Hematologic Malignancies Arising in Patients with Germ Cell Tumors: Secondary Somatic Differentiation of Hematopoietic Malignancies from Germ Cell Precursors
Genomic analyses have recently illuminated our understanding of therapy-associated myeloid neoplasms in patients receiving therapy for other cancers. One of the most intriguing relationships between solid tumors and myeloid neoplasms involves a unique clinical entity of patients with germ cell tumors (GCT) and myeloid neoplasms. One in 17 patients with primary mediastinal germ cell tumor (PMGCT) develops a hematologic malignancy (most commonly AML, MDS, or histiocytosis) and the median survival in such patients is poor at only 5 months. Intriguingly, the presence of isochromosome 12p [i(12p)], a clonal marker common to GCT...
Source: Blood - November 21, 2018 Category: Hematology Authors: Taylor, J., Donoghue, M., Rampal, R. K., Tamari, R., Tallman, M. S., Feldman, D. R., Taylor, B. S., Abdel-Wahab, O. I. Tags: 617. Acute Myeloid Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis I Source Type: research
Prediction of CAR T-Related Toxicities in R/R DLBCL Patients Treated with Axicabtagene Ciloleucel Using Point of Care Cytokine Measurements
Discussion: In this analysis of 20 patients, we observed a correlation between severe CRS and elevated serum cytokine levels of IL-6 and angiopoietin 2/angiopoietin 1 ratio at day one suggesting that these biomarkers may be utilized to predict severe toxicity in patients treated with ACT. While this study is limited by small sample size, our observations correlate with previously published biomarkers data in patients enrolled in clinical trials. To our knowledge this is the first reported cytokine data using commercial axi-cel. Monitoring of cytokines using a POC device is feasible and will be useful clinically. High risk ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Faramand, R., Kotani, H., Morrissey, D., Yu, B., Locke, F. L., Jain, M. D., Chavez, J. C., Wang, X., Mishra, A., Bachmeier, C. A., Brentjens, R. J., Yoo, S., Park, J. H., Davila, M. L. Tags: 627. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)-Results from Retrospective/Observational Studies: Outcomes With CD19 CAR T Therapy and Checkpoint Blockade in the Real World Setting Source Type: research
Niche Heterogeneity Impacts Evolution of Myeloproliferative Neoplasms Driven By the Same Oncogenic Pathway
Different MPNs have distinct rates of malignant transformation (PMF>PV>ET). Although PV and ET can arise from hematopoietic stem/progenitor cells (HSPCs) with similarly activated JAK-STAT oncogenic pathway, the transformation rate into secondary myelofibrosis and leukemia is higher for PV than for ET. However, the underlying reasons are not fully clear. Whereas in some cases secondary mutations might cause transformation, it remains unclear whether distinct bone marrow (BM) microenvironments can influence the progression of MPNs or any preleukemic disorder. Previous studies have suggested that normal BM niches close ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Korn, C., Rak, J., Garcia-Garcia, A., Fielding, C., Khorshed, R., Gonzalez-Anton, S., Li, J., Norfo, R., Baxter, E. J., McKerrell, T., Roberts, T., Eldaly, H., Godfrey, A. L., Castillo-Venzor, A., Kusumbe, A., Mead, A. J., Green, A. R., Kent, D., Lo Celso Tags: 635. Myeloproliferative Syndromes: Basic Science: Mechanisms of Development and Progression Source Type: research
Hippo Kinase Inactivation Contributes to Del(20q) Malignancies and Cooperates with JAK2-V617F to Promote Myelofibrosis in Mice
Recurring chromosome abnormalities are frequent events in cancer and are especially prevalent in hematologic neoplasms. Somatic heterozygous deletions on chromosome 20q are detected in a variety of hematopoietic malignancies including myelodysplastic syndrome (MDS), classical myeloproliferative neoplasm (MPN), MDS/MPN overlap disorders such as chronic myelomonocytic leukemia (CMML), and acute leukemias. Del(20q) is especially prevalent in MPN patients (~10-15%), where it is the most commonly detected cytogenetic abnormality associated with primary myelofibrosis (PMF) and post-polycythemia vera myelofibrosis (MF). This sugg...
Source: Blood - November 21, 2018 Category: Hematology Authors: Stoner, S. A., Yan, M., Liu, K., Shima, T., Wang, H.-Y., Arimoto, K.-I., Bejar, R., Jamieson, C., Guan, K.-L., Zhang, D.-E. Tags: 635. Myeloproliferative Syndromes: Basic Science: Mechanisms of Development and Progression Source Type: research
Myeloproliferative Neoplasm (MPN) Blastic Transformation Occurs at the Level of Hematopoietic Stem Cells
Myeloproliferative neoplasm-blast phase (MPN-BP) and de novo acute myeloid leukemia (AML) each have distinct mutational patterns and clinical courses. MPN-BP patients have a particularly dismal prognosis with a median survival of less than 6 months with currently available therapies. So far, the cellular hierarchy that characterizes MPN-BP and the evolution of various leukemia-initiating clones (LIC) in MPN-BP have not been well delineated. We therefore established an in vivo MPN-BP xenograft model to address these questions.Among the 22 patients with MPN-BP studied 11 were cytogenetically normal while the remainder had mu...
Source: Blood - November 21, 2018 Category: Hematology Authors: Wang, X., Hu, C. S., Tripodi, J., Najfeld, V., Petersen, B., Rampal, R. K., Farnoud, N., Famulare, C., Mascarenhas, J., Hoffman, R. Tags: 635. Myeloproliferative Syndromes: Basic Science: Mechanisms of Development and Progression Source Type: research
Monosomy 7 As the Initial Hit Followed By Sequential Acquisition of SETBP1 and ASXL1 Driver Mutations in Childhood Myelodysplastic Syndromes
Childhood myelodysplastic syndromes (MDS) account for less than 5% of pediatric hematologic malignancies and differ from their adult counterpart in terms of biology, genetics, and cure rates. Complete (-7) or partial loss (del7q) of chromosome 7 constitutes the most common cytogenetic abnormality and is associated with more advanced disease typically requiring timely hematopoietic stem cell transplantation (HSCT). Previously, we and others established a link between -7 and germline GATA2 mutations in pediatric MDS (37% of MDS/-7 cases are GATA2-deficient) as well as constitutional SAMD9/9L disorders where -7 is utilized as...
Source: Blood - November 21, 2018 Category: Hematology Authors: Pastor Loyola, V., Panda, P. K., Sahoo, S. S., Szvetnik, E. A., Kozyra, E. J., Voss, R. K., Lebrecht, D., Wehrle, J., Erlacher, M., Stary, J., Flotho, C., Gohring, G., Schlegelberger, B., Strahm, B., Niemeyer, C., Wlodarski, M. W. Tags: 636. Myelodysplastic Syndromes-Basic and Translational Studies: Somatic Mutations and Germline Predisposition Source Type: research
The Landscape of Structural Variant Signatures in Multiple Myeloma Identifies Distinct Disease Subgroups with Implications for Pathogenesis
In this study, we describe the landscape of SVs and complex events in MM, suggesting that this notation may represent an important step forward in disentangling the genomic complexity and heterogeneity of MM.DisclosuresMoreau: Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board...
Source: Blood - November 21, 2018 Category: Hematology Authors: Maura, F., Leongamornlert, D., Angelopoulos, N., Dawson, K. J., Samur, M. K., Szalat, R., Tai, Y.-T., Minvielle, S., Magrangeas, F., Moreau, P., Corradini, P., Anderson, K. C., Avet-Loiseau, H., Campbell, P. J., Munshi, N., Bolli, N. Tags: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Genomic Landscape of Myeloma and Its Clinical Impacts Source Type: research
Progression Free Survival below 12 Months Following Stem Cell Transplant Is a Hallmark of High-Risk Myeloma Which Is Associated with Inferior Overall Survival -- Data from the Ukmrc Myeloma XI Trial
DiscussionNearly three quarters of those with PFS1<12m had died 3 years after entry to MXI, highlighting an area of urgent unmet need for this poorly understood group. Continuous lenalidomide therapy and deep serological responses did not prevent early progression in some. At 36 months post ASCT 6% of patients with PFS1<12m had not progressed for a second time compared to 33% with a PFS1≥12 months. We found 64% of patients in the short PFS group had at least one HR genetic lesion. Current standard approaches lack efficacy to salvage patients, who have been exposed to immunomodulatory drugs and proteasome inhibitor...
Source: Blood - November 21, 2018 Category: Hematology Authors: Bygrave, C. A., Pawlyn, C., Davies, F. E., Cairns, D., Striha, A., Hockaday, A., Paterson, A., Jones, J. R., Kishore, B., Garg, M., Williams, C., Karunanithi, K., Lindsay, J., Jenner, M. W., Cook, G., Drayson, M. T., Owen, R. G., Russel, N. H., Gregory, W Tags: 731. Clinical Autologous Transplantation: Results: Multiple Myeloma: Upfront Autologous Transplantation Source Type: research
Lack of GDF11 Does Not Ameliorate Erythropoiesis in {beta}-Thalassemia and Does Not Prevent the Activity of the Trap-Ligand RAP-536
Mutations in the HBB gene causes β-thalassemia (BT). Treatment for BT presents a major clinical challenge in the United States, as patients require chronic and expensive treatment for survival. A new drug in Phase III clinical trials, Luspatercept (ACE-536), has been shown to improve BT symptoms via an erythropoietin (EPO) -independent pathway. ACE-536 is a peptide drug identical to the extracellular domain of activin receptor IIB (ACVR2B). Upon administration, it competes with ACVR2B to bind members of the transforming growth factor (TGF) β superfamily. Growth differentiation factor 11 (GDF11) has been pinpointe...
Source: Blood - November 21, 2018 Category: Hematology Authors: Guerra, A., Oikonomidou, R., Gonzalez, S., Zhang, J., Lo Presti, V., Hamilton, C. R., Breda, L., Casu, C., Fleming, M. D., Martinez, P., Suragani, R., Kumar, R., Rivella, S. Tags: 112. Thalassemia and Globin Gene Regulation: Clinical Source Type: research
Clinical Outcomes of Lentiglobin Gene Therapy for Transfusion-Dependent {beta}-Thalassemia Following Completion of the Northstar HGB-204 Study
BackgroundAdvances in red blood cell (RBC) transfusion and chelation have improved the prognosis of patients with transfusion-dependent β-thalassemia (TDT); however, many patients experience organ damage due to iron overload and other complications. While potentially curative, allogeneic hematopoietic stem cell transplantation confers significant risks of morbidity and mortality and is limited by donor availability. Gene therapy (GT) has the potential to be an effective treatment option for patients with TDT without some of these limitations. LentiGlobin GT contains autologous CD34+ cells transduced ex vivo with the B...
Source: Blood - November 21, 2018 Category: Hematology Authors: Rasko, J. E. J., Thompson, A. A., Kwiatkowski, J. L., Hongeng, S., Schiller, G. J., Anurathapan, U., Cavazzana, M., Ho, P. J., Schmidt, M., Kletzel, M., Leboulch, P., Vichinsky, E., Deary, B., Chen, Y., Asmal, M., Walters, M. C. Tags: 112. Thalassemia and Globin Gene Regulation: Clinical Source Type: research
Biomarkers Predicting Venetoclax Sensitivity and Strategies for Venetoclax Combination Treatment
In this study, we investigated approximately 200 AML patient samples and correlated clinical parameters, whole exome sequence data, and RNAseq gene expression data with in vitro drug screening data (drug area under the curve (AUC)) to identify subsets of AML samples with sensitivity or resistance to venetoclax alone and in combinations with 10 small molecular inhibitors (Array-382, dasatinib, JQ-1, idelalisib, quizartinib, palbociclib, panobinostat, ruxolitinib, sorafenib, and trametinib).For gene expression, we observed that venetoclax correlated with 3 gene expression clusters (coefficient frequency: 0.94, 0.80 and 0.71 ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Zhang, H., Wilmot, B., Bottomly, D., Kurtz, S. E., Eide, C. A., Damnernsawad, A., Romine, K., Patel, S., Druker, B. J., Mcweeney, S. K., Majeti, R., Tyner, J. W. Tags: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Mechanisms of Sensitivity, Resistance, and Combination Therapy Source Type: research
Novel BET Protein Degrader-Based Combinations Exert Lethality Against Human AML Resistant to BET Inhibitors Due to Increased Activity of {beta}-Catenin-TCF7L2- MYC Axis
Bromodomain and extra-terminal protein (BETP) inhibitors (BETis) disrupt the chromatin binding and activity of the BETP BRD4 in facilitating RNA pol II-mediated mRNA transcription, thereby depleting levels of active oncoproteins including c-Myc, CDK6, BCL2, PIM1 and MCL1. BETi treatment also increases protein levels of p21, p27 and HEXIM1, thereby causing growth inhibition and apoptosis of AML blast progenitor cells (BPCs), including post-MPN, secondary AML (sAML) BPCs. Treatment with BETi (e.g., OTX015) has been shown to reduce AML burden and induce clinical remissions. However, BETi-refractory AML develops uniformly. Pre...
Source: Blood - November 21, 2018 Category: Hematology Authors: Saenz, D. T., Fiskus, W., Manshouri, T., Saenz, D. N., Soldi, R., Sun, B., Mill, C. P., Nowak, A. J., Kornblau, S. M., Bose, P., Kadia, T. M., DiNardo, C. D., Masarova, L., Horrigan, S., Khoury, J. D., Sharma, S., Verstovsek, S., Bhalla, K. N. Tags: 604. Molecular Pharmacology and Drug Resistance in Myeloid Diseases: Mechanisms of Sensitivity, Resistance, and Combination Therapy Source Type: research
Efficient Scale-up and Pre-Clinical Evaluation of NKG2C+ Adaptive NK Cell Expansion for Therapy Against High-Risk AML/MDS
Natural killer (NK) cells hold great promise as a source for allogeneic cell therapy against hematological malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). NK cell recognition of allogeneic tumors is strictly regulated by inhibitory killer cell immunoglobulin-like receptors (KIR) that bind to groups of HLA class I alleles. However, KIR expression on NK cells is highly diverse due to variation in gene content, polymorphism and copy number in combination with stochastic expression of the protein in individual cells. As a consequence, the number of efficacious allogeneic NK cells within...
Source: Blood - November 21, 2018 Category: Hematology Authors: Sohlberg, E., Haroun-Izquierdo, A., Bjorklund, A. T., Cooley, S., Wiiger, M. T., Goodridge, J. P., Hoel, H. J., Pfefferle, A., Chrobook, M., Kremer, V., Hellstrom-Lindberg, E., Ask, E. H., Pontus, B., Valamehr, B., Guldevall, K., van Ooijen, H., Onfelt, B Tags: 711. Cell Collection and Processing II Source Type: research
Prolonged Lenalidomide Therapy in Multiple Myeloma Patients Does Not Impact Autologous PBSC Mobilization: A Single Center Retrospective Analysis
We examined all patients 18 years of age and older, with a confirmed diagnosis of MM who attempted stem cell mobilization and collection between January 2012 and July 2015 at the Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance. Collected information included: demographics, staging according to the International Staging System, results of cytogenetics by conventional karyotype or FISH, prior treatments, number of cycles of lenalidomide received, mobilization method, receipt of plerixafor, number of stem cells collected, days of collection, and receipt of prior radiation therapy. Patients were also scored...
Source: Blood - November 21, 2018 Category: Hematology Authors: Cowan, A. J., Stevenson, P. A., Kopmar, N., Libby, E. N., Becker, P. S., Coffey, D. G., Tuazon, S. A., Green, D. J., Gopal, A. K., Holmberg, L. A. Tags: 711. Cell Collection and Processing II Source Type: research
Development of a Novel Class of Agents Targeting the RNA-Splicing Machinery in Myeloid Malignancies
We describe a novel targeted approach to drug development for SF3B1MT malignancies.Our investigative strategy started with a high throughput drug screen. We introduced K700E mutation into myeloid cells using CRISPR/Cas9. We then subjected K562+/K700E and matched-parental K562 cells to high throughput drug screen of a library of 3,000 mechanistically annotated, non-redundant, bioactive compounds. Top hits were validated by dose response testing (8 concentrations in half-log dilutions). Our interest focused on compounds with cytostatic activity towards K562+/K700E cells. Among these, a 4-pyridyl-2-anilinothiazole (PAT) showe...
Source: Blood - November 21, 2018 Category: Hematology Authors: Visconte, V., Przychodzen, B. P., Adema, V., Hirsch, C. M., Noe, A., Toth, R., Snider, C., Awada, H., Graham, A. C., Parker, Y., Fedorov, Y., Adams, D., Carraway, H. E., Advani, A. S., Radivoyevitch, T., Rogers, H. J., Kelly, K. R., Nawrocki, S. T., Carew Tags: 802. Chemical Biology and Experimental Therapeutics: New Targeted Therapies and Drug Development Source Type: research
