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.
•Ivosidenib or enasidenib combined with induction and consolidation chemotherapy were both well tolerated in newly diagnosed mIDH1/2 AML.•CR/CRi/CRp rates: 77% (ivosidenib) and 74% (enasidenib); 39% and 23% of patients had mIDH1/2 clearance by digital polymerase chain reaction.
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The BRG/Brahma-associated factors (BAF) family of chromatin remodeling complexes (also referred to as the mSWI/SNF complex) regulates the chromatin landscape of the genome. Through its adenosine ...triphosphate (ATP)-dependent chromatin remodeling activity, BAF complexes regulate the accessibility of gene-control elements, allowing for the binding of transcription factors. Thus, BAF is a major regulator of lineage- and disease-specific transcriptional programs. FHD-286 is a first-in-class, orally administered compound that potently and selectively inhibits the ATPase components of the BAF complexes, SMARCA4 and SMARCA2 (also called BRG1 and BRM, respectively). In preclinical models, acute myeloid leukemia (AML) cell lines were highly sensitive to BAF inhibition. FHD-286-C-002 (NCT04891757) is a multicenter, open-label, Phase 1 dose escalation study designed to determine the safety, tolerability, dose-limiting toxicities (DLTs), and maximum tolerated dose and/or the recommended phase 2 dose(s), as well as to evaluate the preliminary clinical activity of FHD-286, in patients with advanced hematologic malignancies. Patients with relapsed or refractory (R/R) AML or myelodysplastic syndrome (MDS) failing all available standard therapies were eligible to receive FHD-286 doses ranging from 2.5 mg once daily (QD) to 10 mg QD on a continuous dosing regimen. Patients had regularly scheduled assessments to evaluate safety, pharmacokinetics (PK), pharmacodynamics, preliminary clinical activity, and exploratory biomarkers. As of 02 Aug 2022, 40 patients with a median age of 65.5 years (range 25 to 84) with R/R AML (36 patients) or MDS (4 patients) had received at least 1 dose of FHD-286. 67.5% of patients had received ≥3 prior lines of therapy for AML/MDS/other antecedent hematologic disorder, with 22.5% having received ≥5 prior lines. 32.5% of patients had prior hematopoietic stem cell transplant. 65% of patients had adverse risk genetics by 2017 ELN recommendations. 85% of patients experienced a treatment-related adverse event (TRAE) of any grade; the most common (≥20% of patients) were dry mouth (27.5%), increased blood bilirubin (22.5%), and alanine aminotransferase (ALT) increased and rash (20% each). 50% of patients experienced a Grade ≥3 TRAE, the most common of which was increased blood bilirubin (12.5%); stomatitis, ALT increased, differentiation syndrome (DS), and hypocalcemia occurred in 7.5% (each). 2 DLTs were reported: Grade 3 hyperbilirubinemia in 1 patient receiving 5 mg QD and Grade 3 muscular weakness in 1 patient receiving 10 mg QD. Treatment-related DS of any grade was investigator-reported in 4 patients (10%). An independent adjudication committee determined that the rate of suspected DS was 15% (6 patients). 16 patients (15 AML; 1 MDS) had a best overall response of stable disease. Markers of myeloid differentiation with neutrophil recovery and reductions in bone marrow and/or peripheral blasts have been observed in a subset of patients in the study who had a broad range of cytogenetic backgrounds, including patients with enhancer-driven leukemias such as MECOM and KMT2A. Preliminary PK analysis indicates that FHD-286 appears to have a long half-life, at a minimum of >24 hours, and that plasma concentrations of FHD-286 increase with increasing dose. Exploratory flow cytometry assessment of markers of differentiation, hematopoietic stem cell identity, and apoptosis suggested dose-dependent target engagement. Additionally, exploratory sequencing analysis on bone marrow blasts revealed comprehensive impacts on AML-specific expression pathways and stemness genes in response to FHD-286. An exposure-response analysis using the percentage of peripheral blasts showed a trend toward lower blast count with higher FHD-286 area-under-the-curve. Enrollment into the single-agent dose escalation phase of the study is complete. Based on nonclinical, translational, and single-agent clinical data, FHD-286 in combination with decitabine or low-dose cytarabine is being evaluated in the combination dose escalation phase of the study.
Background: Ivosidenib (IVO) and enasidenib (ENA) are oral inhibitors of mutant IDH1 (mIDH1) and mutant IDH2 (mIDH2), respectively, FDA-approved for the treatment of relapsed/refractory IDH-mutant ...acute myeloid leukemia (AML). Here we report updated response and survival results from a phase 1 study of these agents when combined with intensive chemotherapy in patients with newly diagnosed m IDH1/2 AML.
Methods: The design of this open-label, multicenter, phase 1 study (NCT02632708) has been previously described. Briefly, eligible patients with newly diagnosed m IDH1 or m IDH2 AML were treated with induction therapy (daunorubicin 60 mg/m 2/day or idarubicin 12 mg/m 2/day × 3 days with cytarabine 200 mg/m 2/day × 7 days) in combination with either IVO 500 mg once daily (for m IDH1) or ENA 100 mg once daily (for m IDH2). After induction, patients received up to 4 cycles of consolidation therapy while continuing the mIDH inhibitor. Patients who completed or were ineligible for consolidation continued on maintenance IVO or ENA until the end of the study. IDH mutation clearance and measurable residual disease (MRD) negativity were assessed using BEAMing digital PCR and multiparameter flow cytometry (Stein et al. Blood 2021).
Results: As of 16-Jan-2020, 153 patients had been treated: 60 in the IVO cohort (median age 62.5 years, range 24-76) and 93 in the ENA cohort (median age 63.0 years, range 27-77); 2 patients assigned to start ENA on Day 8 had an ongoing adverse event or died on Day 8, and therefore never received ENA and were not included in the efficacy analysis. Secondary AML (sAML; arising after an antecedent hematologic disorder, or after exposure to genotoxic injury) was present in 18/60 (30.0%) IVO-treated patients and in 35/93 (37.6%) ENA-treated patients. In patients with sAML, 4 (22.2%) and 17 (48.6%) IVO-treated and ENA-treated patients, respectively, had previously received a hypomethylating agent. IVO or ENA combined with induction and consolidation were well tolerated (Stein et al . Blood 2021). Among the 60 IVO-treated patients, a response of complete remission (CR), CR with incomplete hematologic recovery (CRi), or CR with incomplete platelet recovery (CRp) was achieved in 37/42 (88.1%) patients with de novo AML and in 10/18 (55.6%) patients with sAML. Among the 91 ENA-treated patients, a response of CR, CRi, or CRp was achieved in 45/56 (80.4%) patients with de novo AML and in 22/35 (62.9%) patients with sAML. Best overall response is reported in Table 1. Patients achieving CR, CRi, or CRp who had available samples were analyzed for IDH mutation clearance and MRD negativity. In those treated with IVO, the IDH1 mutation was cleared in 16/41 (39.0%) patients, and 16/20 (80.0%) were considered MRD negative. In those treated with ENA, the IDH2 mutation was cleared in 15/64 (23.4%) patients, and 10/16 (62.5%) were MRD negative (Stein et al . Blood 2021). Thirty-five (58.3%) IVO-treated patients received ≥1 cycle of consolidation therapy, 18 (30.0%) patients received maintenance after consolidation, 1 (1.7%) patient received maintenance after induction, and 29 (48.3%) patients proceeded to hematopoietic stem cell transplantation (HSCT). Forty-six (49.5%) ENA-treated patients received ≥1 cycle of consolidation therapy, 17 (18.3%) patients received maintenance after consolidation, 7 (7.5%) patients entered maintenance without consolidation, and 43 (46.2%) patients proceeded to HSCT.
Median durations of follow-up were 21.2 and 23.7 months for IVO and ENA, respectively. For patients who entered maintenance, median duration of active maintenance was 13.8 and 11.0 months for IVO and ENA, respectively. Of patients who achieved CR, 7/42 (16.7%) of those treated with IVO and 7/51 (13.7%) of those treated with ENA experienced relapse or death. Overall survival is reported in Figure 1. Updated data from July 2021 will be presented.
Conclusion: IVO or ENA in combination with induction and consolidation therapy have shown acceptable safety profiles, with ≥80% CR+CRi/CRp remission rates in patients with m IDH de novo AML. With over 21 months of follow-up, overall survival rates were high, with 12-month survival probabilities of >75% for both the IVO- and ENA-treated patients. The clinical benefit of adding IVO or ENA to induction, consolidation, and maintenance therapy for patients with newly diagnosed m IDH AML is being further evaluated in the ongoing HOVON150AML randomized phase 3 trial (NCT03839771).
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Stein: Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; PinotBio: Consultancy; Daiichi Sankyo: Consultancy. DiNardo: Takeda: Honoraria; Novartis: Honoraria; AbbVie: Consultancy, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: 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; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Forma: Honoraria, Research Funding. Fathi: Kite: Consultancy, Honoraria; Foghorn: Consultancy, Honoraria; Kura: Consultancy, Honoraria; Trillium: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Blueprint: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria, Research Funding; Servier: Research Funding; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Morphosys: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria. Mims: Syndax Pharmaceuticals: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Kura Oncology: Consultancy; Leukemia and Lymphoma Society: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding; Glycomemetics: Research Funding; Xencor: Research Funding; Daiichi-Saynko: Consultancy. Savona: Karyopharm: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS-Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ALX Oncology: Research Funding; Astex: Research Funding; Incyte: Research Funding. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Stone: Boston Pharmaceuticals: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy; Janssen: Consultancy; Jazz: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Onconova: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Winer: Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy. Döhner: AstraZeneca: Consultancy, Honoraria; Astex: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Berlin-Chemie: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Pfizer: Research Funding; Ulm University Hospital: Current Employment; Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; GEMoaB: Consultancy, Honoraria; Helsinn: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Oxford Biomedicals: Consultancy, Honoraria. Pollyea: Syndax: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Karyopharm: Consultancy, Honoraria; Foghorn: Honoraria; Kiadis: Honoraria; Syros: Consultancy, Honoraria; Novartis: Consu
Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) proteins catalyze production of the oncometabolite D‐2‐hydroxyglutarate (2‐HG). Ivosidenib and enasidenib are oral inhibitors of mIDH1 and mIDH2, ...respectively. An open‐label phase 1 study is evaluating the safety and efficacy of ivosidenib or enasidenib combined with intensive induction and consolidation chemotherapy in adult patients with newly diagnosed mIDH1/2 acute myeloid leukemia (AML; NCT02632708). In this population, we characterized the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD relationships for ivosidenib and enasidenib.
Patients received continuous oral ivosidenib 500 mg once daily or enasidenib 100 mg once daily combined with chemotherapy. Serial blood samples were collected for measurement of the concentrations of the mIDH inhibitors. 2‐HG concentrations were measured in both plasma and bone marrow aspirates. Samples were collected from 60 patients receiving ivosidenib and 91 receiving enasidenib. For both drugs, exposures at steady state were higher than after single doses, with mean accumulation ratios (based on area under the plasma concentration–time curve from time 0 to 24 hours) of 2.35 and 8.25 for ivosidenib and enasidenib, respectively. Mean plasma 2‐HG concentrations were elevated at baseline. After multiple ivosidenib or enasidenib doses, mean trough plasma 2‐HG concentrations decreased to levels observed in healthy individuals and were maintained with continued dosing. There was a corresponding reduction in bone marrow 2‐HG concentrations. When combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML, ivosidenib and enasidenib demonstrated PK/PD profiles similar to those when they are given as single agents. These findings support the dosing of ivosidenib or enasidenib in combination with intensive chemotherapy for the treatment of patients with newly diagnosed mIDH1/2 AML.
Background: Ivosidenib (Ivo) and enasidenib (Ena) are potent, mutant-specific oral inhibitors of the IDH1 and IDH2 proteins, respectively, and are approved as single agents for the treatment of newly ...diagnosed (Ivo) and/or relapsed/refractory (Ivo and Ena) AML. When used as single agents, these inhibitors induce differentiation of leukemic blasts, often without a period of bone marrow (BM) aplasia (PMID 28588020, 29860938). A phase 1 study (NCT02632708) examining the safety and efficacy of Ivo or Ena in combination with intensive induction chemotherapy (IDHi/7+3) in newly diagnosed AML with mutant IDH1 or IDH2 (mIDH) has yielded encouraging response rates in preliminary reports (Stein et al. ASH 2018; Abstract 560). The effect of IDHi/7+3 on BM morphology and whether features of differentiation are seen in this context is unknown. Here, we report the clinicopathologic findings in a cohort of patients treated with IDHi/7+3 and describe a distinct pattern of BM response with implications for post-therapy disease monitoring.
Methods: Investigators from participating sites for NCT02632708 were invited to contribute cases. 36 patients from 4 sites were included with IRB approval at all sites. For each patient, the diagnostic BM biopsy and aspirate smear (BMBx) and all subsequent BMBx performed until end of induction (EOI) or removal from study were reviewed at individual sites based on consensus criteria. A subset of cases was re-reviewed by all pathologists via photomicrographs and digital whole slide images. Patients were categorized into 3 groups based on their Day 14 (D14) BMBx: 1) Aplasia (D14A = <10% cellular; and <5% blasts); 2) Differentiation (D14D = >10% cellular; and >5% blasts at D14; with morphologic or flow cytometric evidence of blast differentiation at D14 or D21); or 3) Persistent AML (D14P = >10% cellular; and >5% blasts; and no differentiation or clearance of blasts at D14 or later time points). Clinicopathologic data was collected from the electronic medical record and from the study database. IDH mutation clearance (MC) was defined as a reduction in the mIDH variant allele frequency in BM mononuclear cells to a level below the limit of detection of the assay (0.02-0.04%) for ≥1 on-treatment time point on or after D28 of induction.
Results: The cohort included 17 mIDH1 patients who received Ivo and 19 mIDH2 patients who received Ena (Table 1, Fig 1); 1 patient in each treatment group had mIDH1 and mIDH2. In the 31 patients evaluable for response at EOI, 27 achieved CR or CRi/p; 2 MLFS; and 2 SD. Of 29 patients with a morphologic response (CR, CRi/p, MLFS), 19 (66%) were classified as D14A (median 5% cellularity; median <5% blasts). Conversely, 10/29 patients (34%) exhibited D14D, with elevated BM cellularity (median 20% 10%, 20%) and increased BM blast percentage (median 45% 5%, 80%). In these cases, granulocytic and/or monocytic differentiation (Fig. 2) was most commonly seen at D14 (8/10) but emerged at D21 for 2/10 patients. Strikingly, despite the elevated cellularity and blast percentages at D14, 7/10 D14D patients subsequently achieved CR/CRi/p by D42 post-induction in the absence of additional intensive therapy; the remaining 3 patients achieved CR/CRi/p after a second cycle of induction. Of the 5 patients not evaluable at EOI, 3 had D14A and 2 had D14P. The 4/36 patients with D14P had a median BM cellularity of 27.5% and a median blast percentage of 33.5% at D14 with no evidence of differentiation.
Differentiation was more common in patients treated with Ena (7/19 36.8%) than patients receiving Ivo (3/17 17.6%) and was seen in 4 of 6 patients with an IDH2R172 mutation. Only 1 of 8 patients with a co-occurring NPM1 mutation showed blast differentiation. Similar rates of IDH MC were seen in patients with D14A (4/22) and D14D (2/10).
Conclusions: We describe here a distinct pattern of BM response, with delayed blast clearance and evidence of leukemic cell differentiation, in mIDH AML patients treated with IDHi/7+3. Our data suggest that patients with relatively high BMBx cellularity and residual blasts at D14 post-induction, even in the absence of evidence of differentiation at D14, should not be considered as induction failures and should be reassessed at later timepoints before being considered for additional induction therapy. Misinterpretation of D14 BMBx may ultimately lead to unnecessary therapy given that a significant subset of patients has an atypical BM response.
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Mason:Sysmex: Honoraria. Pozdnyakova:Sysmex corporation of America: Research Funding. Roshal:Celgene: Other: Provision of Services; Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services. Fathi:Agios, Astellas, Celgene, Daiichi Sankyo, Novartis, Takeda, Amphivena, Kite, Forty Seven,Trovagene, NewLink genetics, Jazz, Abbvie, and PTC Therapeutics: Consultancy; Amphivena, Kite, Jazz, NewLink Genetics,: Honoraria. Stein:Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: 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; 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; Syros: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees. Frattini:Celgene Corporation: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Hua:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Mu:Agios Pharmaceuticals, Inc.: Employment. Almon:Agios Pharmaceuticals: Employment, Equity Ownership. Cooper:Agios: Employment, Equity Ownership. Stone:AbbVie, Actinium, Agios, Argenx, Arog, Astellas, AstraZeneca, Biolinerx, Celgene, Cornerstone Biopharma, Fujifilm, Jazz Pharmaceuticals, Amgen, Ono, Orsenix, Otsuka, Merck, Novartis, Pfizer, Sumitomo, Trovagene: Consultancy; Argenx, Celgene, Takeda Oncology: Other: Data and Safety Monitoring Board/Committee: ; Novartis, Agios, Arog: Research Funding. Hasserjian:Jazz Pharmaceuticals: Consultancy; Promedior, Inc.: Consultancy. Savona:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Ivosidenib and enasidenib are mutant-specific oral inhibitors of the IDH1 and IDH2 proteins, respectively, approved as single agents for the treatment of AML. This study will discuss their use in combination with intensive induction chemotherapy for the treatment of AML.
Abstract
Background: Homozygous deletion of MTAP, the gene encoding the metabolic enzyme methylthioadenosine phosphorylase, occurs in ~15% of human malignancies. Tumor cells with this deletion are ...selectively vulnerable to decreases in the methyl donor S-adenosylmethionine (SAM). AG-270 is a first-in-class, oral, potent, reversible inhibitor of methionine adenosyltransferase 2A (MAT2A), the key enzyme responsible for SAM synthesis. We report preliminary results from an ongoing, first-in-human, phase 1 trial of AG-270 (ClinicalTrials.gov Identifier: NCT03435250). Aims: The primary objective of this study is to determine the maximum tolerated dose (MTD) of AG-270. Secondary objectives include safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Methods: Eligibility requires homozygous deletion of cyclin dependent kinase inhibitor 2A (CDKN2A) in the patient’s tumor (as MTAP is usually co-deleted with CDKN2A), or loss of MTAP by IHC. Patients receive AG-270 daily in 28-day cycles, with intensive PK/PD sampling after the first dose and after 2 weeks of treatment. Paired tumor biopsies are collected at baseline and at the end of cycle 1. Disease evaluation is performed every 2 cycles. Results: As of 20 May 2019, 39 patients had been treated with AG-270: 50 mg once daily (QD; n=3), 100 mg QD (n=7), 150 mg QD (n=6), 200 mg QD (n=11), 400 mg QD (n=6), or 200 mg twice daily (BID; n=6). AG-270 was well absorbed. Plasma concentrations increased in a dose-proportional manner except at 400 mg QD, where exposure was lower than anticipated. The geometric mean area under the curve from 0-24 h at steady state (AUC0-24,ss) in the QD cohorts ranged from 33200 to 199085 ng*h/mL, and the geometric mean AUC0-24,ss in the 200 mg BID cohort was 254616 ng*h/mL. The median half-life of AG-270 ranged from 16.1 to 38.4 h. Decreases in plasma SAM were exposure-dependent. After 2 weeks of dosing, maximal reductions in plasma SAM ranged from 51% to 71% across the tested cohorts. Analysis of 9 paired tumor biopsies by IHC showed decreases in levels of symmetrically di-methylated arginine (SDMA) residues, consistent with MAT2A inhibition; the average H-score reduction compared to baseline was 36.4% -98.8%, +21.4%. Asymptomatic, exposure-dependent increases in unconjugated bilirubin were observed starting at 100 mg QD, consistent with the known potential of AG-270 to inhibit UGT1A1. Three patients (at 100 mg QD, 150 mg QD, and 200 mg BID) developed grade 2 and 3 diffuse erythematous rashes during the second week of dosing that resolved within 1 week of stopping treatment. Exposure-dependent, reversible decreases in platelet counts were first observed at 200 mg QD and were grade 3 and 4 in severity at 200 mg BID. Two patients treated at 200 mg BID developed reversible but dose-limiting grade 3 and 4 increases in liver enzymes. The MTD of AG-270 is 200 mg QD. An unconfirmed partial response has been observed in a patient with a high-grade neuroendocrine carcinoma of the lung. Seven patients have achieved radiographically confirmed stable disease of 2.0 to 9.9 months’ duration. Conclusions: AG-270 causes reductions in plasma SAM and in tumor SDMA levels at well-tolerated doses. This trial will next evaluate the combination of AG-270 with taxane-based chemotherapy, given preclinical data demonstrating enhanced antitumor activity with AG-270 and taxanes in MTAP-deleted cancer models.
Citation Format: Rebecca S Heist, Mrinal M Gounder, Sophie Postel-Vinay, Frederick Wilson, Elena Garralda, Khanh Do, Geoffrey I Shapiro, Patricia Martin-Romano, Gerburg Wulf, Michael Cooper, Caroline Almon, Salah Nabhan, Varsha Iyer, Yanwei Zhang, Kevin Marks, Elia Aguado-Fraile, Frank Basile, Keith Flaherty, Howard A Burris. A phase 1 trial of AG-270 in patients with advanced solid tumors or lymphoma with homozygous MTAP deletion abstract. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr PR03. doi:10.1158/1535-7163.TARG-19-PR03
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Ivosidenib (AG-120) and enasidenib (AG-221) are oral inhibitors of mutant IDH1 (mIDH1) and mutant IDH2 (mIDH2), respectively, approved for the treatment of relapsed/refractory IDH-mutant acute ...myeloid leukemia (AML). Here we report updated results from a phase 1 study on the safety and efficacy of each of these agents when combined with intensive chemotherapy in patients with newly diagnosed AML, as well as data regarding the rate of measurable residual disease (MRD)-negative complete remissions (CRs), mutation clearance and molecular profiling.
In this open-label, multicenter, phase 1 study (NCT02632708), eligible patients with newly diagnosed mIDH1 or mIDH2 AML are treated with induction therapy (daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day x 3 days with cytarabine 200 mg/m2/day x 7 days) in combination with either ivosidenib 500 mg once daily (for mIDH1) or enasidenib 100 mg once daily (for mIDH2). After induction, patients may receive ≤4 cycles of consolidation therapy while continuing the mIDH inhibitor. Patients who complete or are ineligible for consolidation may continue on maintenance ivosidenib or enasidenib until the end of study. For patients who proceed to allogeneic hematopoietic stem cell transplant (HSCT), mIDH inhibitor treatment is discontinued prior to transplant and is not resumed post-transplant.
mIDH1/2 variant allele frequency (VAF) is assessed in bone marrow mononuclear cells using Digital PCR Technology (Sysmex-Inostics Inc). IDH1/2 mutation clearance (IDH-MC) is defined as a reduction in the mIDH1/2 VAF to a level below the limit of detection of this assay (0.02-0.04%) for ≥1 on-treatment time point on or after Day 28 of induction. MRD in bone marrow aspirates is analyzed using multi-parameter flow cytometry. Baseline co-occurring mutations are identified with a 95-gene next generation sequencing panel targeted to hematologic malignancies.
As of May 1, 2018, 134 patients had been treated: 47 with ivosidenib (median age 63 years, range 24-76) and 87 with enasidenib (median age 63 years, range 27-77; Table 1). Secondary AML (sAML; arising after myelodysplastic syndrome or another antecedent hematologic disorder, or after exposure to genotoxic injury) was present in 33/87 (38%) patients with mIDH2 and in 16/47 (34%) patients with mIDH1. The most frequent co-occurring baseline mutations were DNMT3A, NPM1 and NRAS for patients with IDH1 mutations; and DNMT3A, SRSF2 and ASXL1 for patients with IDH2 mutations.
Ivosidenib or enasidenib combined with induction and consolidation was well tolerated, based on the frequency of grade ≥3 non-hematologic adverse events (Table 2) and hematologic recovery (Table 3). Times for ANC and platelet count recovery were nominally longer in patients with sAML.
Among the 41 ivosidenib-treated patients evaluable for efficacy, a response of CR, CRi or CRp was achieved in 26/28 (93%) patients with de novo AML and 6/13 (46%) patients with sAML (Table 4). Twenty-one patients received ≥1 cycle of consolidation therapy and 11 patients received maintenance after consolidation. Seventeen patients proceeded to HSCT.
Among the 77 enasidenib-treated patients evaluable for efficacy, a response of CR, CRi, or CRp was achieved in 33/45 (73%) patients with de novo AML and in 20/32 (63%) patients with sAML (Table 4). Thirty-seven patients received ≥1 cycle of consolidation therapy, 6 patients received maintenance directly after induction and 11 patients received maintenance after consolidation. Thirty-three patients proceeded to HSCT.
Longitudinal VAF data are available for 31 ivosidenib-treated patients and 60 enasidenib-treated patients. In patients who achieved a CR, IDH-MC was observed in 41% (9/22) of those with mIDH1 (Table 5) and in 30% (11/37) of those with mIDH2 (Table 6). Flow cytometry assessments are available for 21 patients achieving a CR: MRD-negative CRs were observed in 89% (8/9) of those with mIDH1 and in 58% (7/12) of those with mIDH2.
Ivosidenib or enasidenib in combination with induction and consolidation therapy has an acceptable safety profile with robust remission rates, MRD-negative CRs, and mutation clearance in a population of older, high-risk patients with mIDH AML. The clinical benefit of adding ivosidenib or enasidenib to induction, consolidation and maintenance therapy for patients with newly diagnosed mIDH AML will be further evaluated in a randomized phase 3 trial.
Stein:Celgene: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. DiNardo:Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Fathi:Jazz: Honoraria; Takeda: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria. Mims:Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Pratz:Boston Scientific: Consultancy; AbbVie: Consultancy, Research Funding; Millenium/Takeda: Research Funding; Agios: Research Funding; Astellas: Consultancy, Research Funding. Savona:Boehringer Ingelheim: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein:Celgene: Speakers Bureau; Amgen: Speakers Bureau. Stone:AbbVie: Consultancy; Merck: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Agios: Consultancy, Research Funding; Sumitomo: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Cornerstone: Consultancy; Astellas: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Otsuka: Consultancy; Jazz: Consultancy; Fujifilm: Consultancy; Arog: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ono: Consultancy; Orsenix: Consultancy. Döhner:Astellas: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; AbbVie: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Pfizer: Research Funding; Celator: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Pfizer: Research Funding. Pollyea:Celgene: Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curis: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees. McCloskey:Amgen Pharmaceuticals: Speakers Bureau; Celgene Pharmaceuticals: Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; COTA: Equity Ownership. Odenike:ABBVIE: Honoraria, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Dava Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncotherapy Science: Research Funding; Agios: Research Funding; Celgene: Research Funding; NS Pharma: Research Funding; Janssen: Research Funding; Astex: Research Funding; Gilead Sciences: Research Funding. Lowenberg:Clear Creek Bio Ltd: Consultancy, Honoraria; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Editorial Board “International Journal of Hematology”: Membership on an entity's Board of Directors or advisory committees; Editorial Board “The Netherlands Journal of Medicine”: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy; “Up-to-Date”, section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Editorial Board “European Oncology & Haemato
Ivosidenib, a small‐molecule inhibitor of mutant isocitrate dehydrogenase 1, is primarily cleared by hepatic metabolism. This open‐label study investigated the impact of hepatic impairment on ...ivosidenib pharmacokinetics (ClinicalTrials.gov: NCT03282513). Otherwise healthy participants with mild (n = 9) or moderate (n = 8) hepatic impairment (Child‐Pugh score) and matched participants with normal hepatic function (n = 16) received 1 oral dose of 500‐mg ivosidenib. Mild hepatic impairment had a negligible effect on total ivosidenib plasma exposure, with geometric mean ratios (90% confidence interval CI) of 0.933 (0.715‐1.22) for maximum concentration (Cmax) and 0.847 (0.624‐1.15) for area under the plasma concentration–time curve (AUC) in participants with mild hepatic impairment versus matched controls. Moderate hepatic impairment reduced total ivosidenib exposure by 28% to 44%, with geometric mean ratios (90%CI) of 0.565 (0.419‐0.763) for Cmax and 0.716 (0.479‐1.07) for AUC, although the 90%CI for AUC included 1.00. The ivosidenib unbound fraction was concentration dependent and higher in participants with mild/moderate hepatic impairment compared with matched controls. There was no apparent trend to increasing unbound Cmax with increased hepatic impairment severity. A single 500‐mg ivosidenib dose was well tolerated, with no serious or severe adverse events and no adverse events leading to discontinuation. We conclude that mild/moderate hepatic impairment did not lead to clinically relevant changes in ivosidenib exposure following a single 500‐mg dose.
Introduction: Isocitrate dehydrogenase (IDH) is a critical enzyme in the citric acid cycle, catalyzing the oxidative decarboxylation of isocitrate to produce alpha-ketoglutarate (a-KG). The mutant ...IDH are not catalytically inactive enzymes, but rather possess novel enzymatic activities, catalyzing the reduction of α-KG to the ‘oncometabolite’ 2-hydroxyglutarate (2-HG), which has been found to be elevated in patients with several tumor types, including acute myelogenous leukemia (AML). AG-221 is an oral, selective, first-in class, potent inhibitor of the IDH2 mutant protein. The compound has been demonstrated to reduce 2-HG levels by >90% and reverse histone and DNA hypermethylation in vitro, and to induce differentiation in leukemia cell models. In vivo pharmacokinetic/pharmacodynamic (PK/PD) studies in a U87MG IDH2 (R140Q) xenograft mouse model demonstrated robust plasma 2-HG lowering, and the correlation between PK (AG-221 exposure) and PD (the inhibition of 2-HG production) was used for human efficacious exposure projection. The PK/PD correlation was further confirmed in a primary human AML xenograft model in mice. These results are compared to early PK/PD results from the ongoing first-in-human Phase I study of AG-221 in patients with advanced IDH2 mutant positive hematologic malignancies NCT01915498.
Methods: This first-in-man Phase I study of oral AG-221 was designed to evaluate the safety, PK, and PD, including 2-HG levels, as well as clinical activity. AG-221 was administered orally once (QD) or twice (BID) per day in continuous 28-day cycles. Sequential cohorts of patients were enrolled at higher dose levels. Patients included in this analysis were enrolled to doses of 30, 50, 75 mg BID and 100 mg QD (total N=21). Patients bearing the two dominant IDH2 mutations, R140Q (85.7%) or R172K (14.3%), were enrolled in the Phase I study. Blood was collected at multiple time points for determination of the PK and PD effects of AG-221. The concentrations of AG-221and 2-HG in plasma samples were determined using a qualified LC-MS/MS based method. PK and PK/PD analyses were performed using WinNonLin®. In addition, PK/PD relationships and efficacy of AG-221 was evaluated in a U87MG IDH2-R140Q xenograft mouse model and a primary human AML xenograft mouse model carrying the IDH2-R140Q mutation following oral doses.
Results: Preliminary analysis of PK demonstrated excellent oral AG-221 exposure in humans. The mean plasma half-life is greater than 40 hours. Plasma 2-HG concentrations decreased rapidly; substantial and constant plasma 2-HG inhibition was achieved following multiple AG-221 doses in patients, and the inhibition was dose and drug exposure dependent. Based on exposure-response analyses with R140Q patients, the AG-221 AUC0-10hr value of 47.1 hr-ug/mL is estimated to result in sustained 90% plasma 2-HG inhibition in human (Figure1) which is associated with IC90 of 66 ng/mL. This is consistent with an in vivo IC90 in an AML xenograft model, U87MG IDH2-R140Q. In addition, up to 50% plasma 2-HG inhibition was observed in limited number of patients with R172K mutation.
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Conclusions: The pharmacokinetic profile for AG-221 supports QD dosing based on the high plasma exposure and long half-life observed in this study. AG 221 suppressed the production of 2-HG in plasma to the normal range found in healthy volunteers. 2-HG inhibition in R140Q mutation was translated well from mice to humans as well as from in vitro to in vivo.
Fan:Agios Pharmaceuticals: Employment, Stockholder Other. Chen:Agios Pharmaceuticals: Employment, Stockholder Other. Wang:Agios Pharmaceuticals: Employment, Stockholder Other. Yen:Agios: Employment. Utley:Agios Pharmaceuticals: Employment, Stockholder Other. Almon:Agios Pharmaceuticals: Employment, Stockholder Other. Biller:Agios Pharmaceuticals: Employment, Stockholder Other. Agresta:Agios Pharmaceuticals: Employment, Stockholder Other. Yang:Agios Pharmaceuticals: Employment, Stockholder Other.
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Mutations in isocitrate dehydrogenase (IDH)1 or IDH2 are seen in ~15-20% of patients with acute myeloid leukemia (AML). Mutant IDH (mIDH) reduces α-ketoglutarate to 2-hydroxyglutarate (2-HG), ...leading to histone hypermethylation and a block in myeloid differentiation, and may also exert leukemogenic effects by inducing dependence on BCL2 and inhibiting homologous recombination. Ivosidenib (AG-120) and enasidenib (AG-221) are oral inhibitors of mIDH1 and mIDH2, respectively, that as monotherapy are associated with robust overall response rates in patients with relapsed/refractory AML. We are assessing the safety and preliminary efficacy of ivosidenib or enasidenib in combination with standard induction chemotherapy.
In this open-label, multicenter, phase 1 study (NCT02632708), eligible patients with newly diagnosed mIDH1 or mIDH2 AML are treated with standard induction chemotherapy (daunorubicin 60 mg/m2/day or idarubicin 12 mg/m2/day x 3 days with cytarabine 200 mg/m2/day x 7 days) in combination with either ivosidenib 500 mg once daily (for mIDH1) or enasidenib 100 mg once daily (for mIDH2). After induction, patients may receive ≤4 cycles of consolidation chemotherapy while continuing the mIDH inhibitor. Patients who either complete or are ineligible for consolidation may continue on maintenance ivosidenib or enasidenib for ≤2 years from the start of induction. Patients may be removed from the study at any point for an allogeneic hematopoietic stem cell transplant (HSCT); these patients do not receive maintenance therapy post-transplant.
As of Apr 18, 2017, 65 patients had been treated: 27 with ivosidenib (median age 60 years, range 24-76) and 38 with enasidenib (median age 63 years, range 32-76, Table 1). Of the 38 patients with mIDH2, 19 (50%) had secondary AML (sAML; arising after myelodysplastic syndrome or another antecedent hematologic disorder, or after exposure to genotoxic injury) compared with 9/27 (33%) with mIDH1. Ivosidenib or enasidenib combined with induction chemotherapy was generally well tolerated. One dose-limiting toxicity was observed (persistent grade 4 thrombocytopenia without leukemia on Day 42 in an enasidenib- and daunorubicin/cytarabine-treated patient). The most frequent grade ≥3 nonhematologic treatment-emergent adverse events during induction therapy, regardless of attribution, in ivosidenib-treated patients were febrile neutropenia (56%), alanine aminotransferase increased (11%), aspartate aminotransferase increased (11%), and colitis (11%); and in enasidenib-treated patients were febrile neutropenia (63%), hypertension (11%), colitis (8%), and maculopapular rash (8%; Table 2). Thirty- and 60-day mortality rates were both 7% in ivosidenib-treated patients, and were 5% and 8%, respectively, in enasidenib-treated patients. Median times for ANC recovery to ≥500/µL were 28 and 34 days for ivosidenib- and enasidenib-treated patients, respectively, and for platelet recovery to >50,000/µL were 28 and 33 days for ivosidenib- and enasidenib-treated patients, respectively. In enasidenib-treated patients with sAML there was an increased time to platelet count recovery (median 50 days). Among 23 efficacy-evaluable ivosidenib-treated patients, a response of CR, CRi, or CRp was achieved in 12/14 (86%) patients with de novo AML and 4/9 (44%) patients with sAML. Among 37 efficacy-evaluable enasidenib-treated patients, a response of CR, CRi, or CRp was achieved in 12/18 (67%) patients with de novo AML and 11/19 (58%) patients with sAML (Table 3). Seven ivosidenib-treated and 14 enasidenib-treated patients received ≥1 cycle of consolidation therapy; 6 ivosidenib-treated and 8 enasidenib-treated patients proceeded to HSCT.
Ivosidenib or enasidenib in combination with standard AML induction therapy is generally well tolerated. The slower platelet recovery observed in patients with mIDH2 sAML may reflect the reduced normal hematopoietic reserve in sAML patients; nevertheless, alternative dosing schedules for enasidenib with induction chemotherapy are being explored to see if delayed platelet recovery can be mitigated. Response rates thus far are encouraging, especially in patients with sAML, many of whom had received hypomethylating agent therapy. To further understand the quality of responses, analyses of minimal residual disease by mutational clearance are underway.
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Stein:Pfizer: Consultancy, Other: Travel expenses; GSK: Other: Advisory Board, Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Constellation Pharma: Research Funding; Seattle Genetics: Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Novartis: Consultancy, Research Funding. DiNardo:AbbVie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mims:Novartis: Honoraria. Savona:Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Equity Ownership; Incyte Corporation: Consultancy, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stein:Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Fathi:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: 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; Pfizer: Honoraria. Stone:Amgen: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Agios: Consultancy; Ono: Consultancy; Astellas: Consultancy; Arog: Consultancy; Jazz: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Fuji Film: Consultancy; Sumitomo: Consultancy. Pollyea:Agios, Pfizer: Research Funding; Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees. Odenike:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; CTI/Baxalta: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Döhner:Agios: Honoraria; Seattle Genetics: Honoraria; Arog Pharmaceuticals: Honoraria, Research Funding; Celator: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Sunesis: Honoraria; Pfizer: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schiller:Celator/Jazz: Research Funding. Gupta:Celgene: Employment, Equity Ownership. Nabhan:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Almon:Agios: Employment, Equity Ownership. Cooper:Agios: Employment, Equity Ownership.
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