Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory ...agent lenalidomide could increase the activity of rituximab.
A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.
A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63%
49%), neutropenia (58%
23%), and cutaneous reactions (32%
12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50%
13%) and leukopenia (7%
2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62;
< .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.
Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.
Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL).
Patients with DLBCL who ...received ≥2 prior therapies were stratified by DLBCL subtype germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC) and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis GCB vs. activated B-cell (ABC) using gene expression profiling (GEP) were exploratory endpoints.
Stage 1: 102 DLBCL patients (by IHC: non-GCB,
= 54; GCB,
= 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks;
= 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively;
= 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively;
= 0.550).
The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping.
.
Patients with indolent non-Hodgkin lymphoma (iNHL) typically respond to first-line immunochemotherapy, but relapse is common. Treatment options for relapsed iNHL include chemotherapy ± rituximab and ...rituximab monotherapy. Lenalidomide plus rituximab (
R
2
) is an immunomodulatory regimen that enhances rituximab-mediated cytotoxicity and improves clinical activity in iNHL. AUGMENT was a double-blind phase III randomized trial of
R
2
vs. rituximab + placebo (R-placebo) in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma who were not refractory to rituximab. The primary endpoint was progression-free survival (PFS). Data reported here focus on Japanese patients from AUGMENT and reflect 36 patients (
n
= 18, each group). PFS was superior in the
R
2
group, HR = 0.32 (95% CI 0.11–0.96). Median PFS was not reached (95% CI 19.7–NE) in the
R
2
group vs. 16.5 months (95% CI 11.3–30.6) in the R-placebo group. Grade 3/4 adverse events were more frequent in patients treated with
R
2
(67%) than with R-placebo (22%), primarily attributable to increased neutropenia (50% vs 17%).
R
2
resulted in significantly longer median PFS than R-placebo in Japanese patients with R/R iNHL, and the efficacy and the safety profile of
R
2
were similar to those reported in the global population.
11β-Hydroxysteroid dehydrogenases (11beta-HSD) modulate mineralocorticoid receptor transactivation by glucocorticoids and regulate access to the glucocorticoid receptor. The isozyme 11beta-HSD2 is ...selectively expressed in mineralocorticoid target tissues and its activity is reduced in various disease states with abnormal sodium retention and hypertension, including the apparent mineralocorticoid excess. As 50% of patients with essential hypertension are insulin resistant and hyperinsulinemic, we hypothesized that insulin downregulates the 11beta-HSD2 activity. In the present study we show that insulin reduced the 11beta-HSD2 activity in cancer colon cell lines (HCT116, SW620 and HT-29) at the transcriptional level, in a time and dose dependent manner. The downregulation was reversible and required new protein synthesis. Pathway analysis using mRNA profiling revealed that insulin treatment modified the expression of the transcription factor family C/EBPs (CCAAT/enhancer-binding proteins) but also of glycolysis related enzymes. Western blot and real time PCR confirmed an upregulation of C/EBP beta isoforms (LAP and LIP) with a more pronounced increase in the inhibitory isoform LIP. EMSA and reporter gene assays demonstrated the role of C/EBP beta isoforms in HSD11B2 gene expression regulation. In addition, secretion of lactate, a byproduct of glycolysis, was shown to mediate insulin-dependent HSD11B2 downregulation. In summary, we demonstrate that insulin downregulates HSD11B2 through increased LIP expression and augmented lactate secretion. Such mechanisms are of interest and potential significance for sodium reabsorption in the colon.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The present study investigated whether activation of the hexosamine biosynthesis pathway might mediate at least in part the high glucose effect on angiotensinogen (ANG) gene expression and ...immortalized renal proximal tubular cell (IRPTC) hypertrophy. IRPTC were cultured in monolayer. ANG, renin, and β-actin mRNA expression were determined by specific RT-PCR assays. Phosphorylation of p38 MAPK, activating transcription factor-2 (ATF-2), and cAMP-responsive element-binding protein (CREB) was determined by Western blot analysis. Cell hypertrophy was assessed by flow cytometry, intracellular p27kip1 protein levels, and 3Hleucine incorporation into proteins. Glucosamine stimulated ANG and renin mRNA expression and enhanced p38 MAPK, ATF-2, and CREB phosphorylation in normal glucose (5 mm) medium. Azaserine and 6-diazo-5-oxo-l-norleucine (inhibitors of glutamine: fructose-6-phosphate amino transferase enzyme) blocked the stimulatory effect of high glucose, but not that of glucosamine, on ANG gene expression in IRPTCs. SB 203580 (a specific p38 MAPK inhibitor) attenuated glucosamine action on ANG gene expression as well as p38 MAPK and ATF-2 phosphorylation, but not that of CREB. GF 109203X and calphostin C (inhibitors of protein kinase C) blocked the effect of glucosamine on ANG gene expression and CREB phosphorylation, but had no impact on p38 MAPK and ATF-2 phosphorylation. Finally, both glucosamine and high glucose induced IRPTC hypertrophy. The hypertrophic effect of glucosamine was blocked in the presence of GF 109203X, but not azaserine and SB 203580. In contrast, the hypertrophic effect of high glucose was blocked in the presence of azaserine and GF 109203X, but not SB203580. Our studies demonstrate that the stimulatory effect of high glucose on ANG gene expression and IRPTC hypertrophy may be mediated at least in part via activation of hexosamine biosynthesis pathway signaling.
We reported previously that insulin inhibits the stimulatory effect of high glucose on the expression of angiotensinogen (ANG) gene in both rat immortalized renal proximal tubular cells (IRPTCs) and ...non-diabetic rat renal proximal tubular cells (RPTCs), but has no effect in diabetic rat RPTCs. In the present study we investigated whether hyperglycaemia-induced resistance to the insulin-induced inhibition of expression of the ANG gene is mediated via the generation of reactive oxygen species (ROS) in RPTCs. Rat IRPTCs were cultured for 2 weeks in high-glucose (25 mM) or normal-glucose (5 mM) medium plus angiotensin II (Ang II) with or without a superoxide scavenger (tiron), or inhibitors of: NADPH oxidase (diphenylene iodinium, DPI), Ang II type 1 and 2 receptors (losartan and PD123319), angiotensin-converting enzyme (perindopril), protein kinase C (GF 109203X), or glutamine:fructose-6-phosphate amino-transferase (azaserine). Cellular generation of ROS, and ANG and renin mRNA levels were assessed by lucigenin assay and specific reverse transcriptase-PCR respectively. Phosphorylation of p44/42 mitogen-activated protein kinase (p44/42 MAPK) was evaluated by western blotting. Prolonged exposure of IRPTCs to high concentrations of glucose or Ang II evoked generation of ROS and resistance to the insulin-induced inhibition of expression of the ANG gene and of p44/42 MAPK phosphorylation. Co-incubation of IRPTCs with tiron, DPI, losartan, PD123319, perindopril, GF 109203X or azaserine prevented ROS generation, restoring the inhibitory action of insulin on ANG gene expression and on p44/42 MAPK phosphorylation. In conclusion, our studies demonstrate that blockade of both ROS generation and activation of the intrarenal renin–angiotensin system improves the inhibitory action of insulin on ANG gene expression in IRPTCs in conditions of high glucose.
Aims
This study aimed to assess safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) effects of ensovibep, a designed ankyrin repeat protein antiviral being evaluated as a COVID‐19 ...treatment, in healthy volunteers in a first‐in‐human ascending single‐dose study.
Methods
Subjects were dosed intravenously, in a randomized double‐blinded manner, with either ensovibep at 3, 9 or 20 mg/kg or with placebo, and followed until Day 100. PK and safety were assessed throughout the study duration. Immunogenicity and PD via viral neutralization in serum were also assessed.
Results
All adverse events were of mild to moderate severity, and no serious adverse events were observed. One subject who received the 20‐mg/kg dose presented with moderate hypersensitivity vasculitis 3 weeks after infusion, which fully resolved using standard procedures. In most subjects ensovibep showed expected mono‐exponential decline with a half‐life of around 2 weeks. Anti‐drug antibodies were detected in 15 of 17 subjects, with the earliest onset detected on Day 29. Viral neutralization assays on subject serum showed effective viral neutralization over the first 3 weeks following dosing with titre values in a dose dependent manner.
Conclusion
Ensovibep proved safe in this first‐in‐human safety study and exhibited PK and PD parameters consistent with the expected treatment period required for acute COVID‐19 infection.
Background: Programmed cell death protein 1 (PD-1) blockade is commonly used to treat relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) but the overall response rates (ORR) and complete ...response rates (CRR) of approved anti-PD1 antibodies remain suboptimal. Tislelizumab blocks PD-1 with a high specificity and affinity and minimized FcγR binding on macrophages leads to reduced clearance. Results of the initial phase 2 study of tislelizumab in Chinese patients with RR cHL were impressive, with ORR and CRR of 87% and 63%, respectively, and 3-year progression free survival (PFS) of 40%, warranting further evaluation in a Western population with different standard of care, including more frequent use of autologous stem cell transplantation (ASCT) and targeted agents. Methods: TIRHOL (NCT04318080) is an international, prospective phase 2 study for patients with RR cHL conducted in France, Belgium, USA and Australia. Cohort 1 includes patients who previously underwent ASCT; cohort 2 includes patients who were ineligible for ASCT. Prior therapy with brentuximab vedotin (BV) was required in initial design; the protocol was amended to remove this criterion for both cohorts in October 2021. Tislelizumab 200 mg is given intravenously every 3 weeks until progressive disease (PD), unacceptable toxicity, or study withdrawal; tumor assessments are performed every 12 weeks. The primary endpoint is the ORR (best overall response of CR or partial response PR), as assessed by investigator, according to PET-CT International Lugano 2014 criteria. Null hypothesis is ORR = 45 % based on previous clinical trials and alternative hypothesis is ORR > 45%. Assuming the observed ORR = 65%, a sample size of 42 patients provides ≥ 80% power of at the one-sided 5% significance level. Secondary endpoints are CRR, time to response (TTR), duration of response (DOR), safety and tolerability of tislelizumab. Main exploratory endpoints are PFS and overall survival (OS). Results: Patients who received at least 1 dose of tislelizumab were included in the analysis. Between August 2020 and September 2022, 45 patients (14 in cohort 1 and 31 in cohort 2) were enrolled and dosed. At inclusion, the median age was 64 years (range 18-87), 67% were male and all had ECOG performance status 0-1; most patients had advanced stage disease (38% III, 42% IV), 11% had bulky disease, 18% had B symptoms and 29% had disease refractory to last therapy. The median prior lines of therapy received was 2 (1 - 4); 12 patients (27%) received ≥3 prior lines of therapy and 33 (73%) received prior BV. At last follow-up, the median number of tislelizumab doses (cycles) was 8 (1 - 33), corresponding to a median duration of treatment 24 weeks (range 3-105). The ORR was 64.4% (90% CI, 51% - 76%) with 14 (31%) patients achieving CR and 15 (33%) patients achieving PR (Figure 1). Remaining patients had stable disease (n=2, 4%), PD (n=13, 29%), or were not evaluated (n=1, 2%). The ORR was similar in cohort 1 (n=9/14, 64.3%) and cohort 2 (20/31, 64.5%). The median TTR was 2.69 months (range 0.3-5.6). The median DOR was 12.3 months (95% CI, 3 - NR) and was not reached for patients achieving CR. Three patients with objective response underwent subsequent ASCT (1) or allogeneic SCT (2). With a median follow-up of 11.4 months (95% CI, 6.7-13.5), the median PFS was 5.6 (95% CI, 5 - 14), 8, and 5 months for both cohorts combined, cohort 1, and 2, respectively. Thirteen patients with SUV increase meeting PD criteria but continued clinical benefit continued tislelizumab for a median of 3.6 months (range Q1:1.8 - Q3: 9.5) after PD. At last follow-up, 19 patients remain on tislelizumab and 11 (24%) have continued treatment for >1 year. The median OS was not reached with a 1-year OS rate of 93.5% (4 deaths; 95%CI, 75.0-98.5) and no treatment-related deaths. Grade ≥ 3 treatment emergent adverse events (TEAE) occurred in 15 (33%) patients, leading to discontinuation or interruption of tislelizumab in 9 and 2 patients, respectively. Immune-related (ir) AEs were observed in 15 (33%) patients and 3 patients had grade ≥ 3 irAEs (maculo-papular rash, hepatitis, hemolytic anemia). Conclusions: TIRHOL met its primary endpoint with an ORR of 64% and a CRR of 31% with an acceptable safety profile. This study confirmed that tislelizumab is a promising treatment option in cHL. Study follow-up is ongoing, but durable responses have been observed, especially in patients achieving CR.
Abstract only
TPS7573
Background: The PD-1/PD-L1 pathway is an important immune checkpoint used by tumor cells and may provide an effective target for enhancing anticancer immune response. In DLBCL, ...high PD-L1 expression has been identified as a negative prognostic factor for overall survival. Durvalumab (MEDI4736) is a high-affinity human IgG1 monoclonal Ab that selectively blocks PD-L1 binding to PD-1 and CD80, and preliminary preclinical and clinical activity support the study of durvalumab in high-risk DLBCL subtypes. The primary study objective is to explore the clinical activity of durvalumab with R-CHOP in non-activated B-cell–like (non-ABC) and durvalumab with lenalidomide + R-CHOP (R
2
-CHOP) in ABC previously untreated DLBCL; secondary objectives are to evaluate safety and identify biomarkers predictive of clinical response. Methods: This is a phase II, two-arm, open-label, global, multicenter study of durvalumab combinations in patients with previously untreated, high-risk DLBCL (MEDI4736-DLBCL-001; EUDRA CT 2015-005173-20; NCT03003520). High risk was defined as Ann Arbor stage III/IV or II with bulky disease (≥7.0 cm), along with intermediate-high/high IPI ≥3 or NCCN-IPI ≥4; patients must also have CD20+ DLBCL, ECOG PS 0-2, and no prior antilymphoma therapy. All patients receive durvalumab + R-CHOP21 in induction cycle 1 simultaneous to cell-of-origin (COO) analysis by gene expression profiling with NanoString technology. Beginning with cycle 2, Arm A (non-ABC) receives durvalumab 1125 mg IV on day 1 with 6 or 8 cycles of R-CHOP21; Arm B (ABC) receives the same durvalumab + R-CHOP21 doses with oral lenalidomide 15 mg/day on days 1-14. Both arms receive durvalumab consolidation 1500 mg IV on day 1 q28d for ≤12 months from induction cycle 1, day 1. The primary endpoint is 2-y progression-free survival (PFS); secondary endpoints include clinical response to treatment in biomarker-defined subpopulations (tumor and peripheral blood) and safety as assessed per NCI CTCAE v4.03 criteria. Exploratory endpoints include PFS at 12 mo, complete response, and PK/PD. Recruitment is ongoing, with a target enrollment of 120 patients. Clinical trial information: NCT03003520.
Background: The combination of lenalidomide+rituximab (R2) recently showed superior efficacy vs R-placebo in patients (pts) with R/R iNHL (Leonard et al. J Clin Oncol 2019). Based on these AUGMENT ...study results, R2 was approved by the US FDA for treatment of adult pts with previously treated follicular lymphoma (FL) or marginal zone lymphoma (MZL). Advanced age at diagnosis is a risk factor in pts with iNHL. We performed post-hoc subgroup analyses by age from AUGMENT and data here focus on pts age ≥ 70 y.
Methods: AUGMENT (NCT01938001) is a multicenter, double-blind, randomized phase III study of R2 vs R-placebo in pts with FL grade 1-3a or MZL previously treated with ≥ 1 systemic therapy with R/R disease but not refractory to rituximab. Pts were randomized 1:1 to R2 or R-placebo. R2 was oral lenalidomide 20 mg/d, d1-21/28 for 12c plus rituximab IV 375 mg/m2 weekly in c1 and d1 of c2-5. R-placebo was rituximab+placebo on the same schedule. The primary endpoint was progression-free survival (PFS) per 2007 IWG response criteria (without PET) as assessed by IRC (central review). Secondary endpoints included overall response rate (ORR), complete response (CR), time to next anti-lymphoma treatment (TTNLT) and safety. Post-hoc analyses were performed by dividing pts into age < 70 y and ≥ 70 y subgroups, the latter group considered unfit for chemotherapy.
Results: Of 358 pts randomized (R2, n = 178; R-placebo, n = 180), 267 pts were age < 70 y (R2, n = 131; R-placebo, n = 136), and 91 pts were age ≥ 70 y (R2, n = 47; R-placebo, n = 44). Baseline characteristics including histology, disease status, and prior treatments are shown in the table and were similar across treatment arms in pts ≥ 70 y. At a median follow-up of 28.3 mo, the study met its primary endpoint of PFS, with a hazard ratio (HR) of 0.46 (95% CI, 0.34-0.62; P < 0.0001) in the overall population. R2 had superior PFS vs R-placebo in both < 70 and ≥ 70 y subgroups, with HR of 0.41 (95% CI, 0.29-0.59) and HR of 0.66 (95% CI, 0.37-1.18), respectively. In pts ≥ 70 y, median PFS with R2 vs R-placebo was 24.9 vs 14.3 mo; ORR/CR was 81%/26% vs 59%/16%; and TTNLT was not reached in either arm. Efficacy results for all pts and those < 70 y are reported in the table; notably in pts receiving R2, mPFS was longer in pts < 70 y vs ≥ 70 y (39.4 mo 95% CI, 22.9-NE vs 24.9 mo 95% CI, 16.4-NE). In pts ≥ 70 y, any-grade adverse events (AEs) with a ≥ 10 % difference between R2 vs R-placebo included neutropenia (63% vs 11%), constipation (33% vs 16%), cough (33% vs 16%), leukopenia (26% vs 2%), anemia (24% vs 9%), pyrexia (24% vs 9%), pruritus/pruritus generalized (24% vs 2%), muscle spasms (22% vs 11%), rash/rash maculopapular (22% vs 5%), headache (20% vs 9%), thrombocytopenia (17% vs 2%), dyspepsia (13% vs 2%), influenza (13% vs 2%), back pain (7% vs 18%), and nasopharyngitis (4% vs 16%). Also, tumor flare was reported in 9% vs 0% of pts, respectively. In pts ≥ 70 y, 75% of R2 pts vs 36% of R-placebo pts had ≥ 1 grade 3/4 AE, mainly due to neutropenia (50% vs 7%). All other grade 3/4 AEs occurred in < 10% of pts ≥ 70 y in both treatment arms. One grade 5 AE occurred in pts ≥ 70 y (R-placebo arm). In the R2 arm, the median number of treatment cycles was 12 for both the < 70 y vs ≥ 70 y subgroups; however, fewer older pts completed 12 cycles of lenalidomide (76% vs 57%), and more started lenalidomide at the lower dose of 10 mg (6% vs 35%) because of low creatinine clearance, respectively. In the R2 < 70 y and ≥ 70 y subgroups, the average daily dose of lenalidomide was 17.9 mg/d (range, 5.6-20.0) and 14.4 mg/d (range 4.2-20.0), and median relative dose intensity was 95% and 86%, respectively.
Conclusions: Similar to the results in the original population, R2 showed superior efficacy vs rituximab monotherapy (plus placebo) as measured by the primary end point of PFS and secondary end points of ORR and CR in pts with R/R FL grade 1-3a and MZL irrespective of age. The efficacy and safety profiles of R2 and R-placebo in pts ≥ 70 y were similar to those reported in the overall population. Older pts treated with R2 vs R-placebo had superior mPFS (24.9 vs 14.3 mo). They were more likely to start lenalidomide at a lower dose and had lower median dose intensity which may have contributed to their shorter mPFS vs younger pts receiving R2. These data show that R2 maintained efficacy improvements vs R-placebo in pts ≥ 70 y, despite higher unfit status and lower overall lenalidomide treatment/exposure. Thus, R2 is an effective and available treatment option for pts with iNHL, including those with advanced age.
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Trněný:Amgen: Consultancy, Honoraria; F. Hoffmann-La Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy; MorphoSys: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria. Leonard:Nordic Nanovector: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Bayer Corporation: Consultancy; Epizyme, Inc: Consultancy; Karyopharm Therapeutics: Consultancy; Sutro Biopharma: Consultancy; Merck: Consultancy; Gilead: Consultancy; BeiGene: Consultancy; ADC Therapeutics: Consultancy; Sandoz: Consultancy; Akcea Therapeutics: Consultancy; Miltenyi: Consultancy; MorphoSys: Consultancy. Nowakowski:F. Hoffmann-La Roche Ltd: Research Funding; NanoString: Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech, Inc.: Research Funding; MorphoSys: Consultancy, Research Funding. Izutsu:Chugai, Celgene, Daiichi Sankyo, Astra Zeneca, Eisai, Symbio, Ono, Bayer, Solasia, Zenyaku, Incyte, Novartis, Sanofi, HUYA Bioscience, MSD, Astellas Amgen, Abbvie, ARIAD, Takeda, Pfizer: Research Funding; Kyowa Kirin, Eisai, Takeda, MSD, Chugai, Nihon Medi-physics, Janssen, Ono, Abbvie, Dainihon Sumitomo, Bayer, Astra Zeneca, HUYA Japan, Novartis, Bristol-Byers Squibb, Mundi, Otsuka, Daiichi Sankyo, Astellas, Asahi Kasei: Honoraria; Celgene: Consultancy; Eisai, Symbio, Chugai, Zenyaku: Research Funding; Eisai, Chugai, Zenyaku: Honoraria. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Zinzani:Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau. Kalambakas:Celgene Corporation: Employment, Equity Ownership. Czuczman:Celgene Corporation: Employment, Equity Ownership. Fustier:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Gribben:Janssen: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding.
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