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https://www.readbyqxmd.com/read/29157092/single-agent-and-synergistic-combinatorial-efficacy-of-first-in-class-small-molecule-imipridone-onc201-in-hematological-malignancies
#1
Varun V Prabhu, Mala K Talekar, Amriti R Lulla, C Leah B Kline, Lanlan Zhou, Junior Hall, A Pieter J Van den Heuvel, David T Dicker, Jawad Babar, Stephan A Grupp, Mathew J Garnett, Ultan McDermott, Cyril H Benes, Jeffrey J Pu, David F Claxton, Nadia Khan, Wolfgang Oster, Joshua E Allen, Wafik S El-Deiry
ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples...
November 20, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29152058/effective-control-of-acute-myeloid-leukaemia-and-acute-lymphoblastic-leukaemia-progression-by-telomerase-specific-adoptive-t-cell-therapy
#2
Sara Sandri, Francesco De Sanctis, Alessia Lamolinara, Federico Boschi, Ornella Poffe, Rosalinda Trovato, Alessandra Fiore, Sara Sartori, Andrea Sbarbati, Attilio Bondanza, Simone Cesaro, Mauro Krampera, Maria T Scupoli, Michael I Nishimura, Manuela Iezzi, Silvia Sartoris, Vincenzo Bronte, Stefano Ugel
Telomerase (TERT) is a ribonucleoprotein enzyme that preserves the molecular organization at the ends of eukaryotic chromosomes. Since TERT deregulation is a common step in leukaemia, treatments targeting telomerase might be useful for the therapy of hematologic malignancies. Despite a large spectrum of potential drugs, their bench-to-bedside translation is quite limited, with only a therapeutic vaccine in the clinic and a telomerase inhibitor at late stage of preclinical validation. We recently demonstrated that the adoptive transfer of T cell transduced with an HLA-A2-restricted T-cell receptor (TCR), which recognize human TERT with high avidity, controls human B-cell chronic lymphocytic leukaemia (B-CLL) progression without severe side-effects in humanized mice...
October 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/29150880/a-slowly-developed-severe-cutaneous-adverse-reaction-to-idelalisib
#3
L Huilaja, O Lindgren, M Soronen, T Siitonen, K Tasanen
Intracellular signal mediator phosphatidylinositol-3-kinase (PIK3K) -δ, an isoform of PIK3K, is expressed in hematopoietic cells especially in lymphoid lineage 1. Idelalisib is a novel PIK3K-δ targeted kinase inhibitor which is approved for relapsed follicular B-cell non-Hodgkin lymphoma as a monotherapy and in combination with rituximab, an anti-CD20 antibody, for relapsed chronic lymphocytic leukemia (CLL) 2. Only one case describing the clinical features of severe cutaneous adverse reaction (SCAR) of idelalisib in detail has been previously published 3...
November 17, 2017: Journal of the European Academy of Dermatology and Venereology: JEADV
https://www.readbyqxmd.com/read/29128555/combined-haploidentical-and-umbilical-cord-blood-allogeneic-stem-cell-transplantation-for-high-risk-lymphoma-and-cll
#4
Jingmei Hsu, Andrew Artz, Sebastian A Mayer, Danielle Guarner, Michael R Bishop, Ronit Reich-Slotky, Sonali M Smith, June Greenberg, Justin Kline, Rosanna Ferrante, Adrienne A Phillips, Usama Gergis, Hongtao Liu, Wendy Stock, Melissa Cushing, Tsiporah B Shore, Koen van Besien
Limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants. We have previously described combining CD34-selected haploidentical grafts with umbilical cord blood (haplo-cord) to accelerate neutrophil and platelet engraftment. Here, we examine the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation at the University of Chicago and Weill Cornell Medical College. We analyzed 42 lymphoma and CLL patients who underwent haplo-cord allogeneic stem cell transplantation...
November 8, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/29123965/ig-like-transcript-2-ilt2-suppresses-t-cell-function-in-chronic-lymphocytic-leukemia
#5
Mónica Villa-Álvarez, Seila Lorenzo-Herrero, Ana P Gonzalez-Rodriguez, Alejandro López-Soto, Angel R Payer, Esther Gonzalez-Garcia, Leticia Huergo-Zapico, Segundo Gonzalez
Chronic lymphocytic leukemia (CLL) is associated with a profound dysregulation of the immune system. Loss of T cell function is frequently caused in cancer by sustained signaling of inhibitory receptors. Here, we analyzed the role of the novel inhibitory receptor Ig-like transcript 2 (ILT2) in the pathogenesis of CLL. We observed that ILT2 expression was markedly reduced on leukemic cells, whereas it was increased on CD8 and CD4 T cells from CLL patients, particularly in those patients harboring chromosome 11q deletion, which includes the ATM gene...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/29118007/pd-1-expression-and-clinical-pd-1-blockade-in-b-cell-lymphomas
#6
Zijun Y Xu-Monette, Jianfeng Zhou, Ken H Young
PD-1 blockade targeting the PD-1 immune checkpoint has demonstrated unprecedented clinical efficacy in the treatment of advanced cancers including hematologic malignancies. This article reviews the landscape of PD-1/PD-L1 expression and current PD-1 blockade immunotherapy trials in B-cell lymphomas. Most notably, in relapsed/refractory classical Hodgkin lymphoma, which frequently has increased PD-1(+) tumor-infiltrating T cells, 9p24 genetic alteration and high PD-L1 expression, anti-PD-1 monotherapy has demonstrated remarkable objective response rates (ORR) of 65-87% and durable disease control in phase I/II clinical trials...
November 8, 2017: Blood
https://www.readbyqxmd.com/read/29069762/cell-lines-generated-from-a-chronic-lymphocytic-leukemia-mouse-model-exhibit-constitutive-btk-and-akt-signaling
#7
Simar Pal Singh, Saravanan Y Pillai, Marjolein J W de Bruijn, Ralph Stadhouders, Odilia B J Corneth, Henk Jan van den Ham, Alice Muggen, Wilfred van IJcken, Erik Slinger, Annemieke Kuil, Marcel Spaargaren, Arnon P Kater, Anton W Langerak, Rudi W Hendriks
Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature CD5(+) B cells in blood. Spontaneous apoptosis of CLL cells in vitro has hampered in-depth investigation of CLL pathogenesis. Here we describe the generation of three monoclonal mouse cell lines, EMC2, EMC4 and EMC6, from the IgH.TEμ CLL mouse model based on sporadic expression of SV40 large T antigen. The cell lines exhibit a stable CD5(+)CD43(+)IgM(+)CD19(+) CLL phenotype in culture and can be adoptively transferred into Rag1(-/-) mice...
September 22, 2017: Oncotarget
https://www.readbyqxmd.com/read/29059151/neurotensin-receptor-type-2-protects-b-cell-chronic-lymphocytic-leukemia-cells-from-apoptosis
#8
A Abbaci, H Talbot, S Saada, N Gachard, J Abraham, A Jaccard, D Bordessoule, A L Fauchais, T Naves, M O Jauberteau
B-cell chronic lymphocytic leukemia (B-CLL) cells are resistant to apoptosis, and consequently accumulate to the detriment of normal B cells and patient immunity. Because current therapies fail to eradicate these apoptosis-resistant cells, it is essential to identify alternative survival pathways as novel targets for anticancer therapies. Overexpression of cell-surface G protein-coupled receptors drives cell transformation, and thus plays a critical role in malignancies. In this study, we identified neurotensin receptor 2 (NTSR2) as an essential driver of apoptosis resistance in B-CLL...
October 23, 2017: Oncogene
https://www.readbyqxmd.com/read/29046749/an-unusual-case-of-chronic-lymphocytic-leukemia-multiple-myeloma-and-cardiac-amyloidosis
#9
Dongyan Liu, Hakim T Uqdah, Alisha D Gordy
Light chain amyloidosis has very rarely been reported in association with chronic lymphocytic leukemia (CLL). We reported on a 76-years-old female who presented with simultaneous kappa-restricted chronic lymphocytic leukemia (CLL) and a lambda-restricted multiple myeloma with plasma cells causing AL amyloidosis involving the heart. While monoclonal immunoglobulins occasionallyproduced by CLL have previously been implicated in AL amyloidosis, there only a few cases reported of AL amyloidosis resulting from a distinct plasma cell dyscrasia that is not clonally related to the concurrent CLL...
October 2017: Journal of Community Hospital Internal Medicine Perspectives
https://www.readbyqxmd.com/read/29038338/infectious-complications-of-cd19-targeted-chimeric-antigen-receptor-modified-t-cell-immunotherapy
#10
Joshua A Hill, Daniel Li, Kevin A Hay, Margaret L Green, Sindhu Cherian, Xueyan Chen, Stanley R Riddell, David G Maloney, Michael Boeckh, Cameron J Turtle
Lymphodepletion chemotherapy with CD19-targeted chimeric antigen receptor-modified T (CAR-T) cell immunotherapy is a novel treatment for refractory or relapsed B cell malignancies. However, infectious complications of this approach have not been systematically studied. We evaluated infection events occurring between days 0-28 and 29-90 in 133 patients treated with CD19 CAR-T cells in a phase 1/2 study (https://clinicaltrials.gov/ct2/show/NCT01865617). We used multivariable Poisson and Cox regression to evaluate pre- and post-treatment risk factors for infection, respectively...
October 16, 2017: Blood
https://www.readbyqxmd.com/read/29032274/assessment-of-impact-of-hla-type-on-outcomes-of-allogeneic-hematopoietic-stem-cell-transplantation-for-chronic-lymphocytic-leukemia
#11
Brian T Hill, Kwang Woo Ahn, Zhen-Huan Hu, Mahmoud Aljurf, Amer Beitinjaneh, Jean-Yves Cahn, Jan Cerny, Mohamed A Kharfan-Dabaja, Siddhartha Ganguly, Nilanjan Ghosh, Michael R Grunwald, Yoshihiro Inamoto, Tamila Kindwall-Keller, Taiga Nishihori, Richard F Olsson, Ayman Saad, Matthew Seftel, Sachiko Seo, Jeffrey Szer, Martin Tallman, Celalettin Ustun, Peter H Wiernik, Richard T Maziarz, Matt Kalaycio, Edwin Alyea, Uday Popat, Ronald Sobecks, Wael Saber
Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with many highly effective therapies. Chemorefractory disease, often characterized by deletion of chromosome 17p, has historically been associated with very poor outcomes, leading to the application of allogeneic hematopoietic stem cell transplantation (allo-HCT) for medically fit patients. Although the use of allo-HCT has declined since the introduction of novel targeted therapy for the treatment of CLL, there remains significant interest in understanding factors that may influence the efficacy of allo-HCT, the sole known curative treatment for CLL...
October 12, 2017: Biology of Blood and Marrow Transplantation
https://www.readbyqxmd.com/read/28984869/bcl2-and-mir-15-16-from-gene-discovery-to-treatment
#12
REVIEW
Yuri Pekarsky, Veronica Balatti, Carlo M Croce
In 1984, we investigated the t(14;18) chromosomal translocations that frequently occur in patients with follicular lymphoma. We first identified a locus on chromosome 18 involved in these translocations with the chromosome 14 containing the immunoglobulin heavy chain locus. Within this region on chromosome 18, we then discovered a gene that we called BCL2, which was activated by the translocations. Since that time, many studies determined that BCL2 is one of the most important oncogenes involved in cancer by inhibiting apoptosis...
October 6, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28983465/myc-immunohistochemistry-predicts-myc-rearrangements-by-fish
#13
Julum Nwanze, Momin T Siddiqui, Keith A Stevens, Debra Saxe, Cynthia Cohen
MYC is the proto-oncogene classically associated with Burkitt lymphoma (BL) located at chromosomal locus 8q24. Rearrangements of MYC are seen in nearly 100% of BL but have been reported in 3-16% of diffuse large B-cell lymphomas (DLBCLs). Rearrangements of MYC are tested for by flourescence in situ hybridization (FISH). In this study, we compared immunohistochemistry (IHC) using a monoclonal antibody directed against the human Myc protein to the current method, FISH. 31 cases were identified that had been tested for MYC rearrangements by FISH over 27 months with heterogeneity in the diagnoses: 5 BL; 10 DLBCL; 3 B-cell lymphoma unclassifiable between DLBCL and BL; 5 B-cell lymphoma not otherwise specified; 1 EBV-related B-cell lymphoma; 1 composite CLL/SLL-large cell lymphoma; and 6 designated as high-grade or aggressive B-cell lymphoma...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28978838/chronic-lymphocytic-leukemia-biology-disease-progression-and-current-treatment-strategies
#14
Takahiro Yano
Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of mature CD5-positive, CD10-negative, CD20 weakly positive, and CD23-positive B-cells within blood, bone marrow, lymph nodes, and spleen. In proliferation centers, the survival and growth of CLL cells requires a permissive microenvironment comprising T-cells, macrophages, and stromal cells. FISH analysis has revealed that almost 80% of CLL cases carry chromosomal abnormalities including the most frequent del (13q14) and the strongest poor prognostic factor del (17p), both related to TP53 mutations...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/28972595/ibrutinib-modulates-the-immunosuppressive-cll-microenvironment-through-stat3-mediated-suppression-of-regulatory-b-cell-function-and-inhibition-of-the-pd-1-pd-l1-pathway
#15
K Kondo, H Shaim, P A Thompson, J A Burger, M Keating, Z Estrov, D Harris, E Kim, A Ferrajoli, M Daher, R Basar, M Muftuoglu, N Imahashi, A Alsuliman, C Sobieski, E Gokdemir, W Wierda, N Jain, E Liu, E J Shpall, K Rezvani
Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naïve chronic lymphocytic leukemia (CLL). Besides directly inhibiting BTK, ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies...
October 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28972490/phagocytosis-and-expression-of-fcg-receptors-and-cd180-on-monocytes-in-chronic-lymphocytic-leukemia
#16
T Tsertsvadze, N Mitskevich, A Bilanishvili, D Girdaladze, N Porakishvili
Chronic lymphocytic leukaemia (CLL) is a lymphoproliferative disease characterised by accumulation of monoclonal CD19+CD5+CD23+ lymphocytes in the peripheral blood and bone marrow. CLL is the most common type of the adult leukemia in the Western world. The disease is incurable, albeit there are new molecular and immunotherapy methods currently available in conjunction with chemotherapy, leading to the "precision therapy". The majority of immunotherapeutic approaches are based on the ability of therapeutic antibodies (Rituximab, Alemtuzumab) to mobilize anti-tumour potential of the Natural Killer cells and macrophages/monocytes through their Fcg-receptors (FcγR)...
September 2017: Georgian Medical News
https://www.readbyqxmd.com/read/28971904/cd40-signaling-instructs-chronic-lymphocytic-leukemia-cells-to-attract-monocytes-via-the-ccr2-axis
#17
Martijn H A van Attekum, Jaco A C van Bruggen, Erik Slinger, M Cristina Lebre, Emilie Reinen, Sabina Kersting, Eric Eldering, Arnon P Kater
Chronic lymphocytic leukemia cells are provided with essential survival and proliferative signals in the lymph node microenvironment. Here, chronic lymphocytic leukemia cells engage in various interactions with bystander cells such as T cells and macrophages. Phenotypically distinct types of tumor infiltrating macrophages can either be tumor supportive (M2) or play a role in tumor immune surveillance (M1). Although recent in vitro findings suggest a protective role for macrophages in chronic lymphocytic leukemia, the actual balance between these macrophage subsets in chronic lymphocytic leukemia lymphoid tissue is still unclear...
September 29, 2017: Haematologica
https://www.readbyqxmd.com/read/28945111/pi3k%C3%AE-selective-and-pi3k%C3%AE-%C3%AE-combinatorial-inhibitors-in-clinical-development-for-b-cell-non-hodgkin-lymphoma
#18
REVIEW
Benjamin L Lampson, Jennifer R Brown
The efficacy of the prototypical phosphatidylinositol-3-kinase (PI3K) inhibitor idelalisib for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL) has led to development of multiple compounds targeting this pathway. Areas Covered: We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of B cell receptor signaling, blockade of microenvironmental pro-survival signals, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells)...
November 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28937430/cutaneous-richter-syndrome-mimicking-primary-cutaneous-cd4-positive-small-medium-t-cell-lymphoma-case-report-and-review-of-the-literature
#19
Miguel Rito, José Cabeçadas, Joaninha Costa Rosa, Mariana Cravo, Alistair Robson
Richter syndrome represents the transformation of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma into an aggressive large B-cell lymphoma. Skin involvement is exceptionally rare, with <20 cases reported and its presence as the first presentation of CLL/small lymphocytic lymphoma, as an isolated skin lesion has never been described. Primary cutaneous CD4-positive small/medium T-cell lymphoma (CD4 PCSM-TCL) characteristically presents with a dense dermal infiltrate consisting primarily of small-/medium-sized pleomorphic T-cells and less than 30% large pleomorphic cells...
September 12, 2017: American Journal of Dermatopathology
https://www.readbyqxmd.com/read/28935990/notch1-mutations-are-associated-with-high-cd49d-expression-in-chronic-lymphocytic-leukemia-link-between-the-notch1-and-the-nf-kb-pathways
#20
D Benedetti, E Tissino, F Pozzo, T Bittolo, C Caldana, C Perini, D Martorelli, V Bravin, T D'Agaro, F M Rossi, R Bomben, E Santinelli, F Zaja, G Pozzato, A Chiarenza, F Di Raimondo, G Del Poeta, D Rossi, G Gaidano, M Dal Bo, V Gattei, A Zucchetto
In chronic lymphocytic leukemia (CLL), stabilizing mutations of NOTCH1, affecting up to 10-15% of cases, have been associated to poor prognosis, disease progression and refractoriness to chemotherapy. NOTCH1 mutations are significantly overrepresented in trisomy 12 CLL, a disease subset frequently expressing CD49d, the α4 chain of the VLA-4 integrin, a well-known key regulator of microenviromental interactions and negative prognosticator in CLL. In the present study, by analysing a wide cohort of 1180 CLL, we observed a very strong association between the presence of NOTCH1 mutations and the expression of CD49d (P<0...
September 22, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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