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Venetoclax cll

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https://www.readbyqxmd.com/read/29382644/venetoclax-data-prompt-rethink-of-cll-therapy
#1
(no author information available yet)
The BCL2 inhibitor venetoclax is approved in the United States for only a subset of patients with refractory chronic lymphocytic leukemia. However, in light of data presented at the American Society of Hematology 2017 Annual Meeting, clinicians are thinking ahead to administering the drug more broadly-in combinations and as a first-line therapy-for other patients with the disease.
January 30, 2018: Cancer Discovery
https://www.readbyqxmd.com/read/29333561/pharmacokinetics-of-the-b-cell-lymphoma-2-bcl-2-inhibitor-venetoclax-in-female-subjects-with-systemic-lupus-erythematosus
#2
Mukul Minocha, Jiewei Zeng, Jeroen K Medema, Ahmed A Othman
BACKGROUND AND OBJECTIVE: Venetoclax is an oral selective Bcl-2 inhibitor approved for the treatment of patients with chronic lymphocytic leukemia with 17p deletion. Mechanistic and preclinical evidence warranted evaluation of venetoclax for the treatment of systemic lupus erythematosus (SLE). This work characterized the pharmacokinetics of venetoclax in female subjects with SLE. METHODS: Single (10-500 mg) and multiple (30-600 mg) escalating doses of venetoclax or matching placebo were evaluated using randomized, double-blind, placebo-controlled designs (6 active and 2 placebo per dose with 73 unique SLE patients enrolled, 25 of whom enrolled twice)...
January 15, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29305552/venetoclax-for-patients-with-chronic-lymphocytic-leukemia-who-progressed-during-or-after-idelalisib-therapy
#3
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/29302721/impact-of-ritonavir-dose-and-schedule-on-cyp3a-inhibition-and-venetoclax-clinical-pharmacokinetics
#4
Kevin J Freise, Beibei Hu, Ahmed Hamed Salem
PURPOSE: Venetoclax is a selective BCL-2 inhibitor indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). It is predominately metabolized by cytochrome P450 (CYP) 3A. The study objective was to determine the effect of different dosage regimens of ritonavir, a strong CYP3A inhibitor, on the pharmacokinetics of venetoclax in 20 healthy subjects. METHODS: In cohorts 1 and 2, subjects received single 10 mg doses of venetoclax in periods 1 and 2 and a single 50- or 100-mg dose of ritonavir in period 2...
January 4, 2018: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29297516/erratum-jayappa-kd-portell-ca-gordon-vl-et-al-microenvironmental-agonists-generate-de-novo-phenotypic-resistance-to-combined-ibrutinib-plus-venetoclax-in-cll-and-mcl-blood-adv-2017-1-14-933-946
#5
(no author information available yet)
[This corrects the article DOI: 10.1182/bloodadvances.2016004176.].
August 22, 2017: Blood Advances
https://www.readbyqxmd.com/read/29250930/management-of-high-risk-chronic-lymphocytic-leukaemia-cll-patients-in-australia
#6
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/29246803/venetoclax-for-chronic-lymphocytic-leukaemia-progressing-after-ibrutinib-an-interim-analysis-of-a-multicentre-open-label-phase-2-trial
#7
Jeffrey A Jones, Anthony R Mato, William G Wierda, Matthew S Davids, Michael Choi, Bruce D Cheson, Richard R Furman, Nicole Lamanna, Paul M Barr, Lang Zhou, Brenda Chyla, Ahmed Hamed Salem, Maria Verdugo, Rod A Humerickhouse, Jalaja Potluri, Steven Coutre, Jennifer Woyach, John C Byrd
BACKGROUND: Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy...
December 12, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29222670/venetoclax-for-treating-chronic-lymphocytic-leukaemia-an-evidence-review-group-perspective-of-a-nice-single-technology-appraisal
#8
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
#9
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
https://www.readbyqxmd.com/read/29222275/the-mutational-landscape-of-chronic-lymphocytic-leukemia-and-its-impact-on-prognosis-and-treatment
#10
REVIEW
Gianluca Gaidano, Davide Rossi
The typical genome of chronic lymphocytic leukemia (CLL) carries ∼2000 molecular lesions. Few mutations recur across patients at a frequency >5%, whereas a large number of biologically and clinically uncharacterized genes are mutated at lower frequency. Approximately 80% of CLL patients carry at least 1 of 4 common chromosomal alterations, namely deletion 13q14, deletion 11q22-23, deletion 17p12, and trisomy 12. Knowledge of the CLL genome has translated into the availability of molecular biomarkers for prognosis and treatment prediction...
December 8, 2017: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/29125406/bruton-s-tyrosine-kinase-inhibitors-first-and-second-generation-agents-for-patients-with-chronic-lymphocytic-leukemia-cll
#11
Philip A Thompson, Jan A Burger
The BTK inhibitor ibrutinib is effective in both low- and high-risk CLL patients, achieving durable remissions with continuous therapy in the majority of patients. Ibrutinib lacks myelotoxicity and is generally well tolerated by older and unfit patients; however, side effects, such as atrial fibrillation or hemorrhage, can result in treatment interruption or discontinuation. Given the high efficacy and overall safety, ibrutinib is increasingly used in untreated and previously treated CLL patients. Second-generation BTK inhibitors are being developed, with different and generally more BTK-selective kinase inhibition profiles, which may increase the safety and/or efficacy...
November 10, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29099493/pharmacodynamics-and-proteomic-analysis-of-acalabrutinib-therapy-similarity-of-on-target-effects-to-ibrutinib-and-rationale-for-combination-therapy
#12
V K Patel, B Lamothe, M L Ayres, J Gay, J P Cheung, K Balakrishnan, C Ivan, J Morse, M Nelson, M J Keating, W G Wierda, J R Marszalek, V Gandhi
Acalabrutinib, a highly selective Bruton's tyrosine kinase inhibitor, is associated with high overall response rates and durable remission in previously treated chronic lymphocytic leukemia (CLL); however, complete remissions were limited. To elucidate on-target and pharmacodynamic effects of acalabrutinib, we evaluated several laboratory endpoints, including proteomic changes, chemokine modulation and impact on cell migration. Pharmacological profiling of samples from acalabrutinib-treated CLL patients was used to identify strategies for achieving deeper responses, and to identify additive/synergistic combination regimens...
November 3, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/29097160/clinical-practice-guidelines-for-diagnosis-and-treatment-of-chronic-lymphocytic-leukemia-cll-in-the-netherlands
#13
Sabina Kersting, Suzanne I M Neppelenbroek, Hein P J Visser, Michel van Gelder, Mark-David Levin, Rogier Mous, Ward Posthuma, Hanneke M van der Straaten, Arnon P Kater
INTRODUCTION: In recent years, considerable progress has been made in the treatment of patients with chronic lymphocytic leukemia (CLL), and new potent drugs have become available. Therefore, the CLL working party revised the Dutch guidelines. Not only efficacy but also quality of life and socio-economic impact were taken into account in the formulation of treatment recommendations. MATERIALS AND METHODS: The working party discussed a set of questions regarding diagnostic tests and treatment and wrote the draft guideline...
January 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29063177/approach-to-richter-transformation-of-chronic-lymphocytic-leukemia-in-the-era-of-novel-therapies
#14
REVIEW
Maliha Khan, Rabbia Siddiqi, Philip A Thompson
Chronic lymphocytic leukemia (CLL) has a highly variable clinical course. About 2-10% of CLL patients develop aggressive histological transformation, most commonly to diffuse large B cell lymphoma (DLBCL), historically called Richter transformation (RT). Clinical features suggestive of RT include elevated LDH and non-specific symptoms such as fever, weight loss, and lymphadenopathy. 18-fluorodeoxyglucose (18-FDG) uptake is increased on PET scan (standardized uptake value max most commonly ≥ 10). PET/CT study can identify optimal site for excisional biopsy, which is the gold standard for RT diagnosis, as well as aid in disease staging and prognostication...
January 2018: Annals of Hematology
https://www.readbyqxmd.com/read/29061914/therapeutics-targeting-bcl-2-in-hematological-malignancies
#15
REVIEW
Astrid Ruefli-Brasse, John C Reed
Members of the B-cell lymphoma 2 (BCL-2) gene family are attractive targets for cancer therapy as they play a key role in promoting cell survival, a long-since established hallmark of cancer. Clinical utility for selective inhibition of specific anti-apoptotic Bcl-2 family proteins has recently been realized with the Food and Drug Administration (FDA) approval of venetoclax (formerly ABT-199/GDC-0199) in relapsed chronic lymphocytic leukemia (CLL) with 17p deletion. Despite the impressive monotherapy activity in CLL, such responses have rarely been observed in other B-cell malignancies, and preclinical data suggest that combination therapies will be needed in other indications...
October 23, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/29058801/pharmacokinetics-of-the-bcl-2-inhibitor-venetoclax-in-healthy-chinese-subjects
#16
Tommy T Cheung, Ahmed Hamed Salem, Rajeev M Menon, Wijith P Munasinghe, Orlando F Bueno, Suresh K Agarwal
Venetoclax has been approved in the United States, Europe, Canada, and Australia for appropriate patients with difficult-to-treat chronic lymphocytic leukemia (CLL). The objective of this phase 1 study was to evaluate the pharmacokinetics of venetoclax in Chinese subjects to inform the dose selection of venetoclax in a phase 2 study of patients with relapsed/refractory (R/R) CLL in China. Twelve healthy first-generation Han Chinese subjects received a single 100-mg dose of venetoclax following a low-fat breakfast...
October 23, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/29034364/microenvironmental-agonists-generate-de-novo-phenotypic-resistance-to-combined-ibrutinib-plus-venetoclax-in-cll-and-mcl
#17
Kallesh D Jayappa, Craig A Portell, Vicki L Gordon, Brian J Capaldo, Stefan Bekiranov, Mark J Axelrod, L Kyle Brett, Julia D Wulfkuhle, Rosa I Gallagher, Emanuel F Petricoin, Timothy P Bender, Michael E Williams, Michael J Weber
De novo resistance and rapid recurrence often characterize responses of B-cell malignancies to ibrutinib (IBR), indicating a need to develop drug combinations that block compensatory survival signaling and give deeper, more durable responses. To identify such combinations, we previously performed a combinatorial drug screen and identified the Bcl-2 inhibitor venetoclax (VEN) as a promising partner for combination with IBR in Mantle Cell Lymphoma (MCL). We have opened a multi-institutional clinical trial to test this combination...
June 13, 2017: Blood Advances
https://www.readbyqxmd.com/read/29025288/-state-of-the-art-molecular-diagnostics-and-therapy-of-chronic-lymphocytic-leukaemia-in-the-era-of-new-targeted-therapies
#18
Tímea Gurbity Pálfi, Viktória Fésüs, Csaba Bödör, Zita Borbényi
Chronic lymphoid leukaemia (CLL) has a heterogeneous clinical course depending on many clinical and molecular prognostic markers, which play an important role in the selection of the best treatment option. So far, TP53 disruption is the key prognostic and predictive factor assisting treatment decisions, especially in the era of novel therapies. Asymptomatic patients in early stages of the disease will still benefit from watchful waiting. In the frontline setting, chemoimmunotherapy is still the standard care in the majority of standard risk CLL patients...
October 2017: Orvosi Hetilap
https://www.readbyqxmd.com/read/28984869/bcl2-and-mir-15-16-from-gene-discovery-to-treatment
#19
REVIEW
Yuri Pekarsky, Veronica Balatti, Carlo M Croce
In 1984, we investigated the t(14;18) chromosomal translocations that frequently occur in patients with follicular lymphoma. We first identified a locus on chromosome 18 involved in these translocations with the chromosome 14 containing the immunoglobulin heavy chain locus. Within this region on chromosome 18, we then discovered a gene that we called BCL2, which was activated by the translocations. Since that time, many studies determined that BCL2 is one of the most important oncogenes involved in cancer by inhibiting apoptosis...
October 6, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28978838/chronic-lymphocytic-leukemia-biology-disease-progression-and-current-treatment-strategies
#20
Takahiro Yano
Chronic lymphocytic leukemia (CLL) is characterized by clonal proliferation and accumulation of mature CD5-positive, CD10-negative, CD20 weakly positive, and CD23-positive B-cells within blood, bone marrow, lymph nodes, and spleen. In proliferation centers, the survival and growth of CLL cells requires a permissive microenvironment comprising T-cells, macrophages, and stromal cells. FISH analysis has revealed that almost 80% of CLL cases carry chromosomal abnormalities including the most frequent del (13q14) and the strongest poor prognostic factor del (17p), both related to TP53 mutations...
2017: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
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