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https://www.readbyqxmd.com/read/27908880/an-anti-cd3-anti-cll-1-bispecific-antibody-for-the-treatment-of-acute-myeloid-leukemia
#1
Steven R Leong, Siddharth Sukumaran, Maria Hristopoulos, Klara Totpal, Shannon Stainton, Elizabeth Lu, Alfred Wong, Lucinda Tam, Robert Newman, Brian R Vuillemenot, Diego Ellerman, Chen Gu, Mary Mathieu, Mark S Dennis, Allen Nguyen, Bing Zheng, Crystal Zhang, Genee Lee, Yu-Waye Chu, Rodney A Prell, Kedan Lin, Steven T Laing, Andrew G Polson
Acute myeloid leukemia (AML) is major unmet medical need. Most patients have poor long-term survival and treatment has not significantly changed in 40 years. Recently, bispecific antibodies that redirect the cytotoxic activity of effector T-cells by binding to CD3, the signaling component of the T-cell receptor, and a tumor target have shown clinical activity. Notably, blinatumomab is approved to treat relapsed/refractory acute lymphoid leukemia. Here we describe the design, discovery, pharmacological activity, pharmacokinetics, and safety of a CD3 T-cell-dependent bispecific (TDB) full-length human IgG1 therapeutic antibody targeting CLL-1 that could potentially be used in humans to treat AML...
December 1, 2016: Blood
https://www.readbyqxmd.com/read/27873237/estimating-long-term-survival-of-adults-with-philadelphia-chromosome-negative-relapsed-refractory-b-precursor-acute-lymphoblastic-leukemia-treated-with-blinatumomab-using-historical-data
#2
Arie Barlev, Vincent W Lin, Aaron Katz, Kuolung Hu, Ze Cong, Beth Barber
INTRODUCTION: Blinatumomab is a bispecific T cell-engaging antibody construct indicated for adult patients with relapsed/refractory (R/R) Ph(-) B-precursor acute lymphoblastic leukemia (ALL), an aggressive disease with poor prognosis. A phase 2 single-arm clinical study showed that 43% of patients achieved CR/CRh within two cycles and approximately 20% of patients receiving blinatumomab were still alive after 2 years. METHODS: The objective of the current analysis was to estimate long-term survival of patients receiving blinatumomab beyond the observed time period in the clinical study using a large historical observational dataset...
November 21, 2016: Advances in Therapy
https://www.readbyqxmd.com/read/27872741/novel-drugs-in-follicular-lymphoma
#3
REVIEW
Antonella Anastasia, Giuseppe Rossi
Follicular lymphoma(FL) is the most common indolent non-Hodgkin lymphoma and constitutes 15% to 30% of lymphoma diagnoses. The natural history of the disease is characterized by recurrent relapses and progressively shorter remissions with a median survival of 10yrs. The impossibility of achieving a definite cure, have prompted investigations into the possible role of more active and less toxic strategies with innovative therapeutic agents. Recently Casulo et al. demonstrated that approximately 20% of patients with FL relapse within two years after achieving remission with R-CHOP and have a poor prognosis...
2016: Mediterranean Journal of Hematology and Infectious Diseases
https://www.readbyqxmd.com/read/27820973/emerging-biological-therapies-to-treat-acute-lymphoblastic-leukemia
#4
Françoise Huguet, Suzanne Tavitian
Various settings of acute lymphoblastic leukemia (ALL) represent unmet medical needs: first remission at high risk of relapse, such as persistent minimal residual disease (MRD); relapse/refractoriness (R/R); elderly patients. Biological therapies targeting widely-shared antigens of blast cells have entered the clinic in B-cell precursor (BCP)-ALL. Area covered. Results of phase II/III trials of monoclonal antibodies (MoAbs) and phase I/II trials of adoptive cell therapy by chimeric antigen receptor-engineered T cells (CAR-T cells) are presented...
November 8, 2016: Expert Opinion on Emerging Drugs
https://www.readbyqxmd.com/read/27816725/blinatumomab-provoked-fatal-heart-failure
#5
REVIEW
Behrad Darvishi, Leila Farahmand, Neda Jalili, Keivan Majidzadeh-A
Mentioned in Blinatumomab (Blincyto®) clinical safety report, a 5 year old boy with acute lymphoblastic leukemia (ALL) receiving Blincyto® with the concentration of 30μg/m(2)/day on the fourth day of therapy developed both Cytokine Release Syndrome (CRS) and Tumor Lysis Syndrome (TLS). Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Bilirubin peaks were 18, 7 and 8 folds more than upper normal limit (UNL) respectively. However, albumin was reduced to approximately half of the lower Normal limit (LNL)...
October 28, 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27799606/successful-reintroduction-of-blinatumomab-in-a-patient-with-relapsed-refractory-acute-lymphoblastic-leukemia-following-grade-4-cytokine-release-syndrome
#6
Bernard L Marini, Yihan Sun, Patrick W Burke, Anthony J Perissinotti
Relapsed/refractory acute lymphoblastic leukemia poses a clinical challenge due to its poor prognosis and lack of effective treatment. Blinatumomab, a novel immunotherapy, has demonstrated excellent efficacy in relapsed/refractory acute lymphoblastic leukemia; however, life-threatening toxicities such as cytokine release syndrome have been reported in pivotal clinical trials. In this report, we describe the safe reintroduction of blinatumomab in an adult patient with relapsed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia after experiencing grade 4 blinatumomab-induced cytokine release syndrome using a unique dosing strategy and a very diligent monitoring approach...
October 31, 2016: Journal of Oncology Pharmacy Practice
https://www.readbyqxmd.com/read/27784674/resistance-to-anti-cd19-cd3-bite-in-acute-lymphoblastic-leukemia-may-be-mediated-by-disrupted-cd19-membrane-trafficking
#7
Friederike Braig, Anna Brandt, Mariele Goebeler, Hans-Peter Tony, Anna-Katharina Kurze, Peter Nollau, Thomas Bumm, Sebastian Böttcher, Ralf C Bargou, Mascha Binder
The CD19 antigen is a promising target for immunotherapy of acute lymphoblastic leukemia (ALL), but CD19-negative relapses remain a major challenge in about 10-20% of patients. Here, we analyzed four CD19-negative ALL relapses after treatment with the CD19/CD3 bispecific T-cell engager blinatumomab. Three were on-drug relapses, with the CD19-negative escape variant first detected after only two treatment courses. In one patient, the CD19-negative clone appeared as a late relapse 19 months after completion of blinatumomab treatment...
October 26, 2016: Blood
https://www.readbyqxmd.com/read/27761200/catch-me-if-you-can-leukemia-escape-after-cd19-directed-t-cell-immunotherapies
#8
Marco Ruella, Marcela V Maus
Immunotherapy is the revolution in cancer treatment of this last decade. Among multiple approaches able to harness the power of the immune system against cancer, T cell based immunotherapies represent one of the most successful examples. In particular, biotechnological engineering of protein structures, like the T cell receptor or the immunoglobulins, allowed the generation of synthetic peptides like chimeric antigen receptors and bispecific antibodies that are able to redirect non-tumor specific T cells to recognize and kill leukemic cells...
2016: Computational and Structural Biotechnology Journal
https://www.readbyqxmd.com/read/27759440/treating-adults-with-acute-lymphocytic-leukemia-new-pharmacotherapy-options
#9
Xavier Thomas, Caroline Le Jeune
Advances in acute lymphocytic leukemia (ALL) therapy has led to long-term survival rates in children. However, only 30%-40% of adults achieve long-term disease-free survival. After relapse, the outcome of salvage chemotherapy is very disappointing with less than 10% of long survival. Novel agents are therefore desperately required to improve response rates and survival, but also the quality of life of patients. Areas covered: The following review is a comprehensive summary of various novel options reported over the past few years in the therapeutic area of adult ALL...
October 31, 2016: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/27742613/blinatumomab-has-activity-in-pediatric-patients-with-advanced-bcp-all
#10
(no author information available yet)
Blinatumomab was active across age and risk groups in patients with relapsed or refractory BCP-ALL.
October 14, 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27713846/advancements-in-therapy-for-acute-lymphoblastic-leukemia-blinatumomab
#11
Lindsay Hladnik, Kristan Augustin, Sean DeFrates
No abstract text is available yet for this article.
January 2016: Journal of the Advanced Practitioner in Oncology
https://www.readbyqxmd.com/read/27708227/t-cell-responses-against-cd19-pediatric-acute-lymphoblastic-leukemia-mediated-by-bispecific-t-cell-engager-bite-are-regulated-contrarily-by-pd-l1-and-cd80-cd86-on-leukemic-blasts
#12
Judith Feucht, Simone Kayser, David Gorodezki, Mohamad Hamieh, Michaela Döring, Franziska Blaeschke, Patrick Schlegel, Hans Bösmüller, Leticia Quintanilla-Fend, Martin Ebinger, Peter Lang, Rupert Handgretinger, Tobias Feuchtinger
T-cell immunotherapies are promising options in relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We investigated the effect of co-signaling molecules on T-cell attack against leukemia mediated by CD19/CD3-bispecific T-cell engager. Primary CD19+ ALL blasts (n≥10) and physiologic CD19+CD10+ bone marrow precursors were screened for 20 co-signaling molecules. PD-L1, PD-1, LAG-3, CD40, CD86, CD27, CD70 and HVEM revealed different stimulatory and inhibitory profiles of pediatric ALL compared to physiologic cells, with PD-L1 and CD86 as most prominent inhibitory and stimulatory markers...
September 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/27695616/recent-advances-and-novel-treatment-paradigms-in-acute-lymphocytic-leukemia
#13
Nikolaos Papadantonakis, Anjali S Advani
This is an exciting time in the treatment of acute lymphoblastic leukemia (ALL) given the advances in the relapsed/refractory setting. The development of antibody treatments (including antibody drug conjugates with toxins) offers a different treatment approach compared with conventional chemotherapy regimens. Moreover, the use of bispecific T-cell-engager antibodies (BiTEs) such as blinatumomab harness the cytotoxic activity of T cells against CD19-positive lymphoblasts. Another strategy involves the use of chimeric antigen receptor (CAR) T cells...
October 2016: Therapeutic Advances in Hematology
https://www.readbyqxmd.com/read/27670965/the-development-of-targeted-new-agents-to-improve-the-outcome-for-children-with-leukemia
#14
Francisco Bautista, Jasper Van der Lugt, Pamela R Kearns, Francis J Mussai, C Michel Zwaan, Lucas Moreno
Survival rates in pediatric leukemia have greatly improved in the last decades but still a substantial number of patients will relapse and die. New agents are necessary to overcome the limitations of conventional chemotherapy and hematopoietic stem cell transplantation and to reduce their undesirable long-term toxicities. The identification of driving molecular alterations of leukemogenesis in subsets of patients will allow the incorporation of new-targeted therapies. Areas covered: In this article the authors present a detailed review of the most recent advances in targeted therapies for pediatric leukemias...
November 2016: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/27668365/a-multidisciplinary-approach-to-standardizing-processes-for-blinatumomab-administration
#15
Samantha DePadova, Christina Howlett, Kimberly Rivera
Blinatumomab (Blincyto®) has received accelerated approval for treatment of relapsed or refractory acute lymphoblastic leukemia. This article describes the authors' experience with a multidisciplinary collaboration among nursing, pharmacy, prescribers, and support staff, which has proven to be key for safe administration. The approach can be applied to other institutions planning to use blinatumomab.
October 1, 2016: Clinical Journal of Oncology Nursing
https://www.readbyqxmd.com/read/27662202/blinatumomab-vs-historical-standard-therapy-of-adult-relapsed-refractory-acute-lymphoblastic-leukemia
#16
N Gökbuget, M Kelsh, V Chia, A Advani, R Bassan, H Dombret, M Doubek, A K Fielding, S Giebel, V Haddad, D Hoelzer, C Holland, N Ifrah, A Katz, T Maniar, G Martinelli, M Morgades, S O'Brien, J-M Ribera, J M Rowe, A Stein, M Topp, M Wadleigh, H Kantarjian
We compared outcomes from a single-arm study of blinatumomab in adult patients with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia (R/R ALL) with a historical data set from Europe and the United States. Estimates of complete remission (CR) and overall survival (OS) were weighted by the frequency distribution of prognostic factors in the blinatumomab trial. Outcomes were also compared between the trial and historical data using propensity score methods. The historical cohort included 694 patients with CR data and 1112 patients with OS data compared with 189 patients with CR and survival data in the blinatumomab trial...
September 23, 2016: Blood Cancer Journal
https://www.readbyqxmd.com/read/27602508/differential-impact-of-minimal-residual-disease-negativity-according-to-the-salvage-status-in-patients-with-relapsed-refractory-b-cell-acute-lymphoblastic-leukemia
#17
Elias Jabbour, Nicholas J Short, Jeffrey L Jorgensen, Musa Yilmaz, Farhad Ravandi, Sa A Wang, Deborah A Thomas, Joseph Khoury, Richard E Champlin, Issa Khouri, Partow Kebriaei, Susan M O'Brien, Guillermo Garcia-Manero, Jorge E Cortes, Koji Sasaki, Courtney D Dinardo, Tapan M Kadia, Nitin Jain, Marina Konopleva, Rebecca Garris, Hagop Kantarjian
BACKGROUND: Minimal residual disease (MRD) assessment predicts survival for patients with newly diagnosed acute lymphoblastic leukemia (ALL). Its significance in relapsed/refractory ALL is less clear. METHODS: This study identified 78 patients with relapsed/refractory B-cell ALL who achieved a morphologic response with inotuzumab ozogamicin (n = 41), blinatumomab (n = 11), or mini-hyperfractionated cyclophosphamide, vincristine, and doxorubicin plus inotuzumab (n = 26) during either salvage 1 (S1; n = 46) or salvage 2 (S2; n = 32) and had undergone an MRD assessment by multiparameter flow cytometry at the time of remission...
September 7, 2016: Cancer
https://www.readbyqxmd.com/read/27601914/clinical-use-of-blinatumomab-for-b-cell-acute-lymphoblastic-leukemia-in-adults
#18
REVIEW
Kum Ja Lee, Vivian Chow, Ashley Weissman, Sunil Tulpule, Ibrahim Aldoss, Mojtaba Akhtari
Adults with relapsed or refractory B-cell acute lymphoblastic leukemia have a dismal prognosis with a short median overall survival that can be measured in months. Because most patients will have chemotherapy-resistant disease, allogeneic hematopoietic stem cell transplantation remains the only potentially curative treatment. Despite advances in current management, patients continue to have poor outcomes and lack of durable responses. Thus, new therapies with alternative modes of actions are currently being investigated...
2016: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/27571406/dual-cd19-and-cd123-targeting-prevents-antigen-loss-relapses-after-cd19-directed-immunotherapies
#19
Marco Ruella, David M Barrett, Saad S Kenderian, Olga Shestova, Ted J Hofmann, Jessica Perazzelli, Michael Klichinsky, Vania Aikawa, Farzana Nazimuddin, Miroslaw Kozlowski, John Scholler, Simon F Lacey, Jan J Melenhorst, Jennifer J D Morrissette, David A Christian, Christopher A Hunter, Michael Kalos, David L Porter, Carl H June, Stephan A Grupp, Saar Gill
Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration...
October 3, 2016: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/27550855/correction-regarding-data-on-blinatumomab-associated-seizures
#20
Max S Topp, Zachary Zimmerman, Hagop M Kantarjian
No abstract text is available yet for this article.
October 2016: Nature Reviews. Clinical Oncology
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