ALBERT

Description: Background: Mutations in IDH2 occur in 8-19% of patients (pts) with AML. Enasidenib (ENA; AG-221) is an oral, small-molecule inhibitor of mutant IDH2 (mIDH2) that promotes myeloid cell differentiation. ENA is approved in the US for use in adult pts with relapsed/refractory mIDH2 AML. Azacitidine (AZA) is a hypomethylating agent that prolongs survival vs. conventional care regimens in older unfit pts with newly diagnosed (ND) AML. AZA promotes DNA hypomethylation by inhibiting DNA methyltransferases. ENA indirectly reduces DNA methylation by suppressing the oncometabolite, 2-hydroxyglutarate (2-HG), thereby restoring function to α-ketoglutarate-dependent TET family enzymes, among other substrates. In vitro, combination ENA + AZA enhances cell differentiation. This is the first report of interim outcomes from the randomized, phase II portion of an ongoing, open-label, phase I/II study of ENA + AZA vs. AZA monotherapy (AZA-only) in pts with mIDH2 ND-AML who are not candidates for intensive chemotherapy (IC) (NCT02677922). Methods: Adult pts with mIDH2 ND-AML who were ineligible to receive IC and had ECOG PS scores ≤2 were randomized in a 2:1 ratio to receive ENA + AZA or AZA-only in repeated 28-day cycles. All pts receive SC AZA 75 mg/m2/day for the first 7 days of each treatment (Tx) cycle; pts randomized to ENA + AZA also receive continuous ENA 100 mg QD. The primary endpoint is overall response rate (ORR), which includes complete remission (CR), CR with incomplete blood or platelet count recovery (CRi/CRp), partial remission (PR), and morphologic leukemia-free state (MLFS), per modified IWG 2003 AML response criteria. P values for response comparisons between Tx arms were derived using chi-square test. Duration of response (DOR) was estimated by Kaplan-Meier method. mIDH2 variant allele frequencies (VAF) in bone marrow mononuclear cells (BMMCs) were assessed by digital PCR. Results: Between Oct. 2016 and Aug. 2018, 101 pts were randomized to receive ENA + AZA (n=68) or AZA-only (n=33). Median ages were 74 years (range 62-85) in the ENA + AZA arm and 75 years (57-85) in the AZA-only arm. Among pts with available data, 78% in the ENA + AZA arm (43/55) and 90% (19/21) in the AZA-only arm had intermediate-risk cytogenetics, respectively, and 18% and 10% had poor-risk cytogenetics. At data cutoff (Feb. 2019), 39 pts were still receiving their randomized Tx. Most common reasons for study discontinuation in the ENA + AZA and AZA-only arms were death (31% and 27%, respectively) and pt decision (4% and 12%). Two pts in the ENA + AZA arm and 1 pt in the AZA-only arm proceeded to transplant. Median number of Tx cycles was 8 (range 1-24) in the ENA + AZA arm and 6 (1-22) in the AZA-only arm; 27% and 19% of pts, respectively, received ≥12 Tx cycles. Response rates were significantly higher with combination treatment vs. AZA alone: ORRs were 68% vs. 42%, respectively (P=0.0155), and CR rates were 50% vs. 12% (P=0.0002) (Table). Median DOR was not reached with ENA + AZA and was 10.2 months in the AZA-only arm (P=0.13). Maximal mIDH2 VAF suppression from baseline was significantly greater with ENA + AZA vs. AZA-only (median -69.3% vs. -14.1%, respectively; P=0.0004). Tx-related grade 3-4 adverse events occurring in ≥10% of pts in the combination arm were neutropenia (34%), thrombocytopenia (34%), anemia (21%), febrile neutropenia (12%), and IDH differentiation syndrome (IDH-DS; 10%); these events occurred in 19%, 19%, 22%, 13%, and 0% of pts in the AZA-only arm. Rate of Tx-related grade 3-4 infections was 16% in the ENA + AZA arm and 31% in the AZA-only arm. In all, 12 pts (18%) in the ENA + AZA arm experienced IDH-DS (any grade) at a median of 37 days. In the first 60 days, 5 deaths (7%) were reported in the ENA + AZA arm (3 due to infectious complications and 2 due to possible IDH-DS) and 1 death (3%) was reported in the AZA-only arm due to progressive disease. Conclusions: ENA + AZA was associated with significantly improved complete remission and overall response rates and significant mIDH2 VAF reductions compared with AZA-only. Combination Tx was generally well tolerated, with a safety profile similar to that reported for either monotherapy. An updated data cutoff that includes at least 1 year of follow-up for all pts will be presented at the conference. Updated data will include overall survival, event-free survival, and comprehensive analyses of 2-HG and co-mutation dynamics. Disclosures DiNardo: syros: Honoraria; jazz: Honoraria; medimmune: Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Schuh:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: 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; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Teva Canada Innovation: 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; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stein:Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Fernandez:Teva: 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; Celgene: 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; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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. Wei:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. De Botton:Novartis: Consultancy; Astellas: Consultancy; AbbVie: Consultancy; Pfizer: Consultancy; Pierre Fabre: Consultancy; Daiichi: Consultancy; Celgene Corporation: Consultancy, Speakers Bureau; Servier: Consultancy; Syros: Consultancy; Janssen: Consultancy; Forma: Consultancy, Research Funding; Bayer: Consultancy; Agios: Consultancy, Research Funding. Zeidan: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; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding. Fathi:Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria; Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy. Quek:Celgene: Research Funding, Speakers Bureau; Agios: Research Funding. Kantarjian:Immunogen: Research Funding; Cyclacel: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Novartis: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Research Funding; Ariad: Research Funding; Daiichi-Sankyo: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Frattini:Celgene Corporation: Employment, Equity Ownership. Lersch:Celgene: Employment, Equity Ownership. Gong:Celgene: Employment, Equity Ownership. Franovic:Celgene: Employment, Equity Ownership. MacBeth:Celgene Corporation: Employment, Equity Ownership. Vyas:Celgene: Research Funding, Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding; Abbvie: Speakers Bureau; Pfizer: Speakers Bureau; Astellas: Speakers Bureau. Döhner:Celgene, Novartis, Sunesis: Honoraria, Research Funding; AbbVie, Agios, Amgen, Astellas, Astex, Celator, Janssen, Jazz, Seattle Genetics: Consultancy, Honoraria; AROG, Bristol Myers Squibb, Pfizer: Research Funding.

Description: Ivosidenib (AG-120) and enasidenib (AG-221) are targeted, oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.

Description: Background: Acute myeloid leukemia (AML), a hematologic malignancy characterized by clonal expansion of abnormal myeloid progenitors, is a disease exhibiting a dynamic mutational landscape over time. Somatic mutations in isocitrate dehydrogenase 1 (IDH1) are reported in 6-10% of patients (pts) with AML. Ivosidenib (IVO) is an oral, potent, targeted inhibitor of mutant IDH1 (mIDH1) and is FDA-approved for the treatment of mIDH1 relapsed/refractory (R/R) AML and newly diagnosed (ND) AML in adults ≥ 75 years (yrs) of age or with comorbidities precluding intensive induction chemotherapy (IC). In an ongoing phase 1b study (NCT02677922), 23 pts (11 male; median age 76 yrs [range 61-88]) with mIDH1 ND AML received IVO 500 mg daily and subcutaneous azacitidine (AZA) 75 mg/m2 on Days 1-7 in 28-day cycles. As of 19Feb2019, median number of treatment cycles was 15 (range 1-30); 10 pts remained on treatment. Overall response rate (complete remission [CR] + CRi [incomplete neutrophil recovery] + CRp [incomplete platelet recovery] + morphologic leukemia-free state [MLFS]) was 78% (18/23): including CR in 61% (14/23) and CR with partial hematologic recovery (CRh) in 9% (2/23). mIDH1 clearance assessed in bone marrow mononuclear cells (BMMCs) by BEAMing digital PCR (detection limit 0.02-0.04%) was observed in 11/16 pts (69%) with CR/CRh, including 10/14 (71%) with CR. Aim: Characterize clonal evolution and resistance in pts with mIDH1 ND AML treated on study with IVO + AZA. Methods: The secondary efficacy endpoint of CRh was sponsor derived and defined as CR with absolute neutrophil count 〉 0.5 X 109/L and platelets 〉 50 X 109/L. Bulk DNA sequencing (DNA-seq, 1400-gene ACE Extended Cancer Panel, 2% variant allele detection limit) was performed on BMMCs and/or peripheral blood mononuclear cells (PBMCs). Single-cell (sc) targeted DNA-seq was performed on PBMCs using a microfluidic platform (Tapestri®) with a 20-gene AML panel capable of detecting rare subclones down to 0.1%. Results: To identify mechanisms of acquired resistance, longitudinal bulk DNA-seq was analyzed for 22/23 pts, including 5 pts with available samples at relapse or disease progression (3 CR and 1 MLFS with morphological relapse; 1 CRh with disease progression). Mutations not detected at baseline but emerging during therapy were categorized into canonical biological pathways (Table). Emerging mutations were observed in 9/22 (41%) pts, including 4 with multiple mutations. 3/22 (14%) pts had emerging IDH2 mutations, with concurrent rise in plasma 2-hydroxyglutarate (2-HG) levels. Within the relapse/progression cases, emerging mutations were observed in 4/5 pts, including 3 where the emerging mutation appeared to be the predominant mutation at relapse/progression (2 CR pts with IDH2 mutations, and 1 CRh pt with a TET2 mutation). To date, from the bulk DNA-seq analysis, no emergence of an IDH1 second-site or receptor tyrosine kinase pathway (FLT3, KRAS, NRAS, PTPN11) mutation has been observed. To further evaluate clonal evolution of clinical response and disease progression, scDNA-seq was performed, with data available for 15 pts (10 CR, 2 CRh, 1 MLFS, and 2 stable disease), including end-of-study time points for 5 relapse/progression pts. In the 2 relapsed pts with an emerging IDH2 mutation observed by bulk DNA-seq, 1 had a minor IDH2 clone present at baseline that expanded independently from IDH1 during therapy (Fig). In a separate case, a subclonal baseline PTPN11 clone evolved to gain both RUNX1 and IDH2 mutations, becoming the predominant clone at relapse. In 2 other cases, scDNA-seq data showed that non-IDH1 clones were selected from baseline clones ancestral (TP53 n = 1) to or emerged separate from mIDH1 (TET2 n = 1). Clonal architecture and evolution from additional pts will be presented. Conclusion: IVO + AZA combination treatment in IC-ineligible ND AML led to deep and durable molecular remissions. Although the dataset is small, IDH2 clones appeared to expand or emerge separate from the IDH1 clone, with no observation of an IDH1 second-site mutation to date. Understanding patterns of emerging mutations/pathways at relapse will allow for comparison with mIDH1 R/R AML and ND AML pts treated with IVO monotherapy. These results underline the importance of mutational testing, particularly at progression to determine optimal salvage therapy. Potential combination or sequential therapies should be evaluated prospectively in future clinical trials. Disclosures Daigle: Agios: Current Employment, Current equity holder in private company. Choe:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. DiNardo:Syros: Honoraria; MedImmune: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Stein:Stemline: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Stein:Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotheryx: Consultancy; Bayer: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Research Funding; Seattle Genetics: Consultancy; Abbvie: Consultancy; Amgen: Consultancy; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fathi:Amphivena: Consultancy, Honoraria; Agios: Consultancy, Research Funding; Forty Seven: Consultancy; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Research Funding; Astellas: Consultancy; Takeda: Consultancy; PTC Therapeutics: Consultancy; Novartis: Consultancy; NewLink Genetics: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; TrovaGene: Consultancy; Amgen: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Blue Print Oncology: Consultancy; Boston Biomedical: Consultancy; Kura: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy; AbbVie: Consultancy. Döhner:Pfizer: Research Funding; Sunesis: Other, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Arog: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding. Martinelli:Celgene: Consultancy, Speakers Bureau; Jazz: Consultancy; Incyte: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; Daichii Sankyo: Consultancy, Research Funding; Janssen: Consultancy; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Roche: Consultancy. Patel:France Foundation: Honoraria; DAVA Pharmaceuticals: Honoraria; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy. Tan:AbbVie: Other: Investigator on an AbbVie funded clinical trial; Agios: Research Funding; Janssen: Research Funding; NOHLA Therapeutics: Research Funding; Novartis: Other, Research Funding. Zeidan:Astellas: Consultancy, Honoraria; Taiho: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria; Ionis: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Trovagene: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Acceleron: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Aprea: Research Funding; MedImmune/Astrazeneca: Research Funding; ADC Therapeutics: Research Funding; Cardiff Oncology: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Research Funding; Astex: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Leukemia and Lymphoma Society: Other; CCITLA: Other; Otsuka: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding. De Botton:Forma Therapeutics: Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Syros: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; Pierre Fabre: Consultancy; Janssen: Consultancy, Honoraria; Seattle Genetics: Honoraria; Bayer: Consultancy, Honoraria; Servier: Consultancy. Stone:Syntrix: Consultancy; Macrogenics: Consultancy; Hoffman LaRoche: Consultancy; Stemline: Consultancy; AbbVie: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy; Trovagene: Consultancy; Jazz: Consultancy; Otsuka: Consultancy; Novartis: Consultancy, Research Funding; Argenx: Consultancy, Other: Data and safety monitoring board; Biolinerx: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Research Funding; Daiichi-Sankyo: Consultancy; Agios: Consultancy, Research Funding; Actinium: Consultancy; Celgene: Consultancy, Other: Data and safety monitoring board; Syros: Consultancy; Syndax: Consultancy; Elevate: Consultancy; Gemoab: Consultancy; Janssen: Consultancy. Frattini:BMS: Current Employment, Current equity holder in private company. Franovic:BMS: Current Employment, Current equity holder in private company. Xu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Winkler:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Wu:Agios Pharmaceuticals: Current Employment, Current equity holder in private company. Vyas:Forty Seven: Research Funding; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Astellas: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau.