ipi 145

PURPOSE: Accurate risk stratification can improve lymphoma management, but current volumetric 18 F-fluorodeoxyglucose (FDG) indicators require time-consuming segmentation of all lesions in the body. Herein, we investigated the prognostic values of readily obtainable metabolic bulk volume (MBV) and bulky lesion glycolysis (BLG) that measure the single largest lesion. METHODS: The study subjects were a homogeneous cohort of 242 newly diagnosed stage II or III diffuse large B-cell lymphoma (DLBCL) patients who underwent first-line R-CHOP treatment...

PURPOSE: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of non-Hodgkin lymphoma, characterized by a variety of clinicopathological, histomorphological, immunophenotypic, and molecular genetic features. The subtype of DLBCL known as double-expressor lymphoma (DEL) is associated with an adverse prognosis when treated with R-CHOP. Our study aimed to investigate the clinicopathologic features of DEL and the prognostic roles of Myc rearrangement and C-Myc expression in DEL patients...

Chronic kidney dysfunction is associated with increased mortality in multiple cancer types. Preliminary evidence suggests the same to be true for B-large cell lymphomas (B-LCL). To analyze the relationship of glomerular filtration rate (GFR) and outcome of B-LCL in detail we collected data on outcomes of 285 consecutive patients with newly diagnosed B-LCL treated at our institution with standard rituximab-containing regimens who did not have preexisting kidney disease or urinary tract obstruction at presentation...

Phosphatidylinositol 3-kinase (PI3K) is the central regulator of cellular functions and is suggested as a target for various diseases; thus, effective PI3K inhibitors provide a promising opportunity for the pharmaceutical intervention of many diseases. Among them, PI3Kγ has received more attention because of its essential role in immune signaling. However, the development of novel selective PI3Kγ inhibitors is a major challenge due to the high sequence homology across the class I PI3K isoforms. Therefore, understanding the substrate specificity and receptor-ligand interaction of PI3Kγ would be an appropriate strategy for the rational design of potent γ-selective inhibitors...

BACKGROUND: Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in the western world which affects mainly the elderly population. Progress of the disease is very heterogeneous both in terms of necessity of treatment and life expectancy. The current scoring system for prognostic evaluation of patients with CLL is called CLL-IPI and predicts the general progress of the disease but is not a measure or a decision aid for the necessity of treatment. Due to the heterogeneous behavior of CLL it is important to develop tools that will identify if and when patients will necessitate treatment for CLL...

Objective: To investigate the relationship between plasma levels of complements before treatment and the clinicopathological feathers and prognoses of diffuse large B-cell lymphoma (DLBCL) patients treated with Rituximab (R)-CHOP or R-CHOP-like therapy. Methods: The clinicopathological data of 105 DLBCL patients treated in cancer Hospital of Chinese Academy of Medical Sciences from 2010 to 2016 were collected. The plasma samples from 105 DLBCL patients treated with R-CHOP or R-CHOP-like therapy and 80 healthy controls were used to detect 34 complement levels before treatment by utilizing antibody microarray...

PURPOSE: Lenalidomide combined with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (R2CHOP) in untreated diffuse large B-cell lymphoma (DLBCL) has shown promising activity, particularly in the activated B-cell-like (ABC) subtype. Eastern Cooperative Oncology Group (ECOG)-ACRIN trial E1412 was a randomized phase II study comparing R2CHOP versus R-CHOP in untreated DLBCL. PATIENTS AND METHODS: Patients with newly diagnosed DLBCL, stage II bulky-IV disease, International Prognostic Index (IPI) ≥ 2, and ECOG performance status ≤ 2 were eligible and randomly assigned 1:1 to R2CHOP versus R-CHOP for six cycles...

The in-clinic phosphatidylinositol 3-kinase (PI3K) inhibitors idelalisib (CAL-101) and duvelisib (IPI-145) have demonstrated high rates of response and progression-free survival in clinical trials of B-cell malignancies, such as chronic lymphocytic leukemia (CLL). However, a high incidence of adverse events has led to frequent discontinuations, limiting the clinical development of these inhibitors. By contrast, the dual PI3Kδ/casein kinase-1-ε (CK1ε) inhibitor umbralisib (TGR-1202) also shows high rates of response in clinical trials but has an improved safety profile with fewer severe adverse events...

Adoptive T cell transfer therapy induces objective responses in patients with advanced malignancies. Despite these results, some individuals do not respond due to the generation of terminally differentiated T cells during the expansion protocol. As the gamma and delta catalytic subunits in the PI3K pathway are abundant in leukocytes and involved in cell activation, we posited that blocking both subunits ex vivo with the inhibitor IPI-145 would prevent their differentiation, thereby increasing antitumor activity in vivo...

PURPOSE: The PI3K/AKT/mTOR pathway is one of the most highly activated cellular signaling pathways in advanced ovarian cancer. Although several PI3K/AKT/mTOR inhibitors have been developed to treat various types of cancer, the antitumor efficacy of many of these compounds against ovarian cancer has remained unclear. METHODS: Here, we tested and compared a panel of 16 PI3K/AKT/mTOR inhibitors (XL765, Miltefosine, Rapamycin, CCI-779, RAD001, FK506, XL147, GSK2110183, IPI-145, GSK2141795, BYL719, GSK458, CAL-101, XL765 analogue SAR245409, Triciribine, and GDC0941) that have entered clinical trials for antitumor activity against ovarian cancer, as well as the front line drug, paclitaxel...

OBJECTIVE: To analyze socioeconomic inequalities in the prevalence of underweight and overweight or obesity in women from low and middle-income countries (LMICs). METHODS: Using the last available Demographic Health Survey between 2010 and 2016 from 49 LMICs, we estimated the prevalence of underweight (BMI < 18.5 kg/m2 ) and overweight or obesity combined (BMI ≥ 25 kg/m2 ) for women aged 20-49 years. We used linear regression to explore the associations between the two outcomes and gross national income (GNI)...

Duvelisib, a potent δ- and γ-PI3K inhibitor, is a potential therapeutic for hematologic malignancies. Rituximab and bendamustine have demonstrated activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Combining duvelisib with either rituximab alone or rituximab and bendamustine may improve response rates and remission durability. We conducted this Phase one study in relapsed/refractory NHL and CLL patients. During expansion, each arm enrolled to disease-specific cohorts to assess efficacy...

P110-γ and -δ act in lymphocytes chemotaxis, presenting distinct, nonredundant roles in B- and T-cell migration and adhesion to stromal cells. Moreover, phosphoinositide-3-kinase-γ inhibition contributes to regulate macrophage polarization inhibiting cancer growth. Duvelisib (IPI-145) is an oral first-in-class, dual phosphoinositide-3-kinase inhibitor targeting p110-δ/γ exerting its activity in preclinical studies across different prognostic groups. In a large Phase III study, duvelisib showed superior progression-free survival and overall response rate compared with ofatumumab, thus leading to its approval for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma...

PURPOSE: Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy...

An intensive short-term chemotherapy regimen has substantially prolonged the overall survival of Burkitt's lymphoma (BL) patients, which has been further improved by addition of rituximab. However, the inevitable development of resistance to rituximab and the toxicity of chemotherapy remain obstacles. We first prepared two BL cell lines resistant to rituximab-mediated CDC. Using a phosphorylation antibody microarray, we revealed that PI3K/AKT pathway contained the most phosphorylated proteins/hits, while apoptosis pathway that may be regulated by PKC displayed the greatest fold enrichment in the resistant cells...

Duvelisib (also known as IPI-145) is an oral, dual inhibitor of phosphatidylinositol 3-kinase δ and γ (PI3K-δ,γ) being developed for treatment of hematologic malignancies. PI3K-δ,γ signaling can promote B-cell proliferation and survival in clonal B-cell malignancies, such as chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). In a phase 1 study, duvelisib showed clinically meaningful activity and acceptable safety in CLL/SLL patients. We report here the results of DUO, a global phase 3 randomized study of duvelisib vs ofatumumab monotherapy for patients with relapsed or refractory (RR) CLL/SLL...

Duvelisib (IPI-145), an oral, dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ, was evaluated in a Phase 1 study in advanced hematologic malignancies, which included expansion cohorts in relapsed/refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and treatment-naïve (TN) CLL. Per protocol, TN patients were at least 65 years old or had a del(17p)/TP53 mutation. Duvelisib was administered twice daily (BID) in 28-day cycles at doses of 8-75 mg in RR patients (n = 55) and 25 mg in TN patients (n = 18...

Duvelisib (IPI-145) is an oral dual inhibitor of phosphoinositide-3-kinase (PI3K)-δ and -γ in clinical development for the treatment of hematologic malignancies, including indolent non-Hodgkin lymphoma (iNHL). In a Phase 1, open-label study to determine the maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, clinical activity, and safety of duvelisib monotherapy in patients with advanced hematologic malignancies, duvelisib was administered at eight dose levels (8-100 mg BID) in a dose-escalation phase (n = 31 evaluable patients)...

Objective: To validate the prognostic value of chronic lymphocytic leukemia-international prognostic index (CLL-IPI) for Chinese CLL patients. Methods: Two hundred and fifteen CLL patients who were initially diagnosed and treated in Jiangsu Province Hospital from January 2002 to November 2017 were included in the retrospective analysis. Risk stratification and prognosis were evaluated by CLL-IPI scoring system. Results: ①Of the 215 patients, 143 were males and 72 were females, with a median age of 60 (16-85) years old...

Duvelisib (IPI-145) is an oral inhibitor of phosphatidylinositol 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...