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Idelalisib

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https://www.readbyqxmd.com/read/29465308/cll2-bxx-phase-ii-trials-sequential-targeted-treatment-for-eradication-of-minimal-residual-disease-in-chronic-lymphocytic-leukemia
#1
Paula Cramer, Julia von Tresckow, Jasmin Bahlo, Anja Engelke, Petra Langerbeins, Anna-Maria Fink, Kirsten Fischer, Clemens-Martin Wendtner, Karl-Anton Kreuzer, Stephan Stilgenbauer, Sebastian Böttcher, Barbara Eichhorst, Michael Hallek
AIM: Four Phase II trials (Clinical Trials numbers: NCT02345863, NCT02401503, NCT02445131 and NCT02689141) evaluate a different combination of targeted agents in an all-comer population of approximately 60 patients with chronic lymphocytic leukemia irrespective of prior treatment, physical fitness and genetic risk factors. Patients with a higher tumor load start with a debulking treatment with bendamustine. The subsequent induction and maintenance treatment with an anti-CD20 antibody (obinutuzumab or ofatumumab) and a targeted oral agent (ibrutinib, idelalisib or venetoclax) are continued until achievement of a complete response and minimal residual disease negativity...
February 21, 2018: Future Oncology
https://www.readbyqxmd.com/read/29454849/escmid-study-group-for-infections-in-compromised-hosts-esgich-consensus-document-on-the-safety-of-targeted-and-biological-therapies-an-infectious-diseases-perspective-intracellular-signaling-pathways-tyrosine-kinase-and-mtor-inhibitors
#2
REVIEW
Mark Reinwald, Jose T Silva, Nicolas J Mueller, Jesús Fortún, Christian Garzoni, Johan W de Fijter, Mario Fernández-Ruiz, Paolo Grossi, Jose María Aguado
BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of therapies targeting different intracellular signaling pathways and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family...
February 15, 2018: Clinical Microbiology and Infection
https://www.readbyqxmd.com/read/29453281/the-pi3k%C3%AE-selective-inhibitor-idelalisib-minimally-interferes-with-immune-effector-function-mediated-by-rituximab-or-obinutuzumab-and-significantly-augments-b-cell-depletion-in-vivo
#3
Adam Palazzo, Sylvia Herter, Laura Grosmaire, Randy Jones, Christian R Frey, Florian Limani, Marina Bacac, Pablo Umana, Robert J Oldham, Michael J E Marshall, Kerry L Cox, Anna H Turaj, Mark S Cragg, Christian Klein, Matthew J Carter, Stacey Tannheimer
Idelalisib is a highly selective oral inhibitor of PI3Kδ indicated for the treatment of patients with relapsed chronic lymphocytic leukemia in combination with rituximab. Despite additive clinical effects, previous studies have paradoxically demonstrated that targeted therapies potentially negatively affect anti-CD20 mAb effector mechanisms. To address these potential effects, we investigated the impact of PI3Kδ inhibition by idelalisib on the effector mechanisms of rituximab and obinutuzumab. At clinically relevant concentrations, idelalisib minimally influenced rituximab- and obinutuzumab-mediated Ab-dependent cellular cytotoxicity and phagocytosis on human lymphoma cell lines, while maintaining the superiority of obinutuzumab-mediated Ab-dependent cellular cytotoxicity...
February 16, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29420244/chronic-lymphocytic-leukaemia-with-necrotic-herpetic-adenitis-an-elusive-clinical-condition
#4
Roma Srivastava, Doreen Griswold, Muhammad Omer Jamil
Herpes simplex virus (HSV) adenitis is a rare but important cause of morbidity in immunocompromised patients. Chronic lymphocytic leukaemia (CLL)/Small lymphocytic lymphoma (SLL) is an indolent disease which impairs the cellular and humoral immunity, predisposing patients to a myriad of infections. Clinically, herpetic adenitis can mimic large cell (Richter's) transformation in patients with CLL. To date, less than 30 cases of HSV adenitis have been reported in the literature. We report a case of a patient with CLL with no prior history of HSV infection, who presented with rapidly enlarging lymph nodes after initial response to idelalisib raising the suspicion of Richter's transformation...
February 2, 2018: BMJ Case Reports
https://www.readbyqxmd.com/read/29398648/cost-effectiveness-of-ibrutinib-compared-with-obinutuzumab-with-chlorambucil-in-untreated-chronic-lymphocytic-leukemia-patients-with-comorbidities-in-the-united-kingdom
#5
Richa Sinha, William Ken Redekop
BACKGROUND: Ibrutinib shows superiority over obinutuzumab with chlorambucil (G-Clb) in untreated patients with chronic lymphocytic leukemia with comorbidities who cannot tolerate fludarabine-based therapy. However, ibrutinib is relatively more expensive than G-Clb. In this study we evaluated the cost-effectiveness of ibrutinib compared with G-Clb from the United Kingdom (UK) health care perspective. MATERIALS AND METHODS: A 3-state semi-Markov model was parameterized to estimate the lifetime costs and benefits associated with ibrutinib compared with G-Clb as first-line treatment...
December 29, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29383130/gsk-3%C3%AE-inhibitor-9-ing-41-reduces-cell-viability-and-halts-proliferation-of-b-cell-lymphoma-cell-lines-as-a-single-agent-and-in-combination-with-novel-agents
#6
Reem Karmali, Vineela Chukkapalli, Leo I Gordon, Jeffrey A Borgia, Andrey Ugolkov, Andrew P Mazar, Francis J Giles
The complexities of GSK-3β function and interactions with PI3K/AKT/mTOR signaling, cell cycling, and apoptotic pathways are poorly understood in the context of lymphomagenesis and cancer therapeutics. In this study, we explored the anti-tumor effects of the GSK-3β inhibitor, 9-ING-41, in lymphoma cell lines as a single agent and in combination with novel agents comprising BCL-2 inhibitor (Venetoclax), CDK-9 inhibitor (BAY-1143572) and p110δ-PI3K inhibitor (Idelalisib). Treatment of Daudi, SUDHL-4, Karpas 422, KPUM-UH1, and TMD8 lymphoma cell lines with 1 μM 9-ING-41 reduced cell viability by 40-70% (p<0...
December 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29381234/balancing-early-access-with-uncertainties-in-evidence-for-drugs-authorized-by-prospective-case-series-systematic-review-of-reimbursement-decisions
#7
Susanna M Wallerstedt, Martin Henriksson
AIMS: To review clinical and cost-effectiveness evidence underlying reimbursement decisions relating to drugs whose authorization mainly is based on evidence from prospective case series. METHODS: A systematic review of all new drugs evaluated in 2011-2016 within a health care profession-driven resource prioritization process, with a market approval based on prospective case series, and a reimbursement decision by the Swedish Dental and Pharmaceutical Benefits Board (TLV)...
January 30, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29359239/the-orally-available-multikinase-inhibitor-regorafenib-bay-73-4506-in-multiple-myeloma
#8
Iris Breitkreutz, Klaus Podar, Vianihuini Figueroa-Vazquez, Scott Wilhelm, Patrick J Hayden, Kenneth C Anderson, Marc S Raab
A promising approach to the treatment of multiple myeloma (MM) involves agents that target not only the myeloma cells directly, but also the tumor microenvironment which promotes tumor cell growth, angiogenesis, and MM bone disease. Here we investigate the orally available multikinase inhibitor, regorafenib (BAY 73-4506), for its therapeutic efficacy in MM. Regorafenib is a potent inhibitor of angiogenic (VEGFR 1-3, PDGFR-b) as well as oncogenic (c-KIT, RET, FGFR, Raf) kinases. We show that regorafenib induces apoptosis in all MM cell lines at below clinically achievable concentrations...
January 23, 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29352719/prognostic-testing-patterns-and-outcomes-of-chronic-lymphocytic-leukemia-patients-stratified-by-fluorescence-in-situ-hybridization-cytogenetics-a-real-world-clinical-experience-in-the-connect-cll-registry
#9
Anthony Mato, Chadi Nabhan, Neil E Kay, Nicole Lamanna, Thomas J Kipps, David L Grinblatt, Christopher R Flowers, Charles M Farber, Matthew S Davids, Pavel Kiselev, Arlene S Swern, Shriya Bhushan, Kristen Sullivan, E Dawn Flick, Jeff P Sharman
INTRODUCTION: Prognostic genetic testing is recommended for patients with chronic lymphocytic leukemia (CLL) to guide clinical management. Specific abnormalities, such as del(17p), del(11q), and unmutated IgHV, can predict the depth and durability of the response to CLL therapy. PATIENTS AND METHODS: In the present analysis of the Connect CLL Registry (ClinicalTrials.gov identifier, NCT01081015), a prospective observational cohort study of patients treated across 199 centers, the patterns of prognostic testing and outcomes of patients with unfavorable-risk genetics were analyzed...
December 6, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29306311/-polymicrobial-lung-infection-associated-with-idelalisib-administration
#10
Adrián Rodríguez-Ferreras, Lucia Velasco-Roces, Eva Lázaro-López, Isabel Zapico-García
No abstract text is available yet for this article.
January 1, 2018: Farmacia Hospitalaria
https://www.readbyqxmd.com/read/29305552/venetoclax-for-patients-with-chronic-lymphocytic-leukemia-who-progressed-during-or-after-idelalisib-therapy
#11
Steven Coutre, Michael Choi, Richard R Furman, Herbert Eradat, Leonard Heffner, Jeffrey A Jones, Brenda Chyla, Lang Zhou, Suresh Agarwal, Tina Waskiewicz, Maria Verdugo, Rod A Humerickhouse, Jalaja Potluri, William G Wierda, Matthew S Davids
B-cell receptor pathway inhibitors (BCRi) have transformed treatment for chronic lymphocytic leukemia (CLL); however, efficacy of therapies for patients whose disease is refractory to/relapses after (R/R) BCRi is unknown. Venetoclax is a selective, orally bioavailable BCL-2 inhibitor with activity in patients with CLL, including those who are heavily pretreated or have 17p deletion. This phase 2 study prospectively evaluated venetoclax in patients with R/R CLL after ibrutinib or idelalisib; here we report on patients who received idelalisib as the last BCRi prior to enrollment...
January 5, 2018: Blood
https://www.readbyqxmd.com/read/29296833/emerging-role-of-bcr-signaling-inhibitors-in-immunomodulation-of-chronic-lymphocytic-leukemia
#12
REVIEW
Kamira Maharaj, Eva Sahakian, Javier Pinilla-Ibarz
Approved therapies that target the B-cell receptor (BCR) signaling pathway, such as ibrutinib and idelalisib, are known to show activity in chronic lymphocytic leukemia (CLL) via their direct effects on crucial survival pathways in malignant B cells. However, these therapies also have effects on T cells in CLL by mediating toxicity and possibly controlling disease. By focusing on the effects of BCR signaling inhibitors on the T-cell compartment, we may gain new insights into the comprehensive biological outcomes of systemic treatment to further understand mechanisms of drug efficacy, predict the toxicity or adverse events, and identify novel combinatorial therapies...
September 26, 2017: Blood Advances
https://www.readbyqxmd.com/read/29250930/management-of-high-risk-chronic-lymphocytic-leukaemia-cll-patients-in-australia
#13
REVIEW
Bryone J Kuss, Constantine S Tam
BACKGROUND: Chronic lymphocytic leukaemia (CLL) frequently responds to chemoimmunotherapy combining cytotoxic chemotherapy and monoclonal antibodies. However, CLL is associated with significant genetic heterogeneity, and some high-risk forms are known to be chemo-resistant and associated with early relapse. AIMS: To review the current treatment paradigm of patients with high-risk disease, in particular those with del(17p) and TP53 variants. RESULTS: A 'watch and wait' approach is recommended for all patients who are asymptomatic...
December 2017: Internal Medicine Journal
https://www.readbyqxmd.com/read/29246942/synergistic-targeting-of-the-regulatory-and-catalytic-subunits-of-pi3k%C3%AE-in-mature-b-cell-malignancies
#14
Jeffrey Cooney, An-Ping Lin, Daifeng Jiang, Long Wang, Avvaru N Suhasini, Jamie Myers, ZhiJun Qiu, Albert Wölfler, Heinz Sill, Ricardo C T Aguiar
PURPOSE: Aberrant activation of the B cell receptor (BCR) is implicated in the pathogenesis of mature B-cell tumors, a concept validated in part by the clinical success of inhibitors of the BCR-related kinases BTK (Bruton's tyrosine kinase) and PI3Kδ (Phosphatidylinositol-4,5-bisphosphate 3-kinase delta). These inhibitors have limitations, including the paucity of complete responses, acquired resistance, and toxicity. Here we examined the mechanism by which the cyclic-AMP/PDE4 signaling axis suppresses PI3K, towards identifying a novel mechanism-based combinatorial strategy to attack BCR-dependency in mature B-cell malignancies...
December 15, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/29235459/pi3k%C3%AE-activates-e2f1-synthesis-in-response-to-mrna-translation-stress
#15
Sivakumar Vadivel Gnanasundram, Slovénie Pyndiah, Chrysoula Daskalogianni, Kate Armfield, Karin Nylander, Joanna B Wilson, Robin Fåhraeus
The c-myc oncogene stimulates ribosomal biogenesis and protein synthesis to promote cellular growth. However, the pathway by which cells sense and restore dysfunctional mRNA translation and how this is linked to cell proliferation and growth is not known. We here show that mRNA translation stress in cis triggered by the gly-ala repeat sequence of Epstein-Barr virus (EBV)-encoded EBNA1, results in PI3Kδ-dependent induction of E2F1 mRNA translation with the consequent activation of c-Myc and cell proliferation...
December 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29233821/activity-of-the-pi3k-%C3%AE-%C3%AE-inhibitor-duvelisib-in-a-phase-i-trial-and-preclinical-models-of-t-cell-lymphoma
#16
Steven M Horwitz, Raphael Koch, Pierluigi Porcu, Yasuhiro Oki, Alison Moskowitz, Megan Perez, Patricia Myskowski, Adam Officer, Jacob D Jaffe, Sara N Morrow, Kerstin Allen, Mark Douglas, Howard Stern, Jennifer Sweeney, Patrick Kelly, Virginia Kelly, Jon C Aster, David Weaver, Francine M Foss, David M Weinstock
Duvelisib (IPI-145) is an oral inhibitor of phosphoinositide-3-kinase (PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making Duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a Phase 1, open-label study of Duvelisib in patients with relapsed or refractory PTCL [n=16] and CTCL [n=19], along with in vitro and in vivo models of TCL...
December 12, 2017: Blood
https://www.readbyqxmd.com/read/29230799/a-retrospective-study-on-the-management-of-patients-with-rituximab-refractory-follicular-lymphoma
#17
Philippe Solal-Céligny, Pierre Leconte, Aurélie Bardet, Juana Hernandez, Xavier Troussard
Given that there are currently no clear recommendations regarding therapeutic options for rituximab refractory/relapsed follicular lymphoma patients, this study aimed to describe the real-life management of patients with refractory follicular lymphoma after systemic rituximab-containing regimens (rFL), and rFL patient characteristics. In this retrospective, national, multicentre study, descriptive analyses were mainly performed according to rituximab-containing regimen at rFL diagnosis [rituximab monotherapy (R-MONO), rituximab + chemotherapy (R-COMBO), and ongoing rituximab maintenance (R-MAINTAIN)]...
December 12, 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/29226472/cost-utility-analysis-of-idelalisib-in-combination-with-rituximab-in-relapsed-or-refractory-chronic-lymphocytic-leukaemia
#18
Luis Felipe Casado, José Ángel Hernández, Isidro Jarque, María Echave, Miguel Angel Casado, Antonio Castro
OBJECTIVE: To evaluate the incremental cost-utility ratio (ICUR) of idelalisib in combination with rituximab (IR) versus rituximab monotherapy (R) in the treatment of patients with relapsed or refractory (R/R) chronic lymphocytic leukaemia (CLL), from the Spanish National Health System (NHS) perspective. METHODS: A partitioned survival Markov model for a lifetime horizon (30 years) was developed to estimate costs (€, 2016) and quality-adjusted life years (QALY) with IR and R...
December 11, 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/29222670/venetoclax-for-treating-chronic-lymphocytic-leukaemia-an-evidence-review-group-perspective-of-a-nice-single-technology-appraisal
#19
REVIEW
Hema Mistry, Chidozie Nduka, Martin Connock, Jill Colquitt, Theodoros Mantopoulos, Emma Loveman, Renata Walewska, James Mason
Venetoclax is licensed to treat relapsed or refractory (R/R) chronic lymphocytic leukaemia (CLL). As part of the Single Technology Appraisal (STA) ID944, the National Institute for Health and Care Excellence (NICE) invited AbbVie, the manufacturer, to submit evidence on the use of venetoclax, within its licensed indication. The Evidence Review Group (ERG), Warwick Evidence, was asked to provide an independent and critical review of the submitted evidence. Evidence came from three single-arm trials in CLL patients with or without 17p deletion [del(17p])/TP53 chromosomal abnormalities...
December 8, 2017: PharmacoEconomics
https://www.readbyqxmd.com/read/29222277/how-should-we-sequence-and-combine-novel-therapies-in-cll
#20
REVIEW
Matthew S Davids
With the recent approval of several effective and well-tolerated novel agents (NAs), including ibrutinib, idelalisib, venetoclax, and obinutuzumab, patients with chronic lymphocytic leukemia (CLL) have more therapeutic options than ever before. The availability of these agents is both an important advance for patients but also a challenge for practicing hematologist/oncologists to learn how best to sequence NAs, both with respect to chemoimmunotherapy (CIT) and to other NAs. The sequencing of NAs in clinical practice should be guided both by an individual patient's prognostic markers, such as FISH and immunoglobulin heavy chain variable region (IGHV)-mutation status, as well as the patient's medical comorbidities and goals of care...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
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