In Vivo Evaluation of Novel Geranylgeranyl Diphosphate Synthase Inhibitors
The enzyme geranylgeranyl diphosphate synthase (GGDPS) synthesizes the 20-carbon isoprenoid geranylgeranyl diphosphate which is used in protein geranylgeranylation reactions. Our work has demonstrated that GGDPS inhibitors (GGDPSIs) represent a novel therapeutic strategy for multiple myeloma (MM) by disrupting Rab protein geranylgeranylation. Treatment of MM cells with GGDPSI results in disruption of monoclonal protein trafficking, leading to induction of the unfolded protein response pathway (UPR) and apoptosis. We have previously reported preclinical studies with a lead GGDPSI, VSW1198 (a mixture of homogeranyl/homoneryl...
Source: Blood - November 21, 2018 Category: Hematology Authors: Haney, S. L., Chhonker, Y. S., Varney, M. L., Talmon, G. A., Murry, D. J., Holstein, S. A. Tags: 802. Chemical Biology and Experimental Therapeutics: New Targeted Therapies and Drug Development Source Type: research
CD20-Tcb (RG6026), a Novel "2:1" Format T-Cell-Engaging Bispecific Antibody, Induces Complete Remissions in Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma: Preliminary Results from a Phase I First in Human Trial
Despite advancements in outcomes with the introduction of anti-CD20 monoclonal antibody therapy, a substantial proportion of B-cell Non-Hodgkin's Lymphoma (B-NHL) patients do not sustain a durable response to standard of care treatment. T-cell bispecific antibodies (TCBs) represent a new class of disease-targeting agents shown to activate T-cells to kill cancer cells, offering this exciting mechanism of action with 'off the shelf' availability. CD20-TCB (RG6026) is a novel T-cell-engaging bispecific antibody whose "2:1" format possesses two CD20 binders in addition to a CD3 binder, enabling increased tumor antigen avidity,...
Source: Blood - November 21, 2018 Category: Hematology Authors: Hutchings, M., Iacoboni, G., Morschhauser, F., Offner, F., Sureda, A., Salles, G. A., Carlo-Stella, C., Martinez Lopez, J., Thomas, D., Morcos, P. N., Quackenbush, B., Ferlini, C., Bacac, M., Broeske, A.-M. E., Dimier, N., Moore, T., Weisser, M., Dickinso Tags: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)-Results from Prospective Clinical Trials: Immunotherapy Source Type: research
Selinexor, a First-in-Class XPO1 Inhibitor, Is Efficacious and Tolerable in Patients with Myelodysplastic Syndromes Refractory to Hypomethylating Agents
There is no standard therapy for patients with myelodysplastic syndromes (MDS) refractory to hypomethylating agents (HMA) and the median overall survival (OS) of HMA-refractory MDS patients with IPSS Intermediate-2/High-risk MDS is ~6 months. Here, we present data from a phase 2 clinical trial of selinexor, an oral, first-in-class Selective Inhibitor of Nuclear Export (SINE) compound that inhibits XPO1, in patients with MDS refractory to HMAs. XPO1 is the major nuclear export protein responsible for shuttling many key cellular regulators out of the nucleus and is overexpressed in many cancers. Preclinical studies of seline...
Source: Blood - November 21, 2018 Category: Hematology Authors: Taylor, J., Coleman, M., Alvarez, K., Pichardo, J., Sen, F., Chung, S. S., Rampal, R. K., Park, J. H., Stein, E. M., Tallman, M. S., Abdel-Wahab, O. I., Klimek, V. M. Tags: 637. Myelodysplastic Syndromes-Clinical Studies: Novel Therapeutics I Source Type: research
Ibrutinib Treatment Reduces Myeloid Derived Suppressor Cell Numbers and Function in Chronic Lymphocytic Leukemia
In chronic lymphocytic leukemia (CLL), bidirectional interactions of leukemic B cells with components of a complex, yet incompletely defined tumor microenvironment (TME) are critical for leukemic cell survival and proliferation. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, blocks signals that are crucial for survival of CLL cells which are delivered by the B cell receptor (BCR) and certain other receptors. However since BTK and its family members are expressed by other cell types, ibrutinib can also affect non-leukemic cells, thereby altering their function. Here, we focused on understanding how myeloid-derived s...
Source: Blood - November 21, 2018 Category: Hematology Authors: Ferrer, G., Jung, B., Rukhsana, A., Chiu, P. Y., Mazzarello, A. N., Palacios, F., Chen, S.-S., Yan, X. J., Barrientos, J. C., Burger, J. A., Kolitz, J. E., Allen, S. L., Rai, K. R., Sherry, B., Chiorazzi, N. Tags: 641. CLL: Biology and Pathophysiology, excluding Therapy: Overcoming Immunodeficiency in CLL Source Type: research
Risk Factors and Predictive Scoring System for Post-Transplant Lymphoproliferative Disorder after Hematopoietic Stem Cell Transplantation
Post-transplant lymphoproliferative disorder (PTLD) following hematopoietic stem cell transplantation (HSCT) is a rare, but life-threatening complication. PTLD typically develops within 6-12 months of HSCT, which is before the reconstitution of EBV-specific cytotoxic T-cell immunity. Several risk factors for developing PTLD have been reported in the literature, including the use of antithymocyte globulin (ATG) and ex vivo T-cell depletion (TCD). However, only a few large-scale retrospective studies have been conducted and risk scores have not yet been well defined. Therefore, to further evaluate the probability of and risk...
Source: Blood - November 21, 2018 Category: Hematology Authors: Fujimoto, A., Hiramoto, N., Yamasaki, S., Inamoto, Y., Uchida, N., Maeda, T., Mori, T., Kanda, Y., Kondo, T., Tanaka, J., Ichinohe, T., Atsuta, Y., Ogata, M., Suzuki, R. Tags: 723. Clinical Allogeneic and Autologous Transplantation: Late Complications and Approaches to Disease Recurrence: HSCT Late Effects and Disease Monitoring Source Type: research
Metabolic Syndrome Is Common Following Haematopoietic Cell Transplantation (HCT) and Is Associated with Increased Cardiovascular Disease and Second Cancers: An EBMT Cross-Sectional Non-Interventional Study
Metabolic syndrome (MetS) is defined as a clustering of five factors including (1) fasting hyperglycaemia (2) hypertriglyceridaemia (3) low HDL cholesterol (4) hypertension (5) obesity (high waist circumference). According to the International Diabetes Federation harmonised definition, a large waist circumference plus any other two features meet criteria for diagnosis of MetS. It is associated with raised risk of cardiovascular disease (CVD) by 3-fold and is increasingly recognised in patients after HCT. Recent guidelines for long-term HCT survivors recommend screening for MetS. We performed a large cross-sectional service...
Source: Blood - November 21, 2018 Category: Hematology Authors: Greenfield, D. M., Salooja, N., Peczynski, C., van der Werf, S., Schoemans, H., Hill, K., Cortelezzi, A., Lupo Stanghellini, M. T., Ozkurt, Z. N., Arat, M., Metzner, B., Turlure, P., Rovo, A., Socie, G., Mohty, M., Nagler, A., Kroeger, N., Luft, T., Labop Tags: 723. Clinical Allogeneic and Autologous Transplantation: Late Complications and Approaches to Disease Recurrence: HSCT Late Effects and Disease Monitoring Source Type: research
Mast Cells Contribute to Brain Microvascular Permeability in Sickle Cell Disease
We examined the ability of mast cells to stimulate P-selectin expression and BBB permeability via ER stress in a sickle microenvironment.We isolated MCs from HbAA-BERK and HbSS-BERK, control and sickle mice, respectively; incubated them in vitro and collected mast cell conditioned media (MCCM) from HbAA MCs and HbSS MCs. Normal mouse brain microvascular endothelial cells (mBMECs) were treated with unconditioned MCCM, HbAA MCCM, or HbSS MCCM to examine the effect of mast cell activation on endothelium. We observed increased mast cell activity in HbSS mice evinced by significantlyhigher plasma and skin histamine levels, comp...
Source: Blood - November 21, 2018 Category: Hematology Authors: Mittal, A. M., Tran, H., Sagi, V., Nguyen, A., Luk, K., Nguyen, J., Lei, J., Gupta, K. Tags: 113. Hemoglobinopathies, Excluding Thalassemia-Basic and Translational Science: Sickle Cell Disease-Role of Coagulation and Inflammation in Pathophysiology Source Type: research
Antibody Stabilization of Neutrophil Extracellular Trap-Platelet Factor 4 Complexes Is Therapeutic in a Murine Model of Endotoxemia
Sepsis is characterized by life-threatening organ dysfunction caused by a dysregulated response to infection. Neutrophils play a crucial role in sepsis during which they release neutrophil extracellular traps (NETs), webs of negatively charged cell-free DNA (cfDNA) complexed with positively-charged histones that kill pathogens but also damage host tissue. While it has been proposed that NET digestion may be beneficial in the treatment of sepsis, it is also possible that this strategy leads to the release of harmful NET degradation products (NDPs), such as cfDNA, histones, and myeloperoxidase (MPO) that cause endothelial da...
Source: Blood - November 21, 2018 Category: Hematology Authors: Sarkar, A., Arepally, G., Kowalska, M. A., Cines, D. B., Rauova, L., Poncz, M., Gollomp, K. Tags: 201. Granulocytes, Monocytes, and Macrophages: Regulation of Neutrophil and Macrophage Functions in Diseases: NETosis and More Source Type: research
DNA Damage-Response Pathway in Lymphoma Determines Interactions with Macrophages By Altered PD-L1 Expression and Exosome Formation
The tumor microenvironment is characterized by multiple interactions of transformed malignant cells with non-transformed stroma or immune cells. Particularly macrophages play a pivotal role in this network determining disease progression and therapeutic response. In previous work we could show that macrophages are an essential mediator of therapeutic response in the synergistic response to the administration of the chemoimmunotherapy. The combination treatment strongly increases tumor clearance by repolarization of tumor-associated macrophages from a suppressive to an activated phenotypic state. Here, se analyzed the funct...
Source: Blood - November 21, 2018 Category: Hematology Authors: Vorholt, D., Izquierdo-Alvarez, E., Sackey, B., Schmitz, J., Nickel, N., Blakemore, S., Knittel, G., Reinhardt, C., Wendtner, C.-M., Bruns, H., Hallek, M., Pallasch, C. Tags: 201. Granulocytes, Monocytes, and Macrophages: Regulation of Neutrophil and Macrophage Functions in Diseases: NETosis and More Source Type: research
Enasidenib Is Highly Active in Previously Untreated IDH2 Mutant AML: Early Results from the Beat AML Master Trial
The majority of patients with acute myeloid leukemia (AML), including nearly all patients older than age 60, present with multiple, sequentially acquired, somatic mutations. The 5-year overall survival (OS) for AML patients ≥ 60 with the current standard-of-care is less than 10 percent and the median OS in most genetically defined subtypes is < 1 year. The Leukemia & Lymphoma Society (LLS) Beat AML Master Trial is a precision medicine trial for previously untreated AML pts age ≥ 60. Eligible patients are assigned to an interventional sub-study based upon an algorithm incorporating cytogenetic and mutational an...
Source: Blood - November 21, 2018 Category: Hematology Authors: Stein, E. M., Shoben, A., Borate, U., Baer, M. R., Stock, W., Patel, P. A., Kovacsovics, T., Blum, W., Vergilio, J.-A., Heerema, N. A., Rosenberg, L., Marcus, S., Stefanos, M., Chervin, J., Druker, B. J., Burd, A., Byrd, J. C., Levine, R. L., Mims, A. S. Tags: 615. Acute Myeloid Leukemia: Commercially Available Therapy, excluding Transplantation: Targeted Therapy For Adults Diagnosed With Acute Myeloid Leukemia Source Type: research
Combination of Lenalidomide and Rituximab in Patients with Treatment-Naive and Relapsed Chronic Lymphocytic Leukemia: Treatment Results and Predictive Factors of Response
Discussion. The combination of lenalidomide and rituximab is an effective and safe regimen for the treatment of pts with TN and/or R CLL. B2M is the only predictive factor of response to this regimen in both in TN and R pts. Gene mutations inducing increased NOTCH1 signaling, such as SPEN and FBXW7 mutations, predicted shorter PFS after treatment with lenalidomide and rituximab.Figure.DisclosuresThompson: Adaptive Biotechnologies: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Honoraria, Membe...
Source: Blood - November 21, 2018 Category: Hematology Authors: Strati, P., Takahashi, K., Keating, M. J., Thompson, P. A., Hinojosa, C., Rodriguez, D., Daver, N. G., Jain, N., Burger, J. A., Estrov, Z. E., O'Brien, S. M., Kantarjian, H. M., Wierda, W. G., Futreal, A., Ferrajoli, A. Tags: 642. CLL: Therapy, excluding Transplantation: Cellular Therapy and Immunomodulation in CLL Source Type: research
Multiple Functional Donor Polymorphisms in IL1RL1 region Associate with Death Due to GvHD or Infection after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation (HCT) for AML and MDS
The last two authors contributed equallyElevated soluble Stimulation-2 (sST2), the decoy IL-33 receptor, in plasma/serum post-HSCT is a biomarker for death due to GvHD. ST2 is the product of IL1RL1 (2q12.1) and this ~.5Mb region contains >300 single nucleotide polymorphisms (SNPs) significantly associated (P<5x10-8) with plasma levels of sST2 in healthy participants from the Framingham Heart Study (FHS). Many of these SNPs are genome-wide associated with infection-related phenotypes, including asthma, Crohn's disease, ulcerative colitis and celiac disease. Given these relationships, we analyzed the association of ST2...
Source: Blood - November 21, 2018 Category: Hematology Authors: Karaesmen, E., Hahn, T. E., Dile, A., Rizvi, A., Wang, J., Wang, T., Haagenson, M. D., Preus, L., Zhu, Q., Liu, Q., Yan, L., Liu, S., Haiman, C., Stram, D., Pooler, L., Cheng, X., Van Den Berg, D., Brock, G., Webb, A., McCarthy, P. L., Spellman, S. R., Le Tags: 732. Clinical Allogeneic Transplantation: Results: Optimizing Outcomes After Allogeneic Transplantation Source Type: research
Response to Venetoclax and Hypomethylating Agents Among Prognostic Risk Groups and Genetic Subtypes of Acute Myeloid Leukemia
We report remarkable activity with venetoclax and HMA across various high-risk genetics and clinical features in AML patients. Prospective studies are warranted to compare this combination directly with chemotherapy in all AML subsets. This is particularly true for high risk AML where response to conventional chemotherapy is poor.DisclosuresAli: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees. Salhotra: Kadmon Corporation, LLC: Consultancy. Khaled: Alexion: Consultancy, Speakers Bureau; Juno: Other: Travel Funding; Daiichi: Consultancy. Stein: Celgene: Speakers Bureau; Amgen Inc.: Sp...
Source: Blood - November 21, 2018 Category: Hematology Authors: Aldoss, I., Yang, D., Pillai, R., Sanchez, J. F., Aribi, A., Ali, H., Sandhu, K. S., Al Malki, M., Mei, M., Salhotra, A., Khaled, S. K., Nakamura, R., Sun, W., O'Donnell, M. R., Snyder, D. S., Stein, A. S., Forman, S. J., Marcucci, G., Pullarkat, V. A. Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Combination Therapy Source Type: research
Targeted Inhibition of CD47-Sirp Alpha Requires Fc-Fc Gamma Receptor Interactions to Maximize Phagocytosis in T-Cell Lymphomas
Outcomes for patients with aggressive T-cell lymphomas (TCLs) remain dismal. Monoclonal antibodies (mAbs) that inhibit engagement of the "don't eat me" signal CD47 with SIRPα on myeloid cells may induce phagocytosis and have exhibited promise in multiple cancers. We dissected the role of CD47 blockade in opsonization and phagocytosis-induction through Fc-Fc gamma receptor (FcR) interactions. CD47 was expressed at higher levels on 22 TCL cell lines by flow cytometry compared to quiescent T cells from 10 healthy donors (mean fluorescent intensity, 176.9 versus 69.85; Welch t-test p=0.002). We determined tumor cell-spec...
Source: Blood - November 21, 2018 Category: Hematology Authors: Jain, S., Van Scoyk, A., Morgan, E. A., Matthews, A., Stevenson, K. E., Newton, G., Autio, A. K., Peluso, M. O., O'Connor, R. W., Paterson, A. M., Holland, P. M., Luscinskas, F. W., Weinstock, D. M. Tags: 625. Lymphoma: Pre-Clinical-Chemotherapy and Biologic Agents: Immunologic approaches Source Type: research
A New Stromal Signature Applicable to Formalin-Fixed Paraffin-Embedded Tissues Identifies Patients at Risk in Prospective Clinical Trials of the German High-Grade Non-Hodgkin Lymphoma Study Group
Diffuse large B-cell-lymphoma (DLBCL) is a heterogeneous disease in its sites of origin, genetic alterations, and clinical behavior. Gene expression profiling (GEP) has led to the identification of two molecular subtypes, GCB-like and ABC-like DLBCL, that follow different molecular circuits and hence, likely represent different diseases. Next to the ABC-like GEP, the rearrangement and/or expression of MYC and TP53 mutations in tumors characterize patient subsets with inferior prognosis. However, the clinical impact of cell of origin (COO) subtyping and the identification of prognostic biomarkers differ between studies. In ...
Source: Blood - November 21, 2018 Category: Hematology Authors: Staiger, A. M., Altenbuchinger, M., Ziepert, M., Kohler, C., Horn, H., Huttner, M., Huettl, K., Klapper, W., Szczepanowski, M., Richter, J., Rosenwald, A., Stein, H., Feller, A., Moeller, P., Hansmann, M.-L., Loeffler, M., Poeschel, V., Held, G., Truemper Tags: 627. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)-Results from Retrospective/Observational Studies: Prognostic Biomarkers and Molecular Signatures for Risk Stratification Source Type: research
