a Single Hospital
http://www.bloodjournal.org/content/132/Suppl_1/4060

Nov 21st, 2018 - Objective: The long-term efficacy (June 2001 - May 2018) of newly diagnosed APL patients (pts) treated with either As4S4 or As2O3 in combination of all-trans retinoid acid (ATRA), and anthracycline-based chemotherapy in Lu Dao-Pei Hospital is analyzed. Methods: Firstly, 8 years from June 2001 to December 2009, a total of 88 newly diagnosed with APL patients were divided into two groups, who wer...

A Network Meta-Analysis of Clinical Trials Assessing Induction Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia Among Young Adults
http://www.bloodjournal.org/content/132/Suppl_1/1432

Nov 21st, 2018 - Introduction: After establishing the diagnosis of acute myeloid leukemia (AML), remission induction chemotherapy is started with curative intent. Due to paucity of direct therapeutic comparison of induction regimens, relative efficacy of two drug standard regimens and three drug induction regimens among newly diagnosed young (<60 years) AML patients is not established. We conducted a systematic...

A Novel Predictor of Response to Gemtuzumab Ozogamicin Therapy in AML Provides Strategies for Sensitization of Leukemia Stem Cells in Individual Patients
http://www.bloodjournal.org/content/132/Suppl_1/2765

Nov 21st, 2018 - Acute myeloid leukemia (AML) patients with normal cytogenetics, NPM1 mutation, and no FLT3-ITD are considered to be at low molecular risk (LMR). We previously reported that most LMR patients have a low LSC17 score; these patients derive benefit from the addition of low fractionated doses of gemtuzumab ozogamicin (GO) to standard treatment and have favorable survival outcomes compared to patient...

A Novel Risk-Model to Predict Time to First Treatment (TTT) in Chronic Lymphocytic Leukemia Based on Heavy+Light Chain Immunoparesis and Serum Free Light Chain Analysis: Results from the Israeli CL...
http://www.bloodjournal.org/content/132/Suppl_1/1849

Nov 21st, 2018 - Introduction: Chronic Lymphocytic Leukemia (CLL) is frequently accompanied by immune dysregulation. Hypogammaglobulinemia is one of the most important immune defects encountered, and all three classes of immunoglobulins (IgG, A and M) can be involved. Recently, novel heavy+light chain (HLC) immunoassays have become available that quantify the light chain types of each immunoglobulin class (e.g....

A Phase 2 Study of Actinium-225 (225Ac)-Lintuzumab in Older Patients with Untreated Acute Myeloid Leukemia (AML) - Interim Analysis of 1.5 µci/Kg/Dose
http://www.bloodjournal.org/content/132/Suppl_1/1457

Nov 21st, 2018 - Background: Older patients (pts) with AML unfit for intense induction chemotherapy have a poor prognosis with a 5 year survival of <10%. 225Ac-lintuzumab is composed of 225Ac linked to a humanized anti-CD33 monoclonal antibody. Data were previously presented on the initial 13 pts who received 2.0 µCi/kg/dose on Days 1 and 8 (ASH, 2017, Abstract 616). Although that dose resulted in a high respon...

A Phase I, First-in-Human Study Evaluating the Safety and Preliminary Antileukemia Activity of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate, in Patients with Relapsed/Refractory Acute M...
http://www.bloodjournal.org/content/132/Suppl_1/27

Nov 21st, 2018 - INTRODUCTION: Overexpression of CD123, the alpha subunit of the IL-3 receptor, in multiple hematological malignancies, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and blastic plasmacytoid dendritic cell neoplasm (BPDCN), makes this antigen an attractive target for the development of new therapeutics. IMGN632 is a CD123-targeting antibody-drug conjugate comprising...

A Phase II Study of Dasatinib and Dexamethasone As Primary Therapy Followed By Transplantation for Adults with Newly Diagnosed Ph/BCR-ABL1-Positive Acute Lymphoblastic Leukemia (Ph+ ALL): Final Res...
http://www.bloodjournal.org/content/132/Suppl_1/309

Nov 21st, 2018 - Dasatinib with corticosteroid yields high complete remission (CR) rates in Ph+ ALL with minimal induction death. Optimal post-remission therapy is not known. We report a prospective study evaluating dasatinib/dexamethasone induction then consolidation with reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), autologous HCT (autoHCT), or chemotherapy alon...

A Phase II Trial of Nivolumab Combined with Ibrutinib for Patients with Richter Transformation
http://www.bloodjournal.org/content/132/Suppl_1/296

Nov 21st, 2018 - Background: Outcomes of patients (pts) with Richter transformation (RT) remain dismal with a median survival of less than 1 year with chemoimmunotherapy (CIT). Dysfunction of T cells, NK cells and other immune subsets is common in pts with CLL. Checkpoint blockade is an emerging treatment approach for pts with RT (Ding et al. Blood 2017; Younes et al. ASH 2017). Methods: We designed an investig...

A Refined Regimen for Maximally Eliminating Early Life-Threatening Complications for Patients with High-Risk Acute Promyelocytic Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/3994

Nov 21st, 2018 - Life-threatening complications, such as severe bleeding and/or differentiation syndrome at admission and/or along with induction treatment, among high-risk patients with acute promyelocytic leukemia (APL) are a worldwide puzzle towards the cure of the disease. Taking the rationale that high WBC count, at least in part, may cause cytokine storm related symptoms, we designed this refined regimen ...

ABL Tyrosine Kinase Inhibitors (TKIs) Are Associated with Increased Rho-Associated Kinase (ROCK) Activity That May Contribute to Vascular Toxicity in Patients with Chronic Myeloid Leukemia (CML)
http://www.bloodjournal.org/content/132/Suppl_1/1739

Nov 21st, 2018 - Introduction The use of 2nd or 3rd generation ABL TKIs in patients with CML is associated with vascular toxicity, including peripheral arterial occlusive disease and cardiovascular and cerebrovascular events. However, Imatinib, a 1st generation TKI, has not been shown to increase risk of cardiovascular events (Douxfils J et al. JAMA Oncol 2016;2:625). Therefore, there is a need to identify risk...

Acalabrutinib in Treatment-Naive (TN) Chronic Lymphocytic Leukemia (CLL): Updated Results from the Phase 1/2 ACE-CL-001 Study
http://www.bloodjournal.org/content/132/Suppl_1/692

Nov 21st, 2018 - Background: Bruton tyrosine kinase (BTK) is a critical component of B-cell receptor signaling pathway and a validated therapeutic target for CLL. Acalabrutinib is a highly selective, potent, covalent BTK inhibitor with minimal off-target activity that has been shown to have an overall response rate (ORR) of 95% (85% partial response [PR]; 10% PR with lymphocytosis [PRL]) after a median follow-u...

Activated CLL B Cells Variably Modulate microRNA-155 Levels in Naïve CD4+ T Cells, and the Direction and Magnitude of microRNA-155 Change Correlates with Th17 Levels and Clinical Course
http://www.bloodjournal.org/content/132/Suppl_1/4402

Nov 21st, 2018 - T-helper 17 (Th17) cells constitute a subset of T cells that characteristically secrete IL-17. In addition to their normal adaptive immune functions, Th17 cells also play roles in supporting dysfunctional immune responses found in autoimmunity and cancer. Several studies suggest that Th17 cells play a protective role in chronic lymphocytic leukemia (CLL). For example, CLL patients exhibit varie...

Activation of NF-Kappa B-p62-NRF2 Signaling Supports the Survival of CLL Cells That Express High Levels of ROR1
http://www.bloodjournal.org/content/132/Suppl_1/3122

Nov 21st, 2018 - Recent studies have linked the autophagy adaptor p62/SQSTM1 to tumorigenesis via NRF2 signaling. Increased accumulation p62 is associated with disease progression in many cancers, however its expression in CLL has yet to be investigated. Importantly, p62, encoded by the SQSTM1 gene, mRNA expression and protein accumulation is regulated by nuclear factor-kappa B (NF-κB), a key transcription fact...

Acute Myeloid Leukemia Expands Osteoprogenitor Rich Niche in the Bone Marrow but Resorbs Mature Bone Causing Osteopenia/Osteoporosis in Animal Models
http://www.bloodjournal.org/content/132/Suppl_1/86

Nov 21st, 2018 - Acute myeloid leukemia (AML) is one of the most aggressive hematological malignancy that originates in the bone marrow (BM). Despite advances in the molecular characterization of AML, factors regulating its progression are still not known. Among several BM niches that support AML growth in the BM, the osteogenic niche has gained attention in recent years owing to its potential role in leukemoge...

Adherence to Tyrosine Kinase Inhibitor Affects Overall Survival in Adult Korean Chronic Myeloid Leukemia Patients; Based on the National Health Information Database
http://www.bloodjournal.org/content/132/Suppl_1/1745

Nov 21st, 2018 - Objectives We evaluated clinical characteristics including adherence and its effects on overall survival (OS) in Korean patients diagnosed with chronic myeloid leukemia (CML) using National Health Information Database "NHID". Methods This study included patients 15 and older who were diagnosed with Philadelphia chromosome positive CML (ICD code C921) from 2005 to 2013 and prescribed with tyrosi...

Adoptive T-Cell Therapy for Acute Lymphoblastic Leukemia Targeting Multiple Tumor Associated Antigens
http://www.bloodjournal.org/content/132/Suppl_1/2693

Nov 21st, 2018 - Background: Leukemic relapse remains the major cause of treatment failure in hematopoietic stem cell transplant (HSCT) recipients. While the infusion of donor lymphocytes to prevent and treat relapse has been clinically implemented this strategy does not provide durable remissions and carries the risk of life-threatening graft-versus-host disease (GVHD). More recently the adoptive transfer of T...

ALKBH5 Functions As an Oncogene in Acute Myeloid Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/3910

Nov 21st, 2018 - N6-methyladenosine (m6A), the most abundant internal modification in eukaryotic messenger RNAs (mRNAs) has been shown to play important roles in diverse cellular and pathological processes (Deng X, et al. Cell Res. 2018;28:507-517). ALKBH5, recently identified as a m6A demethylase, was reported to promote tumorigenesis and proliferation in glioblastoma stem-like cells (GSCs) (Zhang, S. et al. C...

Allogeneic CAR-T Cell Therapy for Treatment of Relapse after Allo-HSCT in Patients with Refractory CML Lymphoid Blast Crisis: Significance of HLA Matched Donor/Patient Pair in the Safety/Efficacy o...
http://www.bloodjournal.org/content/132/Suppl_1/4275

Nov 21st, 2018 - Introduction: CD19-specific CAR-T cells have shown promise in the treatment of relapsed or refractory Ph+ ALL. It remains to be established whether allogeneic CAR-T cells have clinical activity in patients with relapsed CML lymphoid blast crisis with a history of allo-HSCT. Here we report our experience in two cases of allogeneic CAR-T cell therapy for treatment of relapse after allo-HSCT in pa...

AML with Mutations in IDH1 and DNMT3A Exhibits a Distinct Epigenetic Signature with Poorer Overall Survival
http://www.bloodjournal.org/content/132/Suppl_1/1471

Nov 21st, 2018 - Acute Myeloid Leukemia (AML) is a biologically diverse disease with subtypes that can be identified through integrated cytogenetic, mutational, and epigenetic characterization. Mutations in epigenetic regulators such as IDH1, IDH2, and DNMT3A are among the most common gene mutations found in AML (Cancer Genome Atlas Research et al. 2013; Papaemmanuil et al. 2016). Targeted inhibitors of IDH1 an...

AMV564, a Bivalent Bispecific (2×2) CD33/CD3 T-Cell Engager, Is Active and Improves Survival in a Mouse Model of Acute Myeloid Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/2727

Nov 21st, 2018 - Background: AMV564 is a novel bivalent, bispecific (2x2) CD33/CD3 targeted immunotherapy that binds both CD33 and the invariant CD3ε on T-cell receptors with strong avidity, thus creating an immune synapse between CD33-expressing cells and T cells, initiating T-cell directed lysis of CD33 expressing cells, and inducing expansion, differentiation and proliferation of T cells. AMV564 is being eva...

Anti-CD20 Monoclonal Antibodies Hijack the B-Cell Receptor Signaling Cascade Thereby Activating the NOTCH1 Signaling Pathway
http://www.bloodjournal.org/content/132/Suppl_1/588

Nov 21st, 2018 - NOTCH1 is a cell surface receptor, regulation of which depends on the integrity and subsequent cleavage of its inhibitory domain. Subtle mechanical forces transmitted after ligand-binding [Wang et al., 2013] or removal of Ca2+-ions [Rand et al., 2000] make the site accessible for cleavage, resulting in release of the transcription factor NICD1. Mutations in NOTCH1 that prolong NICD1 activity ha...

Anti-Human CD117 CAR T-Cells Efficiently Eliminate Hematopoietic Stem and CD117-Positive AML Cells
http://www.bloodjournal.org/content/132/Suppl_1/4063

Nov 21st, 2018 - Introduction: Acute Myeloid Leukemia (AML) is a clonal disease of the hematopoietic system that originates from immature hematopoietic stem and progenitor cells (HSPC). Because some AML-initiating cells are comparatively resistant to conventional cytotoxic agents, disease relapses are common with current treatment approaches. As an alternative, immunological eradication of leukemic cells by ado...

Argx-110 Targeting CD70, in Combination with Azacitidine, Shows Favorable Safety Profile and Promising Anti-Leukemia Activity in Newly Diagnosed AML Patients in an Ongoing Phase 1/2 Clinical Trial
http://www.bloodjournal.org/content/132/Suppl_1/2680

Nov 21st, 2018 - Outcomes in elderly patients with acute myeloid leukemia (AML) are still adverse, as the majority does not qualify for intensive therapy or allogenic stem cell transplantation (ASCT). DNA hypomethylating agents (HMAs) induce remissions and prolong survival in a fraction of these patients. However, overall prognosis remains dismal and all patients progress due to therapy-resistant leukemia stem ...

AraC-Daunorubicin-Etoposide (ADE) Response Prediction in Pediatric AML Patients Using a Computational Biology Modeling (CBM) Based Precision Medicine Workflow
http://www.bloodjournal.org/content/132/Suppl_1/4034

Nov 21st, 2018 - Background: Pediatric AML (pAML) treatment outcomes can vary due to genomic heterogeneity. Thus, selecting the right drugs for a given patient is challenging. There is a need for a priori means of predicting treatment responses based on tumor "omics". Computational biology modeling (CBM) is a precision medicine approach by which biological pathways of tumorigenesis are mapped using mathematical...

Assessment of the Genomic Landscape of Intermediate Risk Acute Myeloid Leukemia As Defined By 2010 ELN Risk Classification
http://www.bloodjournal.org/content/132/Suppl_1/994

Nov 21st, 2018 - Background: In 2010 an international expert working group (European LeukemiaNet, ELN) has published recommendations for the diagnosis and management of acute myeloid leukemia (AML) including a risk stratification by cyto- and molecular genetics, subdividing AML into four risk groups. Emerging data on molecular markers in AML has led to an update of stratification criteria by ELN in 2017 includi...

Aurora Kinase a/MDM2-Mediated SETD2 Loss of Function in Chronic Myeloid Leukemia Patients in Blast Crisis Induces Genetic Instability and Can be Therapeutically Targeted
http://www.bloodjournal.org/content/132/Suppl_1/1726

Nov 21st, 2018 - The SETD2 protein is a histone methyltransferase that specifically catalyzes the trimethylation of Lysine 36 on histone H3 (H3K36me3). SETD2/H3K36me3 are implicated in transcript elongation and splicing, DNA repair, chromosome segregation. SETD2 gene deletions and/or mutations (mostly frameshift or nonsense) have been reported in solid tumors (clear cell renal cell carcinoma, bladder cancer, lu...

ATG2B/Gskip in De Novo Acute Myeloid Leukemia (AML): High Prevalence of Germline Predisposition in French West Indies and Potential Role of Overexpression in Acquired AML
http://www.bloodjournal.org/content/132/Suppl_1/1482

Nov 21st, 2018 - In 2015, a germline copy number variation of chromosome 14 (CNVdup14) including ATG2B and GSKIP genes was described as a predisposition genetic factor responsible of familial myeloproliferative neoplasms from French West Indies (Saliba et al, Nat Gen 2015), frequently progressing to AML. In this study, we looked at the presence of this CNVdup14 in a cohort of Caribbean islands patients (pts) wi...

BET Inhibitors Potentiate Activation of p53 and Killing of AML By MDM2 Inhibitors — a Candidate Combination Therapy
http://www.bloodjournal.org/content/132/Suppl_1/3912

Nov 21st, 2018 - In 2016, there will be approximately 19,950 new cases of Acute Myeloid Leukaemia (AML) in the United States. After diagnosis, five-year survival is currently ~26%, with available therapeutic approaches. Therefore, there remains a critical requirement for novel therapies for AML. Bromodomain and extra-terminal domain inhibitors (BETi) are emerging as exciting therapeutic agents for haematopoieti...

B-Cell Receptor Signaling Drives Glycolysis in Chronic Lymphocytic Leukemia Cells
http://www.bloodjournal.org/content/132/Suppl_1/3121

Nov 21st, 2018 - A key feature of tumor cell energetics is preferential metabolism of glucose to lactate even in the presence of oxygen (aerobic glycolysis). While this is an inefficient way of producing energy, it enables cancer cells to use glucose to generate biomass to support cellular proliferation. It is unclear whether this process is playing a role in the pathogenesis of chronic lymphocytic leukemia (CL...

Bone Marrow Hematopoietic Dysfunction in Untreated Chronic Lymphocytic Leukemia Is Partially Mediated By Exposure to Constituents of the Leukemic Microenvironment
http://www.bloodjournal.org/content/132/Suppl_1/3132

Nov 21st, 2018 - Peripheral immune dysfunction in B-Chronic Lymphocytic Leukemia (CLL) is well-studied and likely relates to the incidence of serious recurrent infections and second malignancies that plague CLL patients. However, the current paradigms of known immune abnormalities are not able to consistently explain these complications and it is not easy to correct CLL patient immune status. Here, we expand on...

Blinatumomab in Combination with Immune Checkpoint Inhibitors of PD-1 and CTLA-4 in Adult Patients with Relapsed/Refractory (R/R) CD19 Positive B-Cell Acute Lymphoblastic Leukemia (ALL): Preliminar...
http://www.bloodjournal.org/content/132/Suppl_1/557

Nov 21st, 2018 - Background: Blinatumomab, a CD19/CD3 bispecific T cell engager antibody construct, leads to improved outcomes in patients with R/R CD19+ ALL compared to standard chemotherapy. However, most adults fail to achieve complete remission (CR) with blinatumomab, and the median duration of remission is only 7.3 months. Preclinical studies have shown significantly increased PD-L1 expression on leukemic ...

BST-236, a Novel Cytarabine Prodrug, Is Safer and As Effective As Cytarabine in In Vivo Leukemia Models
http://www.bloodjournal.org/content/132/Suppl_1/1451

Nov 21st, 2018 - Introduction: Acute myeloid leukemia (AML) is associated with poor outcomes in older and medically unfit patients, largely due to the severe toxicity associated with cytarabine treatment, which precludes the administration of effective cytarabine doses. BST-236 is a prodrug of cytarabine, inactive in its prodrug form and designed to deliver cytarabine to leukemia cells with reduced systemic tox...

BRCA1/2 Containing Complex 3 (BRCC36) Is Recurrently Mutated in AML with t(8;21) and Associated with Increased Sensitivity to Chemotherapy through Impairment of the DNA Damage Repair Pathway
http://www.bloodjournal.org/content/132/Suppl_1/1487

Nov 21st, 2018 - Introduction BRCA1/BRCA2-containing complex 3 (BRCC36) is a Lys63-specific deubiquitinating enzyme (DUB) involved in DNA damage repair. Mutations in BRCC36 have been identified in 2-3% of patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). The role of BRCC36 mutations in de novo AML and their impact on DNA damage-inducing cytotoxic chemotherapy sensitivity is not clear. Aim ...

Catecholamine Exposure Accelerates In Vivo Leukemogenesis in Acute Myeloid Leukemia Patient Derived Xenografts
http://www.bloodjournal.org/content/132/Suppl_1/1475

Nov 21st, 2018 - Mouse xenografts are routinely used for in vivo studies on human acute myeloid leukemia (AML) cells. However, a significant proportion of primary AML samples (~50-60% of cases) are not able to repopulate mice, or respectively require a particularly long time (up to 9 months) to show detectable engraftment in such models. Here we report that changing the transplantation time-point from day (5:00...

Cardiovascular Mortality Among CML Patients in the Pre-TKI and TKI Eras: A SEER Analysis 1992-2004
http://www.bloodjournal.org/content/132/Suppl_1/1737

Nov 21st, 2018 - Background: Since the US Food and Drug Administration (FDA) approved the first BCR-ABL1-targeted tyrosine kinase inhibitor (TKI) imatinib in 2002 as the first line therapy1, chronic phase chronic myeloid leukemia (CML-CP), once a uniformly fatal disease, now has become a disease that is controlled in >90% patients2. Conventional treatment for CML before TKIs included hydroxyurea, interferon alp...

CD79a Is Associated with Central Nervous System Infiltration of Pediatric B-Cell Precursor Acute Lymphoblastic Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/386

Nov 21st, 2018 - Despite the advances in the treatment of pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), infiltration of the central nervous system (CNS) remains a clinical challenge. Certain cytogenetic subtypes such as E2A-PBX1-and BCR-ABL-positive BCP-ALL confer a higher risk for CNS involvement initially and for CNS relapse. Novel strategies to predict CNS and to eradicate leukemic cells...

CD37 Expression in Acute Myeloid Leukemia Provides New Target for Directed Therapy
http://www.bloodjournal.org/content/132/Suppl_1/4056

Nov 21st, 2018 - Background: Acute myeloid leukemia (AML) is a disease for which there is an urgent need for therapy that is more effective and less toxic. Antibody based therapy has been of limited success due to both the lack of consistent immunophenotype in AML as well as the overlap with normal hematopoetic stem cells (HSCs). CD37 is a tetraspanin best characterized for its role in B-cell development and im...

Characteristic Amino Acid and Energy Metabolism in AML Stem Cells As Revealed By Quantitative Multiplex Proteomics
http://www.bloodjournal.org/content/132/Suppl_1/2780

Nov 21st, 2018 - Acute Myeloid Leukemia (AML) is a rapidly progressing hematologic malignancy characterized by the accumulation of clonal myeloid progenitor cells arrested in their ability to differentiate into mature blood cells. While classic chemotherapy regimens lead to remission in the majority of patients, relapse rates are very high. Relapse and also refractoriness are caused by the hierarchical organiza...

Characteristics, Treatment Patterns and Outcomes Among Newly Diagnosed Patients (pts) with Acute Myeloid Leukemia (AML) Who Present with Hyperleukocytosis: Findings from a Large International Patie...
http://www.bloodjournal.org/content/132/Suppl_1/4040

Nov 21st, 2018 - Introduction: Pts with AML often present with hyperleukocytosis, defined with a white blood cell count (WBC) of >50 or >100 × 109/L. Hyperleukocytosis is associated with higher rates of complications and death especially when associated with clinical leukostasis. There are no clear guidelines outlining the best cytoreductive strategy and the use of leukapheresis is based on institutional practi...

Characteristics and Outcome of Older Patients with Acute Promyelocytic Leukemia Front-Line Treated with or without Arsenic Trioxide — an International Collaborative Study
http://www.bloodjournal.org/content/132/Suppl_1/80

Nov 21st, 2018 - Background: Characteristics and outcome of older patients (pts) with acute promyelocytic leukemia (APL) are unclear due to lack of clinical data. Aims: To describe a large series of older APL pts and compare outcome according to treatment strategy. Methods: We retrospectively studied 475 APL pts (median age, 73.8 yrs; range, 70-90.3 yrs), treated between 1990 and 2018 within four study groups/i...

Chemoimmunotherapy with Inotuzumab Ozogamicin Combined with Mini-Hyper-CVD, with or without Blinatumomab, for Newly Diagnosed Older Patients with Philadelphia Chromosome-Negative Acute Lymphoblasti...
http://www.bloodjournal.org/content/132/Suppl_1/36

Nov 21st, 2018 - Background: Both the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin (INO) and the CD3-CD19 bispecific T-cell engager blinatumomab have single-agent activity in relapsed or refractory acute lymphoblastic leukemia (ALL). We previously reported the promising efficacy and survival of INO in combination with low-intensity mini-hyper-CVD chemotherapy in older adults with newly diagnosed ALL ...

Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/556

Nov 21st, 2018 - CAR T cell therapy in relapsed B-ALL can result in complete response (CR) rates of 80-90%, but relapse-free survival declines to 60% within the first 12-months due to both CD19-positive and negative relapses. CD19-positive relapses that occur during this time are largely due to early CAR T cell loss. We hypothesize that inhibiting the PD-1:PD-L1 (programmed cell death 1) checkpoint axis may dec...

Chloroquine Derivative Lys05 Overcomes Hypoxia-Induced Chemoresistance in Acute Myeloid Leukemia through Metabolic Disruption
http://www.bloodjournal.org/content/132/Suppl_1/3948

Nov 21st, 2018 - Background: Despite initial responses to standard chemotherapy, most patients with acute myeloid leukemia (AML) relapse and have poor prognoses after subsequent therapy. The hypoxic bone marrow (BM) microenvironment is hypothesized to contribute to clinical resistance through the sheltering of AML blasts and leukemia stem cells (LSCs), allowing them to evade chemotherapy and reinitiate the dise...

Chronic Myeloid Leukemia Italian Multicenter Observational Study (CML-IT-MOS): Clinical Characteristics of Chronic Myeloid Leukemia (CML) Patients Treated in Real-Life between 2012 and 2016 in 66 I...
http://www.bloodjournal.org/content/132/Suppl_1/45

Nov 21st, 2018 - Background: The advent of Tyrosine Kinase Inhibitors (TKI) totally changed the outcome of patients affected by Chronic Myeloid Leukemia (CML). Most of informations about the clinical characteristics of CML patients are based on data derived from clinical trials, that often exclude patients not fitting with strict inclusion criteria. In real life may be important to know the characteristics of t...

Cirmtuzumab Inhibits Non-Canonical Wnt Signaling without Enhancing Canonical Wnt/β-Catenin Signaling in Chronic Lymphocytic Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/2652

Nov 21st, 2018 - ROR1 is a receptor tyrosine kinase-like orphan receptor for Wnt5a that is expressed by cells during embryogenesis and by the neoplastic cells of a variety of cancers, including chronic lymphocytic leukemia (CLL). ROR1 can induce activation of β-catenin-independent non-canonical Wnt-signaling. Studies reveal a cross-talk between the non-canonical Wnt-signaling pathway and the β-catenin-dependent...

Clinical Characteristics and Outcomes of 82 Patients with Mixed-Phenotype Acute Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/1124

Nov 21st, 2018 - Objectives: Mixed-phenotype acute leukemia(MPAL) is a rare disease and comprises 2% to 5% of all acute leukemia. Outcomes for MPAL are worse than both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).The complex phenotype exhibited by this type of leukemia resulted in a myriad of treatment approaches.In our study, we retrospective analysis 82 patients in clinical trail, treat...

Clinical Responses of Glasdegibplus Low-Dose Ara-C, Azacitidine, and Decitabine Among Acute Myeloid Leukemia (AML) Patients Ineligible to Receive Intensive Chemotherapy: Comparative Effectiveness U...
http://www.bloodjournal.org/content/132/Suppl_1/2709

Nov 21st, 2018 - OBJECTIVES: Currently there is no standard treatment option for AML patients not fit for intensive chemotherapy. Further clinical challenges include poorer prognosis associated with advanced age. AML treatments among this population have not been directly compared in clinical trials. Furthermore, naïve comparisons of results across multiple trials are subject to bias related to not accounting f...

Clinical Outcomes in Pediatric Mixed Phenotype Acute Leukemia (MPAL) Differ Depending on Disease Classification Criteria; A Multi-Center Cohort Study
http://www.bloodjournal.org/content/132/Suppl_1/4080

Nov 21st, 2018 - INTRODUCTION: Mixed phenotype acute leukemia (MPAL) is a category of acute leukemia established in the World Health Organization (WHO) 2001 classification, significantly modified in WHO2008, and again refined in the most recent WHO2016 update. The current WHO2016 iteration conceptualizes MPAL as a stem cell disorder whereby most cases will manifest heterogeneity of lineage-specific antigen expr...

CLL Intraclonal Fractions Defined By Time Since Cell Birth/Division Promote a Leukemia-Supportive, Immune-Tolerant Microenvironment By Distinct Mechanisms
http://www.bloodjournal.org/content/132/Suppl_1/1836

Nov 21st, 2018 - Chronic lymphocytic leukemia (CLL) cells actively participate in the formation of the tumor microenvironment (TME). The interplay of CLL cells and leukemia-supporting cells such as Th2 cells and regulatory T cells (Tregs) promotes a leukemia-supportive, immune-tolerant TME. In these supportive/tolerogenic niches of lymph nodes (LN) and bone marrow (BM), CLL cells slowly proliferate, and the rat...

Clinical, Immunophenotypic and Genomic Findings of Acute Undifferentiated Leukemia and Comparison to AML with Minimal Differentiation: A Study from the Bone Marrow Pathology Group
http://www.bloodjournal.org/content/132/Suppl_1/1491

Nov 21st, 2018 - Introduction: Acute undifferentiated leukemia (AUL) is a rare type of acute leukemia that shows no evidence of differentiation along any lineage. Clinical, immunophenotypic and genetic data is limited: the largest study to date reported 16 AUL cases but did not use the current WHO classification and included limited genetic data on 5 cases (Ann Hematol 2013 92:747-758). Moreover, it is uncertai...

Combination of BCR-ABL1 Tyrosine Kinase Inhibitors with a Small Molecule LIM kinase1/2 Inhibitor in BCR-ABL1 Positive Acute Lymphoblastic Leukemia (ALL)
http://www.bloodjournal.org/content/132/Suppl_1/2705

Nov 21st, 2018 - Introduction: LIM kinases 1 and 2 (LIMK1/2) are downstream effectors at the crossroads of different signaling pathways implicated in the dynamics of the cytoskeleton via phosphorylation of cofilin family proteins, degradation of the matrix by phosphorylating MT1-MMP and control of the activity of Aurora kinase A. Recently, the oncogenic role of Rho kinases (ROCK) was identified to be constituti...

Coagulation and Fibrinolysis Imbalance Demonstrated By Novel Simultaneous Thrombin and Plasmin Generation Assay during L-Asparaginase Treatment Phase of Induction Therapy in Pediatric Acute Lymphob...
http://www.bloodjournal.org/content/132/Suppl_1/3972

Nov 21st, 2018 - Introduction: L-asparaginase (L-Asp) is one of the risk factor of thromboembolism during ALL chemotherapy. Although the pathogenesis has been still unclarified, L-Asp may have profound effects on hepatic synthesis of pro-, anti-coagulant and fibrinolytic factors. In addition, recent studies demonstrated that the age of over 10-years might be a risk factor for this L-Asp associated coagulopathy....

Combined Ibrutinib and Venetoclax in Patients with Treatment-Naïve High-Risk Chronic Lymphocytic Leukemia (CLL)
http://www.bloodjournal.org/content/132/Suppl_1/696

Nov 21st, 2018 - Background: Ibrutinib (IBR), a BTK inhibitor, and venetoclax (VEN), a BCL-2 inhibitor are approved for patients (pts) with CLL. The rationale for combining IBR and VEN includes: 1) preclinical models showing synergism with the combination, 2) non-overlapping toxicity profiles; 3) non-overlapping mechanisms of action; 4) complementary activity in treating disease compartments. We report results ...

Combinatorial Genetics Uncovers Novel Targets for the Treatment of Npm1/Cohesin Mutated AML
http://www.bloodjournal.org/content/132/Suppl_1/2598

Nov 21st, 2018 - Current precision medicine approaches typically target a single genetic mutation. However, adult acute myeloid leukemia (AML) is difficult to treat due to its genetic complexity. Approximately 30 somatic mutations have been found to be recurrent, with an average of 5-15 mutations present per patient (Cancer Genome Atlas 2013). Therefore, combinatorial genetic approaches have the power to uncove...

Combined Targeting of BET Family Proteins and BCL2 Is Synergistic in Acute Myeloid Leukemia Cells Overexpressing S100A8 and S100A9
http://www.bloodjournal.org/content/132/Suppl_1/2634

Nov 21st, 2018 - Background The 5-year survival rate for acute myeloid leukemia (AML) remains poor with most patients succumbing to relapse or refractory disease. Recently, the BCL2 specific inhibitor venetoclax has shown promising anti-leukemia activity in high-risk AML patients. Most patients, however, ultimately develop resistance to monotherapy and novel combination treatments with venetoclax are needed for...

Comparative Analysis between RQ-PCR, Digital-Droplet-PCR and Next-Generation-Sequencing (NGS) of Immunoglobulin/T-Cell Receptor Gene Rearrangements to Monitor Minimal Residual Disease in Adult Acut...
http://www.bloodjournal.org/content/132/Suppl_1/2828

Nov 21st, 2018 - Background. Minimal residual disease (MRD) is the strongest prognostic factor in both children and adults with acute lymphoblastic leukemia (ALL). Currently, it is most widely monitored by molecular methods based on real-time-quantitative-PCR (RQ-PCR). Digital-droplet-PCR (ddPCR) and next-generation-sequencing (NGS) represent advanced tools that have the potential to overcome some limitations o...

Comparative Effectiveness of Combination Glasdegib+ Low-Dose Cytarabine (GLAS+LDAC) Vs Combination Venetoclax + Low-Dose Cytarabine (VEN+LDAC) Among Older Acute Myeloid Leukemia (AML) Patients Inel...
http://www.bloodjournal.org/content/132/Suppl_1/1429

Nov 21st, 2018 - BACKGROUND: Older AML patients are often NIC and face poorer prognoses. Among less intensive AML treatments, GLAS+LDAC showed improved efficacy vs LDAC alone in a Phase II randomized controlled trial (RCT). Recently, a phase I/II single arm study of VEN+LDAC showed longer overall survival (OS) in naive comparison to GLAS+LDAC. However, naïve comparisons across trials do not account for within-t...

Comparison of Efficacy and Toxicity of CD19-Specific Chimeric Antigen Receptor T-Cells Alone or in Combination with Ibrutinib for Relapsed and/or Refractory CLL
http://www.bloodjournal.org/content/132/Suppl_1/299

Nov 21st, 2018 - Background We reported durable responses to CD19-specific chimeric antigen receptor-modified T-cell therapy (JCAR014) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) patients (pts) after prior failure of ibrutinib (Turtle, JCO 2017; NCT01865617). In those pts, ibrutinib was not administered during CAR-T cell immunotherapy. Continuation of ibrutinib through leukapheresis, lymphod...

Comparison of Salvage Chemotherapy Regimens in Relapsed/Refractory Acute Myeloid Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/2708

Nov 21st, 2018 - Background Induction therapy for acute myeloid leukemia (AML) with a cytarabine-anthracycline regimen (7+3) is well-established; however, there is no standard salvage therapy for patients with relapsed/refractory AML (RR-AML). There is a paucity of data regarding outcomes with salvage regimens in RR-AML that include cladribine, cytarabine, and filgrastim with mitoxantrone (CLAG-M) or without mi...

Spatial Regulation of Thrombopoiesis in the Bone Marrow
http://www.bloodjournal.org/content/132/Suppl_1/SCI-23

Nov 21st, 2018 - Blood platelets play key roles in hemostasis and thrombosis and are the second most abundant cell type in the circulation. Due to their short life span of only a few days, anuclear platelets are continuously replenished and thus provide a classic system to study hematopoiesis. In mammals, platelets are produced by megakaryocytes (MKs) that are predominantly residing in the bone marrow (BM). MKs...

Complex 3q26/EVI1 Rearrangements Genocopy Inv(3)/t(3;3) Acute Myeloid Leukemias By Enhancer Hijacking, EVI1 Overexpression, Absent MDS1-EVI1 and Low GATA2 Expression
http://www.bloodjournal.org/content/132/Suppl_1/2766

Nov 21st, 2018 - Introduction Acute myeloid leukemia (AML) with inv(3)(q21q26) or t(3;3)(q21;q26) overexpress EVI1 and have a very poor prognosis. EVI1 is part of the MECOM (MDS1-EVI1-Combination) locus from which MDS1-EVI1 and EVI1 can be transcribed from two different promoters. Although EVI1 is expressed at high levels, MDS1-EVI1 is absent or expressed at very low levels in inv(3)/t(3;3)-AMLs. Aberrant EVI1 ...

Comprehensive Genomic Analysis of IDH Inhibitor-Treated AML Samples Delineates Molecular Mechanisms of Differentiation and Heterogeneous Patterns of Acquired Resistance
http://www.bloodjournal.org/content/132/Suppl_1/441

Nov 21st, 2018 - Allosteric inhibitors of mutant IDH1 or IDH2 induce differentiation of IDH-mutant AML myeloblasts, which in some patients (pts) can lead to a life-threatening differentiation syndrome (DS). The in vivo mechanism of how IDH inhibitors induce differentiation and occasionally DS is not fully understood. Furthermore, responders to the inhibitors often lose the differentiation effect, after median o...

Comprehensive Analysis of 343 Genes Using Targeted Sequencing Panel By Next-Generation Sequencer in 77 Pediatric AML Patients with Normal and Complex Karyotypes: Jccg Study, JPLSG AML-05
http://www.bloodjournal.org/content/132/Suppl_1/1530

Nov 21st, 2018 - Introduction Acute myeloid leukemia (AML) is a molecularly and clinically heterogeneous disease caused by various genetic alterations. Some prognosis-associated chromosomal aberrations and gene mutations such as t(8;21), inv(16), monosomy 7, and FLT3-ITD have been adopted for risk stratification. Although treatment outcomes have improved via stratification therapy, relapse and mortality are sti...

Lymphopenia As an Early Predictor of Immune Related Adverse Events
http://www.bloodjournal.org/content/132/Suppl_1/4958

Nov 21st, 2018 - Introduction Immune checkpoint inhibitors (ICI) are a novel class of medications which offer a potential curative option for many cancer patients who previously had a more dismal prognosis. Programmed cell death protein 1 (PD-1) is a molecule that modulates cellular immunity to limit autoimmunity, but can also be co-opted by cancers and infections to create immune tolerance. Nivolumab and pembr...

Comprehensive Single-Cell RNA-Sequencing Mapping of Primary Acute Myeloid Leukemias and Profiling of NPM1-Mutated Cells
http://www.bloodjournal.org/content/132/Suppl_1/995

Nov 21st, 2018 - Introduction: Acute myeloid leukemia (AML) evolution is a multistep process in which cells evolve from hematopoietic stem and progenitor cells (HSPCs) that acquire genetic anomalies, such as chromosomal rearrangements and mutations, which define distinct subgroups. Mutations in Nucleophosmin 1 (NPM1), which occur in ~30% patients, are the most frequent subgroup-defining mutations in AML and app...

2nd cycle Remission Achievement with 7+3 Is Associated with Shorter Survival in Adults with Newly Diagnosed Acute Myeloid Leukemia: Analysis of Recent SWOG Trials
http://www.bloodjournal.org/content/132/Suppl_1/3978

Nov 21st, 2018 - Background: Intensive chemotherapy will induce a complete morphologic remission (CR) in many adults with acute myeloid leukemia (AML). Whether it matters that a remission is obtained early, i.e. with the first cycle of chemotherapy, has remained controversial. Data from historic and contemporary trials with double induction chemotherapies showed patients who achieved a CR with the first inducti...

Copy Number Monitoring from Tumor-Only Targeted Gene Sequencing in Hematological Malignancies
http://www.bloodjournal.org/content/132/Suppl_1/4086

Nov 21st, 2018 - The occurrence of copy number variation (CNV) observed in hematological malignancies could be up 20%~70%, variable in specific subtypes, but the available molecular diagnosis directed to the clinic are always limited among SNVs and Indels. In contrast, the copy number variation which cover broader genome region has not yet come to be implemented in clinical examination. Recently, the CNV in hem...

64cu-DOTA-Anti-CD33 PET-CT Imaging for Acute Myeloid Leukemia and Image-Guided Treatment
http://www.bloodjournal.org/content/132/Suppl_1/2747

Nov 21st, 2018 - Introduction: Acute myeloid leukemia (AML) is a highly aggressive form of leukemia that results a poor survival outcome. Currently, diagnosis and prognosis are based on invasive single-point bone marrow biopsies (iliac crest). Although non-invasive positron emission tomography (PET) imaging has been developed for almost all solid tumors and some hematological malignancies, there is currently no...

Critical Role of Jumonji Domain of JMJD1C in AML Leukemogenesis
http://www.bloodjournal.org/content/132/Suppl_1/2599

Nov 21st, 2018 - MLL-rearranged leukemias are found in 5-10% of adult leukemias and over 70% of infant leukemias and are associated with intermediate to poor prognosis. We have recently shown that JMJD1C, a Jumonji domain containing lysine demethylase (KDM), is important for leukemia stem cell (LSC) function in MLL-AF9 and HOXA9 leukemias but dispensable for normal hematopoietic stem cell function, therefore a ...

CXCR4 Has a CXCL12-Independent Essential Role in MLL-AF9 Driven Acute Myeloid Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/774

Nov 21st, 2018 - Acute Myeloid Leukemia (AML) is a clonal hematological disorder associated with poor prognosis, and there is a strong need to develop new therapeutic strategies. AML is propagated by a small population of leukemic cells in the bone marrow with self-renewal capacity, a population termed leukemia stem cells (LSC). To identify in vivo dependencies of LSCs, we conducted a CRISPR/Cas9 drop-out scree...

Cytokine Gene Polymorphisms Are Associated with Disease Response to Blinatumomab in Patients with B-Cell Acute Lymphoblastic Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/1549

Nov 21st, 2018 - Blinatumomab (BT), a CD19/CD3 bispecific T-cell engager (BiTE) antibody recently approved for treatment of relapsed/refractory acute lymphoblastic leukemia (r/r ALL), has resulted in a 40-50% complete response (CR)/CR with incomplete count recovery (CRi) rate and frequent cytokine release syndrome (CRS) events. While extent of disease burden has been identified as a key predictor of disease res...

A Leukemic Progression Model of Severe Congenital Neutropenia Uncovers a Novel Mechanism of AML Development Involving Elevated Inflammatory Responses, Mutation of CXXC4 and Decreased TET2 Levels
http://www.bloodjournal.org/content/132/Suppl_1/540

Nov 21st, 2018 - Introduction: Severe congenital neutropenia (SCN) patients receive life-long treatment with CSF3/G-CSF to alleviate neutropenia and have a high risk to develop MDS or AML. The appearance of hematopoietic clones with CSF3 receptor (CSF3R) mutations represents a first step in MDS/AML progression, which is followed by mutations in RUNX1 shortly before MDS/AML becomes clinically overt. How intracel...

Deep Molecular Response in Imatinib First-Line 418 Newly Diagnosed CP CML Patients.
http://www.bloodjournal.org/content/132/Suppl_1/3014

Nov 21st, 2018 - Introduction Deep molecular response (DMR) are now highly desirable goals in the treatment of CP-CML, especially in the front-line setting, because it can lead to a definitive treatment-free remission (TFR). However, such a goal is difficult to attain and does not concern the majority of patients (pts), but currently the precise number of pts able to access to TFR is unknown. Aims We aim to det...

Detection of Clinically Relevant Molecular Alterations in Chronic Lymphocytic Leukemia (CLL) By Nanopore Sequencing
http://www.bloodjournal.org/content/132/Suppl_1/1847

Nov 21st, 2018 - Introduction Chronic Lymphocytic Leukaemia (CLL) is the most prevalent leukaemia in the Western world and characterised by clinical heterogeneity. IgHV mutation status, mutations in the TP53 gene and deletions of the p-arm of chromosome 17 are currently used to predict an individual patient's response to therapy and give an indication as to their long-term prognosis. Current clinical guidelines...

A Personalized Prediction Model for Outcomes after Allogeneic Hematopoietic Stem Cell Transplant in Patients with Myelodysplastic Syndromes: On Behalf of the CIBMTR Chronic Leukemia Committee
http://www.bloodjournal.org/content/132/Suppl_1/206

Nov 21st, 2018 - Background Allogeneic hematopoietic cell transplantation (HCT) remains the only potentially curative option for myelodysplastic syndromes (MDS). Genetic alterations have an impact on outcomes after HCT in MDS (Lindsley C, et al, NEJM 2017). Given the significant risks of transplant-related mortality and relapse, identifying patients (pts) who may or may not benefit from HCT is clinically import...

Discovery and Development of MEDI7247, a Novel Pyrrolobenzodiazepine (PBD)-Based Antibody Drug Conjugate Targeting ASCT2, for Treating Hematological Cancers
http://www.bloodjournal.org/content/132/Suppl_1/4071

Nov 21st, 2018 - The neutral amino acid transporter, ASCT2, is frequently overexpressed in several cancers to sustain "glutamine addiction" of cancer cells. High expression of ASCT2 is often associated with poor disease prognosis. Immuno-histochemistry (IHC) on formalin-fixed paraffin embedded (FFPE) tissue samples revealed high prevalence of membranous ASCT2 expression in several hematological cancers, includi...

A Phase II Study of the Hyper-CVAD Regimen in Sequential Combination with Blinatumomab As Frontline Therapy for Adults with B-Cell Acute Lymphoblastic Leukemia (B-ALL)
http://www.bloodjournal.org/content/132/Suppl_1/32

Nov 21st, 2018 - Background Multi-agent combination chemotherapy regimens for the treatment of ALL are considered a cancer success story in the pediatric setting. For adults, the same magnitude of success has not been realized using similar strategies. These regimens produce high complete remission (CR) rates of 80-90% but the cure rates are 40-50%. The incorporation of targeted agents (tyrosine kinase inhibito...

Discrepant Mutational Composition between Myeloid Sarcoma and Bone Marrow Leukemia Revealed through Targeted Next Generation Sequencing
http://www.bloodjournal.org/content/132/Suppl_1/1395

Nov 21st, 2018 - Introduction: Myeloid sarcoma (MS) is the involvement of acute myeloid leukemia (AML) cells in extramedullary tissues, whose mechanism remains to be further elucidated. How MS affects AML prognosis at a molecular level is also an open question. This unexplained tropism of leukemic blasts to extramedullary tissues is likely caused by the combination of genetic and epigenetic aberrations. Our stu...

A Scoring System to Predict the Risk of Atrial Fibrillation in Chronic Lymphocytic Leukemia and Its Validation in a Cohort of Ibrutinib-Treated Patients
http://www.bloodjournal.org/content/132/Suppl_1/3118

Nov 21st, 2018 - BACKGROUD. The B-cell receptor inhibitor ibrutinib has significantly improved treatment and overall management of chronic lymphocytic leukemia (CLL). Although several data derived from clinical trials suggest that ibrutinib increases the risk of atrial fibrillation (AF), the incidence of AF in a real-life cohort of CLL patients is unknown. Furthermore, it would be clinically relevant to identif...

A Tumor Suppressor Role for Bank1 in B-Cell Precursor Acute Lymphoblastic Leukemia
http://www.bloodjournal.org/content/132/Suppl_1/1333

Nov 21st, 2018 - Introduction: Since the implementation of next generation sequencing techniques, inherited mutations in malignancy-associated susceptibility genes have become of major interest, to identify high-risk individuals, even before an actual disease onset. One challenge in this regard is that germline susceptibility variants often display incomplete or reduced penetrance, which can be influenced by ge...

Aberrant Splicing of KMT2A As a Potential Molecular MRD Marker in Cytogenetically-Normal AML
http://www.bloodjournal.org/content/132/Suppl_1/1504

Nov 21st, 2018 - Cytogenetically normal acute myeloid leukaemia (CN-AML) accounts for approximately 25%-30% of paediatric AML cases and carries a high risk of relapse. Minimal residual disease (MRD) is an essential factor in predicting relapse in acute leukaemia but is difficult to track for many CN-AML patients, due to the lack of a distinct and stable molecular marker. Consequently, new biomarkers are urgentl...

Absence of NKG2D Ligands Defines Human Acute Myeloid Leukaemia Stem Cells and Mediates Their Immune Evasion
http://www.bloodjournal.org/content/132/Suppl_1/769

Nov 21st, 2018 - Patients with acute myeloid leukaemia (AML) often achieve remission but subsequently die of relapse driven by chemotherapy resistant leukemic stem cells (LSCs). To initiate and maintain cancer, LSCs must also escape immunosurveillance. However, in vivo studies on human LSCs largely disregard lymphocyte mediated anti-tumor immunity due to the use of immunocompromised mice. Here we investigate th...

Donor Cell Leukemia: The Role of Recipient Microenvironment
http://www.bloodjournal.org/content/132/Suppl_1/3853

Nov 21st, 2018 - Acute myeloid leukemia (AML) is one of the extreme outcomes of age-related clonal hematopoiesis (ARCH). In recent years, data on differences between pre-AML and ARCH have emerged. However, it is still enigmatic why ARCH is prevalent in the general aging population, whereas only very few individuals eventually develop AML. Whether ARCH is solely related to abnormal hematopoiesis or originates fr...

Accounting for the Unique Molecular Landscape of Pediatric Malignancies Improves Target-Agent Pair Identification for Pediatric Precision Oncology
http://www.bloodjournal.org/content/132/Suppl_1/2829

Nov 21st, 2018 - Precision medicine has significant potential to improve therapy options for patients who have exhausted treatment options for their relapsed or refractory cancers. Next-generation sequencing has enabled the detection of genetic abnormalities in individual tumours that bestow sensitivity to selective agents targeting these dysregulated cellular pathways. Several programs have recently launched t...

Dosing Patterns of Dasatinib Use in Simplicity, an Observational Study in Chronic Phase Chronic Myeloid Leukemia (CP-CML) Patients (pts) in Routine Clinical Practice
http://www.bloodjournal.org/content/132/Suppl_1/1730

Nov 21st, 2018 - Introduction: Treatment dosing patterns have not been well documented among dasatinib-treated CP-CML pts outside of clinical trials. SIMPLICITY (NCT01244750) is an ongoing observational study of CP-CML adult pts in routine clinical practice receiving tyrosine kinase inhibitors (TKI) since 2010 in the US and Europe, exploring TKI use and management patterns in clinical practice. This analysis re...

Activation of CRLF2/IL7RA Signaling in Normal Human Cord Blood Hematopoietic Progenitors Induces Philadelphia-like B-Cell Precursor Pre-Leukemia and Leukemia In Vivo
http://www.bloodjournal.org/content/132/Suppl_1/566

Nov 21st, 2018 - Philadelphia-like (Ph-like) B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a subgroup of BCP-ALL with an expression pattern similar to BCR-ABL+ BCP-ALL that is associated with poor prognosis. Aberrant expression of CRLF2 in BCP-ALL constitutes the majority of Ph-like BCP-ALL cases. CRLF2 is a receptor subunit that together with the IL7RA subunit comprises the receptor of the proinfl...