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Daniel Primo, Lydia Scarfò, Aliki Xochelli, Mattias Mattsson, Pamela Ranghetti, Ana Belén Espinosa, Alicia Robles, Julian Gorrochategui, Joaquín Martínez-López, Javier de la Serna, Marcos González, Alberto Chaparro Gil, Eduardo Anguita, Sandra Iraheta, Veerendra Munugalavadla, Christophe Quéva, Stacey Tannheimer, Richard Rosenquist, Kostas Stamatopoulos, Joan Ballesteros, Paolo Ghia
PI3Kδ (idelalisib) and BTK (ibrutinib) inhibitors have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) interfering with the cross-talk between CLL cells and the lymph node microenviroment, yet their mechanism of action remains to be fully elucidated. Here, we developed an ex vivo model with the aim of reproducing the effects of the microenvironment that would help shed light on the in vivo mechanism of action of idelalisib and ibrutinib and predict their clinical efficacy in individual patients...
May 25, 2018: Oncotarget
Junjie Zhu, Pengcheng Wang, Amina Ibrahim Shehu, Jie Lu, Huichang Bi, Xiaochao Ma
Idelalisib (ILB) is a selective phosphatidylinositol-3-kinase delta inhibitor approved for the treatment of hematological malignancies. However, ILB frequently causes hepatotoxicity and the exact mechanism remains unclear. The current study profiled the metabolites of ILB in mouse liver, urine and feces. The major metabolites found in the liver were oxidized metabolite GS-563117 (M1) and ILB-glutathione (GSH) adduct (M2). These metabolic pathways were confirmed by analysis of urine and feces from mice treated with ILB...
June 13, 2018: Chemical Research in Toxicology
Matthew S Davids, Michael Hallek, William Wierda, Andrew W Roberts, Stephan Stilgenbauer, Jeffrey A Jones, John F Gerecitano, Su Young Kim, Jalaja Potluri, Todd Busman, Andrea Best, Maria E Verdugo, Elisa Cerri, Monali Desai, Peter Hillmen, John F Seymour
PURPOSE: The oral BCL-2 inhibitor venetoclax is an effective therapy for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), including disease with high-risk genomic features such as chromosome 17p deletion (del[17p]) or progressive disease following B-cell receptor pathway inhibitors. EXPERIMENTAL DESIGN: We conducted a comprehensive analysis of the safety of 400mg daily venetoclax monotherapy in 350 patients with CLL using an integrated dataset from three phase-I/II studies...
June 12, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
M D'Aveni-Piney, M Divoux, H Busby-Venner, M Muller, J Broséus, P Feugier
BACKGROUND: Waldenström's macroglobulinemia is a rare B-cell lymphoma. The gold standard treatment for Waldenström's macroglobulinemia is an anti-CD20 antibody (rituximab) in combination with alkylating agents and dexamethasone. Treatment targeting the B-cell receptor such as ibrutinib (but not idelalisib) is currently approved for treatment of patients with relapsed or refractory Waldenström's macroglobulinemia. CASE PRESENTATION: We report a case of a 71-year-old white French man with Waldenström's macroglobulinemia who presented with acute renal failure and hyperviscosity syndrome...
June 12, 2018: Journal of Medical Case Reports
Sarah K Tasian, Jessica A Casas, David Posocco, Shilpa Gandre-Babbe, Alyssa L Gagne, Ge Liang, Mignon L Loh, Mitchell J Weiss, Deborah L French, Stella T Chou
Juvenile myelomonocytic leukemia (JMML) is an uncommon myeloproliferative neoplasm driven by Ras pathway mutations and hyperactive Ras/MAPK signaling. Outcomes for many children with JMML remain dismal with current standard-of-care cytoreductive chemotherapy and hematopoietic stem cell transplantation. We used patient-derived induced pluripotent stem cells (iPSCs) to characterize the signaling profiles and potential therapeutic vulnerabilities of PTPN11-mutant and CBL-mutant JMML. We assessed whether MEK, JAK, and PI3K/mTOR kinase inhibitors (i) could inhibit myeloproliferation and aberrant signaling in iPSC-derived hematopoietic progenitors with PTPN11 E76K or CBL Y371H mutations...
June 8, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Ee Lyn Lim, Fiorella M Cugliandolo, Dalya R Rosner, David Gyori, Rahul Roychoudhuri, Klaus Okkenhaug
Multiple modes of immunosuppression restrain immune function within tumors. We previously reported that phosphoinositide 3-kinase δ (PI3Kδ) inactivation in mice confers resistance to a range of tumor models by disrupting immunosuppression mediated by regulatory T cells (Tregs). The PI3Kδ inhibitor idelalisib has proven highly effective in the clinical treatment of chronic lymphocytic leukemia and the potential to extend the use of PI3Kδ inhibitors to nonhematological cancers is being evaluated. In this work, we demonstrate that the antitumor effect of PI3Kδ inactivation is primarily mediated through the disruption of Treg function, and correlates with tumor dependence on Treg immunosuppression...
June 7, 2018: JCI Insight
David K Edwards V, David Tyler Sweeney, Hibery Ho, Christopher A Eide, Angela Rofelty, Anupriya Agarwal, Selina Qiuying Liu, Alexey V Danilov, Patrice Lee, David Chantry, Shannon K McWeeney, Brian J Druker, Jeffrey W Tyner, Stephen E Spurgeon, Marc M Loriaux
In many malignancies, the tumor microenvironment includes CSF1R-expressing supportive monocyte/macrophages that promote tumor cell survival. For chronic lymphocytic leukemia (CLL), these supportive monocyte/macrophages are known as nurse-like cells (NLCs), although the potential effectiveness of selective small-molecule inhibitors of CSF1R against CLL is understudied. Here, we demonstrate the preclinical activity of two inhibitors of CSF1R, GW-2580 and ARRY-382, in primary CLL patient samples. We observed at least 25% of CLL samples showed sub-micromolar sensitivity to CSF1R inhibitors...
May 15, 2018: Oncotarget
Stefano Molica
Novel targeted therapies - including ibrutinib, venetoclax, and idelalisib - have revolutionized the treatment landscape of chronic lymphocytic leukemia (CLL). Therefore, studying combinations of novel agents (NAs) with a distinct mechanism of action and nonoverlapping toxicities is challenging. Area covered: The 2017 American Society Hematology Annual Meeting has represented a showcase for several trials combining NAs. These studies are currently evaluating the efficacy NA plus anti-CD20 monoclonal antibody, NA plus NA (with or without anti-CD20 monoclonal antibody), and NA plus chemo-immunotherapy...
June 2018: Expert Review of Hematology
Thomas D Rodgers, Patrick M Reagan
The B-cell receptor (BCR) pathway is a crucial aspect of mature lymphocytes and is maintained in B-cell neoplasms. Many small module inhibitors targeting kinases within the BCR pathway are approved, with others in development, offering alternative treatment options to standard chemoimmunotherapy. Areas Covered: This review covers both approved inhibitors and investigational inhibitors of spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), and phosphoinositide-3-kinase (PI3K) in the treatment of B-cell lymphomas...
May 20, 2018: Expert Opinion on Emerging Drugs
Vineela Chukkapalli, Leo I Gordon, Parameswaran Venugopal, Jeffrey A Borgia, Reem Karmali
Metformin exerts direct anti-tumor effects by activating AMP-activated protein kinase (AMPK), a major sensor of cellular metabolism in cancer cells. This, in turn, inhibits pro-survival mTOR signaling. Metformin has also been shown to disrupt complex 1 of the mitochondrial electron transport chain. Here, we explored the lymphoma specific anti-tumor effects of metformin using Daudi (Burkitt), SUDHL-4 (germinal center diffuse large B-cell lymphoma; GC DLBCL), Jeko-1 (Mantle-cell lymphoma; MCL) and KPUM-UH1 (double hit DLBCL) cell lines...
April 20, 2018: Oncotarget
Christopher Pleyer, Adrian Wiestner, Clare Sun
Ibrutinib and idelalisib are kinase inhibitors that have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Capable of inducing durable remissions, these agents also modulate the immune system. Both ibrutinib and idelalisib abrogate the tumor-supporting microenvironment by disrupting cell-cell interactions, modulating the T-cell compartment, and altering the cytokine milieu. Ibrutinib also partially restores T-cell and myeloid defects associated with CLL. In contrast, immune-related adverse effects, including pneumonitis, colitis, hepatotoxicity, and infections are of particular concern with idelalisib...
May 15, 2018: Leukemia & Lymphoma
John G Gribben
Allogenic stem cell transplantation (allo-SCT) has been considered the treatment of choice for high-risk patients with chronic lymphocytic leukemia (CLL) and the only approach offered with curative intent in this disease. The availability novel agents including the B cell receptor inhibitors (BCRi) ibrutinib, acalabrutinib and idelalisib, as well as venetoclax which targets the BCL2 pathway and the success of these agents in treating high-risk disease patients has made it more difficult to assess who and when in their treatment course allo-SCT should be considered...
May 11, 2018: Blood
Floyd Hassenrück, Eva Knödgen, Elisa Göckeritz, Safi Hasan Midda, Verena Vondey, Lars Neumann, Sylvia Herter, Christian Klein, Michael Hallek, Günter Krause
The antibody-dependent cell-mediated cytotoxicity (ADCC) of the anti-CD20 monoclonal antibodies (mAbs) rituximab and obinutuzumab against the cell line Raji and isolated CLL cells and its potential impairment by kinase inhibitors (KI) was determined via lactate dehydrogenase release or calcein retention, respectively, using genetically modified NK92 cells expressing CD16-176V as effector cells. Compared to peripheral blood mononuclear cells, recombinant effector cell lines showed substantial alloreactivity-related cytotoxicity without addition of mAbs but afforded determination of ADCC with reduced interassay variability...
2018: BioMed Research International
Paolo Strati, Nitin Jain, Susan O'Brien
The complexity of the treatment of patients with chronic lymphocytic leukemia has increased substantially over the past several years as a consequence of the advent of novel biological agents such as ibrutinib, idelalisib, and venetoclax, as well as increasingly potent anti-CD20 monoclonal antibodies. In addition, the identification of molecular predictive markers and the introduction of more sensitive and sophisticated techniques to assess minimal residual disease have allowed optimization of the use of chemoimmunotherapy and targeted therapies and may become standard of care in the future...
May 2018: Mayo Clinic Proceedings
Bartosz Puła, Bożena Katarzyna Budziszewska, Justyna Rybka, Lidia Gil, Edyta Subocz, Monika Długosz-Danecka, Daria Zawirska, Anna Waszczuk-Gajda, Elżbieta Iskierka-Jażdżewska, Agnieszka Kopacz, Agnieszka Szymczyk, Jarosław Czyż, Ewa Lech-Marańda, Krzysztof Warzocha, Krzysztof Jamroziak
BACKGROUND/AIM: There is limited amount of data available on the comparative efficacy of ibrutinib and idelalisib, the B-cell receptor inhibitors (BCRi) newly approved for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) treatment. The aim of our study was to analyze and compare the outcomes of real-world r/r CLL/SLL patients treated with these two BCRi in outside clinical trials. PATIENTS AND METHODS: A comparative case matched 1:2 analysis was performed on idelalisib combined with rituximab and ibrutinib efficacy in 102 patients with r/r CLL/SLL from two observational studies of the Polish Adult Leukemia Group (PALG)...
May 2018: Anticancer Research
Benjamin W Teh, Constantine S Tam, Sasanka Handunnetti, Leon J Worth, Monica A Slavin
Chronic lymphocytic leukaemia (CLL) is the most common leukaemia with infections a leading cause of morbidity and mortality. Recently there has been a paradigm shift from the use of chemo-immunotherapies to agents targeting specific B-lymphocyte pathways. These agents include ibrutinib, idelalisib and venetoclax. In this review, the risks and timing of infections associated with these agents are described, taking into account disease and treatment status. Treatment with ibrutinib as monotherapy or in combination with chemo-immunotherapies is not associated with additional risk for infection...
April 23, 2018: Blood Reviews
Ryohei Kozaki, Meike Vogler, Harriet S Walter, Sandrine Jayne, David Dinsdale, Reiner Siebert, Martin J S Dyer, Toshio Yoshizawa
Bruton's tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines...
April 23, 2018: Cancers
Francesc Bosch, Michael Hallek
No abstract text is available yet for this article.
April 12, 2018: Blood
Joanna Rhodes, Anthony Mato, Jeff P Sharman
PURPOSE REVIEW: B cell signaling agents, including ibrutinib, idelalisib, and the BCL-2 inhibitor venetoclax have become an integral part of therapy for patients with non-Hodgkin's lymphomas. The toxicity profiles of these medications is distinct from chemoimmunotherapy. Here, we will review the mechanism of action of these drugs, their efficacy, and toxicity management. RECENT FINDINGS: Ibrutinib use is associated with increased risk of atrial fibrillation and bleeding which can be managed using dose interruptions and modifications...
April 11, 2018: Current Oncology Reports
Anna-Katharina Zoellner, Nico Peter, Yvonne Zimmermann, Grit Hutter, Wolfgang Hiddemann, Martin Dreyling
INTRODUCTION: PI3K inhibitors are evaluated for relapsed and refractory Diffuse large B-cell lymphoma (DLBCL) patients. OBJECTIVE: As rituximab has shown to influence B-cell receptor (BCR) signaling, we investigated the interaction of anti-CD20 antibody rituximab and the new type II glycoengineered anti-CD20 antibody obinutuzumab in combination with the PI3K delta inhibitor idelalisib. METHODS: Established DLBCL cell lines were treated with either rituximab or obinutuzumab alone or in combination with PI3K delta inhibitor idelalisib...
April 4, 2018: European Journal of Haematology
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