Abstract: BACKGROUND: Isocitrate dehydrogenase 2 (IDH2) mutations are found in about 10-15% of acute myeloid leukemia (AML) cases. Enasidenib (ENA) is a first-in-class mutant IDH2 inhibitor that induces differentiation of IDH2-mutated leukemic cells. However, the clinical efficacy of single agent ENA therapy in relapsed or refractory (R/R) AML is limited, underscoring the need for combination therapy. Preclinical studies have shown that IDH-mutated leukemic cells are particularly sensitive to BCL2 inhibition with venetoclax (VEN), a finding supported by clinical studies of VEN combination therapies. We previously demonstrated that the combination of ENA and VEN can be more effective than each drug alone, in reducing leukemic burden in patient-derived xenograft models of IDH2-mutated AML. Here, we report preliminary safety and efficacy results of an ongoing open-label, single-arm, phase Ib/II trial (NCT04092179) of ENA in combination with VEN in patients with IDH2-mutated myeloid malignancies. METHODS: Patients 18 years of age or above with IDH2-mutated R/R AML or high-risk MDS/MPN and an ECOG performance status of 0-2 were eligible. Patients previously treated with an IDH2 or BCL2 inhibitor were excluded. Participants received VEN continuously starting on cycle 1 day 1 with a 3-day ramp-up to a target dose of 400 mg daily (dose level 0) in cohorts 1 and 2. ENA was administered at 100 mg daily continuously starting on cycle 1 day 15. Each cycle was 28 days. Concurrent use of a moderate or strong CYP3A4 inhibitor was allowed with 50% dose reduction of VEN after completion of the first 2 cycles at 100% target dose. Interruptions of VEN and/or ENA were permitted for management of adverse events (AEs). Primary endpoints were 1) safety and tolerability and 2) overall response rate (ORR) defined as complete remission (CR) + CR with incomplete blood count recovery (CRi) + morphologic leukemia-free state (MLFS) + partial remission (PR) by revised IWG criteria. Secondary endpoints include pharmacokinetic (PK) profiles of VEN, duration of response, overall survival (OS), and IDH2 mutant allele burden in bone marrow by ddPCR. RESULTS: The study opened to recruitment in November of 2020. As of July 28, 2021 (data cutoff), 11 patients were enrolled on study; 10 with R/R AML and 1 with very-high risk MDS by IPSS-R. Six patients had a R140Q mutation, and 5 had a R172K mutation. Median age was 72 years (range: 32 - 80); 6 patients were male. Participants had received a median of 2 prior lines of therapies (range: 1 - 4). Six of 10 AML patients had primary refractory disease. The MDS patient experienced secondary azacitidine failure. Key treatment emergent grade ≥ 3 AEs regardless of attribution were: febrile neutropenia (n=3), intracranial hemorrhage (n=3), lung infection (n=2), other infection (n=2), elevated AST/ALT (n=2), sepsis (n=1), leukocytosis (n=1), TRALI (n=1), and small bowel obstruction (n=1). No cases of differentiation or tumor lysis syndrome were observed. No patients discontinued the study due to AEs. The addition of ENA, a known inhibitor of CYP3A4, did not significantly affect the PK profiles of VEN. Nine of the AML patients completed at least 1 cycle of treatment and are considered evaluable for efficacy. One AML patient died from intracranial hemorrhage prior to completion of cycle 1. Median duration of observation is 3.5 months. Of the evaluable patients, CR was achieved in 2 patients (22%) and CRi in 3 patients (33%) for an ORR of 55% (Fig. 1). Median number of cycles to response was 3. All responders remain in remission and on study with a median of 6 cycles received to date (range: 3 - 8). Of the remaining 4 patients, 2 patients (22%) remain on study with stable disease, and 2 patients (22%) experienced progressive disease and died (one after 7 cycles and the other after 1 cycle). Median OS for the entire cohort has not been reached. A sustained reduction in mutant IDH2 allele frequency in bone marrow correlated with response (Fig. 2). For the MDS patient, no response was observed after 1 cycle of treatment. CONCLUSIONS: VEN in combination with ENA is a well-tolerated regimen with no dose-limiting toxicities observed at the current dose level. The preliminary efficacy of this combination is encouraging with an ORR of 55% in evaluable R/R AML patients, with some responders achieving deep molecular remissions. Patient enrollment in dose-escalation cohorts is ongoing. Figure 1 Figure 1. Disclosures Chan: AbbVie: Research Funding; BMS: Research Funding. Gupta: Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Constellation Pharma: Consultancy, Honoraria; Incyte: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Roche: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy. Maze: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria; Takeda: Research Funding; PharmaEssentia: Research Funding; Kronos Bio: Research Funding. Minden: Astellas: Consultancy. Schimmer: Takeda Pharmaceuticals: Consultancy, Research Funding; Medivir AB: Research Funding; Novartis: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Otsuka Pharmaceuticals: Consultancy, Honoraria; UHN: Patents & Royalties. Schuh: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlycoMimetics: Research Funding; Kite/Gilead: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees; Teva: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee: Pfizer: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; F. Hoffmann La Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Onconova: Research Funding; Bristol-Myers Squibb/Celgene: Membership on an entity's Board of Directors or advisory committees; Otsuka: Membership on an entity's Board of Directors or advisory committees; Paladin: Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding; MedImmune: Research Funding; Jazz: Research Funding; TaiHo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo: Agios/Servier: Consultancy, Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; AbbVie: Consultancy, Research Funding; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Forma: Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. OffLabel Disclosure: Enasidenib is approved for the treatment of relapsed or refractory AML as single agent. Venetoclax, in combination with azacitidine or low-dose cytarabine, is approved for the treatment of newly diagnosed AML patients who are 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy.

Abstract: Introduction: Isocitrate dehydrogenase (IDH) enzymes catalyze the NADP-dependent interconversion of isocitrate and α-ketoglutarate. R132* IDH1 mutations lead to cellular accumulation of 2-hydroxyglutarate (2-HG), an oncometabolite that promotes tumorigenesis. IDH1 mutations are found in glioma (~80%), chondrosarcoma (~50%), cholangiocarcinoma (~20% intrahepatic), acute myeloid leukemia (AML; ~6-9%), and myelodysplastic syndrome (MDS; ~3%). IDH305 is a potent, orally available, mutant-selective, allosteric IDH1 inhibitor. IDH305 suppresses mutant IDH1-dependent 2-HG production and cell proliferation with an IC50 of 24 nM, and has antitumor activity in preclinical studies. Methods: The objectives of this ongoing phase I clinical trial in patients with advanced cancers are to evaluate the safety and tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and preliminary antitumor activity of IDH305 (IDH305X2101, NCT02381886). This trial is specifically designed to evaluate the safety of IDH305 both across and within 3 broad disease areas: glioma, AML/MDS, and other/non-CNS solid tumors with the IDH1R132 mutation. IDH305 is orally administered twice a day (BID) in continuous 21-day cycles. The starting dose of 75 mg BID was determined from 4-week toxicology studies following ICH Guideline S9. Dose escalation is guided by a Bayesian hierarchical model (BHM), which evaluates the dose-limiting toxicity (DLT) relationship to the collective population, as well as to specific disease areas, across dose levels, to model the similarity in the rate of DLTs during the first cycle of treatment. The BHM permits the declaration of different maximum tolerated doses (MTDs)/recommended doses for expansion (RDEs) for 3 disease areas, if suggested by the data. Dose expansions in disease-specific cohorts are designed to further characterize safety and explore antitumor activity. Pre- and on-treatment specimens (blood, tumor) are being collected for PK and PD evaluations. Results: As of the data cut-off, March 30, 2016, 81 patients have been enrolled: glioma (n=32), AML (n=21), MDS (n=3), other/non-CNS solid tumors (n=24), and unknown (n=1). Patients were treated with IDH305 on a BID schedule at various doses: 75 mg (n=6), 150 mg (n=11), 300 mg (n=16), 450 mg (n=9), 550 mg (n=16), 750 mg (n=10), and 900 mg (n=13). During dose escalation, DLTs of Grade 3 elevated bilirubin were observed in 2 patients with solid tumors (2 at 550 mg BID), 1 patient with glioma (900 mg BID) who also experienced a DLT of Grade 3 elevated lipase, and 1 patient with AML (750 mg BID). A DLT of Grade 3 rash was observed in 1 patient with a solid tumor (750 mg BID). All DLTs resolved and were considered reversible. MTDs for each disease area were not determined. RDE was determined for glioma (550 mg BID) and solid tumors (550 mg BID). Dose escalation continues for AML/MDS. Across all 3 disease areas, the most common adverse events (AE) reported as suspected of being related to IDH305 ( 〉 10%, all grades) included: bilirubin increased (30.9%); aspartate aminotransferase (AST) increased (17.3%); alanine aminotransferase (ALT) increased (16.0%); and nausea (13.6%). Grade 3 AEs suspected to be related to IDH305 that occurred in 〉 1 patient included: bilirubin increased (8.6%)/hyperbilirubinemia (2.5%); AST increased (2.5%); and ALT increased (3.7%). Among 24 AML/MDS patients (21 relapsed/refractory AML and 3 MDS), the most common suspected AEs reported as being related to IDH305 ( 〉 5%, all grades) included: raised bilirubin and lipase (8.3% each). There was one Grade 3 AE of increased bilirubin that was also a DLT. Objective responses were reported in 7 (33%) AML patients: complete remission in 2 (9.5%), complete remission with incomplete recovery in 1 (4.8%), and partial remission in 4 (19.0%) patients. Responses appear durable. PK, PD, and updated clinical safety and efficacy data will be reported. Conclusion: Preliminary clinical data suggest that IDH305 has a favorable safety profile and promising antitumor activity in IDH1-mutated AML. Studies to further evaluate the safety, tolerability, and antitumor activity of IDH305 as a single agent and in combination are ongoing. Disclosures DiNardo: Agios: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding. Schimmer:Novartis: Honoraria. Yee:Novartis Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hochhaus:BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Carvajal:Novartis: Consultancy. Janku:Agios: Research Funding; Novartis: Consultancy, Research Funding. Bedard:Novartis: Research Funding. van den Bent:Novartis, Roche, AbbVie, Celgene, BMS: Consultancy. O'Keeffe:Novartis: Employment. Chen:Novartis Pharmaceuticals Corporation: Employment. Pagliarini:Novartis Institutes for Biomedical Research: Employment, Equity Ownership, Patents & Royalties. Schuck:Novartis: Employment. Myers:Novartis Institutes of Biomedical Research: Employment, Equity Ownership. Wei:Novartis: Honoraria, Research Funding.

Abstract: RUNX1 is a master-transcriptional regulator involved in normal and malignant hematopoiesis. Majority of mono-allelic germline mutations in RUNX1 are missense, large deletions or truncation mutations, behaving mostly as loss of function (LOF) mutations. They are ~40%-penetrant and cause Familial Platelet Disorder (RUNX1-FPD) that has a propensity to evolve into myeloid malignancy (FPD-MM), i.e., MDS or AML. FPD-MM harbors co-mutations, most commonly on the second allele of RUNX1, and on BCOR, PHF6, K-RAS, WT1 or TET2, which confer relative resistance to standard therapy for MDS or AML. Although curative in some patients with FPD-MM, allogeneic transplantation from matched, un-related donors carries risk of graft versus host disease and frequent AML relapse. This creates a strong rationale and an unmet need to develop novel targeted therapies for FPD-MM. We previously reported on utilizing the RNA-Seq signature of RUNX1 knockdown, which exerted more lethality in AML cells with mutant (mt) RUNX1 compared to AML harboring two copies of wild-type RUNX1, for conducting LINCS1000-CMap analysis. This identified several expression mimickers (EMs), including the protein synthesis inhibitor homoharringtonine (HHT or omacetaxine) and anthelmintic fenbendazole (analog of mebendazole). Present studies demonstrate that treatment with HHT or mebendazole (MB) dose-dependently induced significantly greater loss of viability in four patient-derived (PD) bone marrow aspirate (BMA) samples of FPD-MM (3 AML and 1 MDS) compared to RUNX1-FPD (3 samples) or in normal CD34+ progenitor cells. In a patient with RUNX1-FPD (expressing mtRUNX1 K194N), who developed FPD-MM, following co-mutations were documented by NGS: BCOR A1437fs, PHF6 L324fs, SF3B1 D781G and SRSF2 P95R/L. From BMA of this patient, we successfully established the first ever, continuously cultured cell line (GMR-AML1) expressing the same germline mtRUNX1. GMR-AML1 cells were cytogenetically diploid and lacked MYC or MLL1 rearrangement, or any copy number gains or losses on array CGH. However whole exome sequencing (WES) identified additional mutations in TP53 (P72R), AIM2 (K340fs), NELFB (L523F), CEP152 (Y370X), SUGP2 (H23L), RRM2B (R71fs), TADA3 (T27R), SPDYE6 (G292C) and PRDM9 (S814R) with % VAF ranging between 33 to 55%. GMR-AML1 cells exhibited high surface expression of CD117 (c-KIT), CD123 (IL3R), CD86 and CD33, but without expression of CD34, CD14, CD11b, MPO or CD135 (FLT3). Compared to the AML OCI-AML5 cells with somatic mtRUNX1, GMR-AML1 cells demonstrated markedly reduced protein expression of RUNX1, RUNX2, PU.1, c-Myb, GFI1, GFI1B, FLT3, MEIS1 and CEBPα (p42), but much higher protein expression of RUNX3 and NOTCH (p120). CRISPR-Cas9 knockout of RUNX3 in GMR-AML1 cells restored RUNX1 expression, while significantly increasing % of differentiated cells. Although dose-dependently sensitive to daunorubicin, etoposide, cytarabine and panobinostat (class I and II HDAC inhibitor), GMR-AML1 cells were relatively insensitive to venetoclax, A1155463 (Bcl-xL inhibitor), AZD-5991 (MCL1 inhibitor), azacytidine or decitabine. Notably, treatment with HHT or MB dose-dependently induced loss of viability of GMR-AML1 cells (LD50: 40 and 330 nM, respectively). Additionally, co-treatment with HHT and venetoclax synergistically induced apoptosis in GMR-AML1 cells, as determined by the SynergyFinder algorithm. This synergy in GMR-AML1 cells was associated with abrogation of venetoclax-induced increase in MCL1 and Bcl-xL levels, as well as greater decline in levels of RUNX3, PU.1, c-Myb, c-Myc, MPL and CDK4/6. Tail vein infusion and engraftment of luciferase-transduced GMR-AML1 (10 6 cells) caused marked splenomegaly and 100% mortality of NSG mice by day-18, post-infusion. We will present at the ASH meeting findings of ongoing in vivo studies determining effects of treatment with HHT and/or venetoclax, versus vehicle control, on AML burden and overall survival of NSG mice engrafted with GMR-AML1 cells. Overall, preclinical findings presented here highlight the molecular and genetic features associated with progression of RUNX1-FPD to FPD-MM, especially in the newly established GMR-AML1 cell line. They also demonstrate that HHT or MB are preferentially more lethal against FPD-MM versus RUNX1-FPD cells and exert synergistic lethality with venetoclax against GMR-AML1 cells. Disclosures DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Takahashi: GSK: Consultancy; Celgene/BMS: Consultancy; Symbio Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Khoury: Stemline Therapeutics: Research Funding; Angle: Research Funding; Kiromic: Research Funding.

Abstract: Background: Bromodomain and extra-terminal domain (BET) family proteins represent a novel target class for patients (pts) with myeloid malignancies. Pharmacologic inhibition of BET proteins transcriptionally downregulates critical pro-survival and anti-apoptotic genes. We hypothesized that combination of BET inhibitor (BETi) with hypomethylating agent (HMA) azacitidine (AZA) could lead to clinical benefit for high-risk (HR) pts with R/R MDS and AML. Methods: We conducted an investigator-initiated, single-center, phase I, 3+3 dose-escalation and cohort expansion study of PLX51107 (BETi) + AZA in pts with R/R HR MDS (intermediate-2 score or & gt;10% blasts) or R/R AML. PLX51107 was administered PO on days 1-21 and AZA 75 mg/m2 IV on days 8-14 of a 28-day cycle. Dose-escalation phase of PLX51107 doses included: 40mg (n=4), 80mg (n=3), and 120mg; ultimately, no formal MTD was reached, therefore the 120mg dose was administered to the remaining 30 pts treated on study. Results: 37 pts were treated [R/R AML (n=33); R/R HR MDS (n= 4)]. Baseline characteristics included in Table. Median age was 64 years [18-85 years] . 51% female. Baseline cytogenetics: Notably, 18 pts (49%) had chromosome (chr) 3 abnormalities (abnl) [(either alone or with complex cytogenetics) with 15/18, or 89%, + for EVI1/MECOM gene rearrangement by FISH. 81-gene panel Next Generation Sequencing (NGS) showed: NRAS (n=11); TP53 (n=9); ASXL1, PTPN11, RUNX1, SF3B1, & WT1 (n=6 each). Median prior # therapies = 3 [1-9]; 97% had prior HMA therapy; 84% had prior venetoclax (VEN).17 (46%) pts had prior stem cell transplant (SCT); 7 of whom were on concurrent active immunosuppressive therapy for GVHD prophylaxis at time of enrollment and continued on study (n=6 tacrolimus; n=1 sirolimus). 9 had prior myeloproliferative neoplasm (MPN) or MDS preceding AML. 16 (43%) had prior malignancy (including lymphoma n=3). Toxicities: Median # cycles on therapy = 2 [1-19+] . Most common grade 1/2 non-hematologic toxicities: fatigue 3%; cholecystitis 3% and vomiting 3%. Notable grade 3/4 non-hematologic toxicities: 9 (24%) pts had elevated bilirubin/liver function tests (n=2 Grade 4 and n=7 Grade 3) and n=24 had infections. Hematologic toxicities were n=7 (4 Grade 3, 3 Grade 4) anemia; n=6 (all Grade 4) thrombocytopenia, n=3 (2 Grade 3, 1 Grade 4) neutropenia. Outcomes: Overall Response Rate (ORR) = 8/37 (22%): complete remission with incomplete platelet counts (CRp) (n=1); morphological leukemia-free state (MLFS) (n=2) (both MLFS responders had chr 3 abnl); hematologic improvement (HI) (n=5). Additionally, 5 other pts had & gt;50% bone marrow blast reduction. 4 pts were able to stay on study ≥6 months, with one patient staying on active therapy with ongoing clinical benefit for ≥1 year (16.7 months+). Notably, 10/13 (77%) of all of these responding pts occurred in prior VEN-treated pts. 6/13 (46%) of all responses occurred in RUNX1 or NRAS/KRAS family-mutated pts. Median time on study was 4.8 months [0.4-16.7]. Median overall survival was 3.6 [0.4 - 16.7] months (Figure). One remarkable responder, a 70 year-old woman with R/R AML and extensive leukemia cutis, (prior VEN-based therapy), achieved CRp and almost complete resolution of all skin lesions with no major toxicities after 3 cycles of therapy. Laboratory correlative analysis: RNA-Seq analysis of mononuclear cells harvested on- treatment (day 3) vs pre-treatment demonstrated markedly greater fold changes in mRNA expressions in the complete responders, with downregulation of MYC, BCL2, IL7R and CDK6 genes and upregulation of HEXIM, CD93, DCXR and CDKN1A genes. Immunoblot analyses confirmed reduction in the protein levels of c-Myc, CDK6, BCL2 and BCL-xL and induction of BRD4 and HEXIM1 protein levels in the responding pts. Conclusions: In a heavily pre-treated, high-risk group of pts with R/R HR MDS and AML, with 49% chr 3 abnl, 46% prior SCT, and 25% TP53-mutated, we demonstrate that the combination of BETi and HMA is safe, well-tolerated, and results in modest clinical benefit predominantly in prior VEN-treated pts. Future directions may include investigation of novel BETi combinations in VEN-naïve pts, further investigation into high-risk subsets of pts with chr 3 abnl/EVI1/MECOM rearrangements, RUNX1, and RAS-family mutated pts, and further clinical/translational investigation of BETi activity in leukemia cutis/skin lesions in myeloid malignancies. ClinicalTrials.gov Identifier: NCT04022785. Figure 1 Figure 1. Disclosures Pemmaraju: Sager Strong Foundation: Other; Samus: Other, Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; Cellectis S.A. ADR: Other, Research Funding; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; Springer Science + Business Media: Other; DAVA Oncology: Consultancy; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Clearview Healthcare Partners: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Daver: Abbvie: Consultancy, Research Funding; Novartis: Consultancy; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Trovagene: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Ravandi: Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Prelude: Research Funding. Kadia: AstraZeneca: Other; Genfleet: Other; Astellas: Other; Cellonkos: Other; Ascentage: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Pfizer: Consultancy, Other; Novartis: Consultancy; Liberum: Consultancy; Jazz: Consultancy; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; Cure: Speakers Bureau; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. DiNardo: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding. Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Burger: Beigene: Research Funding, Speakers Bureau; TG Therapeutics: Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Novartis: Other: Travel/Accommodations/Expenses, Speakers Bureau; Pharmacyclics LLC: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; Gilead: Consultancy, Other: Travel/Accommodations/Expenses, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Janssen: Consultancy, Other: Travel/Accommodations/Expenses, Speakers Bureau. Short: Novartis: Honoraria; NGMBio: Consultancy; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Alvarado: Astex Pharmaceuticals: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; Jazz Pharmaceuticals: Research Funding; MEI Pharma: Research Funding; Sun Pharma: Consultancy, Research Funding. Jain: TG Therapeutics: Honoraria; Beigene: Honoraria; Precision Biosciences: Honoraria, Research Funding; Incyte: Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pfizer: Research Funding; AstraZeneca: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Servier: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Verstovsek: Promedior: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Roche: Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Issa: Novartis: Consultancy, Research Funding; Kura Oncology: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Khoury: Kiromic: Research Funding; Angle: Research Funding; Stemline Therapeutics: Research Funding. Konopleva: Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Cellectis: Other: grant support; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Rafael Pharmaceuticals: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Sanofi: Other: grant support, Research Funding; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; KisoJi: Research Funding. Kantarjian: Astra Zeneca: Honoraria; Aptitude Health: Honoraria; Jazz: Research Funding; Daiichi-Sankyo: Research Funding; Astellas Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; AbbVie: Honoraria, Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Borthakur: Takeda: Membership on an entity's Board of Directors or advisory committees; ArgenX: Membership on an entity's Board of Directors or advisory committees; Ryvu: Research Funding; Astex: Research Funding; University of Texas MD Anderson Cancer Center: Current Employment; Protagonist: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy.