Citations

Background: Mutations in isocitrate dehydrogenase 1 (IDH1) occur in ~3% of individuals with myelodysplastic syndrome (MDS) and have been associated with increased transformation to acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, potent, targeted inhibitor of the mutant isocitrate dehydrogenase 1 enzyme (mIDH1) and is approved in the US for the treatment of newly diagnosed AML with a susceptible IDH1 mutation in patients ≥75 years of age or who have comorbidities that preclude the use of intensive induction chemotherapy, and in adult patients with relapsed or refractory (R/R) AML. The first-in-human, phase 1 dose escalation and expansion study of ivosidenib (NCT02074839) enrolled adults with mIDH1 advanced hematologic malignancies, including R/R MDS, and the study is ongoing. In the initial phase of the study (DiNardo et al. N Engl J Med 2018), the 12 patients with R/R MDS received 500 mg ivosidenib once daily and were characterized as follows: 75% were male, median age was 72.5 years (range 52-78), and 42% were ≥75 years of age; median number of prior therapies was 1 (range 1-3). Adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were diarrhea, fatigue, back pain, rash (n=4 each, 33.3%), anemia, urinary tract infection, decreased appetite, hypokalemia, arthralgia, dyspnea, pruritus, and hypotension (n=3 each, 25.0%). No AEs led to permanent discontinuation of treatment. Response was assessed according to International Working Group 2006 criteria for MDS. According to investigators, five of 12 patients achieved complete remission (CR) (41.7%; 95% CI 15.2%, 72.3%); median duration of CR was not estimable for these patients (95% CI 2.8 months, not estimable). Nine of 12 patients were transfusion independent for at least 56 days during study treatment. Mutation clearance was observed in one of the 5 CR patients. Here we report the design of a new sub-study of this trial, which is being undertaken to further assess the safety, tolerability, and clinical activity of treatment with ivosidenib in patients with R/R MDS. Methods: This sub-study is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Adults with R/R MDS with an IDH1 mutation will be enrolled in the MDS sub-study. These individuals must have R/R disease after treatment with standard agents indicated for MDS. Eligible patients must have a platelet count of ≥20,000/μL, and adequate hepatic function (total bilirubin ≤1.5 × upper limit of normal [ULN]; aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≤3.0 × ULN) and renal function (serum creatinine ≤2.0 × ULN or creatinine clearance >40 mL/min). Additional key inclusion criteria are bone marrow blasts >5% and/or transfusion dependence. Ivosidenib is to be administered at a dose of 500 mg once daily orally on Days 1 to 28 of 28-day cycles. The addition of the MDS sub-study to this phase 1 clinical study in patients with hematological malignancies will provide additional insights into the use of ivosidenib for the treatment of mIDH1 R/R MDS. Disclosures Foran: Agios: Honoraria, Research Funding. DiNardo:notable labs: Membership on an entity's Board of Directors or advisory committees; medimmune: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; jazz: Honoraria; celgene: Consultancy, Honoraria; syros: Honoraria. Watts:Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stein:Agios: Consultancy, 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; 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; Genentech: Membership on an entity's Board of Directors or advisory committees; 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; Syros: Membership on an entity's Board of Directors or advisory committees. De Botton:Daiichi Sankyo: Consultancy; Astellas: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Syros: Consultancy; Forma: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Servier: Consultancy; Pierre Fabre: Consultancy; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy, 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. Stein:Stemline: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau. 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. Patel:France Foundation: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dava Oncology: Honoraria. Tallman:UpToDate: Patents & Royalties; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: 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; Cellerant: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees. Choe:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership; Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Oluyadi:Agios: Employment, Equity Ownership. Winkler:Agios: Employment. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership. Attar:Aprea Therapeutics: Employment; Agios: Employment, Equity Ownership. Kantarjian:Astex: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Jazz Pharma: Research Funding; Agios: Honoraria, Research Funding; Ariad: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding. OffLabel Disclosure: Ivosidenib (AG-120) is an IDH1 inhibitor indicated for the treatment of AML with a susceptible IDH1 mutation as detected by an FDA-approved test in: 1) adult patients with newly-diagnosed AML who are more than 75 years old or who have comorbidities that preclude use of intensive induction chemotherapy and 2) adult patients with relapsed or refractory AML. It is being evaluated in clinical trials for mutant IDH1 advanced hematologic malignancies.

Abstract Background The epidemiology of fungal infections in hematologic malignancies has changed in the past decade. Triazole prophylaxis has decreased Candida spp infections while infections due to other molds such as Aspergillus and Fusarium species have increased. Fusariosis has very poor prognosis, and after aspergillosis, is the most common invasive fungal infection in this patient population. We sought to describe fusariosis in patients with hematologic malignancy at the Mayo Clinic. Methods We performed a retrospective review of patients with culture-positive Fusarium infection from January 2003 to October 2016 at the Mayo Clinic, Rochester, MN. The records of patients were reviewed for demographics, diagnosis, treatment, and outcomes including mortality. Patients without a diagnosis of hematologic malignancy were excluded. Patients were classified with proven or probable Fusariosis based on the Revised Definitions of Invasive Fungal Disease from the EORTC/MSG Consensus Group. Results We identified 14 patients with hematologic malignancies (age range 17–76 years; median 60 years) with a confirmed culture diagnosis of Fusarium infection classified as proven (9 patients) or probable (5 patients). Two cases were isolated pulmonary infections, 3 extra-pulmonary, and 9 disseminated cases. Two patients had previously undergone stem cell transplantation. Eight patients (57%) were receiving antifungal prophylaxis at the time of diagnosis: 2 on voriconazole, 1 on posaconazole, 1 on fluconazole, 3 on echinocandins, and 1 on Amphotericin B. Nine patients (64%) were neutropenic at the time of diagnosis. Amphotericin was the initial treatment in 7 (50%) patients, with voriconazole added for 4 patients for combination therapy the first week. Voriconazole monotherapy was given initially in 5 patients. Seven patients (50%) were deceased at 6 weeks after culture positivity, with an additional 2 patients deceased by 12 weeks. Conclusion Fusarium infection outcomes in patients with hematologic malignancies are poor. Neutropenia was common in those diagnosed, and infections were more likely to be disseminated, with high mortality rates. Amphotericin was commonly used as initial treatment, with many physicians recommending combination therapy with two agents, commonly voriconazole. Disclosures All authors: No reported disclosures.

Abstract Background Tumor necrosis factor (TNF)-α antagonist therapy has revolutionized the practice of management of inflammatory bowel disease (IBD); however, these medications carry a boxed warning from the Food and Drug Administration for risk of serious infection. We aimed to study the invasive fungal infection, histoplasmosis, in the setting of TNF-α antagonist therapy. Methods We performed a retrospective review of patients with IBD receiving TNF-α antagonist therapy who developed histoplasmosis during the time period January 2001–May 2018 at the Mayo Clinic, Rochester, MN. The medical records of patients were reviewed for demographics, medications, symptoms, diagnosis, treatment, and outcomes including mortality. IBD was diagnosed by biopsy, radiographic, or endoscopic evidence of disease. Results We identified 49 patients (age range 19–74; median 44 years) with a confirmed diagnosis of histoplasmosis while receiving a TNF-α antagonist. 73.5% of cases were classified as disseminated. Median time from starting TNF-α antagonist to histoplasmosis diagnosis was 2.1 years. Liposomal amphotericin B was given in 17 cases as the initial treatment. Itraconazole was given to all 49 patients. Initial treatment was split evenly between inpatient (49%) and outpatient (51%) locations with 6 patients (12%) requiring ICU-level care. Median length of stay was 9.5 days. The total length of treatment for all antifungals was 38.4 weeks, with 20.4% of patients developing documented antifungal side effects. TNF-α antagonist was continued in 9 patients (18.4%) and another 10 patients resumed TNF-α antagonist. Half of those who resumed TNF-α antagonists were on antifungal therapy. There was one histoplasmosis recurrence while off TNF-α antagonist, and three deaths (6%). Conclusion Histoplasmosis outcomes in IBD patients on TNF-α antagonists were mostly favorable; however, approximately half required hospitalization. Many patients were young with few co-morbidities, and over one-third were able to continue or resume TNF-α antagonists without documented recurrence of histoplasmosis. Practitioners should be vigilant for histoplasmosis infections in this patient population who reside in histoplasma-endemic regions. Disclosures All authors: No reported disclosures.

Abstract Background Previous studies suggest that autoantibodies against cardiac myosin lead to dilated cardiomyopathy (DCM). Anti-cardiac myosin antibodies cross-react with the beta adrenergic receptor (βAR) and signal cAMP-dependent protein kinase A (PKA) in cardiomyocytes leading to apoptosis, fibrosis, dilated cardiomyopathy and arrhythmias. Purpose To determine if cross-reactive anti-cardiac myosin/anti-βAR autoantibodies which signal cardiomyocytes through PKA might play a role to establish DCM by promoting remodeling, apoptosis, and fibrosis. Methods Forty-one adults with DCM were enrolled <6 months from symptom onset and followed for 12 months. Serum and myocarditis/DCM-derived human mAb were analyzed by ELISA for autoantibodies, and a PKA assay measured anti-HCM/βAR antibody-mediated signaling of cardiomyocytes (ATCC primary heart cell line H9c2). The top 50 genes differentially expressed in the cardiomyocytes treated with sera or human mAb were identified and compared to genes differentially expressed in blood of DCM patients to identify shared disease-specific genes. Results Anti-HCM autoantibodies including autoantibody responses against 32 overlapping synthetic peptides of the S2 fragment of HCM were significantly elevated in patients whose ejection fraction did not improve over 1-year compared to those with improved ejection fraction. The human mAb confirmed our results with HCM, βAR, specific HCM peptides, and PKA signaling. RNA sequencing revealed differentially expressed genes in serum/mAb-treated cardiomyocytes compared to genes identified after RNA sequencing of peripheral blood of patients (n=10) with DCM for >1 year from onset. A primary heart cell line (H9c2-ATCC) treated with myocarditis/DCM patient sera or human mAb revealed differentially expressed genes associated with cardiac hypertrophy and heart failure, and included inflammasome component NLRP3 and complement factor H. Ingenuity Pathway Analyses revealed 27, 7, and 1 differentially expressed genes related to apoptosis, fibrosis, and hypoxia, respectively. Gene expression of CASZ1, a transcription factor important in protection against DCM, was strongly correlated with PKA signaling (r=0.89). The KDM6B gene for lysine demethylase associated with hypoxia and apoptosis pathways and was shared between cardiomyocyte and peripheral blood analysis of DCM patients. Overall, 5 genes were shared in heart failure vs in vitro Ab-treated cardiomyocyte RNA sequencing analysis: CYP4F3, KDM6B, MBOAT7, SMAP2, and DDIT4, which affects phosphorylation of mTOR to promote autophagy and cell death, cardiac hypertrophy and dysfunction. Conclusions Significantly higher responses to cardiac myosin in patients with DCM were related to lack of left ventricular function improvement and to differential expression of genes promoting apoptosis, fibrosis and disease severity. These studies identify autoantibody-directed gene signaling as a potential novel therapeutic target in DCM. Acknowledgement/Funding National Heart, Lung, and Blood Institute, Bethesda, MD, USA

Abstract Background Cardiomyopathy may occur due to viral infections or drug induced heart damage. Cardiac myosin released from damaged heart has been shown to be a damage associated molecular pattern which binds to TLR2 or TLR8 and can act as an adjuvant to induce a strong autoimmune response against the heart. The result is autoimmunity against the heart which can lead to apoptosis, fibrosis and heart failure. Purpose Immune biomarkers of the early stages of heart failure are needed to identify individuals who develop progressive heart failure, do not recover their ejection fraction and may be candidates for immunotherapies. Methods Forty-one patients with myocarditis and heart failure <6 months after onset were followed for 12 months and compared to age matched controls. Peripheral blood mononuclear cells were analyzed by FACS analysis and serum analyzed by ELISA for autoantibodies and cytokines. Statistical analysis was determined by Mann Whitney test. Peripheral blood of 10 patients with dilated cardiomyopathy (DCM) vs 19 healthy controls were analyzed for gene expression by RNA sequencing and pathway analysis using Reactome. Results Autoantibodies against human cardiac myosin and the beta-adrenergic receptor were significantly elevated in our cohort and functionally acted on cardiomyocytes to activate protein kinase A. Concomitantly, a Th17+ immunophenotype was significantly elevated in blood as well as in cardiac biopsies. CD4+IL17+ T cells (p=0.0008) and Th17-promoting cytokines TGF beta (p<0.0001), IL-6 (p<0.0001), IL-23 (p=0.0001), GMCSF (p=0.0336) and GMCSF-secreting CD4+ T cells (p=0.0006) were significantly elevated in blood. A Th17 immunophenotype was significantly associated with heart failure primarily in males (p=0.029). Persistent heart failure (NYHA class III and IV) and non-recovery of left ventricular function were associated with significantly higher percentages of IL17A-producing T cells at baseline, 6 and 12 months after onset, and IL-17A (p=0.019) and elevated Th17-promoting cytokines IL-6 (p=0.0001) and TGF-beta (p=0.0076). Decreased T regulatory immunosuppressive cells were significantly (p=0.0006) decreased and correlated with elevated Th17 cytokines in heart failure. Overrepresentation analysis of differentially expressed genes (adj p<0.05) in blood of patients with DCM >1year were identified using Reactome which revealed significant (FDR = 1.52E-13) enrichment of neutrophil degranulation (48 genes). Conclusion Our study illustrates a strong Th17 signature in more severe heart failure early in disease with elevated anti-cardiac myosin autoantibodies in non-recovery of left ventricular function. We observed a strong correlation with Th17-related neutrophil degranulation pathways in later disease, which may be biomarkers of fibrosis progression and disease severity in patients with heart failure. Cardiomyopathy with a Th17 signature might be treated with preventive immunomodulatory therapies such as anti-IL17A. Acknowledgement/Funding National Heart Lung and Blood Institute, Bethesda, MD, USA

Key Points The ClinGen MM-VCEP has specified RUNX1-specific curation rules to address gene function, gene-specific domains, and phenotypic criteria. RUNX1-specific criteria resulted in a reduction in CONF and VUS variants by 33%, emphasizing the need for expert variant curation.

299 Background: In 2011, ASCO launched a forum for the oncology research community to facilitate and promote the implementation of quality clinical research. The ASCO Research Community Forum (RCF) was created to provide a solution-oriented venue for research sites to address common challenges with conducting clinical trials. It offers in-person and virtual forums and resources to learn and share best practices with peers on a variety of topics, including site quality assessment and improvement, research site operations, and clinical trial access and accrual. Methods: An assessment was performed to measure the ASCO RCF output and to gather information on its potential impact on the cancer community. Results: The ASCO RCF has provided an in-person venue for physicians and research administrators with a steady increase in attendance, from 52 attendees in 2012 to 159 in 2018. Multi-stakeholder meetings and manuscripts have promoted best practices and solutions to address challenges with implementing quality clinical trials. Tools and resources to facilitate best practices and quality improvement at trial sites have been accessed by a range of types of research sites from across the U.S. and internationally. Its web-based library of resources was accessed over 27,000 times in 2018, alone. An online forum was launched in 2019 to provide a new opportunity to connect and impact the research community. Conclusions: The ASCO RCF is a productive and esteemed resource for the cancer research community. In-person and virtual forums, along with practical tools, promote access and accrual to clinical trials by facilitating networking, developing solutions, and providing education and resources. The ASCO RCF impact has extended from community-based oncology practices to larger research networks and academic centers across the U.S. and internationally. Its efforts to promote and facilitate access to quality clinical trials align with the vision and mission of ASCO to conquer cancer through research, education, and promotion of the highest quality patient care.

Abstract Background: It has been known for approximately 19 years that germline mutations in RUNX1, lead to familial platelet disorder with predisposition to myeloid malignancy (FPD-MM, OMIM 601399). Since that time researchers have identified a broad range of different RUNX1 mutations, in over 100 families. In large families, the diagnosis of malignancy shows variable penetrance among family members with the same mutation; some carriers of RUNX1 mutations do not develop malignancy. The causes of this heterogeneity are currently not known, complicating counselling and risk analysis for individual carriers. Recent advances in genetic sequencing technology applied by many FPD-MM research groups around the world have highlighted their value in understanding the somatic genetic changes that are associated with development of malignancies in germline RUNX1 mutation carriers. Collectively this information could lead to powerful insights essential for more precise risk assessment, monitoring, and therapeutic intervention. Specifically, a growing catalogue of somatic mutations associated with germline RUNX1 malignancy offers the opportunity for informed monitoring of asymptomatic RUNX1 carriers for additional high-risk somatic mutations, in turn providing the possibility for early therapeutic intervention to arrest the leukemic process. The challenge in advancing these goals for FPD-MM is the relative rarity of the disorder in individual populations. Global data sharing in a highly interactive FPD-MM research community offers a solution to this problem that benefits all patients world-wide. Aims: To create a global RUNX1 network through identifying and contacting researchers and clinicians with known and novel germline RUNX1 families, seeking their collaboration to share genomics data. To create a RUNX1.db portal to collectively house and analyse genomics data from germline RUNX1 carriers, with associated phenotype and clinical information, such that researchers have an ongoing means by which to combine their data with those generated by other groups around the world. Methods: RUNX1 network : Through existing collaborative networks, a systematic review of the literature, and referrals from initial contacts, we have identified a global network of researchers managing FPD-MM cases and families. RUNX1.db: We have adapted a custom-built variant analysis platform, VariantGrid, that is a visual web application and database designed to help scientists manage and analyse DNA variants that can be used to aggregate and analyse multiple datasets. Results: Preliminary analysis of aggregated data from the literature suggests there are features of germline RUNX1 syndrome that can be ascertained. These include frequent somatic mutation of RUNX1 in malignancy development, as well as mutations in genes associated with clonal hematopoiesis that may precede development of overt leukemia. This analysis also suggests that different types of germline RUNX1 mutations may be associated with different combinations of somatic mutations in the tumour. To further this analysis, we have identified over 70 groups internationally that either manage RUNX1 families or have identified potential germline carriers through genomics initiatives. This represents a large and growing resource for both scientific studies and clinical programs to benefit individuals with FPD-MM. Many of these groups have generated NGS data sets from patient samples which will be available for analysis through this portal. Further details and activities of the network, and results from the genomics aggregation database will be presented. Conclusion: We have created a global RUNX1 network, aggregated their data, and generated a RUNX1.db genomics portal for the continuous curation of genomics data from germline RUNX1 carriers. A preliminary analysis has already identified specific features of germline RUNX1 mutated malignancies that have clinical importance. Ongoing scientific and clinical studies through the RUNX1 network will enhance the power of aggregated data analysis, with RUNX1.db providing a central link, driving new insights that benefit patients. Disclosures Natsoulis: Imago BioSciences, Inc.: Consultancy, Equity Ownership. Guzman:Cellectis: Research Funding. DiNardo:Bayer: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Abbvie: Honoraria. Borate:Novartis: Consultancy; Agios: Consultancy. Wei:Amgen: Honoraria, Other: Advisory committee, Research Funding; Pfizer: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau. Dokal:MRC, Bloodwise, Telomerase Activator Sciences: Research Funding; The Gary Woodward Dyskeratosis Congenita Trust: Membership on an entity's Board of Directors or advisory committees; Action Medical Research, European School of Haematology: Membership on an entity's Board of Directors or advisory committees; Barts and The London School of Medicine and Dentistry, Queen Mary University of London,: Employment, Research Funding; Telomerase Activator Sciences: Research Funding; Barts and The London, Queen Mary University of London: Employment; Gary Woodward Dyskeratois Congenita Trust: Membership on an entity's Board of Directors or advisory committees. Hiwase:Novartis: Research Funding; Celgene: Research Funding. Branford:Cepheid: Honoraria; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kramer:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Daiichi Sankyo: Consultancy. Owen:Merck: Honoraria; Teva: Honoraria; AbbVie: Research Funding; Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding. Fitzgibbon:Epizyme: Consultancy, Research Funding; Gilead: Consultancy. Rienhoff:Imago BioSciences, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Kurokawa:Astellas Pharma: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Eizai: Research Funding; MSD: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Takeda Pharmaceutical: Research Funding; Otsuka Pharmaceutical: Research Funding; Teijin Pharma: Research Funding; Chugai Pharmaceutical: Research Funding.

Abstract BACKGROUND: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) are observed in approximately 4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia. Ivosidenib (AG-120), an oral, potent, targeted, small-molecule inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for the treatment of patients with mIDH1 MDS. Through inhibition of mIDH1, ivosidenib suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from patients with relapsed or refractory (R/R) MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of ivosidenib in patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Trial enrollment was completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose to be tested in expansion. Expansion Arm 3 enrolled patients with mIDH1 advanced hematologic malignancies, including MDS. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present safety and efficacy data for patients with MDS in expansion Arm 3 and in dose escalation whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 12 patients with MDS (9 from expansion and 3 from escalation) whose starting dose was 500 mg QD. Baseline characteristics for these 12 patients were: 9 men/3 women; median age, 72.5 years (range, 52-78) and 42% were ≥75 years of age; median number of prior therapies, 1 (range, 1-3). As of 10Nov2017, 7 of 12 (58.3%) patients remained on treatment and 5 (41.7%) had discontinued (one for allogeneic stem cell transplantation). The median duration of exposure to ivosidenib was 11.0 months (range, 3.3-31.1). The most common adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were back pain (n=4, 33.3%) and anemia, decreased appetite, diarrhea, dyspnea, fatigue, hypokalemia, pruritus, and rash (n=3, 25.0% each). The majority of these AEs were grade 1-2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome (IDH-DS) was observed in 2 of 12 (16.7%) patients; the events were grade 1 and 2, respectively. Of the 12 patients with MDS receiving ivosidenib 500 mg QD, 5 achieved CR (41.7%; 95% CI 15.2%, 72.3%) and 6 achieved marrow CR (50.0%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median durations of CR and overall response were not estimable at the time of the data cutoff. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for at least 56 days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels on ivosidenib therapy will be presented. CONCLUSION: In patients with mIDH1 R/R MDS, ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS. Disclosures 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. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Stein:Celgene: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Bayer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Fathi:Takeda: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Stein:Amgen: Speakers Bureau; Celgene: Speakers Bureau. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Stone:AbbVie: Consultancy; Agios: Consultancy, Research Funding; Cornerstone: Consultancy; Orsenix: Consultancy; Fujifilm: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Ono: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Jazz: Consultancy; Merck: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership.

Abstract Abstract 4000 Poster Board III-936 Background There is insufficient information regarding the epidemiology and outcomes of DVT in children. The CDC began a consented registry in August 2003 at eight pilot Centers for Thrombosis and Thrombophilia including six pediatric sites in order to assess the scope and severity of DVT morbidity in children. Methods Data for this analytic project were extracted from the CDC thrombosis registry. We performed a nested case-control study within the registry cohort. Children and adults are eligible to enroll onto this consented registry if they have a history of thrombosis, thrombophilia or a positive family history or either. DVT site, extent, recurrence and BMI were determined clinically. In addition, thrombophilia testing batteries, imaging protocols and determinations of PTS outcomes of DVT were made locally and criteria were not standardized among participating centers. Results As of March 2009 the CDC registry included 316 cases of DVT in infants and children (ages 0-21), and 2414 cases in adults (> 21). There were 16 cases reported to have lower extremity (LE) PTS in children and 184 in adults. Table 1 displays effects of thrombus site, recurrence and BMI on PTS prevalence. The proportion of LE DVT involving the inferior vena cava (IVC) was 5.5-fold higher in children compared to adults (11% vs 2%). Furthermore, among cases of IVC involvement, the prevalence of PTS following IVC thrombosis was remarkably higher in children compared with adults (38.9 vs 6.3%, P < 0.001). The prevalence of PTS following LE DVT overall in children did not differ from adults. Results for upper extremity DVT and resultant PTS were similar. Fifteen percent of children had recurrence. Increasing number of DVT events was associated with an increased risk of PTS. BMI was higher in children who developed PTS (p = 0.06; BMI > 28, OR 3.3 [1.08, 9.59]). In addition, thrombophilia was a risk factor for developing PTS in children (p = 0.02; OR = 2.9 [CI 1.03, 8.05]), with the highest risk determined with antiphospholipid syndrome (p = 0.02; OR = 3.4 [1.09, 9.93]) and protein C deficiency (p = 0.02, OR = 10.9 [0.84, 99.3]). Discussion Children with LE DVT demonstrate a high rate of IVC thrombosis, and a higher relative risk of PTS in cases of IVC involvement. Elevated BMI and thrombophilia augment the risk of PTS in children. The limitations of this study include the lack of standardization in DVT diagnostic and PTS evaluations. The study findings support application of standardized approaches to the diagnosis and follow-up evaluation of children with DVT in order to more meaningfully determine outcomes for future interventive trials. Disclosures: Moll: Ovation: Consultancy; GTC Biotherapeutics: Consultancy; Talecris: Consultancy.