Kurzfassung: With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

Kurzfassung: Double-hit (DHIT) lymphoma is a heterogeneous group of non-Hodgkin lymphomas characterized by concurrent translocations involving MYC and BCL2 and typified by aggressive behavior and poor prognosis with only rare long-term survivors. There is no established treatment for DHIT lymphoma. Since 2003, the British Columbia Cancer Agency (BCCA) has adopted the use of intensive chemotherapy CODOX-M/IVAC combined with rituximab (R) followed by high-dose chemotherapy and hematopoietic cell transplantation (HSCT) as definitive treatment for DHIT lymphoma. In younger patients, an ablative matched sibling donor allotransplant (AlloSCT) is preferred over an autotransplant (AutoSCT). For all patients over the age of 60 years only AutoSCT is offered. Total Body Irradiation (TBI) is used as a part of the conditioning regimen for patients younger than 60 years of age. Here we report our provincial experience with this strategy, focusing on the ability to deliver this treatment and survival outcomes. Methods The Leukemia/BMT Program of British Columbia database and the BCCA Lymphoid Cancer Database were searched to identify all patients diagnosed with non-Hodgkin lymphomas with concurrent translocation of MYC and BCL2 (DHIT lymphoma) diagnosed between January 2003-September 2012. Results 27 cases of DHIT lymphoma were identified with the following characteristics: median age at diagnosis was 55.8 years (range 35.5-70.9 years); 19 (70%) were male; 26 (96%) patients had stage 3/4 disease; 16 (59%) had bone marrow involvement. All cases were HIV negative. Histological diagnosis based on the WHO 2008 classification were: diffuse large B-cell lymphoma (DLBCL) n=8 (30%); B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCL-U) n=17 (63%); B-cell acute lymphoblastic lymphoma (ALL) n=1; high-grade B-cell lymphoma, not otherwise specified (NOS) n=1. 13 cases (48%) were transformed from an underlying indolent B-cell lymphoma (12 follicular lymphoma, 1 low-grade B-cell lymphoma NOS). CODOX-M/IVAC + R was administered in 20 patients (74%). 7 patients received alternative chemotherapy regimen (5 R-CHOP, 1 R-CVP, 1 R-ICE) due to patient and/or physician preference. 14 patients (52%) underwent HSCT (7 AutoSCT, 7 AlloSCT), including 11 patients treated CODOX-M/IVAC + R pre-transplant, and 3 patients who received other therapy. 13 patients did not undergo HSCT: primary refractory disease n=7; patient preference n=2; deconditioning n=1; age 〉 65 and poor performance status n=3. The clinical status at time of transplantation was CR in 5 patients (19%), PR in 8 (30%), progressive disease in 1 (4%). The conditioning regimens included: cyclophosphamide/TBI n=6, VP-16/cyclophosphamide/TBI n=4, BEAM n=3, busulfan/cyclophosphamide n=1. At last follow-up, 15 (56%) patients have died, 14 from disease progression and 1 from complications of AlloSCT. 10 (37%) patients are alive and in remission and 2 patients are alive but have relapsed. 8 of 14 HSCT recipients (6 AutoSCT, 2 AlloSCT) remain alive and free of disease compared with 2 of 13 patients who did not receive HSCT; both disease free survivors received CODOX-M/IVAC + R. Median follow-up for living patients was 31 months (range 6.5-67.3 months). 2-year EFS and OS from the diagnosis of all DHIT lymphoma patients were 35% (95% CI 16%-54%) and 45% (95% CI 20%-65%), respectively. For patients who received CODOX-M/IVAC + R, the 2-year EFS was 37%. For patients who received CODOX-M/IVAC + R followed by SCT, the 2-year EFS was 43%. Patients with BCLU/ALL/High-grade lymphoma NOS had a 2-year EFS of 27% and patients with DLBL had a 2 –year EFS of 50%. Conclusion Patients with DHIT lymphoma treated with CODOX-M/IVAC + R followed by SCT can have durable remissions. Regardless, progression during initial therapy prior to SCT remains a significant problem. Patients with DLBCL histology may have a more favorable outcome than those with BCLU. Disclosures: Savage: Eli-Lilly: Consultancy. Toze:Roche Canada: Research Funding; F Hoffmann-La Roche: Research Funding. Sehn:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Connors:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Gerrie:F Hoffmann-La Roche: Research Funding; Roche Canada: Research Funding. Sutherland:Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Villa:Roche: Honoraria, Research Funding; Lundbeck: Honoraria; Celgene: Honoraria. Song:Roche: Research Funding.

Kurzfassung: Background: Peripheral T-cell lymphomas (PTCL) are a rare and heterogeneous group of non-Hodgkin lymphomas (NHLs) that accounts for approximately 10% of all aggressive NHLs in Western countries. The optimal management remains unclear, however, given the poor outcome, allogeneic transplant (allo-SCT) has been integrated into the front-line treatment for some rare extranodal subtypes as well in relapsed/refractory setting. We report our provincial experience of the outcome of patients with PTCL who have undergone allo-SCT at the British Columbia Cancer Agency (BCCA). Methods: The Leukemia/BMT Program of British Columbia database and the BCCA Lymphoid Cancer Database were searched to identify all patients diagnosed with PTCL who have undergone allo-SCT between November 1990 and January 2016. Overall survival and relapse free survival were estimated using the Kaplan-Meier method. Results: We identified 36 cases of PTCL patients who have undergone allogeneic transplant from a median time of 11 months from primary diagnosis (range 4-64) with the following clinical features: median age at transplant was 45 years (range 16-58 years); 24 (67%) were male; 32 (89%) patients had advanced stage disease; 22 (61%) had B-symptoms at diagnosis. Bone marrow involvement detected in 13/34 (38%) patients. Histological diagnosis based on the WHO 2008 classification were: Peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) n=15 (42%); anaplastic large cell lymphoma (ALCL) n=7 (19%) out of which three were ALK positive, angioimmunoblastic T-cell lymphoma (AITL) n=6 (17%), hepatosplenic T-cell lymphoma n=5 (14%), enteropathy associated T-cell lymphoma type I n=1, advanced primary cutaneous gamma-delta T-cell lymphoma n=1 and Sezary syndrome n=1. Ten patients (28%) underwent allo-SCT as part of planned primary therapy after achieving their first remission [6 were in complete remission 1 (CR1) and 4 were in partial remission 1 (PR1)] , whereas 26 patients (72%) underwent allo-SCT for relapsed/refractory disease. CHOP was administered in 19 patients (53%) as the primary therapy. 17 (47%) patients received alternative chemotherapy regimen due to patient and/or physician preference. The clinical status at the time of transplantation was CR in 12 patients (33%), relapsed sensitive disease n=10 (28%), relapsed untreated n=5 (14%), partial remission (PR) in 5 (14%), primary progressive disease n=3 (8%) and relapsed resistant disease n=1 (3%). Thirty two patients (89%) underwent myeloablative conditioning, 4 (11%) underwent reduced intensity conditioning (RIC). The conditioning regimens included: cyclophosphamide/TBI n=24 (67%), busulfan/cyclophosphamide n=5 (14%), fludarabine containing reduced intensity n=4 (11%), and other regimens n= 3 (8%). With a median follow-up of alive patients from the time of allo-SCT of 69 months (range 1-186 months). At last follow-up, 17 (47%) patients have died, 6 from disease relapse, 5 from graft vs host disease (GVHD), 2 from regimen related toxicity and 4 from other causes. Nineteen patients (53%) still alive at last follow up post-transplant of which 14 (39%) still in remission. The 5-year event free survival (EFS) and overall survival (OS) from the time of allo-SCT of all patients were 43% and 63%, respectively. For PTCL-NOS the 5-year EFS and OS were 52% and 69%, respectively. Table 1 summarizes the patients' characteristics. Figures 1 and 2 shows the Kaplan-Meier curves for OS and EFS respectively. Conclusion: Allo-SCT can be effective strategy in select patients with relapsed/refractory PTCL and those with high risk histologies in the upfront setting PTCL with an acceptable toxicity. Disclosures Toze: Roche Canada: Research Funding. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria. Scott:NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies. Villa:Lundbeck: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria. Connors:NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Bristol Myers Squib: Research Funding; Seattle Genetics: Research Funding; Millennium Takeda: Research Funding. Song:Janssen: Honoraria; Otsuka: Honoraria; Celgene: Honoraria, Research Funding.

Kurzfassung: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype worldwide, accounting for 40% of all non-Hodgkin lymphomas. DLBCL presents as an aggressive disease requiring immediate treatment. Although significant improvement in outcome has been achieved, ~40% of patients still experience treatment failure. Here, we characterized the recurrent genetic alterations and transcriptomic signatures in diagnostic biopsies from a population registry-based cohort of 347 patients with de novo DLBCL uniformly treated with R-CHOP. This analysis revealed bi-allelic loss of function mutations of TMEM30A that were associated with favorable treatment outcome. TMEM30A is a chaperone protein, involved in maintaining the asymmetric distribution of phosphatidylethanolamine and phosphatidylserine, an integral component of the plasma membrane and “eat-me” signal recognized by macrophages. Using TMEM30A knockout systems by CRISPR genome editing techniques, we have functionally characterized this loss-of-function mutation in representative human and mouse DLBCL cell line models. We have discovered that TMEM30A loss is associated with increased B-cell signaling following antigen stimulation, including a two-fold increase in the diffusion rate of B-cell receptor (BCR) clustering, using high resolution Single Particle Tracking (SPT) technology. In addition, we have measured three-fold increase in chemotherapeutic drug accumulation in both knockout cell lines and randomly selected patient biopsies with TMEM30A biallelic loss. This observation was validated in a xenograft mouse model, which presented improved survival and limited tumor growth following vincristine treatment in mice injected with TMEM30A null DLBCL cell lines compared with native cell lines. This phenotype explains the improved prognosis observed in DLBCL patients following R-CHOP treatment. Furthermore, we have observed over two fold higher numbers of tumor-associated macrophages in B-cell lymphoma syngeneic mouse models with Tmem30a loss-of-function, prior to any form of treatment, suggesting the existence of “hot” and primed tumors. Our data highlight a multi-faceted role for TMEM30A and plasma membrane physiology in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited. Characterization of these mechanisms will address a missing link in the cancer field as related insights in lymphoma will outline therapeutic approaches that can be extended to cancer therapy in general. Citation Format: Shannon Healy, Daisuke Ennishi, Ali Bashashati, Saeed Saberi, Christoffer Hother, Anja Mottok, Fong Chun Chan, Lauren Chong, Robert Kridel, Merrill Boyle, Barbara Meissner, Tomohiro Aoki, Katsuyoshi Takata, Bruce W. Woolcock, Elena Vigano, Libin Abraham, Michael Gold, Adele Telenius, Pedro Farinha, Graham Slack, Susana Ben-Neriah, Daniel Lai, Allen W. Zhang, Sohrab Salehi, Hennady P. Shulha, Derek S. Chiu, Sara Mostafavi, Alina S. Gerrie, Diego Villa, Laurie H. Sehn, Kerry J. J. Savage, Andrew J. J. Mungall, Andrew P. Weng, Marcel Bally, Ryan D. Morin, Gabriela V. Cohen Freue, Joseph M. Connors, Marco A. Marra, Sohrab P. Shah, Randy D. Gascoyne1, David W. Scott, Christian Steidl, Ulrich Steidl. TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3480.

Kurzfassung: CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. PATIENTS AND METHODS Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti–CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). RESULTS Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30] ; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, –1.5 to 4.4; all-pts) and 1.4% (95% CI, –1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. CONCLUSION In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.

Kurzfassung: To assess the incidence and predictive factors for development of transformed lymphoma in a population-based series of patients with follicular lymphoma (FL). Patients and Methods The Lymphoid Cancer Database was used to identify patients with FL diagnosed and treated in the province of British Columbia, Canada. Transformed lymphoma was defined as the development of aggressive non-Hodgkin's lymphoma (NHL) in patients with FL. Factors present at the time of initial diagnosis of indolent NHL and at transformation were analyzed for their impact on risk of transformation and subsequent outcome. Results Between 1986 and 2001, 600 patients with newly diagnosed FL met the inclusion criteria. With a median follow-up of 109 months (range, 10 to 244), 170 (28%) developed transformation, 107 (63%) based on biopsy confirmation. The annual risk of transformation was 3% continuously through 15 years. A multivariate analysis of clinical factors at diagnosis identified advanced stage as the only predictor of future transformation. The median post-transformation survival was 1.7 years. The 5-year survival was superior for patients with limited extent transformation compared with those with advanced cases (66% v 19%, P 〈 .0001). Patients with transformation based on clinical versus histological criteria had an identical median survival of 1.8 years (P = .2). Conclusion The annual risk of transformation of FL is 3% continuing without plateau beyond 15 years. Advanced stage at diagnosis is predictive of future transformation. Clinically diagnosed transformation has an equal impact on outcome as biopsy proven transformation.

Kurzfassung: When the WHO defined high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/TH) as a clinical category, rearrangements were the only structural variant (SV) incorporated. An "atypical double-hit" entity has been proposed, encompassing tumors with concurrent MYC and BCL2 SVs other than co-occurring translocations - i.e. copy number variations (CNVs). While the identification of a gene expression signature (DHITsig) shared among tumors harboring MYC and BCL2 rearrangements (HGBL-DH/TH-BCL2) has confirmed a shared underlying biology, the biological implication of MYC and BCL2 CNVs requires further elucidation. We performed a comprehensive analysis of MYC and BCL2 SVs, as determined by fluorescent in situ hybridization (FISH), in a cohort of 802 de novo tumors with diffuse large B-cell lymphoma (DLBCL) morphology. While BCL2 CNVs were associated with increased expression, MYC CNVs were not. Furthermore, MYC and BCL2 CNVs, in the context of atypical double-hit, did not confer a similar gene expression profile as HGBL-DH/TH-BCL2. Finally, while MYC IHC has been proposed as a screening tool for FISH testing, two mechanisms were observed that uncoupled MYC rearrangement from IHC positivity. 1) low MYC mRNA expression and 2) false-negative immunohistochemistry (IHC) staining mediated by a single nucleotide polymorphism resulting in an asparagine to serine substitution at the 11th amino acid residue of MYC (MYC-N11S). Taken together, these results support the current exclusion of MYC and BCL2 CNVs from HGBL-DH/TH and highlight the ability of a molecular based classification system to identify tumors with shared biology that FISH and IHC fail to fully capture.

Kurzfassung: Introduction: While an association between AI diseases and the development of lymphoma (LYM) is known, the impact of AI diseases on patient (pt) outcome across varying LYM subtypes, including the role of immunosuppressive medications (ISM), is not well understood. Methods: We conducted a large, multicenter, RWE retrospective analysis of adult pts with a diagnosis (dx) of lymphoma (LYM) between 1/2000 and 12/2020 and a pre-existing AI disease (see full list AI in Table 1). We examined baseline clinical features at LYM diagnosis, underlying AI disease characteristics, type/duration of ISM, LYM therapy received and survival outcomes. Multinomial regression models adjusted for age and sex identified associations between LYM subtypes, AI diseases, and ISM exposure, and were reported as relative risk ratio (RRR). Survival rates were estimated by Kaplan-Meier. Univariate associations of baseline factors with survival in cases with non-missing data were examined by Cox model and stratified by International Prognostic Index (IPI). Results: In total, 785 pts were identified across 14 North American institutions, of which 694 pts with complete data were included in the final analysis. Rheumatoid arthritis was the most common AI disease (30%) (Table 1). Diffuse large B-cell lymphoma (DLBCL) was the most common histologic subtype (n=303, 44%), and it was the most prevalent histology for nearly every AI disease. The median duration between AI disease and LYM diagnosis was 108 months (mo) (1-816 mo). Several associations were found between specific AI diseases and LYM subtypes, including: Hashimoto's thyroiditis with marginal zone lymphoma (MZL, RRR 2.78 (95% CI 1.14-6.78, P=0.024), Waldenstrom's macroglobulinemia (RRR 7.12 (95% CI 1.07-47.3, P=0.031), and follicular lymphoma (RRR, 2.71, 95% CI 1.01-7.24, P=0.047); Polymyalgia rheumatica with CLL/SLL (RRR 21.27 (95% CI 4.57-98.96), P=0.0001) and MZL (RRR 6.62 (95% CI 1.38-31.80), P=0.018); Psoriasis with peripheral T-cell lymphoma (PTCL, RRR 3.85 (95% CI 1.21-12.22), P=0.022); and Inflammatory bowel disease with CLL/SLL (HR 4.60 (95% CI 1.72-12.34), P=0.002). Overall, 402 (58%) pts had ISM exposure prior to LYM dx, with 279 (40%) pts on active ISM at time of LYM dx. The most commonly used ISM agent was methotrexate (26%); the median duration of ISM prior to LYM diagnosis was 60 mo (1-480). Compared with DLBCL pts, those diagnosed with PTCLs were more likely to have had exposure to TNF-α inhibitors (RR 1.89, 95% CI 1.23-2.89, P=0.004) or apremilast, a phosphodiesterase-4 inhibitor (RR 19.2, 95% CI 2.6-149.9, P=0.005). Rituximab +/- chemotherapy was used as frontline therapy in the majority of B-cell LYM pts, including 90% of DLBCL. Of LYM pts on ISM at initial dx, 41% had a reduction in immunosuppression (RIS), of whom 81% stopped ISM completely (Table 1). Only 10% of pts who underwent RIS were reported to have a flare of AI disease during initial therapy, compared with 7% of pts who had a flare despite no RIS (P=NS). Survival by histology is depicted in Figure A/B. For DLBCL pts (n=303), survival appeared overall comparable to historically reported outcomes in the general DLBCL population. Neither antecedent use of ISM nor duration of ISM were associated with pt outcomes (data not shown). However, a survival advantage was identified among DLBCL pts whose ISM was stopped completely during frontline therapy compared with pts who were not on ISM at diagnosis (Figure C/D). In addition, 10 DLBCL pts underwent 100% RIS +/- rituximab with therapeutic intent and did not receive cytotoxic chemotherapy as part of frontline therapy. Among these, 4 pts (mean age 62 years (26-84); ISM: n=2 MTX, and 1 each azathioprine and etanercept/MTX; EBV+ 2/4) achieved complete remission and remain disease-free at time of last follow-up at 5, 74, 105, and 221 months post-DLBCL dx. Conclusions: Altogether, we identified several novel histologic associations of AI diseases with LYM histologic subtypes. Furthermore, prior receipt of TNF-α inhibitor or a phosphoediesterase 4 inhibitor were associated with a diagnosis of PTCL. For DLBCL pts with antecedent AI disease, complete cessation of ISM during frontline LYM therapy appeared to be associated with improved survival. Finally, there were a small number of select DLBCL pts who garnered long-term disease-free survival using RIS +/- rituximab as frontline therapy, similar to the treatment paradigm in post-transplant lymphoproliferative disorders. Figure 1 Figure 1. Disclosures Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Karmali: Karyopharm: Consultancy; Epizyme: Consultancy; Morphosys: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy; AstraZeneca: Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; EUSA: Consultancy; Janssen/Pharmacyclics: Consultancy; Roche: Consultancy; Takeda: Research Funding. Lunning: TG Therapeutics: Consultancy; Janssen: Consultancy; Verastem: Consultancy; Spectrum: Consultancy; Myeloid Therapeutics: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; ADC Therapeutics: Consultancy; Beigene: Consultancy; Daiichi-Sankyo: Consultancy; Kyowa Kirin: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; Legend: Consultancy; Acrotech: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy; Karyopharm: Consultancy; AbbVie: Consultancy. Palmisiano: Genentech: Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Consultancy; Foundation One: Consultancy. Danilov: Bristol-Meyers-Squibb: Honoraria, Research Funding; Gilead Sciences: Research Funding; Pharmacyclics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Bayer Oncology: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding; Rigel Pharm: Honoraria. Barta: Kyowa Kirin: Honoraria; Acrotech: Honoraria; Daiichi Sankyo: Honoraria; Seagen: Honoraria. Lansigan: Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Savage: Astra-Zeneca: Consultancy, Honoraria; Takeda: Other: Institutional clinical trial funding; Roche: Research Funding; Merck: Consultancy, Honoraria, Other: Institutional clinical trial funding; BMS: Consultancy, Honoraria, Other: Institutional clinical trial funding; Seattle Genetics: Consultancy, Honoraria; Servier: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Beigene: Other: Institutional clinical trial funding; Genentech: Research Funding.