21 research outputs found
Clinical Study Clinical Safety and Immunogenicity of Tumor-Targeted, Plant-Made Id-KLH Conjugate Vaccines for Follicular Lymphoma
We report the first evaluation of plant-made conjugate vaccines for targeted treatment of B-cell follicular lymphoma (FL) in a Phase I safety and immunogenicity clinical study. Each recombinant personalized immunogen consisted of a tumor-derived, plantproduced idiotypic antibody (Ab) hybrid comprising the hypervariable regions of the tumor-associated light and heavy Ab chains, genetically grafted onto a common human IgG1 scaffold. Each immunogen was produced in Nicotiana benthamiana plants using twin magnICON vectors expressing the light and heavy chains of the idiotypic Ab. Each purified Ab was chemically linked to the carrier protein keyhole limpet hemocyanin (KLH) to form a conjugate vaccine. The vaccines were administered to FL patients over a series of ≥6 subcutaneous injections in conjunction with the adjuvant Leukine (GM-CSF). The 27 patients enrolled in the study had previously received non-anti-CD20 cytoreductive therapy followed by ≥4 months of immune recovery prior to first vaccination. Of 11 patients who became evaluable at study conclusion, 82% (9/11) displayed a vaccine-induced, idiotype-specific cellular and/or humoral immune response. No patients showed serious adverse events (SAE) related to vaccination. The fully scalable plant-based manufacturing process yields safe and immunogenic personalized FL vaccines that can be produced within weeks of obtaining patient biopsies
New models and online calculator for predicting non-sentinel lymph node status in sentinel lymph node positive breast cancer patients
<p>Abstract</p> <p>Background</p> <p>Current practice is to perform a completion axillary lymph node dissection (ALND) for breast cancer patients with tumor-involved sentinel lymph nodes (SLNs), although fewer than half will have non-sentinel node (NSLN) metastasis. Our goal was to develop new models to quantify the risk of NSLN metastasis in SLN-positive patients and to compare predictive capabilities to another widely used model.</p> <p>Methods</p> <p>We constructed three models to predict NSLN status: recursive partitioning with receiver operating characteristic curves (RP-ROC), boosted Classification and Regression Trees (CART), and multivariate logistic regression (MLR) informed by CART. Data were compiled from a multicenter Northern California and Oregon database of 784 patients who prospectively underwent SLN biopsy and completion ALND. We compared the predictive abilities of our best model and the Memorial Sloan-Kettering Breast Cancer Nomogram (Nomogram) in our dataset and an independent dataset from Northwestern University.</p> <p>Results</p> <p>285 patients had positive SLNs, of which 213 had known angiolymphatic invasion status and 171 had complete pathologic data including hormone receptor status. 264 (93%) patients had limited SLN disease (micrometastasis, 70%, or isolated tumor cells, 23%). 101 (35%) of all SLN-positive patients had tumor-involved NSLNs. Three variables (tumor size, angiolymphatic invasion, and SLN metastasis size) predicted risk in all our models. RP-ROC and boosted CART stratified patients into four risk levels. MLR informed by CART was most accurate. Using two composite predictors calculated from three variables, MLR informed by CART was more accurate than the Nomogram computed using eight predictors. In our dataset, area under ROC curve (AUC) was 0.83/0.85 for MLR (n = 213/n = 171) and 0.77 for Nomogram (n = 171). When applied to an independent dataset (n = 77), AUC was 0.74 for our model and 0.62 for Nomogram. The composite predictors in our model were the product of angiolymphatic invasion and size of SLN metastasis, and the product of tumor size and square of SLN metastasis size.</p> <p>Conclusion</p> <p>We present a new model developed from a community-based SLN database that uses only three rather than eight variables to achieve higher accuracy than the Nomogram for predicting NSLN status in two different datasets. </p
Unravelling higher order chromatin organisation through statistical analysis
Recent technological advances underpinned by high throughput sequencing have
given new insights into the three-dimensional structure of mammalian genomes.
Chromatin conformation assays have been the critical development in this area,
particularly the Hi-C method which ascertains genome-wide patterns of intra and
inter-chromosomal contacts. However many open questions remain concerning the
functional relevance of such higher order structure, the extent to which it varies, and
how it relates to other features of the genomic and epigenomic landscape.
Current knowledge of nuclear architecture describes a hierarchical organisation
ranging from small loops between individual loci, to megabase-sized self-interacting
topological domains (TADs), encompassed within large multimegabase chromosome
compartments. In parallel with the discovery of these strata, the ENCODE project has
generated vast amounts of data through ChIP-seq, RNA-seq and other assays applied
to a wide variety of cell types, forming a comprehensive bioinformatics resource.
In this work we combine Hi-C datasets describing physical genomic contacts with
a large and diverse array of chromatin features derived at a much finer scale in the
same mammalian cell types. These features include levels of bound transcription
factors, histone modifications and expression data. These data are then integrated
in a statistically rigorous way, through a predictive modelling framework from the
machine learning field. These studies were extended, within a collaborative project, to
encompass a dataset of matched Hi-C and expression data collected over a murine
neural differentiation timecourse.
We compare higher order chromatin organisation across a variety of human cell
types and find pervasive conservation of chromatin organisation at multiple scales.
We also identify structurally variable regions between cell types, that are rich in active
enhancers and contain loci of known cell-type specific function. We show that broad
aspects of higher order chromatin organisation, such as nuclear compartment domains,
can be accurately predicted in a variety of human cell types, using models based upon
underlying chromatin features. We dissect these quantitative models and find them
to be generalisable to novel cell types, presumably reflecting fundamental biological
rules linking compartments with key activating and repressive signals. These models
describe the strong interconnectedness between locus-level patterns of local histone
modifications and bound factors, on the order of hundreds or thousands of basepairs,
with much broader compartmentalisation of large, multi-megabase chromosomal
regions.
Finally, boundary regions are investigated in terms of chromatin features and
co-localisation with other known nuclear structures, such as association with the
nuclear lamina. We find boundary complexity to vary between cell types and link
TAD aggregations to previously described lamina-associated domains, as well as
exploring the concept of meta-boundaries that span multiple levels of organisation.
Together these analyses lend quantitative evidence to a model of higher order genome
organisation that is largely stable between cell types, but can selectively vary locally,
based on the activation or repression of key loci
Robust estimation of bacterial cell count from optical density
Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data
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A First-in-Human Phase 1 Study of Oral LOXO-338, a Selective BCL2 Inhibitor, in Patients with Advanced Hematologic Malignancies (Trial in Progress)
Abstract
Background: B-cell lymphoma 2 (BCL2) is a key regulator of apoptosis and provides protection from cell death in many hematological malignancies. The BCL2 inhibitor venetoclax is approved for the treatment of CLL/SLL and acute myeloid leukemia and has activity in other lymphoid malignancies. LOXO-338 is a novel, orally bioavailable small molecule inhibitor of BCL2, designed to achieve selectivity over BCL-xL and thus avoid dose-limiting thrombocytopenia associated with BCL-xL inhibition. In preclinical studies, LOXO-338 showed a favorable pharmacological profile, selectively inhibited BCL2, and was well-tolerated in vivo. LOXO-338 also demonstrated dose-dependent tumor growth inhibition in various murine xenograft models, and showed improved efficacy in combination with pirtobrutinib, a highly selective, non-covalent BTK inhibitor (Brandhuber et al. Cancer Res 2021; 81, 13 Supplement, 1258).
Study Design and Methods: LOXO-BCL-20001 is an open-label, multi-center, first-in-human Phase 1 study of oral LOXO-338 in patients with advanced hematologic malignancies who have received standard therapy. The study will be conducted in 2 parts. Part 1 will evaluate LOXO-338 as monotherapy, and will explore different dosing strategies. Part 2 will evaluate LOXO-338 in combination with pirtobrutinib. The dose escalation portion of the study in Part 1 will follow an i3+3 design. Each cycle will be 28 days (4 weeks).
Eligible patients include those with CLL/SLL, mantle cell lymphoma (MCL), and Waldenstrӧm macroglobulinemia (WM) who have already received standard therapy. Patients with other B-cell non-Hodgkin lymphomas (NHLs) who failed standard therapy or, in the opinion of the investigator, have no known available options to provide benefit for the patient's condition, are also eligible. Patients must have recovered from prior treatment-related adverse events. Patients with active or suspected Richter transformation, transformed low grade lymphoma, Burkitt or Burkitt-like lymphoma, and multiple myeloma (MM) are eligible in dose-expansion. Key exclusion criteria include history of CNS involvement, stem cell transplant or CAR-T therapy <60 days, concurrent anticancer therapy, and clinically significant cardiovascular disease.
The primary objective of Part 1 is to determine the maximum tolerated dose (MTD)/ recommended Phase 2 dose (RP2D) of oral LOXO-338 in patients who were previously treated for CLL/SLL and other B-cell NHLs. Key secondary objectives include determining the safety and tolerability, and pharmacokinetic properties of LOXO-338. Antitumor activity will be evaluated based on overall response rate (ORR), progression-free survival (PFS), time to progression (TTP) and duration of response (DOR) based on disease-specific response criteria per investigator assessment. Key objectives of part 2 are to determine the safety profile and tolerability, PK properties, and anti-tumor activity of LOXO-338 in combination with pirtobrutinib.
Disclosures
Alencar: Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Epizyme: Consultancy; Celgene: Consultancy; BeiGene: Consultancy; Amgen: Consultancy. Roeker: AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Pharmacyclics: Consultancy; Pfizer: Consultancy, Research Funding; Loxo Oncology: Consultancy; TG Therapeutics: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company. Hoffmann: TG Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmcyclics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Consultancy, Honoraria. Guru Murthy: Cancerexpertnow: Honoraria; Guidepoint: Consultancy; Techspert: Consultancy; Qessential: Consultancy; Cardinal Health Inc.: Honoraria; TG therapeutics: Other: Advisory board. Patel: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Ku: Loxo Oncology at Lilly: Current Employment, Current holder of stock options in a privately-held company. Pauff: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Eyre: Incyte: Consultancy; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Research Funding; Roche: Consultancy, Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Janssen: Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding. Jurczak: Celtrion: Research Funding; Celgene: Research Funding; Debbiopharm: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Sandoz: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding.
OffLabel Disclosure:
LOXO-338 is a novel, orally bioavailable small molecule inhibitor of BCL2 for advanced hematologic malignancies
Clinical Safety and Immunogenicity of Tumor-Targeted, Plant-Made Id-KLH Conjugate Vaccines for Follicular Lymphoma
We report the first evaluation of plant-made conjugate vaccines for targeted treatment of B-cell follicular lymphoma (FL) in a Phase I safety and immunogenicity clinical study. Each recombinant personalized immunogen consisted of a tumor-derived, plant-produced idiotypic antibody (Ab) hybrid comprising the hypervariable regions of the tumor-associated light and heavy Ab chains, genetically grafted onto a common human IgG1 scaffold. Each immunogen was produced in Nicotiana benthamiana plants using twin magnICON vectors expressing the light and heavy chains of the idiotypic Ab. Each purified Ab was chemically linked to the carrier protein keyhole limpet hemocyanin (KLH) to form a conjugate vaccine. The vaccines were administered to FL patients over a series of ≥6 subcutaneous injections in conjunction with the adjuvant Leukine (GM-CSF). The 27 patients enrolled in the study had previously received non-anti-CD20 cytoreductive therapy followed by ≥4 months of immune recovery prior to first vaccination. Of 11 patients who became evaluable at study conclusion, 82% (9/11) displayed a vaccine-induced, idiotype-specific cellular and/or humoral immune response. No patients showed serious adverse events (SAE) related to vaccination. The fully scalable plant-based manufacturing process yields safe and immunogenic personalized FL vaccines that can be produced within weeks of obtaining patient biopsies
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LOXO-305, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated Mantle Cell Lymphoma, Waldenström's Macroglobulinemia, and Other Non-Hodgkin Lymphomas: Results from the Phase 1/2 BRUIN Study
Background: Covalent BTK inhibitors (BTKi) have transformed the management of MCL, WM, and MZL. Despite the marked efficacy of covalent BTKi, treatment failure can occur through the development of resistance and discontinuation for adverse events. Covalent BTKi also share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover, ultimately manifesting as acquired resistance in some patients (pts). To address these limitations, LOXO-305, a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency was developed. The aim of the BRUIN trial was to define the safety and early efficacy of LOXO-305 in pts with B-cell malignancies. Here we report these data in pts with previously treated MCL, WM, and other NHLs.
Methods: BRUIN is a multicenter phase 1/2 trial (NCT 03740529) enrolling pts with advanced B-cell malignancies who have received >2 prior therapies. Dose was escalated according to a standard 3+3 design with LOXO-305 dosed orally in 28-day cycles. The primary endpoint was MTD/RP2D identification. Intra-patient dose-escalation to previously cleared dose levels was permitted. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to Lugano Classification or iWWM. Safety was assessed in all pts (CLL/SLL and NHL, n=186).
Results: As of 30 April 2020, 186 pts with B-cell malignancies (94 CLL/SLL, 38 MCL, 19 DLBCL, 17 WM, 6 FL, 5 MZL, and 7 Other [B-PLL and Richter's transformation]) were treated on 7 dose levels (25mg to 300mg QD). Among the 92 pts with NHL, the median age was 68 (range 27-87) years. Median number of prior lines of therapy was 2 for MCL (range 2-8), and 3 for other NHLs (range 2-11). 92% of MCL pts had received a prior BTKi; 87% received at least an anti-CD20 antibody, chemotherapy, and BTKi; 10 pts had received SCT/CAR-T; 71% of WM pts had received a prior BTKi. LOXO-305 demonstrated high oral exposures, with doses ≥100mg QD exceeding the BTK IC90 for the entirety of the dosing interval. There were no DLTs or dose reductions. Consistent with LOXO-305's selectivity, the only treatment emergent adverse events regardless of attribution or grade seen in >10% of pts (n=186) were fatigue (n=29, 16%) and diarrhea (n=28, 15%). Responses were observed at the first dose level of 25mg QD. A RP2D of 200mg QD was selected for future studies. At the efficacy cutoff date, 24 MCL pts (63%) and 35 other NHL pts (65%) remained on therapy. Among the 35 efficacy-evaluable MCL pts treated across all dose levels, the ORR was 51% including 9 CRs, 9 PRs, 7 SDs, 8 PDs, and 2 NEs. An additional 3 MCL pts were awaiting initial radiologic assessment. Among the subset of 20 efficacy evaluable MCL pts who started at the RP2D (200mg QD), the ORR was 65% including 7 CRs, 6 PR, 4 SDs, 1 PD and 2 NEs. Of the 18 responding pts treated at any dose, all except 2 remain on therapy, with the longest followed responding pt on treatment for 14 months and ongoing. Of the 2 responding pts who have discontinued treatment, 1 progressed and 1 achieved a CR and electively discontinued treatment to undergo allogeneic stem cell transplant. Responses in MCL have been observed in pts who received prior cell therapy, including 3 of 7 patents with prior SCT, and 1 of 2 with prior CAR-T. Among the 15 efficacy-evaluable pts with WM, the ORR was 60% (1 VGPR, 4 PRs, 4 MRs, 5 SDs, 1 NE), and also 60% in the subset with prior BTKi treatment. 8 of 9 WM responders were ongoing (follow-up time from initial response: 0.1-4.8 months). For the remaining 29 efficacy-evaluable other NHL pts, best response was as follows: DLBCL (3 CRs, 1 SD, 6 PDs, 5 NEs), FL (3 PRs, 1 SD, 1 PD), MZL (2 PRs, 1 SD) and Other [5 Richter's transformation, 1 B-PLL] (2 PRs, 2 SDs, 2 NEs).
Conclusion: LOXO-305 demonstrated promising efficacy in heavily pretreated, poor-prognosis MCL pts following multiple prior lines of therapy, including covalent BTKi. Early efficacy was also observed in BTK-treated WM, as well as heavily pretreated other NHLs. LOXO-305 was well tolerated and exhibited a wide therapeutic index.
Disclosures
Wang: Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Loxo Oncology: Consultancy, Research Funding; Verastem: Research Funding; Molecular Templates: Research Funding; Dava Oncology: Honoraria; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; VelosBio: Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Targeted Oncology: Honoraria; Juno: Consultancy, Research Funding; BioInvent: Research Funding; Lu Daopei Medical Group: Honoraria; OncLive: Honoraria; Beijing Medical Award Foundation: Honoraria; MoreHealth: Consultancy; Guidepoint Global: Consultancy; Acerta Pharma: Research Funding; Pulse Biosciences: Consultancy. Shah:Cell Vault: Research Funding; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy; Lily: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Verastim: Consultancy; TG Therapeutics: Consultancy. Alencar:Genentech, Celgene, KITE, Loxo Oncology at Lilly: Consultancy. Gerson:Loxo: Research Funding; Pharmacyclics: Consultancy; Abbvie: Consultancy; Genentech: Consultancy. Fakhri:University of California San Francisco: Current Employment. Jurczak:MeiPharma: Research Funding; Roche: Research Funding; Takeda: Research Funding; Jagiellonian University, Krakow, Poland: Ended employment in the past 24 months; Pharmacyclics: Research Funding; Bayer: Research Funding; Janssen: Research Funding; Acerta: Research Funding; TG Therapeutics: Research Funding; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland: Current Employment. Tan:Sir Charles Gairdner Hospital and Linear Clinical Research: Current Employment. Lewis:Sir Charles Gairdner Hospital and Linear Clinical Research: Current Employment. Fenske:Medical College of Wisconsin: Current Employment. Coombs:Novartis: Honoraria; Octapharma: Honoraria; LOXO Oncology: Honoraria; MEI Pharma: Honoraria; AstraZeneca: Honoraria; Genentech: Honoraria; Abbvie: Consultancy, Honoraria. Flinn:Calithera Biosciences: Research Funding; Loxo: Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche: Research Funding; Gilead Sciences: Consultancy, Research Funding; Agios: Research Funding; Karyopharm Therapeutics: Research Funding; Incyte: Research Funding; BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Curio Science: Consultancy; MorphoSys: Consultancy, Research Funding; Curis: Research Funding; Nurix Therapeutics: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding; Teva: Research Funding; Constellation Pharmaceuticals: Research Funding; Great Point Partners: Consultancy; Forma Therapeutics: Research Funding; Iksuda Therapeutics: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Merck: Research Funding; Celgene: Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Forty Seven: Research Funding. Le Gouill:Loxo Oncology at Lilly: Consultancy; Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria. Palomba:Celgene: Honoraria; Pharmacyclics: Honoraria; Genentech: Research Funding; Novartis: Honoraria; Merck: Honoraria; Juno Therapeutics, a Bristol-Meyers Squibb Company: Honoraria, Research Funding; Regeneron: Research Funding. Woyach:Janssen, Pharmacyclics, AstraZeneca, Abbvie, Arqule: Consultancy; Pharmacyclics, Janssen, Morphosys, Karyopharm, Verastem, Abbvie, Lox: Research Funding; Pharmacyclics LLC, an AbbVie Company, AbbVie, Janssen, AstraZeneca, ArQule: Honoraria. Lamanna:Columbia University Medical Center: Current Employment; MingSight: Other: Institutional research grants, Research Funding; Octapharma: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity