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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
Sohita Dhillon
Obinutuzumab (Gazyva(®), Gazyvaro(®)) is a recombinant, monoclonal, humanized and glycoengineered, type II, anti-CD20, IgG1 antibody. It has recently been granted an additional indication for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen. In the primary analysis of the large, phase III GADOLIN study, induction therapy with obinutuzumab plus bendamustine followed by obinutuzumab maintenance prolonged progression-free survival (PFS) to a statistically significant extent relative to induction with bendamustine monotherapy in patients with indolent non-Hodgkin's lymphoma (iNHL)...
April 2017: Targeted Oncology
Lori A Leslie, Alan P Skarbnik, Coleen Bejot, Susan Stives, Tatyana A Feldman, Andre H Goy
Due to recent advancements in the understanding of the molecular pathogenesis of B-cell malignancies, there has been an explosion of innovative agents in development. The purpose of this review is to efficiently summarize novel therapies with activity in indolent non-Hodgkin lymphoma (iNHL) targeting surface antigens, signaling pathways, and the tumor microenvironment. Areas covered: A literature search was performed to identify preclinical data and clinical trials focused on the use of targeted therapies in iNHL subtypes including follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia...
April 2017: Expert Review of Hematology
Georgios Pongas, Bruce D Cheson
In chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphomas (NHLs), B-cell receptor signaling leads to activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Idelalisib, a PI3Kδ inhibitor was approved in 2014 by the US Food and Drug Administration (FDA) in combination with rituximab for the treatment of patients with CLL for whom single-agent rituximab would be considered appropriate and as a single agent for patients with relapsed small lymphocytic lymphoma (SLL) and relapsed follicular lymphoma (FL)...
December 2016: Seminars in Oncology
V M Patel, K Balakrishnan, M Douglas, T Tibbitts, E Y Xu, J L Kutok, M Ayers, A Sarkar, R Guerrieri, W G Wierda, S O'Brien, N Jain, H M Stern, V Gandhi
Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes...
September 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Ranjana H Advani, Daniel Lebovic, Andy Chen, Mark Brunvand, Andre Goy, Julie E Chang, Ephraim Hochberg, Sreeni Yalamanchili, Robert Kahn, Dan Lu, Priya Agarwal, Randall C Dere, Hsin-Ju Hsieh, Surai Jones, Yu-Waye Chu, Bruce D Cheson
Purpose: Pinatuzumab vedotin is an antibody-drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days...
March 1, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Saveria Capria, Walter Barberi, Salvatore Perrone, Antonietta Ferretti, Adriano Salaroli, Giorgia Annechini, Gianna Maria D'Elia, Robin Foà, Alessandro Pulsoni
INTRODUCTION: Indolent non-Hodgkin lymphomas (iNHL) remain incurable with standard approaches. The timing of autologous stem cell transplant (ASCT) is changing following the introduction of new drugs that can potentially defer the transplant, improved reduced intensity conditioning (RIC) and haploidentical allogeneic SCT (allo-SCT). AREAS COVERED: The most relevant aspects concerning the role of hematopoietic stem cell transplantation in the management of iNHL are discussed...
October 2016: Expert Review of Hematology
Jacqueline C Barrientos
Idelalisib is a first-in-class, oral, selective phosphatidylinositol 3-kinase δ inhibitor that offers a chemotherapy-free option for patients with relapsed or refractory (R/R) indolent non-Hodgkin lymphoma (iNHL). Clinical trials in iNHL have evaluated idelalisib as monotherapy and as combination therapy with rituximab, bendamustine, and rituximab + bendamustine. When administered to heavily pretreated patients with R/R iNHL, idelalisib monotherapy or combination therapy showed durable antitumor activity accompanied by sustained or improved quality-of-life outcomes...
2016: OncoTargets and Therapy
Yazeed Sawalha, Basel Rouphail, Xuefei Jia, Robert M Dean, Brian T Hill, Deepa Jagadeesh, Brad L Pohlman, Mitchell R Smith
Rituximab pharmacokinetics are affected by gender, age and weight and can affect outcomes in aggressive B cell lymphoma. Less is known about the pharmacokinetics of rituximab in indolent B cell lymphoma (iNHL). We analysed the effects of gender, age, weight and body surface area on the outcomes of 303 patients treated with first line rituximab-based regimens for iNHL. The patients were divided into 3 treatment cohorts: rituximab only, rituximab + chemotherapy (R-CTX) and R-CTX followed by rituximab maintenance; furthermore, each cohort was subdivided as follicular (FL) or non-FL, based on histology...
September 2016: British Journal of Haematology
M A Hassan Talukder, Marilena Preda, Larisa Ryzhova, Igor Prudovsky, Ilka M Pinz
Insulin resistance and diabetes are comorbidities of obesity and affect one in 10 adults in the United States. Despite the high prevalence, the mechanisms of cardiac insulin resistance in obesity are still unclear. We test the hypothesis that the insulin receptor localizes to caveolae and is regulated through binding to caveolin-3 (CAV3). We further test whether haploinsufficiency forCAV3 increases the susceptibility to high-fat-induced insulin resistance. We used in vivo and in vitro studies to determine the effect of palmitate exposure on global insulin resistance, contractile performance of the heart in vivo, glucose uptake in the heart, and on cellular signaling downstream of theIR We show that haploinsufficiency forCAV3 increases susceptibility to palmitate-induced global insulin resistance and causes cardiomyopathy...
March 2016: Physiological Reports
M Alzahrani, T C El-Galaly, M Hutchings, J W Hansen, A Loft, H E Johnsen, V Iyer, D Wilson, L H Sehn, K J Savage, J M Connors, R D Gascoyne, P Johansen, E Clasen-Linde, P Brown, D Villa
BACKGROUND: The added diagnostic and prognostic value of routine bone marrow biopsy (BMB) in patients with diffuse large B-cell lymphoma (DLBCL) undergoing positron emission tomography combined with computed tomography (PET/CT) staging is controversial. PATIENTS AND METHODS: Patients with newly diagnosed DLBCL who underwent both staging PET/CT and BMB were retrospectively identified in British Columbia, Aalborg, and Copenhagen. Original written PET/CT and pathology reports were retrospectively reviewed to determine Ann Arbor stage and outcomes, with and without the contribution of BMB...
June 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
John Kuruvilla
Despite improvements over the past decade in the overall survival of patients with indolent non-Hodgkin lymphomas, these lymphomas remain largely incurable with standard therapies. Immunochemotherapy with rituximab-based regimens has become a well-established standard of care in the primary and relapsed disease settings. The role of hematopoietic stem cell transplantation in indolent lymphoma has been defined by the adoption of this therapy largely in the relapse setting because randomized trials in the first-line setting have not shown survival advantages...
April 28, 2016: Blood
Federico De Angelis, Maria Elena Tosti, Saveria Capria, Eleonora Russo, Gianna Maria D'Elia, Giorgia Annechini, Caterina Stefanizzi, Robin Foà, Alessandro Pulsoni
The occurrence of secondary hypogammaglobulinemia (SH) after chemo-immunotherapy represents a potential side effect in patients with indolent non-Hodgkin lymphomas (iNHL). Few data are available on SH occurring after chemotherapy and/or Rituximab (R). We retrospectively investigated the incidence and the risk factors for SH and infectious complications in patients with iNHL after chemo-immunotherapy. Two hundred and sixty six patients treated between 1993 and 2011 were studied. Patients with a basal hypogammaglobulinemia or a monoclonal component were excluded...
December 2015: Leukemia Research
E A Wehler, S Kowal, J G Ariza, C Zambrano, J A de Anda, P Anaya, J Munakata, L Gonzalez
No abstract text is available yet for this article.
November 2015: Value in Health: the Journal of the International Society for Pharmacoeconomics and Outcomes Research
Andrew Davies
Indolent non-Hodgkin's lymphoma (iNHL) describes a group of B-cell lymphomas with a long median survival and a relapsing-remitting clinical course. Although existing treatments are initially effective, patients often relapse, demonstrating decreasing efficacy with successive treatment courses. Alternative treatments are needed. PI3Kδ plays an essential, non-redundant role in B-cell receptor signaling critical to the pathogenesis of iNHL. It is expressed predominantly in hematopoietic cells, making PI3Kδ an attractive therapeutic target...
October 2015: Expert Review of Hematology
C T Kouroukis, M Crump, D MacDonald, J F Larouche, D A Stewart, J Johnston, S Sauvageau, E Beausoleil, P Sage, S G Dubois, A Christofides, S Di Clemente, L Sehn
BACKGROUND: Bendamustine is a bifunctional alkylating agent with unique properties that distinguish it from other agents in its class. Bendamustine is used as monotherapy or in combination with other agents to treat patients with non-Hodgkin lymphoma (nhl) and chronic lymphocytic leukemia (cll). METHODS: The prospective interventional open-label bend-act trial evaluated bendamustine in patients with rituximab-refractory indolent nhl (inhl) and previously untreated cll...
August 2015: Current Oncology
Zengjun Li, Fei Li, Shuhua Yi, Zhimin Gu, Zhen Yu, Yan Xu, Xiaoyan Feng, Wei Liu, Dehui Zou, Junyuan Qi, Fenghuang Zhan, Lugui Qiu
BACKGROUND: Rituximab has been confirmed to improve the survival of patients with B cell indolent non-Hodgkin lymphomas (B-iNHLs) in Western world as previously reported, however, it is rarely reported in Chinese cohort. This study is to investigate the efficacy and safety of rituximab-based chemoimmunotherapy and select subpopulations most sensitive to the regimen in Chinese B-iNHL patients. METHODS: 334 B-iNHL patients from our center were retrospectively assessed...
2015: BMC Cancer
Maxwell M Krem, Ajay K Gopal
Molecularly targeted agents have become an established component of the treatment of indolent B-cell malignancies (iNHL). iNHL disproportionately affects older adults, so treatments that have excellent tolerability and efficacy across multiple lines of therapy are in demand. The numbers and classes of targeted therapies for iNHL have proliferated rapidly in recent years; classes of agents that show promise for older patients with iNHL include anti-CD20 antibodies, phosphatidyl-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway inhibitors, immunomodulators, proteasome inhibitors, epigenetic modulators, and immunotherapies...
2015: American Society of Clinical Oncology Educational Book
Felipe Samaniego, Fredrick Hagemeister, Jorge E Romaguera, Michelle A Fanale, Barbara Pro, Peter McLaughlin, M Alma Rodriguez, Sattva S Neelapu, Luis Fayad, Anas Younes, Lei Feng, Zuzana Berkova, Tamer Khashab, Lalit Sehgal, Francisco Vega-Vasquez, Larry W Kwak
We conducted a prospective phase II trial of pentostatin, cyclophosphamide and rituximab as initial therapy for patients with previously untreated advanced stage low-grade or indolent B-cell lymphomas (iNHLs). Of 83 evaluable patients, 91·6% attained an overall response and 86·8% a complete or unconfirmed complete response. The 3-year progression-free survival (PFS) and overall survival rates were 73% and 93%, respectively. The 3-year PFS rate was significantly different for different diagnoses (P = 0·01): 83% [95% confidence interval (CI): 0·72, 0·96] for follicular lymphomas, 73% (95% CI: 0·54, 1·0) for marginal zone lymphomas and 61% (95% CI: 0·46, 0·81) for small lymphocytic lymphomas...
June 2015: British Journal of Haematology
Tracy C Okoli, Cody J Peer, Kieron Dunleavy, William D Figg
Indolent Non-Hodgkin Lymphomas (iNHL) are typically B-cell malignancies and are incurable with current standard approaches. Thus, there is a demand for novel agents specific for this group of disorders. In a phase II study published by Gopal et al. in the New England Journal of Medicine, idelalisib, a small molecule inhibitor of PI3Kδ that was FDA approved in July of 2014, was shown to be effective when combined with rituximab in patients who cannot tolerate chemotherapy and as last line therapy in patients with iNHL refractory to 2 prior systemic therapies...
2015: Cancer Biology & Therapy
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