CC-90009 is a novel cereblon (CRBN) E3 ligase modulator (CELMoD) that has demonstrated antileukemic activity and is under investigation in the CC-90009-AML-001 phase I trial (NCT02848001) in patients with relapsed or refractory acute myeloid leukemia (AML). In preclinical studies, CC-90009 drives the binding of translation termination factor G1 to S phase transition I (GSPT1) to CRBN. This results in ubiquitination and proteasome-dependent degradation of GSPT1, leading to activation of the integrated stress response, inhibition of nonsense-mediated decay, and induction of apoptosis. Hypotension, contemporaneous with blast and white blood cell (WBC) decreases, has emerged as a dose-limiting toxicity (DLT) in this ongoing phase I trial. Based on clinical observations, CC-90009-induced cytokine release during leukemic cell death was investigated as a potential cause of hypotension. Using electrochemiluminescence, flow cytometry and western blots, CC-90009-induced IL-1b release was observed in AML cell lines and primary AML bone marrow mononuclear cells. Induction of IL-1b was typically observed after caspase 3 and 8 activation, suggesting a cell-death-related mechanism consistent with clinical findings of hypotension reported after rapid WBC loss. In vitro models showed compounds leading to GSPT1 degradation were more potent IL-1b inducers compared to compounds with other mechanisms, including standard-of-care agents for AML, other cytotoxic agents, protein translation inhibitors, and unfolded protein response inducers. IL-1b induction as a downstream result of GSPT1 degradation was further confirmed by cells expressing non-degradable GSPT1 mutant protein where compound treatment did not induce IL-1b. CC-90009 activates the GCN2 pathway, resulting in caspase-3 and -8-mediated apoptosis. Caspase 8 is known to directly process pro-IL-1b into mature IL-1b. Using an isogenic MV4-11 Cas9 cell pair with wild-type vs null GCN2 status, GCN2 activation downstream of GSPT1 degradation was shown to be required for pro-IL-1b upregulation and caspase 8 activation. Furthermore, genetic and pharmacologic suppression of caspase 8 revealed that its activity was necessary, but not sufficient, for IL-1b release by CC-90009. Of note, dexamethasone (DEX) dampened CC-90009-mediated IL-1b induction without altering the rate or depth of AML cell killing, providing a mechanism-based strategy to manage CC-90009-induced hypotension. The ongoing trial was amended to allow the use of prophylactic DEX; dose escalation is still ongoing, including dose levels higher than the non-tolerated dose defined prior to mandating the use of prophylactic DEX. The insights derived from this study have facilitated GSPT1 targeting in AML therapy by enabling the testing of higher drug exposures. Citation Format: Tsun-Wen Sheena Yao, Yumin Dai, Carla Guarinos, Manuel Sanchez, Alicia Benitez, Hongbin Wang, Soraya Carrancio, Tonia Buchholz, Gang Lu, Michael Pourdehnad, Daniel Pierce, Jinhong Fan. Discovery of induction and release of IL-1b are unique and on-target effects of GSPT1 degradation that provide potential mitigation strategies to hypotension in the CC-90009-AML-001 phase 1 trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2048.

Background: CC-90009 is a cereblon (CRBN) E3 ligase modulator (CELMoD) and a first-in-class small molecule that drives the binding of a novel target protein, G1 to S phase transition 1 (GSPT1), to CRBN, resulting in the proteasome-dependent degradation of GSPT1. GSPT1 plays a central role in mRNA translation, and loss of GSPT1 activates an integrated stress response that leads to AML cell death (Matyskiela ME, et al. Nature. 2016;535:252-7; Zhouravleva G, et al. EBMO J. 1995;14:4065-72). In preclinical testing, CC-90009 is active across a range of AML cell lines and primary AML patient (pt) samples in vitro and in vivo and exerts its GSPT1- and CRBN-dependent effects through rapid induction of apoptosis. Here we share the first clinical results in pts with R/R AML. Methods: Adult pts with R/R AML enrolled in the dose-finding phase of this first-in-human, multicenter, open-label phase 1 study to evaluate tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of CC-90009; and to establish the recommended phase 2 dose and schedule (RP2D) (CC-90009-AML-001; NCT02848001). Dose escalation proceeded via a modified 3 + 3 design. Treatment was by daily intravenous administration on either Days 1-5 (D1-5) or Days 1-3 and 8-10 (D1-3/8-10) of a 28-day cycle. Treatment response was assessed after Cycles 1, 2, and 4 by modified International Working Group 2003 criteria. Safety and preliminary response data are presented for all treated pts. PK and PD were analyzed for evaluable pts. Results: As of May 15, 2019, 45 pts with R/R AML had been treated, including 35 pts on the D1-5 and 10 pts on the D1-3/D8-10 schedule. Median age was 66 years (range 27-81); 73% were male. Most pts (n = 36; 80%) were refractory to their last therapy and 17 pts (38%) were refractory to all prior therapy; 14 pts (31%) had secondary AML. Pts were treated at dose levels from 0.3 to 3.6 mg. Dose-limiting toxicities (DLTs) reported (only in dose levels from 2.4 to 3.6 mg) included hypotension, systemic inflammatory response syndrome (SIRS), hyperbilirubinemia, pneumonitis, and pericarditis with tamponade. Exploration of the 3.6 mg dose level is ongoing; the RP2D has not yet been determined. CC-90009-related grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 23 pts (51%); those occurring in >1 pt were hypocalcemia (22%); hypotension (13%); and hyperbilirubinemia, hyperglycemia, hypophosphatemia, pneumonitis, sepsis, thrombocytopenia, and tumor lysis syndrome (4%). Preclinically identified hypocalcemia was confirmed as a CC-90009 on-target toxicity in the clinic; it was reversible, manageable and did not lead to any treatment discontinuations. The majority of treated pts experienced ≥1 serious TEAE (80%); most were infections (47%). Two (4%) pts experienced TEAEs leading to permanent discontinuation of the study drug. Dose interruptions due to TEAEs occurred in 12 pts (27%) and dose reductions in 2 pts (4%). Of 40 pts who discontinued treatment, 24 (60%) discontinued due to progressive disease or lack of efficacy. Seven pts discontinued treatment due to death; 4 deaths were secondary to progression from AML, 2 due to sepsis and 1 due to hyperglycemic hyperosmolar nonketotic syndrome. Responses to single-agent treatment were observed in pts treated at 3.0 or 3.6 mg on the D1-5 schedule, with a best response of complete remission (CR; n = 1), morphologic CR with incomplete blood count recovery (CRi; n = 1) and morphologic leukemia-free state (MLFS; n = 1). A dose-dependent decrease in GSPT1 levels in peripheral blood blasts and T cells was observed, with a >90% decrease observed for higher dose levels. Evidence of antileukemic activity (decreases in bone marrow and/or peripheral blasts) was seen in pts treated with CC-90009 at 1.2 mg and above with a trend to more sustained reductions at the highest dose levels. Plasma PK analysis demonstrated dose-dependent exposure. Conclusions: In this phase 1 study of CC-90009, a first-in-class agent, evidence of deep GSPT1 degradation, on-target activity and promising antileukemic activity was observed. The observed TEAEs, in addition to those expected in this heavily pretreated R/R AML pt population, were generally well manageable. The study is ongoing with further optimization of dose, schedule and toxicity mitigation. Expansion cohorts in R/R AML and higher-risk myelodysplastic syndromes are planned. Disclosures Uy: GlycoMimetics: Consultancy; Curis: Consultancy; Astellas: Consultancy; Pfizer: Consultancy. Montesinos:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. DeAngelo:Blue print Medicines: Consultancy, Research Funding; Celgene Corporation: Consultancy; Shire: Consultancy; Pfizer, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; GlycoMimetics: Research Funding; AbbVie, Inc.: Research Funding; Takeda Pharmaceuticals: Consultancy; Amgen: Consultancy. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; France Foundation: Speakers Bureau; PeerView: Speakers Bureau; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Cancer Expert Now: Consultancy; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; prIME Oncology: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Koprivnikar:Amgen: Speakers Bureau; Pfizer: Honoraria; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Vyas:Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding; Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Fløisand:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Honoraria. Gjertsen:BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; EU Horizon 2020: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; The Norwegian Cancer Society: Research Funding; KinN Therapeutics AS: Equity Ownership; ACTII AS: Equity Ownership; ERA PerMed: Research Funding; Helse Vest Health Trust: Research Funding; Research Council of Norway: Research Funding. Esteve:Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Buchholz:Celgene Corporation: Employment, Equity Ownership. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Fan:Celgene Corporation: Employment, Equity Ownership. Hanna:Celgene Corporation: Employment, Equity Ownership. Li:Celgene Corporation: Employment, Equity Ownership. Pierce:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Zeidan:Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Cardinal Health: Honoraria; Daiichi Sankyo: Honoraria; Novartis: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Astellas: Honoraria.

Acute myeloid leukemia (AML) is a clonal malignant disease initiated and propagated by leukemia stem cells (LSCs). Both LSCs and normal hematopoietic stem cells (HSCs) share many biological properties including self-renewal and quiescence. One such shared property that we have recently established involves the pro-survival features of proteostatic stress signaling. Stem cells have reduced protein translation initiation due to scarcity of the eIF2α translation initiation complex (van Galen et al Nature 2014; Cell Reports 2018). This in turn, increases the activity of activating transcription factor 4 (ATF4) uniquely in HSCs and LSCs. In homeostasis, this level of ATF4 facilitates stem cell persistence and survival, but upon stronger stress activation stem cell apoptosis ensues. This mechanism predicts that agonists of the integrated stress response (ISR) could provide a novel therapeutic approach to eradicate LSCs. Here we report that the novel cereblon E3 ligase modulator (CELMoD) CC-90009, which causes degradation of the translation termination factor G1 to S phase transition protein 1 (GSPT1) and downstream activation of ISR, is potent against primary AML both in vitro and in vivo, and reduces self-renewing LSCs in preclinical xenograft models for human AML. We first carried out in vitro assays to evaluate the effect of CC-90009 on primary AML samples. We found that CC-90009 degraded GSPT1 in primary AML cells and induced leukemic cell apoptosis in 24 hours. Leukemic colony forming progenitors were also reduced by CC-90009 in a dose-dependent manner. We next tested the efficacy of CC-90009 against primary AML samples in xenografts in NOD/SCID mice. Leukemia cells were transplanted intrafemorally 21 days prior to CC-90009 treatment. Mice were treated with vehicle or CC-90009 at 2.5mg/kg BID for 4 weeks. Heterogeneous responses to the CC-90009 treatment were observed. Of 35 AML samples tested, 16 were highly responsive to CC-90009 with >75% reduction of AML engraftment, 10 showed moderate response between 45% and 75% reductions, and 9 showed reductions of <25%. AML is clinically characterized by accumulation of blasts that are impaired for differentiation and maturation. We observed that, in addition to the reduction of total AML graft, CC-90009 also induced myeloid differentiation of AML blasts in the CC-90009 responders, as evidenced by increases in late myeloid cell surface markers (CD14, CD15 and CD11b) and reductions of the immature marker CD34. To determine the efficacy of CC-90009 against AML cases at high risk of relapse following standard induction chemotherapy, we assessed CC-90009 efficacy vs. the status of an expression-based 17-gene leukemia stem cell score (the LSC17 score) that was recently implemented for rapid risk stratification of AML patients (Ng et al, Nature 2016). LSC17-high patients are predicted to have poor treatment response and poor clinical outcome. We found that, while 8 out of 9 poor responders to CC-90009 had high LSC17 scores, 20 out of 28 samples that had high LSC17 scores responded well to CC-90009, indicating that the drug is able to target high risk cases. Serial transplantation utilizing limiting dilution analysis showed that CC-90009 targeted self-renewing LSCs. Our data established that a new CELMoD CC-90009 has anti-proliferative effects on human primary AML cells and self-renewing LSCs evaluated in xenograft assays. These observations provide important implications for CC-90009 in its clinical development as a new therapeutic agent to treat AML patients with high risk disease when treated with standard of care therapies. Currently, a phase I study evaluating CC-90009 in relapsed or refractory AML is ongoing (CC-90009-AML-001; NCT02848001). Disclosures Jin: Trillium Therapeutics: Other: licensing agreement. Ng:Celgene: Research Funding. Wang:Pfizer AG Switzerland: Honoraria, Other: Travel and accommodation; Trilium therapeutics: Other: licensing agreement, Research Funding; NanoString: Other: Travel and accommodation; Pfizer International: Honoraria, Other: Travel and accommodation. Minden:Trillium Therapetuics: Other: licensing agreement. Fan:Celgene Corporation: Employment, Equity Ownership. Pierce:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership.

Background: CC-90009 is a novel cereblon E3 ligase modulator (CELMoD), which is currently under investigation in a first-in-human, phase I study (CC-90009-AML-001; NCT02848001) in patients with R/R AML. In preclinical models, CC-90009 drives the binding of the target protein, translation termination factor G1 to S phase transition 1 (GSPT1), to cereblon and induces its ubiquitination and proteasome-dependent degradation. Loss of GSPT1 results in activation of the integrated stress response (ISR), inhibition of nonsense-mediated decay (NMD), and induction of apoptosis. Deep degradation of GSPT1, mediated by CC-90009, led to AML cell death in vitro and potent antitumor activity in patient-derived AML xenograft models. In the ongoing phase I study, CC-90009 has demonstrated antileukemic activity. Here, we characterize the pharmacodynamic responses using a suite of novel assays to support CC-90009 dose and schedule optimization. Methods: Adult patients with R/R AML received intravenous CC-90009 daily on Days 1-5 (D1-5 schedule) or on Days 1-3 and 8-10 (D1-3/8-10 schedule) of a 28-day cycle. Peripheral blood samples taken before, during, and after dosing in the first treatment cycle were analyzed. Levels of intracellular GSPT1 in blasts and normal blood cell types were quantitated by flow cytometry analysis. Transcript levels of ISR and NMD variants in peripheral blood mononuclear cells (PBMC) were measured by qPCR. Bone marrow (BM) core biopsies at screening, Cycle 1 Day 5 and 28, and Cycle 2 and 4 Day 28, were analyzed for GSPT1, cleaved caspase 3, and CD34 protein expression by immunohistochemistry. ATF3 and DDIT3 mRNA levels were assessed in BM samples by RNA in situ hybridization. Results: The rate and depth of GSPT1 loss in T cells and in circulating AML blasts increased with dose. A marked reduction in GSPT1 was observed in T cells and blast cells of most patients after the first dose of CC-90009 at all dose levels, and GSPT1 levels approached the assay floor between Days 2 and 5 at doses of 1.2 mg and higher on the D1-5 schedule. At 2.4 mg and higher on the D1-5 schedule, a reduction in GSPT1 levels of > 90% was observed in T cells (19 of 29 patients) and in blast cells (11 of 29 patients), with stronger GSPT1 reductions detected in AML blasts and normal T cells compared with B cells or granulocytes. In the 3 mg D1-5 cohort, patients with sustained GSPT1 reduction in peripheral blasts in the days following treatment had more persistent blast suppression compared with patients showing an earlier rebound of GSPT1. At 3 mg and 3.6 mg dose levels, continuous treatment (D1-5) resulted in slower kinetics of GSPT1 rebound and conferred superior antileukemic activity compared with the intermittent dosing schedule (D1-3/D8-10). In addition to measuring the direct target of CC-90009, GSPT1, we also investigated markers downstream of GSPT1 degradation. Several patients with deep and sustained GSPT1 loss in the high-dose cohorts (2.4 mg and above) showed increased levels of ISR-related transcripts (ATF3 and DDIT3) and NMD-associated splice variants (SRSF3 and SRSF6) in on-treatment PBMC samples. Similarly, in BM, deep GSPT1 loss coincided with induction of ATF3 and DDIT3 mRNA, increased cleaved caspase 3 expression, and reduced CD34+ blasts. These clinical findings are consistent with our preclinical studies in which GSPT1 loss culminated in apoptosis, which may be mediated through activation of ISR and inhibition of NMD pathways. Conclusions: CC-90009 is a novel CELMoD and a first-in-class GSPT1 degrader. A suite of novel pharmacodynamic assays performed on patient-derived peripheral blood cells and BM demonstrated a dose-dependent modulation of GSPT1, and showed that the preclinical mechanisms of ISR induction, NMD inhibition, and apoptosis can be confirmed in AML cells in patients. Deeper and more rapid GSPT1 degradation as well as delayed rebound were associated with more rapid, deeper, and more persistent blast reductions. Characterization of these pharmacodynamic responses in ongoing dose-schedule explorations will help identify the optimal scheme for the expansion phase and provide further insight into the mechanism of clinical response. Disclosures Fan: Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Yao:Celgene Corporation: Employment. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Zeidan:Pfizer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Montesinos:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Jazz Pharmaceuticals, Inc.: Consultancy; Takeda Pharmaceuticals: Consultancy; Shire: Consultancy; GlycoMimetics: Research Funding; Pfizer, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy; Celgene Corporation: Consultancy; AbbVie, Inc.: Research Funding; Blue print Medicines: Consultancy, Research Funding; Amgen: Consultancy. Altman:Novartis: Consultancy; Cancer Expert Now: Consultancy; Biosight: Other: US Lead; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee. Koprivnikar:Amgen: Speakers Bureau; Abbvie: Speakers Bureau; Pfizer: Honoraria; Novartis: Speakers Bureau. Vyas:Astellas: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding. Fløisand:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Honoraria. Gjertsen:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; EU Horizon 2020: Research Funding; KinN Therapeutics AS: Equity Ownership; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; ERA PerMed: Research Funding; The Norwegian Cancer Society: Research Funding; Helse Vest Health Trust: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Research Council of Norway: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ACTII AS: Equity Ownership. Buchholz:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Pierce:Celgene Corporation: Employment, Equity Ownership.