Citations

In 2007, the Bárány Society embarked on a project to establish definitions of vestibular syndromes and disorders based on best available evidence, referred to as the International Classification of Vestibular Disorders (ICVD). Since then, numerous publications providing consensus-driven diagnostic criteria for vestibular symptoms, syndromes, and disorders have been published. Here, we reflect on the rationale for developing the ICVD as well as its subsequent achievements, challenges, and outlook. In this summary of the work of the ICVD to date, the authors will focus on practical aspects to help improve the utility and applicability of these diagnostic criteria moving forward.

Abstract High-count monoclonal B-cell lymphocytosis (HCMBL) is a precursor condition to chronic lymphocytic leukemia (CLL). We have shown that among individuals with HCMBL, the CLL-International Prognostic Index (CLL-IPI) is prognostic for time-to-first therapy (TTFT). Little is known about the prognostic impact of somatically mutated genes among individuals with HCMBL. We sequenced DNA from 371 individuals with HCMBL using a targeted sequencing panel of 59 recurrently mutated genes in CLL to identify high-impact mutations. We compared the sequencing results with that of our treatment-naïve CLL cohort (N = 855) and used Cox regression to estimate hazard ratios and 95% confidence intervals (CIs) for associations with TTFT. The frequencies of any mutated genes were lower in HCMBL (52%) than CLL (70%). At 10 years, 37% of individuals with HCMBL with any mutated gene had progressed requiring treatment compared with 10% among individuals with HCMBL with no mutations; this led to 5.4-fold shorter TTFT (95% CI, 2.6-11.0) among HCMBL with any mutated gene vs none, independent of CLL-IPI. When considering individuals with low risk of progression according to CLL-IPI, those with HCMBL with any mutations had 4.3-fold shorter TTFT (95% CI, 1.6-11.8) vs those with none. Finally, when considering both CLL-IPI and any mutated gene status, we observed individuals with HCMBL who were high risk for both prognostic factors had worse prognosis than patients with low-risk CLL (ie, 5-year progression rate of 32% vs 21%, respectively). Among HCMBL, the frequency of somatically mutated genes at diagnosis is lower than that of CLL. Accounting for both the number of mutated genes and CLL-IPI can identify individuals with HCMBL with more aggressive clinical course.

Given its polygenic nature, there is a need for a personalized approach to schizophrenia. The aim of the study was to select laboratory biomarkers from blood, brain imaging, and clinical assessment, with an emphasis on patients’ self-report questionnaires. Metabolomics studies of serum samples from 51 patients and 45 healthy volunteers, based on the liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS), led to the identification of 3 biochemical indicators (cortisol, glutamate, lactate) of schizophrenia. These metabolites were sequentially correlated with laboratory tests results, imaging results, and clinical assessment outcomes, including patient self-report outcomes. The hierarchical cluster analysis on the principal components (HCPC) was performed to identify the most homogeneous clinical groups. Significant correlations were noted between blood lactates and 11 clinical and 10 neuroimaging parameters. The increase in lactate and cortisol were significantly associated with a decrease in immunological parameters, especially with the level of reactive lymphocytes. The strongest correlations with the level of blood lactate and cortisol were demonstrated by brain glutamate, N-acetylaspartate and the concentrations of glutamate and glutamine, creatine and phosphocreatine in the prefrontal cortex. Metabolomics studies and the search for associations with brain parameters and self-reported outcomes may provide new diagnostic evidence to specific schizophrenia phenotypes.

Abstract Objective The purpose of this study was to establish the psychometric properties of the 9-Item Vestibular Activities Avoidance Instrument (VAAI-9), a patient-reported outcome measure developed to identify fear avoidance beliefs in persons with vestibular disorders. Methods This prospective cohort study included 100 participants 18 years and older seeking care at a balance disorders clinic for dizziness. Participants completed the VAAI-9, the Dizziness Handicap Inventory (DHI), and other patient-reported outcomes at the initial visit and the 3-month follow-up. To measure test–retest reliability, the VAAI-9 was completed again 5 days after the initial visit and was analyzed using a 2-way mixed ICC for absolute agreement. Internal consistency was determined using the Cronbach alpha. The Spearman correlation coefficient was used to assess convergent validity of the VAAI-9 with other outcomes. Receiver operating characteristic curves were used to identify baseline VAAI-9 cutoff scores for those who reported mild (DHI ≤ 30) or moderate or severe (DHI > 30) perceived disability at the 3-month follow-up. Results The mean age of the study cohort was 49 (SD = 16) years; 73 (73%) were women. Seventy-one participants completed the 5-day follow-up, and 68 completed the 3-month follow-up. The VAAI-9 demonstrated excellent internal consistency (α = 0.91) and test–retest reliability (ICC = 0.90). Baseline VAAI-9 scores had moderate to strong associations with other outcome measures at baseline and 3 months. A baseline VAAI-9 score of 26 or higher had a sensitivity of 80.6% and a specificity of 78.4% for identifying a DHI score of >30 at 3 months (area under the curve = 0.86). Conclusions The results provide evidence of excellent reliability and validity for the 9-item VAAI in persons with vestibular disorders. A baseline VAAI-9 score of ≥26 identified individuals at risk of persistent moderate to severe disability due to dizziness. Impact Initial levels of fear avoidance beliefs measured using the VAAI-9 provided important prognostic information about outcomes for persons with vestibular symptoms.

Abstract ELEVATE-RR demonstrated noninferior progression-free survival and lower incidence of key adverse events (AEs) with acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia. We further characterize AEs of acalabrutinib and ibrutinib via post hoc analysis. Overall and exposure-adjusted incidence rate was assessed for common Bruton tyrosine kinase inhibitor–associated AEs and for selected events of clinical interest (ECIs). AE burden scores based on previously published methodology were calculated for AEs overall and selected ECIs. Safety analyses included 529 patients (acalabrutinib, n = 266; ibrutinib, n = 263). Among common AEs, incidences of any-grade diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia were higher with ibrutinib, with 1.5- to 4.1-fold higher exposure-adjusted incidence rates. Incidences of headache and cough were higher with acalabrutinib, with 1.6- and 1.2-fold higher exposure-adjusted incidence rate, respectively. Among ECIs, incidences of any-grade atrial fibrillation/flutter, hypertension, and bleeding were higher with ibrutinib, as were exposure-adjusted incidence rates (2.0-, 2.8-, and 1.6-fold, respectively); incidences of cardiac events overall (the Medical Dictionary for Regulatory Activities system organ class) and infections were similar between arms. Rate of discontinuation because of AEs was lower for acalabrutinib (hazard ratio, 0.62; 95% confidence interval, 0.41-0.93). AE burden score was higher for ibrutinib vs acalabrutinib overall and for the ECIs atrial fibrillation/flutter, hypertension, and bleeding. A limitation of this analysis is its open-label study design, which may influence the reporting of more subjective AEs. Overall, event-based analyses and AE burden scores demonstrated higher AE burden overall and specifically for atrial fibrillation, hypertension, and hemorrhage with ibrutinib vs acalabrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02477696.

Abstract Background: The phase 3 head-to-head trial of acalabrutinib (acala) vs ibrutinib (ibr) (NCT02477696) demonstrated noninferior efficacy and improved tolerability with acala in previously treated CLL (Byrd J Clin Oncol 2021). We now report additional data to further characterize BTKi-related adverse events (AEs) and the safety profile of acala and ibr, including measures of AE burden that account for frequency, duration, and drug exposure, which are not captured by incidence alone. Methods: Patients (pts) received oral acala 100 mg BID or ibr 420 mg QD until disease progression or unacceptable toxicity. Overall incidence, exposure-adjusted (exp-adj) incidence, and exp-adj time with event (sum of event durations [all grades]*100/sum of treatment-emergent period [for all pts in each arm]) were assessed for the most common BTKi-related AEs. Atrial fibrillation (afib)/flutter, hypertension (htn), and bleeding events were further characterized by time to onset, cumulative incidence by Kaplan-Meier method, pt subgroup, and AE management. Results: A total of 533 pts (acala, n=268; ibr, n=265) were randomized; median treatment exposures were 38.3 and 35.5 mo, respectively. Incidence and exp-adj incidence and time with event are reported for the most common AEs and events of clinical interest (ECIs) (Table). Among cardiovascular (CV) ECIs, incidences of any-grade afib/flutter, htn, and bleeding were statistically higher with ibr, with higher exp-adj incidence (2.0-, 2.8-, and 1.6-fold, respectively) and exp-adj time with event (2.8-, 3.7-, and 1.8-fold). Ventricular arrhythmias were reported in 3 ibr-treated pts vs 0 pts in the acala arm. Among other BTKi-related AEs, incidences of any-grade diarrhea, arthralgia, contusion, urinary tract infection (UTI), back pain, muscle spasms and dyspepsia were statistically higher with ibr, with a 1.5- to 4.1-fold higher exp-adj incidence, and a 1.4- to 13.1-fold higher exp-adj time with event (except for UTI, which had a 1.4-fold lower exp-adj time with event for ibr). Incidences of headache and cough were statistically higher with acala, with a 1.6- and 1.2-fold higher exp-adj incidence, respectively, and a 1.4- and 1.1-fold higher exp-adj time with event. The total exp-adj time with event for all any-grade AEs was 37% higher with ibr (234 [acala] vs 320 [ibr] mo/100 person-mo). For any-grade afib/flutter, median time to onset was longer for acala vs ibr (28.8 vs 16.0 mo), and cumulative incidence was lower for acala at 6 mo (2% vs 6%), 12 mo (3% vs 8%), 18 mo (4% vs 10%), and 24 mo (5% vs 12%). Afib/flutter also occurred less frequently with acala vs ibr in subgroups of age (<65 y: 3% vs 7%; ≥65 y: 15% vs 23%), prior line of therapy (1-3: 10% vs 16%; ≥4: 7% vs 19%), and among pts without prior history (6% vs 15%). Cox proportional-hazards (PH) analysis of new-onset afib/flutter showed a 63% rate reduction favoring acala (Figure 1). Among all pts, concomitant medication use for afib/flutter was less common for acala (8%) vs ibr (14%), with antithrombotic use reported in 5% vs 9% of pts, respectively. For any-grade htn, median time to onset was similar for acala and ibr (8.1 vs 7.0 mo), but cumulative incidence was lower for acala at 6 mo (5% vs 12%), 12 mo (6% vs 16%), 18 mo (8% vs 20%), and 24 mo (8% vs 23%). Htn also occurred less frequently with acala vs ibr in subgroups of age (<65 y: 9% vs 23%; ≥65 y: 10% vs 23%), prior line of therapy (1-3: 10% vs 25%; ≥4: 4% vs 11%), and among pts without prior history (7% vs 23%). Cox PH analysis of new-onset htn showed a 77% rate reduction favoring acala (Figure 2). No dose reductions or treatment discontinuations due to htn occurred in either arm. Concomitant medication use for htn was less common for acala (5%) vs ibr (19%). For any-grade bleeding events, the median time to onset was similar for acala vs ibr (1.2 vs 1.2 mo), and cumulative incidence was lower for acala at 6 mo (29% vs 42%), 12 mo (32% vs 45%), 18 mo (34% vs 49%), and 24 mo (38% vs 51%). Bleeding events also occurred less frequently with acala vs ibr in most subgroups of age (<65 y: 26% vs 47%; ≥65 y: 49% vs 55%) and prior line of therapy (1-3: 39% vs 54%; ≥4: 32% vs 30%). Bleeding events were associated with dose reduction in 3 vs 2 pts in the acala vs ibr arms, respectively, and led to treatment discontinuation in 2 vs 4 pts. Conclusions: In this head-to-head trial of BTKis in CLL, event-based analyses demonstrated a higher BTKi-related toxicity burden with ibr, with a lower impact of CV-related toxicity with acala across subgroups. Figure 1 Figure 1. Disclosures Seymour: AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria; BeiGene: Honoraria. Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Chanan-Khan: Ascentage: Research Funding; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; BeiGene, Jansen, Ascentage: Honoraria; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BieGene, Jansen, Ascentage: Consultancy. Furman: Genentech: Consultancy; Sanofi: Consultancy; Morphosys: Consultancy; Incyte: Consultancy; Beigene: Consultancy; Loxo Oncology: Consultancy; TG Therapeutics: Consultancy; X4 Pharmaceuticals: Consultancy; Sunesis: Consultancy; Acerta/AstraZeneca: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; Pharmacyclics: Consultancy; Oncotracker: Consultancy; Janssen: Consultancy, Honoraria; Verastem: Consultancy; AstraZeneca: Honoraria. O'Brien: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy; Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding. Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. Mato: Genmab: Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; MSKCC: Current Employment; Acerta/AstraZeneca: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding. Kuptsova-Clarkson: AstraZeneca: Current Employment, Current equity holder in publicly-traded company; AbbVie: Current holder of individual stocks in a privately-held company. Miranda: ASTRAZENECA: Current Employment; ASTRAZENECA: Current equity holder in publicly-traded company. Wagner: AstraZeneca: Current Employment. Higgins: AstraZeneca: Current Employment; PROMETRIKA, LLC: Ended employment in the past 24 months. Sohoni: AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Revolution Medicines: Current Employment, Current equity holder in publicly-traded company; Theravance: Current equity holder in publicly-traded company. Jurczak: AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Jagiellonian University: Ended employment in the past 24 months; European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy.

Abstract Introduction: The management of CLL patients historically utilized FD chemoimmunotherapy (CIT), including fludarabine, cyclophosphamide and rituximab (FCR), or bendamustine and rituximab (BR). That changed with the introduction of Bruton Tyrosine Kinase inhibitors (BTKi) as an option for oral targeted monotherapy delivered continuously until disease progression or intolerance. Recently, novel combinations that include a B-cell lymphoma 2 inhibitor (BCL2i), such as venetoclax, have been developed as FD therapy. In addition, though not FDA approved, MRD assessment is emerging as a potential tool to guide FD therapy. Understanding the patient and their caregiver perspectives on FD and MRD is critical to providing the best care. Methods: CLL Society developed a web-based survey instrument of multiple-choice questions to assess patient and caregiver awareness, understanding, and preferences with MRD and FD therapies, where FD referred to both time and MRD guided limited duration therapies. Patients and caregivers were invited to participate via message boards, CLL Society's website, email, and online communities. Results: A total of 607 (96%) self-identified US patients and 36 (5%) caregivers, who answered on behalf of patients in their care, completed the survey between 31/AUG/2020 and 31/JAN/2021. The mean patient age was 64 (range, 30-90) years, 54% were female, 169 patients (27%) treatment-naïve, 239 (38%) with one line of prior therapy, and 214 (34%) with two or more. Targeted agents (e.g., venetoclax, ibrutinib, acalabrutinib, idelalisib, and duvelisib) had been used by 401 (64%). FD use with some novel therapies was known of by 565 (90%) patients, while 588 (93%) knew some were used as continuous daily treatment until disease progression or intolerance. If effectiveness and side effects were assumed similar, 485 (77%) preferred FD, and 398 (63%) wanted that finite treatment to be guided by MRD status. Only 42 (7%) preferred continuous therapy until disease progression or intolerance. The chance for continued remission while off treatment was ranked as a very important potential benefit after stopping a FD therapy by 581 (92%) patients. When considering therapy, 589 (93%), 575 (91%), 447 (71%), 415 (66%), 302 (48%), and 288 (46%) rated having overall survival, having future therapeutic options, avoiding chemotherapy, the ability to reach undetectable (u)MRD, minimal lab and office visits, and FD therapy as very important, respectively (Fig. 1). Being tested for MRD at least once was reported by 215 (34%), while 327 (52%) had not been tested, and 88 (14%) were unsure. There were 562 (89%) who were somewhat or very familiar with the term MRD, while 450 (71%) were confident of understanding what MRD testing measures, and 446 (70%) understood its role in CLL. Only 225 (36%) stated they understood different testing methods. While self-rated understanding of the indications for MRD testing was relatively high, some wanted testing done when not clinically indicated, such as when there was persistent CLL by routine laboratory findings, or at the time of diagnosis (Fig. 2). Respondents were mixed in their stated understanding as to which therapies could result in uMRD, with 241 (38%), 197 (32%), and 195 (32%) not knowing if CIT, BCL2i, and BTKi, could lead to uMRD, respectively. Two hundred and sixty-five (42%), 84 (13%), and 57 (9%) believed it was possible for most on a BCL2i, BTKi, or CIT to achieve uMRD, respectively (Fig. 3). If patients had evidence of MRD at the end of treatment, 365 (58%) would request frequent monitoring but would make no immediate treatment decisions based on MRD status, 279 (44%) were unsure, and only 88 (14%) would want further treatment immediately. Conclusions: The results from this patient-based study reveal a high awareness of FD therapies and MRD testing, as well as a clear preference for FD among internet-active patients and caregivers. However, there are gaps in the knowledge base, thus significant educational opportunities. Limitations included the opt-in sample where the survey results may not be projectable to the total CLL population. Moreover, the survey was not designed to assess preferences if either FD or continuous therapy offered improved outcomes. Nonetheless, as the potential role of MRD and FD therapy grows in CLL it will be incumbent on clinicians to ensure patients are well informed and engaged to help them better share therapeutic decisions. Figure 1 Figure 1. Disclosures Koffman: AbbVie: Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company, Honoraria; Beigene: Current equity holder in publicly-traded company; Bristol Myer Squibb: Current equity holder in publicly-traded company, Honoraria; Gilead: Current equity holder in publicly-traded company; Johnson & Johnson: Current equity holder in publicly-traded company, Honoraria; Sunesis Pharmaceuticals: Current equity holder in publicly-traded company; TG Therapeutics: Current equity holder in publicly-traded company; Regeneron: Current equity holder in publicly-traded company; Miragen Therapeutics: Current equity holder in publicly-traded company; Novartis: Membership on an entity's Board of Directors or advisory committees; Portola Pharma: Current equity holder in publicly-traded company; MEI Pharma: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company. Stewart: Johnson & Johnson: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company; Dr. Reddy's Laboratories Limited: Current equity holder in publicly-traded company; Adaptive Biotechnologies: Current equity holder in publicly-traded company; Pacific Biosciences: Current equity holder in publicly-traded company. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees. Danilov: Bayer Oncology: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda Oncology: Research Funding; Rigel Pharm: Honoraria; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead Sciences: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; SecuraBio: Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding. Davids: BeiGene: Consultancy; Janssen: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Surface Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy; Verastem: Consultancy, Research Funding; Eli Lilly and Company: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy. Furman: Beigene: Consultancy; Acerta/AstraZeneca: Consultancy; Janssen: Consultancy, Honoraria; Sunesis: Consultancy; Genentech: Consultancy; Incyte: Consultancy; Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Loxo Oncology: Consultancy; Sanofi: Consultancy; Morphosys: Consultancy; Verastem: Consultancy; X4 Pharmaceuticals: Consultancy; Oncotracker: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; AstraZeneca: Honoraria. Jain: Bristol Myers Squibb: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Beigene: Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Research Funding; TG Therapeutics: Honoraria; Cellectis: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Servier: Honoraria, Research Funding; Janssen: Honoraria; Incyte: Research Funding; Pharmacyclics: Research Funding. Kay: Oncotracker: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Research Funding; MEI Pharma: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Abbvie: 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; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Research Funding; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna: Juno Therapeutics, Inc.: Research Funding; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; MingSight Pharmaceuticals, Inc.: Research Funding; Genentech, Inc.: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy; TG Therapeutics, Inc: Research Funding; Verastem Oncology: Research Funding; Celgene Corporation: Consultancy; Oncternal Therapeutics: Research Funding; Pharmacyclics: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy. Mato: MSKCC: Current Employment; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Genmab: Research Funding; AstraZeneca: Consultancy; Sunesis: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Ujjani: Adaptive Biotechnologies: Research Funding; Atara Bio: Consultancy; Janssen: Consultancy; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Honoraria; Gilead: Honoraria; ACDT: Honoraria; Kite, a Gilead Company: Honoraria; Loxo: Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Pagel: Kite, a Gilead Company: Consultancy; Incyte/MorphoSys: Consultancy; AstraZeneca: Consultancy; Actinium Pharmaceuticals: Consultancy; Gilead: Consultancy; Pharmacyclics/AbbVie: Consultancy; MEI Pharma: Consultancy; Epizyme: Consultancy; BeiGene: Consultancy.