Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study

Chanan‐Khan, Asher; Cramer, Paula; Demırkan, Fatih; Fraser, Graeme; Silva, Rodrigo Santucci; Grosicki, Sebastian; Pristupa, Aleksander; Janssens, Ann; Mayer, Jiřı́; Bartlett, Nancy L.; Dilhuydy, Marie Sarah; Pylypenko, Halyna; Loscertales, Javier; Avigdor, Abraham; Rule, Simon; Villa, Diego; Samoilova, Olga; Panagiotidis, P.; Goy, André; Mato, Anthony R.; Pavlovsky, Miguel Arturo; Karlsson, Claes; Mahler, Michelle; Salman, Mariya; Sun, Steven; Phelps, Charles E.; Balasubramanian, Sriram; Howes, Angela; Hallek, Michael

doi:10.1016/s1470-2045(15)00465-9

Cited by 378 publications

(346 citation statements)

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“…In randomized trials, ibrutinib is effective as first-line treatment of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) (compared with chlorambucil), 1 for relapsed/refractory CLL/SLL (compared with ofatumumab or combined with bendamustine/rituximab), 2,3 or for relapsed/refractory mantle cell lymphoma (compared with temsiroliums), 4 with promising results in the treatment of Waldenström macroglobulinemia. 5 It is anticipated that ibrutinib will become an important part of the therapeutic armamentarium for these conditions.…”

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confidence: 99%

“…No study reported methods for identifying AF cases. Because allocation was masked in only one of the randomized trials of ibrutinib, 3 bias in the detection of AF between the ibrutinib and comparator arms may have occurred. Furthermore, in populations at high risk for AF (but without known AF), the yield of AF increases with the intensity of For personal use only.…”

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The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis

Leong

Caron

Hillis

et al. 2016

Blood

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Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase in the B-cell receptor signaling pathway. In randomized trials, ibrutinib is effective as first-line treatment of chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) (compared with chlorambucil), 1 for relapsed/refractory CLL/SLL (compared with ofatumumab or combined with bendamustine/rituximab), 2,3 or for relapsed/refractory mantle cell lymphoma (compared with temsiroliums), 4 with promising results in the treatment of Waldenström macroglobulinemia. 5 It is anticipated that ibrutinib will become an important part of the therapeutic armamentarium for these conditions. Randomized trials suggest that ibrutinib may increase the risk of atrial fibrillation (AF) as compared with chlorambucil 1 or ofatumumab. 2 In the general population, AF is strongly associated with heart failure and arterial thromboembolism, which result in substantial morbidity and mortality. There is uncertainty over the magnitude of the increase in AF risk attributable to ibrutinib because the absolute numbers of incident AF cases are small in individual studies.We undertook a systematic review and meta-analysis to (1) estimate the magnitude of the increase in AF risk among ibrutinib recipients, as compared with alternative therapies and (2) quantify the frequency of AF reported among ibrutinib recipients. We searched MEDLINE and EMBASE, and proceedings from the American Society of Hematology, the European Haematology Association, and the American Society of Clinical Oncology for articles describing AF rates in recipients of ibrutinib. The following search terms were used: ibrutinib; imbruvica; or PCI-32765. Animal studies, case reports, case series (ie, that reported on consecutive AF cases), cross-sectional studies, editorials, phase I/dose-finding studies, and conference abstracts more than 12 months old were excluded.Two independent reviewers screened the articles' titles and abstracts for eligibility. Cases of disagreement were resolved by a third reviewer. Papers identified after title and abstract screening were obtained in full. When data from the same cohort of participants were presented in different papers, only the manuscript with the larger sample size was included in the meta-analysis. The following data were extracted from eligible full text manuscripts: design, disease, sample size, treatments, participant age and sex, follow-up duration, AF rates, and where reported, AF ascertainment strategies, past history of cardiovascular disease, AF, or hypertension.Statistical analysis was performed using STATA 14 (StataCorp, College Station, TX). To evaluate the increase in the risk of incident AF, the primary meta-analytic approach was a fixed effects model using the Mantel-Haenszel method. A sensitivity analysis was performed using a DerSimonian and Laird random effects model. Heterogeneity of studies was evaluated by Cochran's Q and the I 2 statistic. Pooled AF rates were estimated as follows: we multiplied the median follow-up duration by the sample siz...

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confidence: 99%

The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis

Leong

Caron

Hillis

et al. 2016

Blood

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200

117

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“…As the current focus of the PHEDRA project is to compare ibrutinib-treated patients from RCTs to RW treatments, only the treatment line involving ibrutinib from RCTs [8,10,16] is included in the analyses performed.…”

Section: Methodological Considerations/challengesmentioning

confidence: 99%

“…Despite the availability of a range of RCTs investigating the treatment of these diseases, there is still a lack of comparative evidence on treatment selection, duration of treatment and disease outcomes across different lines of therapy. Since ibrutinib is relatively new to the market (first US FDA approval in 2013 and European Medicines Agency [EMA] approval in 2014), head-to-head comparisons of ibrutinib versus other widely used treatments in CLL, MCL and WM are limited (outside the RCTs used for approval) [8][9][10], and although there are growing RWD for ibrutinib, comparative effectiveness studies using RWD only are yet to reach optimal data volume and quality.…”

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PHEDRA: using real-world data to analyze treatment patterns and ibrutinib effectiveness in hematological malignancies

et al. 2018

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Aim: PHEDRA (Platform for Haematology in EMEA: Data for Real World Analysis) is a unique, noninterventional project based on secondary data collection from real-world (RW) patient-level (health record) databases to understand treatment patterns in hematological malignancies. It compares ibrutinib's effectiveness with alternative treatments using RW data (RWD) and randomized clinical trials data. Randomized clinical trials (RCTs) enable medicines to be rigorously evaluated in a controlled environment, through the application of inclusion/exclusion criteria for patient entry into the trial and randomization of treatments administered [1]. However, they do not establish the comparative effectiveness of drugs in real-world (RW) populations, which are often more heterogeneous than trial populations and where treatment is often subject to less close monitoring and frequency of data collection [1][2][3]. There remains insufficient knowledge and limited published literature on routine clinical practice, treatment pathways and outcomes in the management of patients with hematological malignancies. This is needed to guide optimal therapeutic decisions in patients with cancer at different stages of disease, particularly as the number of available treatments and possible drug combinations multiply [4].There is increasing recognition of the value of using real-world data (RWD) alongside RCT data (i.e., historical controls) to generate comparative effectiveness research on new therapies [2,5]. Indeed, with advances in cancer therapy and a multiplicity of comparators/standards of care depending on local routine practice (making it impractical or impossible to obtain data on all potentially relevant comparisons in an RCT setting), the need for RWD to educate regulators, payers, healthcare providers, healthcare decision makers and patients about treatment patterns and outcomes has never been greater [2]. RWD can further demonstrate the comparative effectiveness of a treatment once available on the market as well as inform clinical drug development, for example, by providing information on existing therapies and the profile of patients with poor outcomes who may have specific unmet needs. Although RWD cannot replace RCT data with regard to efficacy and safety, it can challenge and improve understanding of the 'standard of care' [1]. RWD can provide useful outcomes information across multiple relevant

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“…At a median follow up of 17 months, the m-PFS was not reached in patients receiving ibrutinib with CIT whereas the m-PFS was 13.2 months in patients treated with BR. 35 The major critique concerning this trial was the question if chemotherapy added any benefit to ibrutinib, as the combination therapy yielded similar results that were comparable to single agent ibrutinib in prior studies. In an ongoing frontline CLL phase III trial in elderly patients (>65 years), otherwise ineligible for chemotherapy are being randomized to receive either obinutuzumab and ibrutinib or obinutuzumab and chlorambucil (ILLUMINATE study; NCT02264574).…”

Section: Bruton Tyrosine Kinase Inhibitorsmentioning

confidence: 98%

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

Sethi¹,

Reddy²

2017

Oncology &Amp; Hematology Review (US)

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U ntil recently, chemoimmunotherapy has been the mainstay of treatment approach in chronic lymphocytic leukemia (CLL) patients requiring intervention. With the emergence of targeted treatments, there has been a shift in CLL therapy. With a better understanding of disease biology and risk stratification, a tailored approach based on patient age and comorbidities has evolved over time. The development of new and potent, next generation CD20 antibodies has refined therapy options especially for elderly unfit patients. Furthermore, agents targeting important pathways involved in proliferation and survival of CLL cells including B-cell receptor (BCR) signaling have provided additional treatment options in traditionally chemo-refractory CLL. Given the rapidly expanding repertoire of drugs, current research is focused on optimizing treatment sequence, duration of treatment and assessing long-term toxicities. Several immune mediated therapies are emerging and new combinations are being tested to re-establish antitumor immune effector response in CLL. While embracing the advances in CLL therapy, a few longstanding lessons remain. There is still little role of treatment of asymptomatic individuals. This review presents an overview of current and emerging drug therapies in the rapidly changing area of CLL treatment. Keywords CLL, novel agents, targeted therapyDisclosure: Tarsheen K Sethi and Nishitha M Reddy have nothing to disclose in relation to this article. No funding was received for the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors.Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. In those that meet criteria for treatment, important considerations include: patient age, performance status, comorbidities, and presence of chromosomal aberrations. Recent advancements in the understanding of disease biology have highlighted the importance of several potentially targetable pathways contributing to disease pathogenesis such as aberrant activation of BCR signaling pathway, anti-apoptotic BCL2 pathway, and the role of the microenvironment. These novel agents have expanded the repertoire for patients ineligible for chemoimmunotherapy (CIT) due to age or comorbidities and those with poorly responsive disease (high risk genomics such as del [17p]).This review aims to outline the role of standard CIT, targeted agents and ongoing studies of novel agents defining the present landscape of CLL drug treatment. Currently approved therapies and general tr...

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Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study

Cited by 378 publications

References 21 publications

The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis

The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis

PHEDRA: using real-world data to analyze treatment patterns and ibrutinib effectiveness in hematological malignancies

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

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