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International audience; BACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 10(6) CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p

Asparaginases, key agents in treatment of acute lymphoblastic leukemia (ALL), are associated with venous thromboembolism (VTE). While risks of short-acting asparaginase-related VTE is well-known, we studied VTE incidence and risk factors in adult ALL patients treated with and without long-acting pegylated asparaginase (PegA). Single-center, retrospective analysis of 89 ALL patients treated with (n = 61) or without (n = 28) PegA at Greenebaum Comprehensive Cancer Center. Reviewed patient and disease characteristics, treatment, and VTE incidence. VTE during treatment occurred in 31 patients (35%), and was associated with PegA (p = 0.001) and Philadelphia chromosome negativity (p = 0.002). Among PegA recipients, VTE was associated with a significantly higher mean body mass index (BMI) of 31.3 kg/m2 (p = 0.037), and was more common with pre-T/T cell compared to pre-B/B cell ALL (68.2% vs. 33.3%, p = 0.009). Antithrombin-III (ATIII) levels were measured for 26 patients; 16 (61.5%) were

Complex karyotype acute myeloid leukemia (CK-AML) has a dismal outcome with current treatments, underscoring the need for new therapies. Here, we report synergistic anti-leukemic activity of the BCL-2 inhibitor venetoclax (Ven) and the asparaginase formulation Pegylated Crisantaspase (PegC) in CK-AML in vitro and in vivo. Ven-PegC combination inhibited growth of multiple AML cell lines and patient-derived primary CK-AML cells in vitro. In vivo, Ven-PegC showed potent reduction of leukemia burden and improved survival, compared with each agent alone, in a primary patient-derived CK-AML xenograft. Superiority of Ven-PegC, compared to single drugs, and, importantly, the clinically utilized Ven-azacitidine combination, was also demonstrated in vivo in CK-AML. We hypothesized that PegC-mediated plasma glutamine depletion inhibits 4EBP1 phosphorylation, decreases the expression of proteins such as MCL-1, whose translation is cap dependent, synergizing with the BCL-2 inhibitor Ven. Ven-PegC treatment decreased cellular MCL-1 protein levels in vitro by enhancing eIF4E-4EBP1 interaction on the cap-binding complex via glutamine depletion. In vivo, Ven-PegC treatment completely depleted plasma glutamine and asparagine and inhibited mRNA translation and cellular protein synthesis. Since this novel mechanistically-rationalized regimen combines two drugs already in use in acute leukemia treatment, we plan a clinical trial of the Ven-PegC combination in relapsed/refractory CK-AML.

Background: ENA is an oral, selective inhibitor of IDH2 approved for the treatment (Tx) of patients (pts) with relapsed/refractory IDH2 mutated (IDH2m) AML. Here we report the results of a Phase 2 expansion and Phase 1b of the Beat AML Master Trial Phase 2/1b sub-study to assess the efficacy of Tx of newly diagnosed (ND) IDH2m AML pts ≥ 60 years of age with ENA monotherapy (ENAm) and subsequent response-driven addition of AZA Tx. (ClinicalTrials.gov NCT03013998). Methods: The study initiated with a 3-outcome, 2-stage Phase 2 design, which enrolled patients on ENAm for up to 5 cycles. Pts without CR/CRi after 5 cycles of ENAm, or progression/intolerance prior to this time, were transferred to Phase 1b to receive ENA + AZA (Figure 1). Key eligibility included ND IDH2m AML pts with age ≥ 60 years and ECOG performance status 0-2. Pts received ENAm 100 mg/day in continuous 28-day cycles and ENA + AZA (75 mg/m2 days 1-7 every 28 days) for Phase 1b. Response was assessed using 2017 ELN AML criteria. The primary endpoint was CR/CRi rate. The 2-stage design required 24 pts and tested the null hypothesis (H0) that CR/CRi rate equaled 20% vs 50% and then expanded to test a revised H0 of 30% vs 50% in 60 pts (conditional alpha=0.025, power=77%). Expansion also allowed further assessment of safety of this treatment regimen. Results: At data cut off (06/18/2020), 60 pts enrolled, received ENAm, and were evaluable for the primary endpoint. Median age was 75 years and 52% were female (Table 1). Median time on ENAm was 4.7 months (mos). At data cut off, 12 pts were still on ENAm Tx. Most common reasons for discontinuing ENAm were Tx failure (defined as no response to treatment) (23 or 38%), disease progression (loss of response to treatment) (7 or 12%) and adverse events (AEs; 6 or 10%). Five pts (8%) went to transplant. CR/CRi was achieved in 28 pts (47%; adjusted 95% CI 28-59, unadjusted exact 95% CI 34-60) (Table 2). Responses were higher (p=0.04) among the 44 pts with IDH2 R140 (55%) as compared to the 16 with IDH2 R172 mutation (25%) further supporting distinct biology between these subsets. After a median follow up of 14.6 mos, the median overall survival (mOS) was 24.4 mos (95% CI 10.6-not reached). The median duration of response was not reached with 12 mos estimation of 57% (95% CI 34-75). Overall, 20 ENA-related serious adverse events (SAEs) occurred in 15 pts, the most common was differentiation syndrome (12 or 20%) and 1 had ENA-related SAE of tumor lysis syndrome (1.7%). One pt had ENA-related Grade 5 AE (renal failure/death). Most common AEs of any grade (in ≥20%) were nausea, anemia, and low potassium (Table 3). The 7-day/30-day/60-day deaths observed with ENAm were 2%/5%/11%, respectively. Phase 1b: Seventeen pts had inadequate response to ENAm and transferred to Phase 1b to receive ENA + AZA. Median time on Tx (including ENAm) was 6.2 mos and median time on Tx after pts started ENA + AZA was 2.1 mos (Table 2). Most common reasons for discontinuing ENA + AZA included Tx failure (5 or 29%), disease progression (2 or 12%), transplant, death and AEs (each 2 or 12%). CR/CRi was 41% (exact 95% CI 18-67). After a median follow up of 12.7 mos, the mOS from start of ENA + AZA combination Tx was 8.9 mos. Four ENA-related SAEs occurred in 3 pts on ENA + AZA Tx and the most common was differentiation syndrome (2 or 12.5%). One dose-limiting toxicity (Grade 3 nausea) related to both Txs was observed. Most common AEs (≥20%) of any grade were anemia, low albumin and vomiting (Table 3). One death occurred at day 13 of ENA + AZA. Conclusions: In newly diagnosed pts ≥60 years old with IDH2m AML, ENA had a low early death rate, high CR/CRi rate (47%, adjusted 95% CI 28-59), and yielded durable remissions. The most common unique toxicity with ENA was differentiation syndrome that occurred in 20% of patients. In pts who did not achieve CR/CRi with ENAm, a subset of patients achieved CR/CRi with addition of AZA. This combined approach of serial therapy with ENA monotherapy followed by AZA addition in pts with sub-optimal response resulted in a mOS exceeding 2 years for pts enrolled on study. Further focus on improving response among patients with IDH2 R172 mutations, identifying subsets of pts not responding to ENA monotherapy, and integrating new targeted agents into this treatment regimen are warranted. Figure 1 Disclosures Stein: Syndax: Consultancy, Research Funding; Celgene Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Biotheryx: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; Abbvie: Consultancy. Borate:Genentech: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: 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; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Baer:Takeda: Other: Institutional research funding; AbbVie: Other: Institutional research funding; Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Incyte: Other: Institutional research funding. Kovacsovics:Agios: Honoraria; Astella: Honoraria; Pfizer: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Jazz: Honoraria. Schiller:Astellas Pharma: Honoraria, Research Funding; Celator: Research Funding; Constellation: Research Funding; Abbvie: Research Funding; Actinium: Research Funding; Ariad: Research Funding; Stemline: Speakers Bureau; Cyclacel: Research Funding; Daiichi Sankyo: Research Funding; Deciphera: Research Funding; DeltaFly: Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; FujiFilm: Research Funding; Gamida: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding; Jazz Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Kite Pharma: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Gilead: Speakers Bureau. Olin:Astellas: Other: Site PI; Genentech: Other: Site PI; Pfizer: Other: Site PI; Daiichi Sankyo: Other: Site PI; Genentech: Consultancy; Amgen: Consultancy. Foran:Trillium: Research Funding; Xencor: Research Funding; H3Biosciences: Research Funding; Agios: Honoraria, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Boehringer Ingelheim: Research Funding; Actinium: Research Funding; Aprea: Research Funding; Aptose: Research Funding; Kura Oncology: Research Funding; Takeda: Research Funding; Revolution Medicine: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees. Lin:Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Prescient Therapeutics: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Aptevo: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Mateon Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; Jazz: Research Funding; Gilead Sciences: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Celgene: Research Funding. Patel:DAVA Pharmaceuticals: Honoraria; Celgene: Consultancy, Speakers Bureau; Agios: Consultancy; France Foundation: Honoraria. Foster:Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Druker:Leukemia & Lymphoma Society: Research Funding; Henry Stewart Talks: Patents & Royalties; Iterion Therapeutics (formerly Beta Cat Pharmaceuticals): Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Patient True Talks: Consultancy; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millipore (formerly Upstate Biotechnology): Patents & Royalties; MolecularMD (acquired by ICON): Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; McGraw Hill: Patents & Royalties; Merck & Co: Patents & Royalties; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dana-Farber Cancer Institute: Patents & Royalties; EnLiven: Consultancy, Research Funding; Aptose Therapeutics Inc. (formerly Lorus): Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Blueprint Medicines: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Aileron Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Oregon Health & Science University: Patents & Royalties. Byrd:Acerta Pharma: Research Funding; Syndax: Research Funding; Vincera: Research Funding; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding. Levine:Loxo: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Imago: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Qiagen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Amgen: Honoraria; Astellas: Consultancy; Morphosys: Consultancy; Novartis: Consultancy; Isoplexis: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Lilly: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Gilead: Honoraria. Mims:Abbvie: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Novartis: Speakers Bureau. OffLabel Disclosure: Enasidenib is not approved for the treatment of newly diagnosed AML.

Objective To demonstrate feasibility of performing geriatric assessment (GA) in the National Clinical Trials Network (NCTN) and to explore the utility of GA to characterize treatment tolerance. Materials and methods We conducted a multisite companion study (CALGB 361006) to CALGB 11001, a phase 2 trial of adults ≥60 years old with newly diagnosed FLT3- mutated AML, testing the efficacy of adding sorafenib to intensive chemotherapy. On 361006, a GA was administered prior to induction and prior to post-remission therapy. The GA is divided into items requiring administration by a health care professional (HCP) and patient self-administered questionnaires. Feasibility outcomes were recruitment rate, time to GA completion, difficulty with GA administration, percent of patients requiring assistance, and satisfaction. Change in GA measures pre- and post-induction were compared using Wilcoxon signed rank test and McNemar's tests. Results The recruitment rate was 80% (N = 43, median age 68 years). Median completion time of the GA was 30 min; (10 and 21 min for HCP and patients, respectively). HCP reported no difficulty completing assessments (100%). Most patients completed questionnaires without assistance (77%), and were satisfied with the length (89%). Self-reported physical function, mental health, social activity and nutritional parameters worsened after induction. Conclusion GA is feasible to administer in the setting of intensive induction for older adults with AML in the NCTN and provides evidence of the impact of induction therapy on physical and emotional health.

Hereditary breast cancer is caused by autosomal dominant germline mutations in human breast cancer genes, mainly BRCA1 and BRCA2. BRCA mutations are associated with increased risk of breast and ova...

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

PURPOSE Patients with myelofibrosis who are relapsed or refractory (R/R) to Janus-associated kinase inhibitors (JAKis) have poor clinical outcomes including dismal overall survival (OS) that ranges between 13 and 16 months. Imetelstat, a telomerase inhibitor, was evaluated in patients with intermediate-2 or high-risk myelofibrosis R/R to JAKi in a phase II multicenter study (ClinicalTrials.gov identifier: NCT02426086 ). PATIENTS AND METHODS Patients were randomly assigned to receive either imetelstat 9.4 mg/kg or 4.7 mg/kg intravenous once every 3 weeks. Spleen response (≥ 35% spleen volume reduction) and symptom response (≥ 50% reduction in total symptom score) rates at week 24 were coprimary end points. Secondary end points included OS and safety. RESULTS Study enrollment was closed early, and patients treated with 4.7 mg/kg were permitted to continue treatment with 9.4 mg/kg. At week 24, spleen and symptom response rates were 10.2% and 32.2% in the 9.4-mg/kg arm and 0% and 6.3% in the 4.7-mg/kg arm. Treatment with imetelstat 9.4 mg/kg led to a median OS of 29.9 months and bone marrow fibrosis improvement in 40.5% and variant allele frequency reduction of driver mutations in 42.1% of evaluable patients. Fibrosis improvement and variant allele frequency reduction correlated with OS. Target inhibition was demonstrated by reduction of telomerase activity and human telomerase reverse transcriptase level and correlated with spleen response, symptom response, and OS. Most common adverse events on both arms were grade 3 or 4 reversible cytopenias. CONCLUSION In this phase II study of two imetelstat doses, 9.4 mg/kg once every 3 weeks demonstrated clinical benefits in symptom response rate, with an acceptable safety profile for this poor-risk JAKi R/R population. Biomarker and bone marrow fibrosis assessments suggested selective effects on the malignant clone. A confirmatory phase III study is currently underway.

Background: Hypomethylating agents (HMA) form the current standard treatment for patients with higher-risk myelodysplastic syndrome (HR-MDS) who are not eligible for allogeneic hematopoietic stem cell transplantation (HSCT). However, overall response rates (ORRs) remain low in patients receiving azacitidine (Aza), and median overall survival (OS) is reported as ~15 months (Sekeres et al. J Clin Oncol. 2017). In addition, there are few data on patient-reported outcomes (PROs) published in this population while on treatment. Venetoclax (Ven) is a selective, potent, orally bioavailable BCL-2 inhibitor, which has demonstrated synergy with HMA in preclinical studies of HR-MDS. From an ongoing, open-label, dose-escalation, Phase 1b study (NCT02942290) evaluating Ven+Aza for the treatment of treatment-naïve HR-MDS, we report the updated safety and efficacy in all treated patients and the exploratory analysis of key PROs in patients who received the recommended Phase 2 dose (RP2D). Methods: Patients aged ≥18 years with treatment-naïve HR-MDS, International Prognostic Scoring System intermediate-2 or high, bone marrow blasts Results: At data cutoff, December 31, 2019, 57 patients had received Ven+Aza, with a median follow-up of 13.0 months (95% confidence interval [CI] 11.3, 15.6 months). The majority of patients were male (75%); median age was 71 years (range 26-85 years); and 89% had ECOG score 0-1. All patients experienced ≥1 adverse event (AE), the most common being constipation (54%), neutropenia (51%), and nausea (51%). Grade ≥3 AEs were experienced by 97% of patients, with neutropenia (51%), febrile neutropenia (46%), and thrombocytopenia (30%) the most common. Febrile neutropenia was the most common serious AE (42%). The 30-day mortality rate was 2%. The ORR was 77%, including complete remission (CR) and marrow CR (mCR) achieved by 42% and 35% of patients (of whom 40% achieved mCR + hematological improvement), respectively; none achieved partial remission. Median OS was not reached (95% CI 16.2 months, not estimable; Figure 1). Median duration of response was 14.8 months (95% CI 12.9 months, not estimable). Median progression-free survival was 17.5 months (14.5, not estimable). Of the patients who received the RP2D of Ven 400 mg for 14 days/28-day cycle in combination with Aza, physical functioning, as measured by the EORTC QLQ-C30, was maintained through 48 weeks of treatment. In addition, clinically meaningful improvement in fatigue and dyspnea, as measured by the EORTC QLQ-C30, was achieved by the beginning of Cycle 5 and was maintained through Week 48 (Cycle 13; Figure 2). Conclusions: The combination of Ven+Aza demonstrates promising efficacy, including response durability, and an acceptable safety profile for patients with HR-MDS. Maintenance in physical functioning and clinically meaningful improvement in dyspnea and fatigue were observed throughout the first 48 weeks, although these data are not yet mature and low patient numbers beyond Cycle 7 limit conclusions. Additional follow-up data and correlation with disease risk features including mutations will be presented at the meeting. Disclosures Garcia: Pfizer: Research Funding; Eli Lily: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wei:Amgen: Consultancy, Honoraria, Research Funding; MacroGenics: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee and receives a fraction of its royalty stream related to venetoclax; Pfizer: Honoraria; Genentech: Honoraria; Astra Zeneca: Honoraria, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Borate:Genentech: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: 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; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Research Funding; AbbVie: Other: Investigator in AbbVie-funded clinical trials; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fong:Astellas: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; AbbVie: Honoraria. Baer:Forma: Other: Institutional research funding; Astellas: Other: Institutional research funding; AbbVie: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding. Nolte:AbbVie: Other: Investigator on an AbbVie funded clinical trial. Jurcic:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog Pharmaceuticals: Research Funding; Astellas: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Kura Oncology: Research Funding; PTC Therapeutics: Research Funding; Syros Pharmaceuticals: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Jacoby:Takeda: Consultancy; AbbVie: Research Funding; Jazz Pharmaceuticals: Research Funding. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Platzbecker:Geron: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Odenike:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Incyte: Other: Institutional research funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cunningham:AbbVie: Research Funding; Amgen: Research Funding; Astex: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Principia Biopharma: Research Funding; Rigel Ilona: Research Funding. Zhou:AbbVie: Current Employment, Other: may hold stock or other options. Tong:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Hogdal:AbbVie: Current Employment, Other: may hold stock or other options. Kamalakar:AbbVie: Current Employment, Other: may hold stock or other options. Hutti:AbbVie Inc.: Current Employment, Other: may hold stock or stock options. Kye:AbbVie: Current Employment, Other: may hold stock or other options. Garcia-Manero:Novartis: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Jazz Pharmaceuticals: Consultancy; Acceleron Pharmaceuticals: Consultancy, Honoraria; Onconova: Research Funding. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor approved for use in CLL and in combination with azacitidine, decitabine, or low-dose cytarabine for the treatment of newly-diagnosed AML who are 75 years or older or who have comorbidities that preclude use of intensive induction chemotherapy; the current clinical trial reports use in MDS

BACKGROUND Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P

Essential thrombocythemia (ET) and polycythemia vera (PV) are myeloproliferative neoplasms (MPNs) characterized by an increased risk of developing venous and arterial thromboses and of evolution to myelofibrosis or acute leukemia (1). MPNs are recognized as a major cause of splanchnic vein thromboses (SVT), which include hepatic, splenic, portal and mesenteric vein thromboses (2). Patients with SVT are at an increased risk of developing bleeding events and arterial thrombotic events (3), as well as recurrent SVT and the use of anticoagulation and cytoreduction do not clearly modify this risk (3–5). Management of SVT in MPN patients remains a challenge and most therapeutic recommendations are based on retrospective analyses (6). Recently, De Stefano reported that hydroxyurea failed to prevent recurrent thromboses in the splanchnic vasculature in patients with a prior SVT (7). We conducted a prospective, open-label, multi-center phase II clinical trial of Pegylated Interferon Alfa-2a (PEG) in 20 subjects with SVT and an MPN, who represented a cohort of patients who participated in the Myeloproliferative Disorders - Research Consortium (MPD-RC) 111 trial (). MPD-RC 111 was a prospective study of patients with high-risk ET/PV who were resistant or intolerant to hydroxyurea (HU), but prior HU therapy was not a requirement for patients to enter the SVT cohort. Here we report the outcomes of the 20 SVT patients who were treated with PEG.

Outcomes and life expectancy for patients with multiple myeloma (MM) have improved substantially over the last two decades with advancements in therapy, including autologous stem cell transplantati...

Background: Venous thromboembolism (VTE) is a recognized complication of sickle cell disease (SCD), yet the optimal pharmacologic anticoagulant is unknown. Methods: A retrospective single-institution cohort study of patients with SCD complicated by first VTE from January 2009 through July 2017 was performed using ICD 9/10 codes. Data collected included the anticoagulant used, VTE recurrence, and incidence of bleeding. Results: 109 patients with VTE were identified. SCD genotypes included HbSS in 92 (84%), HbSC in 13 (12%), and HbS-β+ thalassemia in 4 (4%). After the initial VTE event, 32 patients received a vitamin K antagonist (VKA), 34 for low-molecular-weight heparin (LMWH), and 43 for direct oral anticoagulants (DOACs). 16 patients (15%) experienced a clinically significant bleeding event, including 9 on VKA, 5 on LMWH, and 2 on DOACs. At a median follow-up of 11.8 (range, 3.4–60) months, 33 patients had a recurrent VTE, including 10 on VKA, 10 on LMWH, and 13 on DOACs (p = 0.833). Bleeding incidence was least with the DOACs, which were associated with fewer bleeding events (OR 0.22), and greatest with VKA (OR 1.55) (p < 0.05). Conclusion: There was no difference between VTE recurrence and choice of anticoagulation in SCD patients with VTE. Bleeding events were lower for DOACs compared to VKA or LMWH.

BackgroundAcute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML.MethodsThis randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1-hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1-hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (

In acute myeloid leukaemia (AML) t(8;16)(p11;p13)/MYST3-CREBBP is a very rare abnormality. Previous small series suggested poor outcome. We report on 59 patients with t(8;16) within an international, collaborative study. Median age was 52 (range: 16-75) years. AML was de novo in 58%, therapy-related (t-AML) in 37% and secondary after myelodysplastic syndrome (s-AML) in 5%. Cytogenetics revealed a complex karyotype in 43%. Besides MYST3-CREBBP, whole-genome sequencing on a subset of 10 patients revealed recurrent mutations in ASXL1, BRD3, FLT3, MLH1, POLG, TP53, SAMD4B (n = 3, each), EYS, KRTAP9-1 SPTBN5 (n = 4, each), RUNX1 and TET2 (n = 2, each). Complete remission after intensive chemotherapy was achieved in 84%. Median follow-up was 5·48 years; five-year survival rate was 17%. Patients with s-/t-AML (P = 0·01) and those with complex karyotype (P = 0·04) had an inferior prognosis. Allogeneic haematopoietic cell transplantation (allo-HCT) was performed in 21 (36%) patients, including 15 in first complete remission (CR1). Allo-HCT in CR1 significantly improved survival (P = 0·04); multivariable analysis revealed that allo-HCT in CR1 was effective in de novo AML but not in patients with s-AML/t-AML and less in patients exhibiting a complex karyotype. In summary, outcomes of patients with t(8;16) are dismal with chemotherapy, and may be substantially improved with allo-HCT performed in CR1.

INTRODUCTION: Obesity has become increasingly prevalent worldwide and is a risk factor for many malignancies. We studied the correlation between body mass index (BMI) and the incidence of acute promyelocytic leukemia (APL), non-APL acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and control hospitalized patients without leukemia in the same community. METHODS: Multi-center, retrospective analysis of 71,196 patients: APL (n=200), AML (n=437), ALL (n=103), non-leukemia hospitalized (n=70,456) admitted to University of Maryland and Johns Hopkins Cancer Centers, and University of Maryland Medical Center. RESULTS: Patients with APL had a significantly higher unadjusted mean and median BMI (32.5 kg/m(2) and 30.3 kg/m(2)) than those with AML (28.3 kg/m(2) and 27.1 kg/m(2)), ALL (29.3 kg/m(2) and 27.7 kg/m(2)), and others (29.3 kg/m(2) and 27.7 kg/m(2)) (p

Context: The incidence of both myeloid malignancies and cardiovascular disease (CVD) increases with age. We aimed to study whether the presence of CVD is associated with worse outcomes in patients with myeloid malignancies and to delineate a possible mechanism. Objective: Compare overall survival (OS) and marrow vascular density among patients with and without CVD. Design: We retrospectively reviewed 295 previously untreated patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or MDS/myeloproliferative neoplasm (MDS/MPN). CVD included congestive heart failure, coronary artery disease, arrhythmia, peripheral vascular disease, congenital heart disease, and/or cerebrovascular accident. CVD and no-CVD patient characteristics were compared using Fisher’s exact and t-tests. OS was estimated by Kaplan-Meier analysis. Microvascular density (MVD) was determined in CD34-stained bone marrow sections of 20 MDS patients (11 with and 9 without CVD). The mean number of blood vessels was calculated for each sample and compared using the t-test. Setting: University of Maryland Greenebaum Comprehensive Cancer Center, in Baltimore, Maryland. Patients: The study included 228 (77%) patients with AML and 67 (23%) with MDS or MDS/MPN, of whom 92 had CVD (31%) and 203 (69%) did not. Median age at diagnosis was 66 years (range 19–89). Results: For AML patients, 1-, 2- and 3-year OS in CVD vs no-CVD groups was 46% vs 70%, 34% vs 53%, and 26% vs 43%, respectively [HR 1.9, 95% CI = 1.35, 2.67]. For MDS patients, 44% vs 81%, 26% vs 51%, and 26% vs 49% [HR 2.52, 95% CI = 1.27, 5]. In a multivariable regression model accounting for age, performance status, and karyotype, CVD independently predicted worse OS. We hypothesized that treatment response might be affected by MVD, but we did not find a significant difference in MVD in patients with CVD vs no-CVD (mean score 17 vs 22, p=0.4), ever smoker vs never smoker (mean score 19 vs 20, p=0.9), or with vs without diabetes mellitus (mean score 23 vs 13, p=0.1), although the lack of significant difference may be attributed to the small sample size. Conclusions: CVD is a predictor of survival outcomes in patients with AML and MDS. Variability in MVD is a possible mechanism of impaired treatment response in CVD patients, which warrants further evaluation.

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome1,2. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient’s leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60–92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival. Preliminary results from the Beat AML umbrella trial demonstrates the feasibility and efficacy of applying prospective genomic profiling for matching newly diagnosed patients with AML with targeted therapies.

ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We report the phase 1 results. After fludarabine-cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2 × 106, 1 × 106, or 0.5 × 106 cells per kg. The rate of dose-limiting toxicities (DLTs) within 28 days after KTE-X19 infusion was the primary end point. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age, 46 years; range, 18-77 years). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 31% and 38% of patients, respectively. To optimize the risk-benefit ratio, revised adverse event (AE) management for CRS and NEs (earlier steroid use for NEs and tocilizumab only for CRS) was evaluated at 1 × 106 cells per kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NEs, with no grade 4 or 5 NEs. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1 × 106 cells per kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At a median follow-up of 22.1 months (range, 7.1-36.1 months), the median duration of remission was 17.6 months (95% confidence interval [CI], 5.8-17.6 months) in patients treated with 1 × 106 cells per kg and 14.5 months (95% CI, 5.8-18.1 months) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1 × 106 cells per kg with revised AE management. This trial is registered at www.clinicaltrials.gov as #NCT02614066.

Moxifloxacin is a rare but important cause of drug-induced immune thrombocytopenia (DIT). We describe a patient who presented with an acute onset of severe thrombocytopenia complicated by petechial rash, epistaxis, and melena. Recent new drug exposures included moxifloxacin and two proton pump inhibitors. On presentation to the hospital, all recently initiated medications were discontinued and the patient’s thrombocytopenia was treated with platelet transfusions, intravenous immunoglobulin, and high-dose corticosteroids. Her thrombocytopenia improved over the next seven days and she was discharged on hospital day 8. Serologic testing revealed strongly positive moxifloxacin-dependent IgM and IgG antiplatelet antibodies, confirming a diagnosis of moxifloxacin-induced immune thrombocytopenia. DIT has been reported with other fluoroquinolone antibiotics, especially ciprofloxacin. This case documents a rare but potentially fatal complication of exposure to moxifloxacin and is the first to demonstrate objective evidence of acute sensitization with IgM antibody positivity. It highlights the need to consider this potential reaction when choosing antibiotic therapy, particularly in patients who are at high risk for bleeding, have hematologic disorders, or are receiving myelosuppressive therapies, and perhaps in those with a history of multiple drug allergies.

PURPOSE Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1−21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL. EXPERIMENTAL DESIGN Adults ≥60 years with ND ALL/ABL or ≥21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m2/day IV for 5 days, days 3–7) (Arm A). Adults aged 40–59 years with ND ALL/ABL or age ≥21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy. RESULTS Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32 %; it was 50 % for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined. CONCLUSION Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

Acute promyelocytic leukemia (APL) is an uncommon cancer, comprising approximately 10% of acute myeloid leukemia (AML) with annual incidence of approximately 1500 cases in the United States (U.S.) ...

Acute leukemias of ambiguous lineage (ALAL) are rare hematologic malignancies with poor outcomes. Retrospective studies have suggested that acute lymphoblastic leukemia (ALL) regimens are more effective than acute myeloid leukemia (AML) regimens. We retrospectively examined the effectiveness of the widely-used adult ALL regimen hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD) as initial therapy in patients with ALAL at five academic institutions. Twenty-five patients were identified, including 23 with mixed phenotype acute leukemia (MPAL) and two with acute undifferentiated leukemia. Five of 8 tested (63%) had FLT3-ITD and 3 of 25 (12%) were Philadelphia chromosome-positive. The complete remission (CR) rate was 76%, with CR with incomplete count recovery (CRi) in an additional 8%, for an overall response rate of 84%. Median number of cycles to CR/CRi was 1. There were no deaths in the first 30 days. Of the 21 patients achieving CR or CRi, 14 (66%) proceeded to allogeneic hematopoietic stem cell transplantation. With a median follow-up time of 31.6 months, median overall survival for the entire cohort was not reached, and the estimated 2-year survival was 63%. HyperCVAD can be considered an effective and tolerable front-line regimen for patients with ALAL, and warrants further prospective study.

Outcomes of acute lymphoblastic leukemia (ALL) in older adults treated with chemotherapy are poor. The CD19/CD3 bispecific T-cell engager (BiTE) antibody blinatumomab is approved for refractory, relapsed or minimal/measurable residual disease (MRD)-positive B-cell ALL, but there is little experience in the upfront setting, including in older patients. We retrospectively analyzed outcomes of blinatumomab monotherapy in five newly diagnosed Philadelphia chromosome-negative B-cell ALL patients over 70 years. Three had cytokine release syndrome, treated with dexamethasone and/or tocilizumab, and four patients had neurotoxicity, treated with dexamethasone, without blinatumomab interruption. All five achieved complete remission (CR) after cycle one, three with undetectable MRD. All five were alive at 8 to 15 months. Three remained in MRD-negative CR. Two relapsed after cycle 3, one with extramedullary disease. In our small cohort of patients over 70 years, blinatumomab was safe initial therapy and produced a high response rate.

Currently, no standard of care exists for the treatment of relapsed or refractory acute myeloid leukemia (AML). We present our institutional experience with using either CLAG-M or HAM-pegA, a novel regimen that includes pegaspargase. This is a retrospective comparison of 34 patients receiving CLAG-M and 10 receiving HAM-pegA as first salvage cytotoxic chemotherapy in the relapsed or refractory setting. Composite complete response rates were 47.1% for CLAG-M and 90% for HAM-pegA (p = 0.027). Event-free survival was significantly different in favor of HAM-pegA (p = 0.045), though overall survival was similar between groups. There were no significant differences in toxicities experienced by patients treated with the two regimens, including adverse events of special interest related to pegaspargase (venous thromboembolism, hemorrhage, hepatotoxicity, pancreatitis, and hypersensitivity reactions). HAM-pegA is a novel regimen for relapsed or refractory AML that resulted in improved response rates and similar toxicities compared to CLAG-M.

We describe two patients with acute promyelocytic leukemia (APL) with an unusual immunophenotype with co-expression of myeloperoxidase (MPO) with cytoplasmic CD3 (cCD3) representing myeloid and T-lineage differentiation. Both harbored FLT3-ITD mutations. One additionally had a deletion in the PML gene affecting the primer binding site, thus limiting measurable residual disease (MRD) analysis during follow-up. Both patients achieved durable remission with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)-based therapy, thus mitigating the need for repetitive conventional chemotherapy cycles and allogeneic stem cell transplantation. Our report highlights the complexity and challenge of diagnosis and management of APL due to the variant immunophenotype and genetics, and underscores the importance of synthesizing information from all testing modalities. The association of the unusual immunophenotype and FLT3-ITD mutation illustrates the plasticity of the hematopoietic stem cell and the pathobiology of leukemia with mixed lineage or lineage infidelity.

The probability that adult patients with de novo acute myeloid leukemia (AML) receiving intensive chemotherapy in the absence of allogeneic hematopoietic stem cell transplantation (Allo-HCT) in first complete remission (CR1) will be disease-free at 10 years after diagnosis, a long-term surrogate of cure, is unknown. To address this question, we examined 2551 AML patients (1607 aged

Background Human immunodeficiency virus (HIV) infection increases the risk of thrombotic microangiopathy (TMA), but TMA in the setting of HIV infection is not well characterized. The experience with TMA in the setting of HIV infection at the University of Maryland Medical Center was reviewed. Study design and methods Patients undergoing therapeutic plasma exchange (TPE) for TMA from January 1, 2000 through December 31, 2012 were reviewed. Those with known HIV-positive and -negative status were compared. Results Among 102 patients with known HIV status, 28 (27%) were HIV-positive, including 3 with previously undiagnosed HIV. HIV-positive patients had a median viral load of 89 500 copies/mL (range, 0->750 000 copies/mL) and a median CD4 count of 58 cells/µL (range, 2-410 cells/µL). Compared to HIV-negative patients, HIV-positive patients more frequently presented with concurrent infections (60.7% vs. 23.7%; P = .0007), had a trend toward lower median platelet counts (3000/µL vs. 15 000/µL; P = .07) and more frequently had platelet counts less than 10 000/mcL (P = .02). Nevertheless, number of TPE procedures required for remission, remission rate, mortality, and relapse incidence were similar in HIV-positive and HIV-negative patients. Conclusions The incidence described herein of HIV infection among TMA patients is the highest reported outside of South Africa. More severe thrombocytopenia in HIV-positive patients may reflect TMA in the setting of preexisting HIV-associated thrombocytopenia. HIV should be considered in patients with TMA, and TMA should be considered in HIV-positive patients with severe thrombocytopenia.

Introduction: The COVID-19 pandemic significantly impacted emergency department (ED) and overall hospital utilization, with a substantial decline in non-COVID-19-related medical presentations. In the weeks following the declaration of a national health emergency, ED visits declined by 42%. Patients with sickle cell disease (SCD) are at risk for needing ED-based care and hospitalization due to disease-specific complications. We examined the impact of the COVID-19 pandemic on acute care utilization by patients with SCD at our institution. Methods: We performed a retrospective cohort study at our institution comparing the period of the first "stay at home" order in Baltimore, MD (3/30/2020-6/8/2020) to the same date range in 2019. We included all adult patients with SCD who either presented to the ED or were directly admitted to the hospital. All SCD genotypes were included (HbSS, HbSC, HbSβ +/0 thalassemia). Data collected included presenting symptoms, disposition for ED visits, admission length of stay (LOS), re-admission within 7 days, as well as frequency of sickle cell-specific complications during hospitalization. We collected data regarding the acuity of patients' initial presentation using the emergency severity index (ESI), a five-tiered grading tool utilized by triage nurses to indicate the acuity and resource-intensiveness of a patient's presenting symptoms (1= highest urgency, 5= least urgency). We performed statistical analyses using Pearson's chi square test, Fisher's exact test and the Mann-Whitney U test. Results: During the initial stay at home order in 2020, 77 patients presented to acute care services at our institution, compared to 163 patients during the same dates in 2019, a decrease of > 50%. Statistically significant demographic differences between 2020 and 2019 included gender (53% vs 34% male gender, p = 0.004) and hemoglobinopathy type (2020: SS (66%), SC (27%), Sβ-thal (6.5%) vs 2019: SS (48%), SC (42%), Sβ-thal (10%), p = 0.03), whereas there was no difference in severity on presentation measured by ESI (median score of 3: 88% vs 90%, p = 0.13) or age (30 vs 30 years old, p = 0.925). More patients in 2020 presented with dyspnea (22% vs 11%, p = 0.02), and/or nausea or vomiting (22% vs 11%, p = 0.02), but more patients in 2019 presented with cough (7% vs 17%, p = 0.025). None of the patients tested positive for SARS-CoV-2. There was no statistically significant difference between the study periods in hospitalization rate (44% vs 37%, p = 0.32), LOS (60 vs 64 hrs, p = 0.73), admission to the ICU (3% vs 2.5%, p = 1.0) or step-down unit (0% vs 1%, p = 1.0), or death (0% vs 1%, p = 1.0). There was a difference in ED re-presentation within 7 days of the index visit (14% vs 47%, p < 0.001), but no difference in rate of readmission within 7 days (9% vs 15%, p = 0.225). Discussion: Although fewer patients with SCD presented for acute care in 2020, there was no significant difference in objective metrics, including admission rates, LOS, readmissions, and disease-specific complications. The decrease in ED return visits in 2020 may reflect patients' concerns regarding exposure to SARS-CoV-2 while in the ED. Our data demonstrate that although fewer patients with SCD presented for acute care utilization, they did not appear to be sicker. The data support more frequent management of uncomplicated pain crises outside of the ED, through optimization of outpatient services including infusion centers and telehealth. The advent of new care delivery models as a result of the Covid-19 pandemic may have a positive impact on frequency of ED utilization for patients with SCD. Disclosures No relevant conflicts of interest to declare.

Introduction Mutations have become essential in determining risk stratification for acute myeloid leukemia (AML) and are often used to guide treatment. Variants of unknown significance (VUS) can be classified as pathogenic or benign once their roles are better understood. Therefore, studying VUS in mutated genes may improve overall risk stratification and prognostication for AML patients. Mutations in isocitrate dehydrogenases, IDH1 or IDH2, occur in approximately 20% of AML. R132 (in IDH1) and R140/R172 (in IDH2) mutations lead to the production of oncometabolite 2-hydroxyglutarate and have been targeted with selective oral inhibitors; however, the clinical impact of the synonymous single nucleotide polymorphism (SNP) in codon 105 in exon 4 of the IDH1 gene (c.315C>T (p.Gly105Gly), s11554137) is poorly understood. This VUS is not commonly screened for in myeloid mutation panels. Here, we aimed to investigate the prognostic significance of the c.315C>T SNP in AML patients. Methods We conducted a single-site retrospective study to compare overall survival (OS), event-free survival (EFS), complete remission (CR) and complete remission with incomplete hematologic recovery (CRi) rates in adults with AML with and without the IDH1:c.315C>T (p.Gly105=) between 2013 and 2020. The IDH1 c.315C>T SNP was identified using Sanger's technique. Data collected included age, gender, ethnicity, ECOG performance status, baseline comorbidities, AML category, cytogenetics, myeloid mutations including IDH1/IDH2/FLT3, treatments received, and survival outcomes. Data were analyzed using propensity score-weighting to obtain adjusted estimands. CR+CRi rates in patients with and without c.315C>T IDH1 mutation were compared using Fisher's exact test or Chi-square test. Survival outcomes were compared using the Gehan-Breslow-Wilcoxon rank test and adjusted Cox proportional hazards regression. Results We included 228 patients (median age 65.2 years [IQR: 54-75]). The IDH1 c.315C>T SNP was identified in 21 (9%) patients. Table 1 shows unadjusted baseline characteristics. The presence of IDH1 c.315C>T SNP was not mutually exclusive with conventional IDH mutations. The CR+CRi adjusted rates were 60% and 51% with first-line treatment in patients with and without the mutation (P=0.42). The adjusted-median OS was 26.1 (95 CI: 9.8-NA) and 17 (95 CI: 12.6-21.8) months (P=0.69). The adjusted hazard ratio for mortality was 1.4 higher in the unmutated category (95 CI: 0.997-1.98, P=0.05). The adjusted-median EFS was 9.53 (95 CI: 4.17-NA) and 5.57 (95 CI: 4.43-7.87) months (P=0.89). The adjusted hazard ratio for mortality or relapse was 1.1 higher in the unmutated category (95 CI: 0.81-1.47, P=0.56). Figures 1 and 2 show OS and EFS survival curves. Conclusions Unlike in previous studies, the presence of IDH1 c.315C>T SNP was not associated with inferior OS, PFS or CR+CRi rates compared with its absence. Figure 1 Figure 1. Disclosures Emadi: Secura Bio.: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder.

Genetic profiling of leukemic cells forms the basis for risk stratification in acute myeloid leukemia (AML). Genetic markers in AML are used to make recommendations for distinct treatment approaches, such as remission consolidation with chemotherapy rather than stem cell transplant for patients with favorable risk genetics as defined by the current guidelines from the European LeukemiaNet (ELN). Yet, several limitations remain, such as overall rarity of many mutations, hierarchical complexity in cases with multiple mutations, conflicting reports of associations with outcomes for some genetic markers, and the absence of markers with prognostic significance in some patients. We have recently described genome-wide DNA methylation signatures that underlie biological features of AML cells and their utility to classify patients [Giacopelli et al. Genome Res. 2021;31:747]. The additional value of epigenetic information for risk assessment in AML in the context of current genetic and other clinical prognostic markers remains largely unexplored. In this study, we have first developed a targeted approach for assessment of DNA methylation-based signatures and employed it to classify 1,262 patients with de novo AML enrolled onto the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology studies. We successfully classified 87.5% of patients into one of 13 DNA methylation subgroups, termed 'epitypes' (Figure 1A,B). We found that epitypes are composed of a majority of patients with a specific genetic alteration (or a unique combination of alterations) in 9 of 13 epitypes. However, we also identified subgroups of patients that lack these highly recurrent alterations, and, instead, represent an epigenetic phenocopy of the dominant genetic feature (epiphenocopy). Epiphenocopies within epitypes were often enriched in specific lower frequency mutations, suggesting convergence of biological function(s) for these rare mutations. Epiphenocopying was also exhibited by patients displaying a DNA methylation signature involving hypomethylation of STAT DNA sequence motifs (termed the STAT hypomethylation signature, SHS) that mimicked FLT3-ITD mutations. Epitype and SHS DNA methylation signatures affected clinical outcomes separately to ELN risk groups (P To broadly examine the prognostic power of DNA methylation signatures, we combined methylation-based classifications into a knowledge bank containing a compendium of other prognostic markers. Using a recently developed machine-learning approach [Gerstung et al. Nat Genet. 2017;49(3):332], we found that DNA methylation retained a high degree of importance for clinical outcomes, including overall survival (Figure 1F). Specifically, SHS and 6 epitypes were the most significant features negatively associated with overall survival along with age (P Our study demonstrates that DNA methylation signatures advance our understanding of the biology of AML and improve risk stratification through the identification of patients with epiphenocopies that mimic genetic mutations and other biological features. Use of DNA methylation signatures may lead to more effective assignment of patients to existing and novel therapeutic approaches. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org; ClinicalTrials.gov Identifiers: NCT00048958 (8461), NCT00899223 (9665), and NCT00900224 (20202) Figure 1 Figure 1. Disclosures Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Blum: Abbvie: Honoraria; AmerisourceBergen: Honoraria; Celyad Oncology: Research Funding; Xencor: Research Funding; Nkarta: Research Funding; Forma Therapeutics: Research Funding; Leukemia and Lymphoma Society: Research Funding; Syndax: Honoraria. Stone: Agios Pharmaceuticals Inc, Novartis;: Research Funding; ACI Clinical, Syntrix Pharmaceuticals, Takeda Oncology: Other: Data Safety & Monitoring; AbbVie Inc, Actinium Pharmaceuticals Inc, Aprea Therapeutics, BerGenBio ASA, ElevateBio, Foghorn Therapeutics, GEMoaB, GlaxoSmithKline, Innate Pharma, Syndax Pharmaceuticals Inc, Syros Pharmaceuticals Inc, Takeda Oncology: Other: Advisory Committee. Eisfeld: Karyopharm (spouse): Current Employment. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees.

Background: IVO is an oral potent inhibitor of mutated IDH1 (IDH1m) enzyme, recently approved for the treatment (Tx) of ND adult patients (pts) with IDH1m AML ≥75 years old or with comorbidities precluding use of intensive induction chemotherapy, and adult pts with relapsed or refractory AML. In this Phase 2 sub-study of the Beat AML Master Trial, we evaluated the efficacy of IVO + AZA combination Tx in ND pts aged ≥60 years with IDH1m AML (ClinicalTrials.gov: NCT03013998) Methods: This open-label multicenter (16 sites / 9 enrolling) combination Tx study enrolled ND pts with R132 mIDH1 AML, utilizing the modified minimax Simon's 2-stage Phase 2 design. Pts received IVO + AZA for 6 cycles in the absence of disease progression (PD), unacceptable toxicity or stem cell transplant. Pts who achieved complete remission (CR)/complete remission with hematologic improvement (CRh)/complete remission with incomplete hematologic recovery (CRi) continued IVO + AZA for a total of 12 cycles, then IVO monotherapy until PD. Pts without CR/CRh/CRi after 6 cycles continued IVO + AZA if they demonstrated Tx benefit, as defined in Figure 1. Key eligibility included ND IDH1 R132 mutated AML pts aged ≥60 years and ECOG performance status 0 - 2 (Karnofsky ≥60). All pts received IVO 500 mg/day orally in continuous 28-day cycles + AZA 75 mg/m2 IV or SC on days 1-7 every 28 days. The primary endpoint was CR+CRh+CRi rate after 6 cycles of Tx. Response was assessed using modified 2017 ELN AML criteria. The modified minimax Simon's 2-stage design required 40 pts and tested the null hypothesis that the CR/CRh/CRi rate equaled 25% vs the alternative of 50% (one-sided alpha = 0.025, power 90%). Stage 1 required >5/16 responses for continued enrollment. Even though these criteria were met, the sponsor decided to discontinue the trial on 12/12/2019. Here we report the final primary endpoint results. Data were frozen 02/03/2021. Results: Between 07/2018 and 11/2019, 19 patients were enrolled with IDH1m AML; 18 started IVO + AZA Tx and are included in the analyses. At data freeze, 5 pts had died and 7 pts still on Tx were offered standard of care IVO. Median age of the pts was 75 years, 50% were ≥75 years, 61% were female and 89% were White (Table 1). The most common reasons for Tx discontinuation were trial discontinued by sponsor (7 or 39%), stem cell transplant (4 or 22%), and PD (3 or 17%). A total of 13 pts achieved CR/CRh/CRi (72%) by up to 6 cycles of Tx (Table 2 & Figure 2). Over the entire study period, 14 pts achieved CR/CRh/CRi (78%) with 8 CR (44%), 3 CRh (17%) and 3 CRi (17%). No deaths occurred within the first 60 days of Tx. After a median follow up of 19.8 months (mos), Page 2 median response duration was not reached, with 12-mos disease-free survival rate of 69%; also, median OS was not reached, with 12- and 18-mos OS rates of 100% and 73%, respectively. The median (range) time on Tx was 12 mos ( Conclusions: In ND pts with IDH1m AML and ≥60 years of age, IVO + AZA Tx was associated with a high CR/CRh/CRi rate, no early deaths (60 days) and a 1-year OS of 100%. IVO + AZA was acceptably tolerated and no unexpected toxicities occurred. Most common unique toxicities of IVO observed during the study were differentiation syndrome and QTc prolongation; these led to Tx discontinuation in only 1 pt. CR/CRh/CRi rate obtained with IVO +AZA is higher than that previously reported in studies with the individual agents or intensive chemotherapy approaches, suggesting a synergistic effect. Our overall response rate is similar to that reported recently for IVO + AZA in older ND IDH1 mutant AML pts, despite not including pts with morphologic leukemia-free state and partial remission. Based on these results, a global Phase 3 evaluation of IVO or placebo plus AZA is ongoing (NCT03173248). Figure 1 Figure 1. Disclosures Patel: BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Peerview: Honoraria. Ruppert: Telios Pharma: Consultancy. Borate: Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Astellas: 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; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Stein: Syros Pharmaceuticals, Inc.: Consultancy; Daiichi Sankyo: Consultancy; PinotBio: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Kovacsovics: AbbVie: Research Funding; Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Novartis: Research Funding; Stemline: Honoraria; Jazz Pharmaceutials: Honoraria. Blum: Leukemia and Lymphoma Society: Research Funding; Nkarta: Research Funding; Celyad Oncology: Research Funding; Syndax: Honoraria; Xencor: Research Funding; Abbvie: Honoraria; Forma Therapeutics: Research Funding; AmerisourceBergen: Honoraria. Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Schiller: Sangamo: Research Funding; Takeda: Research Funding; Ono-UK: Consultancy, Research Funding; Gamida Cell Ltd.: Research Funding; Tolero: Research Funding; Samus: Research Funding; Karyopharm: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Mateon: Research Funding; Genentech-Roche: Research Funding; FujiFilm: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Actinium Pharmaceuticals, Inc: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Arog: Research Funding; Delta-Fly: Research Funding; Celator: Research Funding; Forma: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; PrECOG: Research Funding; Constellation Pharmaceuticals: Research Funding; Trovagene: Research Funding; Elevate: Research Funding; Deciphera: Research Funding; Actuate: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Daiichi-Sankyo: Research Funding; Onconova: Research Funding; Geron: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Abbvie: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Olin: Actinium: Honoraria; Abbvie: Honoraria; Amgen: Honoraria; Cellectis: Research Funding; Pfizer: Research Funding; Genentech: Research Funding; Daiichi Sankyo: Research Funding; Astellas: Honoraria, Research Funding. Foran: pfizer: Honoraria; gamida: Honoraria; servier: Honoraria; kura: Research Funding; abbvie: Research Funding; takeda: Research Funding; trillium: Research Funding; revolution medicine: Honoraria; novartis: Honoraria; certara: Honoraria; sanofi aventis: Honoraria; bms: Honoraria; syros: Honoraria; taiho: Honoraria; OncLive: Honoraria; actinium: Research Funding; aptose: Research Funding; boehringer ingelheim: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: Pluristem: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Jazz: Other: Advisory Board; Amgen: Research Funding; Actinium: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Foster: Agios: Consultancy; Daiichi Sankyo: Consultancy; Macrogenics: Consultancy; Rafael Pharmaceuticals: Research Funding; Macrogenics: Research Funding; Bellicum Pharmaceuticals: Research Funding. Cogle: Celgene: Membership on an entity's Board of Directors or advisory committees; Aptevo therapeutics: Research Funding. Vergilio: Roche: Current equity holder in publicly-traded company; Foundation Medicine: Current Employment. Gana: Bausch: Current holder of individual stocks in a privately-held company; The Leukemia & Lymphoma Society: Consultancy. Druker: The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; EnLiven: Consultancy, Research Funding; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; GRAIL: Current equity holder in publicly-traded company; Nemucore Medical Innovations, Inc.: Consultancy; Merck & Co: Patents & Royalties; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Bristol-Myers Squibb: Research Funding; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Iterion Therapeutics: Membership on an entity's Board of Directors or advisory committees; Recludix Pharma, Inc.: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; Aileron: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Vincerx Pharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Levine: QIAGEN: Membership on an entity's Board of Directors or advisory committees; Imago: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Zentalis: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Celgene: Research Funding; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Research Funding; Incyte: Consultancy; Janssen: Consultancy; Astellas: Consultancy; Morphosys: Consultancy; Gilead: Honoraria; Amgen: Honoraria; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Prelude: Membership on an entity's Board of Directors or advisory committees; Auron: Membership on an entity's Board of Directors or advisory committees. Mims: Leukemia and Lymphoma Society: Consultancy; Kura Oncology: Consultancy; Genentech: Consultancy; Abbvie: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Aptevo: Research Funding; Xencor: Research Funding; Glycomemetics: Research Funding; Jazz Pharmaceuticals: Consultancy; Daiichi-Saynko: Consultancy. OffLabel Disclosure: IVO is an oral potent inhibitor of mutated IDH1 enzyme, recently approved for the treatment of ND adult patients with IDH1m AML âââ,¬Â°Ã,Â¥75 years old or with comorbidities precluding use of intensive induction chemotherapy, and adult pts with relapsed or refractory AML. The combination of AZA, a hypomethylating agent, and venetoclax, an oral BCL-2 inhibitor, is also FDA approved for newly diagnosed AML in adults 75 years or older, or who have comorbidities precluding intensive chemotherapy. This presentation will discuss the combination of IVO and AZA.

Introduction: Patients (pts) with higher-risk myelodysplastic syndromes (MDS) are typically treated with azacitidine (Aza). Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor that has demonstrated synergy with Aza in preclinical studies of myeloid malignancies. Higher-risk MDS is associated with mutations in genes involved in RNA splicing, epigenetic regulation, transcription, and cellular signaling. Assessing the dynamics of genetic variants during treatment of higher-risk MDS enables understanding of the molecular determinants of response. This phase 1b study (NCT02942290) evaluates Ven + Aza for treatment-naïve higher-risk MDS, and we report efficacy among mutationally defined subgroups as well as the depth of molecular response. Methods: Pts (≥18 years) with higher-risk MDS enrolled in the study had International Prognostic Scoring System intermediate-2 or high-risk MDS, bone marrow (BM) blasts Molecular responses were quantified by mutation analysis of baseline and serial BM aspirate (BMA) or peripheral blood (PB) samples collected at protocol-specified time points. Mutations were identified in BMA using Archer VariantPlex Myeloid 75-gene panel [limit of detection (LOD) 5%; time points: pre-treatment (n=43), on-treatment (n=32), and treatment completion visit (TCV) (n=25)] or TruSight Myeloid 54-gene Sequencing Panel in PB [LOD 2%; time points: pre-treatment (n=21), on-treatment (n=19), and TCV (n=8)] to assess molecular dynamics during Ven + Aza treatment. Molecular responses were only compared within the same tissue type. Results: At the Dec 15, 2020 cutoff, 78 pts had received Ven+Aza, including 51 who received Ven at the RP2D of 400 mg x 14 d, with median follow up time of 23 mos (range 0.1-44.2). Median age was 70 years (range 26-87); 72% male; and 91% had excess BM blasts (>5 to ≤10%, n=21; >10 to ≤20%, n=49; >20%, n=1). For the entire population, mORR was 80% (CR 40% and mCR 40%; no PR). 42% with mCR also had hematologic improvement [HI]. Screening mutational profiling was performed on 46/51 pts who received the RP2D of Ven + Aza. The most common mutations were TP53 (26%), ASXL1 (24%), U2AF1 (17%), and RUNX1 (15%), consistent with a higher-risk MDS population. Clinical responses (CR + mCR) were observed across the mutational spectrum, including in pts with poor prognostic mutations in TP53 (83%), ASXL1 (82%), and RUNX1 (71%). Sixty-four pts treated with Ven + Aza (all Ven dosing cohorts) had paired BMA or PB pre-treatment and on-treatment and/or end of study samples available for serial analysis at the Dec 15, 2020 data cutoff. Ven + Aza resulted in robust and rapid molecular responses across the mutational spectrum. Pts who achieved CR at the time of serial sample acquisition had more significant reduction of variant allele frequencies (VAFs) (n=18 pts, mean VAF pre-treatment = 38.3; mean VAF at CR = 11.8) compared to pts who achieved stable disease or HI (n=11 pts, mean VAF pre-treatment = 29.8; mean VAF at SD or HI = 24.0) or progressive disease (n=10 pts, mean VAF pre-treatment = 27.4; mean VAF at PD = 26.9). Reductions of VAFs below the LOD were observed across the mutational spectrum, including in genes that are considered poor prognostic in higher-risk MDS (e.g., TP53, ASXL1 and RUNX1), demonstrating the broad molecular activity of Ven + Aza (Figure). Finally, molecular responses were observed quickly, with VAF reductions below the LOD observed as early as end of Cycle 1, consistent with the mechanism of action of Ven directly activating the mitochondrial apoptotic pathway in cells. Conclusions: Pts with higher-risk MDS treated with Ven + Aza had rapid, durable responses and high remission rates. Pts across key mutational profiles achieved meaningful clinical and molecular responses, supporting an all-comers approach. Updated data will be presented, which will provide more follow up time and durability of responses among mutational subsets. Figure 1 Figure 1. Disclosures Garcia: Genentech: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding; Prelude: Research Funding; Pfizer: Research Funding. Wei: Novartis, Celgene, AbbVie, Servier, AstraZeneca, and Amgen: Research Funding; Novartis, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, BMS, Macrogenics, Agios, Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria. Jacoby: Abbvie: Research Funding; Jazz: Research Funding. Fong: Amgen, BMS: Speakers Bureau; AbbVie, Amgen, Novartis, Pfizer, Astellas: Honoraria; Amgen: Research Funding. Borate: Jazz Pharma: Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: 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; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Cunningham: AbbVie, Amgen, Astex, Celgene, Janssen, Novartis, Principia Biopharma, Rigel: Research Funding. Odenike: Celgene, Incyte, AstraZeneca, Astex, NS Pharma, AbbVie, Gilead, Janssen, Oncotherapy, Agios, CTI/Baxalta, Aprea: Research Funding; AbbVie, Celgene, Impact Biomedicines, Novartis, Taiho Oncology, Takeda: Consultancy. Jurcic: AbbVie, BMS/Celgene, Novartis: Consultancy; AbbVie, Arog Pharmaceuticals, Astellas, BMS/Celgene, Forma Therapeutics, Genentech, Gilead Sciences, PTC Therapeutics, Syros Pharmaceuticals: Research Funding. Nowak: Pharmaxis: Current holder of individual stocks in a privately-held company, Research Funding; AbbVie: Other: Investigator on funded clinical trial; Affimed: Research Funding; Tolero Pharma, Pharmaxis, Apogenix: Research Funding; Celgene: Honoraria; Takeda: Honoraria. Platzbecker: Janssen: Honoraria; Celgene/BMS: Honoraria; Geron: Honoraria; AbbVie: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Dunshee: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Zhou: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Hoffman: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Sun: AbbVie: Current Employment. Popovic: AbbVie: Current Employment, Current equity holder in publicly-traded company. Ainsworth: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Naqvi: Genentech/Roche: Current Employment, Current holder of stock options in a privately-held company. Kye: AbbVie: Current Employment, Other: May hold equity. Hogdal: AbbVie: Current Employment, Current holder of stock options in a privately-held company.

Background : The identification of mutations in IDH1 and IDH2 in ~20% of AML pts has ushered in the modern era of precision medicine in AML. The functional implications of the resulting neomorphic activity of these mutated enzymes, has resulted in FDA-approved targeted therapies. Similarly, the changes in methylation due to IDH mutations (IDHm) have shown high responses with HMA-based regimens. In the frontline setting, where traditional IC regimens are also used, no clear guidance exists which choice elicits the best outcomes for IDHm pts. Furthermore, emerging data on the importance of the biologic context on the response to different agents, including co-existing gene mutations and pt age, pose additional questions that need to be systematically addressed in order to determine the best-individualized approach. We set out to address this question, and provide data-driven treatment decision support for the ~20% of AML pts harboring IDHm. Methods : Using the AML pt collection from the Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance, 1986-2013), and a new multicenter collaboration between four major US Cancer Centers (consecutive pts, 2015-2019), we have assembled the thus far largest cohort of 804 IDH1/2m adult AML pts, treated with standard 7+3 IC (n=578), IDH-directed inhibitors (IDHi, n=58) or HMA (without IDH2i or BCL2i, n=75). We investigated the role of different IDH1/2m, co-mutational patterns, and clinical features in predicting response to different frontline therapies. Results : IDH1/2m pts were predominantly older, with 64% aged ≥60 y. Nineteen percent of pts presented with extramedullary disease (EMD) at diagnosis. Pts with all IDHm mutation types commonly harbored DNMT3Am (IDH1-R132m, 38%; IDH2-R140m, 31%; IDH2-R172m, 48%), but differed with respect to other co-occurring mutations (Fig. 1). IDH1m pts most frequently had mutations in the NPM1 (43%), FLT3-ITD (19%), SRSF2 (15%), and NRAS (14%) genes. IDH2-R140m pts harbored mutations in NPM1 (37%), SRSF2 (33%), FLT3-ITD (19%) and RUNX1 (16%) most often, whereas IDH2-R172m pts frequently had BCORm (21%) and RUNX1m (20%), but rarely harbored FLT3-ITD (6%) or NPM1m (2%). Clinical outcomes had notable differences in complete remission (CR) rates, relapse rates (RR) and overall survival (OS), both with respect to IDHm-type, and also frontline therapy (Table 1). IDH1m pts treated with IC (n=239) had a CR rate of 69%. The CR rates were differentially impacted by clinical characteristics and co-occurring mutations, which were identified in multivariate analysis (MVA; positive prognosticator [PP] for CR: NPM1m; negative prognosticator [NP]: WT1m, FLT3-TKD, higher age, Table 2). IC-treated IDH1m pts had a RR of 60% (NP: ASXL1m), with a 3y-OS of 41% (NP: U2AF1m, WT1m, higher age, higher WBC). When treated with IDH1i (n=20), pts had a high CR rate of 70%, RR of 36%, and a 3y-OS of 44%. In contrast, pts treated with HMAs had a low CR rate of 37% (NP: higher BM blast %), and 3y-OS of 26%. IDH2-R140m pts treated with IC (n=231) had a CR rate of 68% (PP: NPM1m, FLT3-ITD NP: higher WBC), RR of 64% (NP: SRSF2m), with a 3y-OS of 37% (PP: NPM1m, WT1m; NP: PHF6m, higher age, higher WBC). The positive prognostic association of FLT3-ITD for CR achievement was surprising, but seemed to be independent of co-occurring NPM1m, with CR rates for pts with NPM1wt/ITD+: 70%, NPM1wt/ITD-: 57%, NPM1m/ITD+:83%, and NPM1m/ITD-:76%. When treated with IDH1i (n=27), pts had a CR rate of 48%, RR of 8%, with a 3y-OS of 29%. Again, pts treated with HMAs had a low CR rate of 28%, RR of 90% and 3y-OS of 21%. IDH2-R172m pts treated with IC (n=66) had a relatively low CR rate of 58% (NP: higher age, male sex, presence of EMD), RR of 53%, but a relatively high 3y-OS rate of 45% (median: 2.5y; NP: RUNX1m, higher WBC). The number of IDH2i- or HMA-treated pts with IDH2-R172m was too small for analyses. Conclusions: Given the relatively high response rates to IC of IDH1/2m pts, consideration of co-occurring mutations or clinical features (eg, WT1m or FLT3-TKD as NP for IDH1m, SRSF2m for IDH2-R140m or EMD for IDH2-R172m pts) may help guide frontline treatment decisions. Likewise, encouragingly high response and survival rates of pts treated with frontline IDHi should also factor into decision-making. As more information on high response and survival rates with HMA-based combination regimens comes forth, we will be adding these pts to our on-going analysis. *first: UB,PP,CT; #last:ASM,KS,AKE Figure 1 Figure 1. Disclosures Borate: Jazz Pharma: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: 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; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Talati: AbbVie: Honoraria; Astellas: Speakers Bureau; Jazz: Speakers Bureau; Pfizer: Honoraria; BMS: Honoraria. Madanat: Onc Live: Honoraria; Blue Print Pharmaceutical: Honoraria; Stem line pharmaceutical: Honoraria; Geron Pharmaceutical: Consultancy. Blachly: KITE: Consultancy, Honoraria; INNATE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Walker: Karyopharm Therapeutics: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Marcucci: Agios: Other: Speaker and advisory scientific board meetings; Abbvie: Other: Speaker and advisory scientific board meetings; Novartis: Other: Speaker and advisory scientific board meetings. Blum: Leukemia and Lymphoma Society: Research Funding; Forma Therapeutics: Research Funding; Xencor: Research Funding; Nkarta: Research Funding; Celyad Oncology: Research Funding; AmerisourceBergen: Honoraria; Abbvie: Honoraria; Syndax: Honoraria. Larson: Novartis: Research Funding; Takeda: Research Funding; CVS/Caremark: Consultancy; Gilead: Research Funding; Astellas: Consultancy, Research Funding; Epizyme: Consultancy; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding. Stone: GlaxoSmithKline: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Aprea: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Innate: Consultancy; Janssen: Consultancy; Novartis: Consultancy, Research Funding; Jazz: 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; AbbVie: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Mims: Xencor: Research Funding; Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Aptevo: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomemetics: Research Funding; Kartos Pharmaceuticals: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Sweet: Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Eisfeld: Karyopharm (spouse): Current Employment.

Background: GILT is an oral potent selective FLT3 kinase inhibitor approved for marketing for the treatment (Tx) of patients (pts) with relapsed/refractory FLT3 mutated (FLT3m) AML but efficacy in older ND FLT3m AML pts is unknown. Furthermore, FLT3m can be present as a dominant or subclone and impact of FLT3 inhibitor therapy in this setting is uncertain. Here we report the results of a Phase 2/1b sub-study of the Beat AML Master Trial to assess the efficacy of GILT monotherapy (GILTm) in ND FLT3m AML pts aged ≥60 years with high and low VAF and the subsequent response-driven addition of DEC Tx. (ClinicalTrials.gov NCT03013998) Methods: The study was an open-label multicenter (15 sites), 3-outcome, 2-stage Phase 2 design that assigned pts to either Dominant FLT3/Group 1 (GP1) or Non-Dominant FLT3/Group 2 (GP2) as shown in Figure 1. Key eligibility criteria included ND FLT3m AML pts with high and low VAF and/or ITD ratio, aged ≥60 years, and ECOG performance status 0-2. In the Phase 2 study, all pts received GILTm 120 mg/day on days 1 - 28. Pts without CR/CRi after cycle 2 were transferred to the Phase 1b study to receive GILT + DEC (Figure 1). Phase 1b study utilized a standard 3+3 design to evaluate the safety/tolerability of concurrent GILT + DEC. Pts received GILT (dose level 1 [DL1] = 80 mg/day or dose level 2 [DL2] = 120 mg/day on days 1-28) + DEC 20 mg/m 2 IV on days 1-10 or 1-5 every 28 days. Primary endpoint was CR+CRi rate (Phase 2). Response was assessed using modified 2017 ELN AML criteria. The non-dominant GP2 was stopped for futility, GP1 was stopped early to modify trial to include venetoclax. Results: Phase 2 - Between 9/10/2018 to 2/11/2020, 19 / 20 enrolled pts (GP1: n = 9; GP2: n = 10) received GILTm and were included in analyses. Baseline pt characteristics are shown in Table 1. Median (range) time on GILTm was 3 cycles (1 - 18) in GP1 and 1 cycle (1 - 9) in GP2. Most common reasons for discontinuing Tx were Tx failure (TF; 44%) and relapse (33%) in GP1 and TF (70%) and disease progression (PD; 20%) in GP2. Overall CR+CRi was achieved in 4 pts (44%) in GP1 and 1 pt (10%) in GP2. Response duration are shown in Table 2. After median follow-up of 14.3 months (mos) and 19 mos in GP1 and GP2, respectively, 1-year OS was 56% and 76%. Most common Grade ≥3 adverse events (AEs) were febrile neutropenia and colitis (each 25%) in GP1; anemia and low platelet count in GP2 (each 30%). Overall, 7 pts had 15 serious AEs (SAEs) and all SAEs occurred in GP1 pts; most common SAE was colitis (25%) and 1 pt (13%) had a Tx-related Grade 3 SAE of tumor lysis syndrome. In GP2, 1 pt (10%) had Tx-related Grade 2 AE of differentiation syndrome. In GP1, 2 pts died within 60 days of Tx and none in GP2. Phase1b - After up to 2 cycles of GILTm, 12 pts with no CR/CRi (GP1: n = 4; GP2: n = 8) were transferred to receive GILT + DEC (Figure 1). At the time of this report, 1 pt with CRh remained on Tx. Median total time on Tx (including GILTm) was 4 cycles and median time on GILT + DEC Tx was 3 cycles (Table 2). Most common reasons for discontinuing Tx were PD (33%) and TF (25%); and 2 pts (17%) stopped Tx due to an AE. Pts were treated with DL1 GILT + DEC (n = 3), then DL2 GILT + DEC (n = 9); only 1 pt had dose-limiting toxicity (DLT) at DL2 (Grade 3 hyperbilirubinemia and pneumonitis requiring steroid therapy), hence, DL2 GILT + DEC was considered the MTD. CR+CRi rate was 25% in 3 pts, all at DL2 (Table 2). After a median follow-up of 17.8 mos, the 1-year OS from start of GILT + DEC Tx was 57%. Most common Grade ≥3 Tx-related AEs were anemia, febrile neutropenia and low WBC count (each 22%). Overall, 6 pts had 12 SAEs; 1 pt with SAE of Grade 4 sepsis died. Three GILT-related SAEs occurred in 1 pt - Grade 3 hyperbilirubinemia, and pneumonitis and Grade 1 transaminases increased. One pt died within 30 days and a second within 60 days of Tx. No difference was observed in GILT pharmacokinetics (PK) with or without DEC, however steady state Ctrough values were 1.4 to 2.3-fold greater than in relapsed/refractory AML pts (Admiral trial). Conclusions: In ND pts ≥60 years old with dominant FLT3 AML, GILTm induced a high 44% CR+CRi rate and long median OS (21.7 mos). Pts with non-dominant FLT3 had low 10% CR+CRi rate. GILTm was generally safe and was associated with differentiation syndrome in 1 pt. Concurrent GILT + DEC was acceptably tolerated, only 1 pt had a DLT, and the MTD was 120 mg/day GILT + DEC. A subset of pts with no CR/CRi during GILTm achieved remission with addition of DEC. Based on these results, a triple combination Tx study with venetoclax is currently enrolling. Figure 1 Figure 1. Disclosures Traer: Genentech: Membership on an entity's Board of Directors or advisory committees; Schrodinger: Research Funding; Incyte: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier/Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; ImmunoGen: Membership on an entity's Board of Directors or advisory committees. Mims: Glycomemetics: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Aptevo: Research Funding; Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Genentech: Consultancy; Xencor: Research Funding; Kartos Pharmaceuticals: Research Funding; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Stein: Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; PinotBio: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Jazz Pharmaceuticals: Consultancy; Foghorn Therapeutics: Consultancy; Blueprint Medicines: Consultancy; Gilead Sciences, Inc.: Consultancy; Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Genentech: Consultancy. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Kovacsovics: AbbVie: Research Funding; Jazz Pharmaceutials: Honoraria; Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Stemline: Honoraria; Novartis: Research Funding. Blum: Xencor: Research Funding; Abbvie: Honoraria; Nkarta: Research Funding; Celyad Oncology: Research Funding; AmerisourceBergen: Honoraria; Forma Therapeutics: Research Funding; Leukemia and Lymphoma Society: Research Funding; Syndax: Honoraria. Arellano: Syndax Pharmaceuticals, Inc: Consultancy; KITE Pharma, Inc: Consultancy. Schiller: Actinium Pharmaceuticals, Inc: Research Funding; Mateon: Research Funding; Tolero: Research Funding; Geron: Research Funding; Regimmune: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Celator: Research Funding; Sangamo: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; PrECOG: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Karyopharm: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gamida Cell Ltd.: Research Funding; FujiFilm: Research Funding; Samus: Research Funding; Trovagene: Research Funding; Daiichi-Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Abbvie: Research Funding; Actuate: Research Funding; Arog: Research Funding; Delta-Fly: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Ono-UK: Consultancy, Research Funding; Onconova: Research Funding; Deciphera: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Forma: Research Funding; Genentech-Roche: Research Funding; Bio: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Olin: Astellas: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Cellectis: Research Funding; Amgen: Honoraria; Abbvie: Honoraria; Actinium: Honoraria. Foran: taiho: Honoraria; syros: Honoraria; kura: Research Funding; boehringer ingelheim: Research Funding; sanofi aventis: Honoraria; trillium: Research Funding; aptose: Research Funding; abbvie: Research Funding; pfizer: Honoraria; gamida: Honoraria; actinium: Research Funding; takeda: Research Funding; certara: Honoraria; OncLive: Honoraria; bms: Honoraria; revolution medicine: Honoraria; servier: Honoraria; novartis: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: AbbVie: Research Funding; Jazz: Other: Advisory Board; Pluristem: Research Funding; Amgen: Research Funding; Omeros: Other: Advisory Board; Actinium: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Patel: BMS-Celgene, Agios: Membership on an entity's Board of Directors or advisory committees; Peerview: Honoraria; Aptevo Therapeutics: Research Funding. Foster: Bellicum Pharmaceuticals: Research Funding; Macrogenics: Research Funding; Rafael Pharmaceuticals: Research Funding; Macrogenics: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy. Cogle: Aptevo therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Vergilio: Foundation Medicine: Current Employment. Gana: The Leukemia & Lymphoma Society: Consultancy; Bausch: Current holder of individual stocks in a privately-held company. Druker: VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; GRAIL: Current equity holder in publicly-traded company; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; EnLiven: Consultancy, Research Funding; Iterion Therapeutics: Membership on an entity's Board of Directors or advisory committees; Recludix Pharma, Inc.: Consultancy; Pfizer: Research Funding; Merck & Co: Patents & Royalties; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Nemucore Medical Innovations, Inc.: Consultancy; Bristol-Myers Squibb: Research Funding; Blueprint Medicines: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aileron: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees. Levine: Auron: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Ajax: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy; Celgene: Research Funding; Roche: Honoraria, Research Funding; Zentalis: Membership on an entity's Board of Directors or advisory committees; Prelude: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Consultancy; Gilead: Honoraria; Morphosys: Consultancy; Imago: Membership on an entity's Board of Directors or advisory committees; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria. Borate: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharma: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Astellas: 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; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy.

Background: In vitro studies and emerging clinical data suggest that inhibition of spleen tyrosine kinase may have an antileukemic effect in human AML. Pts with AML and TP53 mutations (TP53m) are commonly associated with older age (≥60 years) and complex karyotype (CK) and respond poorly to standard 7 + 3 induction (IND) chemotherapy with Methods: This multicenter (13 sites), open-label, Phase 2 combination Tx study utilized Simon's 2-stage Phase 2 design and enrolled AML pts with TP53m (identified molecularly) ± CK (Cohort A) or CK (≥3 metaphase abnormalities) without TP53m (Cohort B). Pts initially received 5 days of ENTO lead-in (which was later discontinued), followed by ENTO + DEC and those who achieved CR/CRh/CRi/MLFS with up to 3 cycles of IND proceeded to consolidation (CON) Tx for up to 11 cycles (Figure 1). Pts with CRi/MLFS after IND were allowed up to 6 cycles (IND + CON) to achieve CR/CRh or stayed on Tx if they got clinical benefit or went off Tx. CON was followed by maintenance (MTN) Tx for up to 2 years from start of study Tx. Pts were eligible if aged ≥60 years, ND, and had ECOG performance status 0 - 2. Pts received ENTO 400 mg orally twice daily for 5 days during ENTO lead-in, and then every 28 days during IND, CON, and MTN + DEC 20 mg/m 2 IV days 1-10 (IND) or days 1-5 (CON) every 28 days. Response was assessed using modified 2017 ELN AML criteria. The primary endpoint was composite complete remission (CCR) rate (CR + CRh) with up to 3 cycles of IND, and CRi/MLFS that achieved CR/CRh by up to 6 cycles (IND + CON). Beyond stage 1, pt accrual to Cohort A was allowed based on pts with CRi and to Cohort B was stopped early for futility. Results: Between Oct 2017 and Feb 2020, of the 63 pts enrolled (Cohort A = 48; Cohort B = 15), pts with confirmed eligibility who started study Tx were included in the analyses (Cohort A = 45; Cohort B = 13). During lead-in, 27 pts in Cohort A and 6 pts in Cohort B received ENTOm for 5 days. All pts received ENTO + DEC except 1 pt in Cohort A who withdrew consent (WOC). Median ages of the pts were 70 years (range 60 - 84) in Cohort A and 74 years (range 65 - 86) in Cohort B. Median time (range) on Tx was 2.2 mos and 4.8 mos in Cohort A and B, respectively. Most common reasons for Tx discontinuation were adverse event (AE; 27%), Tx failure (TF; 27%) and WOC (18%) in Cohort A; TF (31%), disease progression and relapse (each 15%) in Cohort B. In each cohort, 1 pt discontinued Tx due to death from leukemia and 1 pt in Cohort A in CRh due to development of an additional genetic abnormality. Four pts (9%) in Cohort A and 1 pt (8%) in Cohort B proceeded to transplant. The CCR (CR + CRh) rates with up to 6 cycles of Tx for Cohort A and B were 13.3% and 30.8%, respectively; overall CR + CRh rates were 17.8% and 38.5% (Table 1). In Cohort A, with a median follow-up of 11.5 months, 0% were 1-year disease-free and median OS (mOS) was 6.5 months. In Cohort B, with a median follow-up of 15.1 months, 25% were 1-year disease-free and mOS was 11.5 months. Deaths within 7-, 30-, and 60-days of Tx were 0, 3 and 11 in Cohort A and 0, 0 and 2 in Cohort B. Most common treatment-related Grade ≥3 AEs in Cohort A and B were febrile neutropenia (31% and 39%) and anemia (22% and 31%) (Table 2). Overall, 83 serious AEs (SAEs) were reported in 33 pts in Cohort A and 12 SAEs in 6 pts in Cohort B; most common SAEs in Cohort A were pneumonia (18%) and respiratory failure (11%), and in Cohort B sepsis, dehydration and acute kidney injury (each 15%). Most common treatment-related grade ≥3 laboratory abnormalities in Cohort A and B were neutrophils decreased (27% and 31%), WBC count decreased (20% and 23%), and lymphocyte count decreased (18% and 15%). Conclusions: ENTO + DEC demonstrated activity in ND AML pts aged ≥60 years with TP53m ± CK and CK without TP53 but induced low CR/CRh rates and short OS consistent with previously published poor CR rates and OS in these pts. Our results differ from the high remission rate and longer OS previously reported for DEC monotherapy in AML pts with TP53m. ENTO + DEC was safe and acceptably tolerated. Novel Tx strategies that can benefit AML pts with these most adverse risk factors are urgently needed. Figure 1 Figure 1. Disclosures Ruppert: Telios Pharma: Consultancy. Mims: Leukemia and Lymphoma Society's Beat AML clinical study: Consultancy, Research Funding; Aptevo: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomemetics: Research Funding; Kartos Pharmaceuticals: Research Funding; Xencor: Research Funding; Genentech: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Kura Oncology: Consultancy; Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Aptevo: Research Funding. Borate: Jazz Pharma: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: 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; Rampal: Membership on an entity's Board of Directors or advisory committees; Galecto, Inc.: Consultancy; Promedior: Consultancy. Stein: Abbvie: Consultancy; Janssen Pharmaceuticals: Consultancy; Gilead Sciences, Inc.: Consultancy; Foghorn Therapeutics: Consultancy; Syros Pharmaceuticals, Inc.: Consultancy; Daiichi Sankyo: Consultancy; Blueprint Medicines: Consultancy; PinotBio: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Agios Pharmaceuticals, Inc: Consultancy; Novartis: Consultancy; Astellas: Consultancy; Syndax Pharmaceuticals: Consultancy. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Kovacsovics: AbbVie: Research Funding; Janssen Pharmaceuticals: Research Funding; Amgen Inc.: Research Funding; Novartis: Research Funding; Stemline: Honoraria; Jazz Pharmaceutials: Honoraria. Blum: Amerisource Bergen; Abbvie, Syndax: Honoraria; Forma Therapeutics, Xencor; Celyad: Research Funding. Arellano: KITE Pharma, Inc: Consultancy; Syndax Pharmaceuticals, Inc: Consultancy. Schiller: Actinium Pharmaceuticals, Inc: Research Funding; Gamida Cell Ltd.: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Karyopharm: Research Funding; Daiichi-Sankyo: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kaiser Permanente: Consultancy; Abbvie: Research Funding; AstraZeneca: Consultancy; Genentech-Roche: Research Funding; Delta-Fly: Research Funding; Cyclacel: Research Funding; Mateon: Research Funding; Actuate: Research Funding; Onconova: Research Funding; Geron: Research Funding; Sangamo: Research Funding; Arog: Research Funding; Ariad: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Trovagene: Research Funding; Ono-UK: Consultancy, Research Funding; Tolero: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Celator: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy; Novartis: Consultancy, Research Funding; Deciphera: Research Funding; FujiFilm: Research Funding; Samus: Research Funding; Regimmune: Research Funding; PrECOG: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Bio: Research Funding; Elevate: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biomed Valley Discoveries: Research Funding; Ono: Consultancy; Eli Lilly: Research Funding; Sellas: Research Funding; ASH foundation: Other: Chair-unpaid; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Olin: Astellas: Honoraria, Research Funding; Actinium: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Genentech: Research Funding; Pfizer: Research Funding. Foran: certara: Honoraria; pfizer: Honoraria; syros: Honoraria; taiho: Honoraria; boehringer ingelheim: Research Funding; servier: Honoraria; revolution medicine: Honoraria; trillium: Research Funding; takeda: Research Funding; abbvie: Research Funding; novartis: Honoraria; bms: Honoraria; OncLive: Honoraria; gamida: Honoraria; sanofi aventis: Honoraria; aptose: Research Funding; actinium: Research Funding; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Litzow: AbbVie: Research Funding; Omeros: Other: Advisory Board; Astellas: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Actinium: Research Funding; Amgen: Research Funding; Biosight: Other: Data monitoring committee. Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Cogle: Aptevo therapeutics: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Vergilio: Foundation Medicine: Current Employment; Roche: Current equity holder in publicly-traded company. Gana: Bausch: Current holder of individual stocks in a privately-held company; The Leukemia & Lymphoma Society: Consultancy. Druker: The RUNX1 Research Program: Membership on an entity's Board of Directors or advisory committees; Aileron: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Recludix Pharma, Inc.: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; VB Therapeutics: Membership on an entity's Board of Directors or advisory committees; GRAIL: Current equity holder in publicly-traded company; Iterion Therapeutics: Membership on an entity's Board of Directors or advisory committees; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; EnLiven: Consultancy, Research Funding; Merck & Co: Patents & Royalties; Pfizer: Research Funding; Nemucore Medical Innovations, Inc.: Consultancy; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees. Byrd: Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees. Levine: Isoplexis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Zentalis: Membership on an entity's Board of Directors or advisory committees; Imago: Membership on an entity's Board of Directors or advisory committees; Ajax: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Prelude: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Janssen: Consultancy; Celgene: Research Funding; Roche: Honoraria, Research Funding; Auron: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Astellas: Consultancy; Morphosys: Consultancy; QIAGEN: Membership on an entity's Board of Directors or advisory committees; Mission Bio: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Off-label use of entospletinib and decitabine.

Background: Despite new therapeutic advances, acute myeloid leukemia (AML) still has poor outcomes, especially in patients with relapsed or refractory (R/R) disease with complex karyotype (CK) and/or TP53 mutation. Venetoclax (Ven), an oral BCL-2 inhibitor, in combination with DNA methyltransferase inhibitors (DNMTIs) has been approved by the FDA for treatment of newly diagnosed AML in adults who are unfit for intensive therapy with encouraging results, but the combination has been found to be less effective in patients with R/R AML. AML cells have been shown to be sensitive to extracellular glutamine depletion or manipulation of intracellular glutamine metabolism. Asparaginase converts asparagine and glutamine to aspartate and glutamate, decreasing plasma concentrations of asparagine and glutamine, with anti-leukemia activity. We previously published that crisantaspase produced complete plasma glutamine depletion in patients without dose-limiting toxicities and was associated with anti-leukemic activity in R/R AML (Emadi et al. Cancer Chemother Pharmacol 2018). In preclinical studies, we found that Pegcrisantaspase (PegC), a long-acting crisantaspase, not only had potent single-agent anti-AML activity, but also synergized with Ven in CK-AML cell lines and primary cells in vitro and in vivo (Emadi et al. Leukemia 2021). Ven-PegC targets the mTOR-eIF4E-driven ribosomal translational protein synthesis apparatus in AML. With no standardized treatment and poor outcomes for R/R AML, there is an unmet need for effective treatment options. Trial Design: We present an ongoing, non-randomized, open-label Phase 1 clinical trial evaluating Ven administered orally daily in combination with PegC administered intravenously every 14 days in 28-day treatment cycles in adults patients with R/R AML. The trial consists of two phases: dose escalation (four cohorts) and dose expansion at the final recommended phase 2 doses (RP2Ds). Adult patients with a pathologically confirmed diagnosis of AML whose disease has relapsed or is refractory to at least one line of AML therapy and with adequate organ function and no prior history of pancreatitis or ≥ Grade 3 thrombohemorrhagic events are eligible for this trial. All patients with FLT3, IDH1 or IDH2 mutation must have received at least one line of therapy with an available FLT3/IDH1/IDH2 inhibitor to be eligible for this trial. The study will include CK-AML and TP53-mutated AML. The primary objectives of the trial are to evaluate the safety and tolerability of Ven-PegC and estimate the maximum tolerated doses (MTDs) and/or biologically active doses (e.g. RP2D) of Ven-PegC in patients with R/R AML. The primary endpoints of the trial are incidences of regimen-limiting toxicities (RLTs) and treatment-emergent adverse events (TEAEs). The secondary endpoints include the rates of complete remission (CR) and composite complete remission (CR+CRh+CRi), event-free survival, overall survival, the rate of conversion from transfusion dependence to transfusion independence, and achievement of MRD The study uses a 3+3 design. Up to 24 subjects will be enrolled during dose escalation (in case exactly one RLT occurs in the first three patients enrolled at each of the four dose levels). Another 10 subjects will be enrolled at the final RP2D in an expansion cohort, for a total of 16 patients treated at the RP2D. The study is currently open at the University of Maryland Greenebaum Comprehensive Cancer Center. ClinicalTrials.gov Identifier is NCT04666649. Figure 1 Figure 1. Disclosures Emadi: Jazz Pharmaceuticals: Research Funding; NewLink Genetics: Research Funding; Servier: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Secura Bio.: Consultancy; KinaRx, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder.

Background: Venetoclax (Ven), a selective oral BCL-2 inhibitor, demonstrated synergy with azacitidine (Aza) in patients with higher-risk myelodysplastic syndromes (HR-MDS). Objective: We report updated safety and efficacy in an ongoing phase 1b study (NCT02942290) evaluating Ven+Aza for treatment-naive HR-MDS patients. Methods: Patients (≥18yrs) with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, bone marrow (BM) blasts Main Outcomes Measures: Primary objectives were assessing Ven+Aza safety profile and establishing RP2D. Key secondary objectives included overall response rate (ORR) and overall survival (OS). Results: At data cutoff (Dec. 15, 2020), 78 patients received Ven+Aza (51 at RP2D 400 mg x 14 d), with median follow-up time of 23 mos. Median age was 70 yrs; 72% male; 90% had excess BM blasts (>5 to 10%, n=21; >10 to 20%, n=49). Grade 3/4 neutropenia (59%) or thrombocytopenia (33%) were present at baseline. All patients experienced ≥1 treatment-emergent adverse event (TEAE), the most common being neutropenia (83%), nausea (55%), and constipation (54%); 96% experienced grade 3/4 TEAEs, with neutropenia (82%), febrile neutropenia (49%), and thrombocytopenia (42%) being most common. Neutropenia (49%), including febrile neutropenia (45%), was the most common serious TEAE. The 30-d mortality rate after first dose was 1%. Intention-to-treat ORR was 80%, including complete remission (CR,40%) and marrow CR (mCR, 40%); 42% mCR had hematologic improvement; no partial remissions recorded. For 31 CR patients, median time to CR and median duration of response was 2.6 and 13.8 mos (95% CI 8.9,–), respectively. Post-baseline transfusion independence rate (defined as no transfusion ≥8 weeks), for patients transfusion-dependent for RBC and/or platelets at baseline, was 46.5%. Median OS was 28.2 mos (95% CI 17.7, –). Median OS for 31 patients achieving CR was 28.6 mos (95% CI 27.5, –). Twenty-three percent moved on to post-study allogeneic HSCT (including BM and peripheral blood stem cells). Conclusions: The combination of Ven+Aza was associated with rapid and durable response, promising efficacy, including remission rates and OS, and an acceptable safety profile for patients with HR-MDS. Additional correlation with disease risk features, including TP53 mutations, will be presented.

Internal tandem duplications within the juxtamembrane domain of fms-like tyrosine kinase 3 (FLT3-ITD) are present in approximately 25% of patients with acute myeloid leukemia (AML) and is an independent predictor of poor prognosis. FLT3-ITD is a constitutively active form of the receptor and aberrantly signals through signal transducer and activator of transcription (STAT) 5 which feeds-back to stabilize FLT3 through the downstream effector, Pim-1 kinase. FLT3-specific tyrosine kinase inhibitors (TKI) have clinical effects in FLT3-ITD AML but responses are limited due to the development of resistance through various means, including point mutations in the FLT3 tyrosine kinase domain commonly at D835 in the activation loop and F691 in the gate-keeper residue. Novel therapeutic strategies are therefore required for overcoming TKI-resistance. Poly (ADP-ribose) polymerase (PARP) 1 functions by poly-ADP-ribosylating (PAR) itself and other proteins primarily to catalyze DNA repair, however, PARP can also regulate the activity and function of proteins involved in other various processes. Notably, PARP inhibitors (PARPi) are novel cancer therapeutics that induce synthetic lethality in cancers with BRCA mutations. Recent studies also show that concurrent treatment of PARPi and TKI can effectively induce synthetic lethality in BRCA-proficient TKI-sensitive FLT3-ITD AML. However, the effects of PARPi in TKI-resistant disease has yet to be explored. We previously reported elevated reactive oxygen species (ROS) in FLT3-ITD AML leading to upregulated PARP1 and we now show that, compared to parental TKI-sensitive Molm14 cells, D835Y and F691L point-mutated TKI-resistant forms have significantly increased ROS production, and subsequently increased DNA damage and PARP1 protein expression. Interestingly, TKI-resistant cells also have elevated phospho-STAT5 (pSTAT5) and subsequent CRISPR-Cas9 knockout of PARP1 leads to reduction in pSTAT5 as well as the downstream targets, Pim-1 and FLT3. Significantly, STAT5 protein was found to immunoprecipitate with PAR and PARP1, suggesting for the first time that PARP1 may play a direct role in regulating STAT5. Finally, we have found that low doses (5-50nM) of the potent PARPi, Talazoparib (Tal), in combination with low dose (10nM) of the TKIs, Quizartinib (Quiz) or Gilteritinib (Gilt), is synergistically lethal in the otherwise TKI-resistant cells. Additionally, sequential treatment of TKI-resistant cells with Tal (72hr) prior to treatment with Quiz (72hr) or Gilt (72hr) was still synergistic whereas the reverse is not. This suggests a novel model whereby Tal may resensitize cells to TKI by decreasing PARP1 effects on pSTAT5 activity which feeds back to reduce FLT3 receptor activation. Therefore, this combination has potential for treatment of TKI-resistant AML and studies are underway to translate these findings with the intent of developing an effective therapy for patients with this disease. Citation Format: Anna J. Dellomo, Rena G. Lapidus, Mariusz Karbowski, Maria R. Baer, Tami J. Kingsbury, Feyruz V. Rassool. PARP inhibitor resensitizes TKI-resistant AML to TKI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1428.

Summary Background Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. Methods In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations ( FLT3 mut+ ) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3 mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Findings Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (41 [16%] of 252]), fatigue (37 [15%]), elevated aspartate aminotransferase (33 [13%]), and elevated alanine aminotransferase (24 [10%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (78 [31%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission. Interpretation Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Funding Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.

Background: Myelofibrosis (MF) is a life-threatening myeloproliferative neoplasm characterized by splenomegaly and debilitating symptoms, such as fatigue, pruritus, night sweats, fever, bone pain, and weight loss that impact quality of life (QoL). Imetelstat, a first-in-class telomerase inhibitor, demonstrated clinical benefits in terms of symptom response and potential improvement in overall survival in a pilot study in MF patients (pts) (Tefferi et al, NEJM 2015) and in IMbark, a Phase 2 study in MF pts relapsed or refractory (R/R) to a Janus associated kinase (JAK) inhibitor (Mascarenhas et al, ASH 2018 #685). Aims: We assessed the effects of imetelstat on MF symptom burden and QoL in IMbark, and the correlations of MF-related symptoms measured by modified Myelofibrosis Symptom Assessment Form (MFSAF) 2.0 and other patient-reported outcome (PRO) endpoints. Methods: IMbark (MYF2001; NCT02426086) is a two-dose, randomized, single-blinded, Phase 2 study of imetelstat in R/R intermediate-2/high-risk MF pts, who received imetelstat 9.4 mg/kg or 4.7 mg/kg IV every 3 weeks. Symptom response, one of the co-primary endpoints, was defined as ≥50% reduction in total symptom score (TSS) from baseline to Week 24 as measured by the modified MFSAF 2.0 e-diary. The TSS was calculated as the 7-day average of daily TSS, which is the summation of 6 individual symptom scores (night sweats, itchiness, abdominal discomfort, pain under ribs on left side, early satiety, bone or muscle pain). Correlation of TSS with other PROs was explored: European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Brief Pain Inventory (BP-I), and Patient Global Impression of Change (PGIC). Results: All 107 pts enrolled in IMbark were symptomatic, with baseline mean TSS scores of 25.7 in the 9.4 mg/kg arm (N=59) and 24.6 in the 4.7 mg/kg arm (N=48), indicating a high symptom burden. Pts in both arms had ≥96.5% mean compliance rates with completion of the e-diary. Treatment with imetelstat demonstrated a statistically significant dose-related improvement in TSS symptom response rate at Week 24 for 9.4 mg/kg vs 4.7 mg/kg (32.1% vs 6.3%, p=0.001) and at any time (52.5% vs 27.1%, p=0.010). A higher proportion of pts in the 9.4 mg/kg arm than in the 4.7 mg/kg arm achieved ≥50% reduction in 5 individual symptoms, including night sweats, itchiness, abdominal pressure, pain under left ribs, and early satiety. Based on EORTC QLQ-C30, improvements at Week 24 relative to baseline were seen in the imetelstat 9.4 mg/kg arm for global health status, all 5 function subscales, and all 3 symptoms. Notably for fatigue (a common MF symptom which was not measured in MFSAF v2.0), pts in the 9.4 mg/kg arm had improvement at Week 24 relative to baseline, compared to the pts in the 4.7 mg/kg arm (LS means -13.3 vs -3.1, p=0.042). The TSS symptom responses were shown to correlate with other PROs. Compared to pts in the 4.7 mg/kg arm, TSS symptom responders in the 9.4 mg/kg arm achieved significantly greater improvements in the global health status (p=0.004), fatigue (p=0.009), pain (p=0.033), and most of the functional scales in EORTC QLQ-C30. Pain scores per the modified MFSAF v2.0 correlated with the pain scores in EORTC QLQ-C30 and BP-I (correlation coefficients 0.5-0.6). More than 90% of TSS symptom responders in the 9.4 mg/kg arm also characterized their condition as having had either "very much improvement" (36.4%) or "somewhat improvement" (54.6%) in PGIC. Conclusion: These data show a dose-related, clinically meaningful improvement in overall and individual MF symptoms as measured by MFSAF 2.0 with imetelstat treatment in pts who are JAK inhibitor R/R. TSS symptom responders treated with imetelstat 9.4 mg/kg also had improvement in QoL as measured by EORTC QLQ-C30. The data further support the robustness of overall and individual symptom improvement in pts with MF as evidenced by the correlation of modified MFSAF v2.0 with other PROs such as EORTC QLQ-C30, PGIC, and BP-I. Disclosures Mascarenhas: Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy. Komrokji:Geron: Honoraria; BMS: Honoraria, Speakers Bureau; Acceleron: Honoraria; Novartis: Honoraria; Incyte: Honoraria; JAZZ: Honoraria, Speakers Bureau; AbbVie: Honoraria; Agios: Honoraria, Speakers Bureau. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Niederwieser:Novartis: Speakers Bureau; Amgen: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Daiichi: Research Funding. Reiter:Gilead: Other: travel support ; Incyte: Consultancy, Other: travel support ; AOP: Consultancy, Other: travel support ; Celgene,: Consultancy, Other: travel support ; Abbvie: Consultancy, Other: travel support ; Deciphera: Consultancy, Other: travel support ; Blueprint: Consultancy, Other: travel support ; Novartis: Consultancy, Honoraria, Other: travel support , Research Funding. Scott:Agios, BMS: Honoraria; BMS, Novartis: Research Funding; Alexion, Incyte, Novartis, Regeneron: Consultancy. Baer:AbbVie: Other: Institutional research funding; Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding. Hoffman:Dompe: Research Funding; Protagonist: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Forbius: Consultancy. Odenike:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Incyte: Other: Institutional research funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees.

Background: Imetelstat is a first-in-class telomerase inhibitor currently in clinical development for hematologic myeloid malignancies. IMbark (MYF2001; NCT02426086) was a 2-dose (9.4 mg/kg or 4.7 mg/kg IV every 3 weeks), randomized Phase 2 study of imetelstat in intermediate-2/high-risk myelofibrosis (MF) relapsed or refractory to prior Janus kinase inhibitor treatment. Comparing the 9.4 mg/kg arm to the 4.7 mg/kg arm, the rate of symptom response (total symptom score [TSS] reduction ≥50%) at Week 24 was 32.2% and 6.3%, respectively (Mascarenhas et al, ASH 2018 #685), and median overall survival (OS) was 28.1 months (mos) (95% confidence interval [CI]: 22.8, 31.6) for the 9.4 mg/kg arm and 19.9 mos for the 4.7 mg/kg arm (95% CI: 17.1, 33.9) with an overall study follow up of 42 mos (Mascarenhas et al, EHA 2020, EP1107). Dose-dependent on-target pharmacodynamic (PD) activity of imetelstat was observed and it correlated with clinical responses and longer OS (Mascarenhas et al, EHA 2020 EP1098). Here we report the results of imetelstat exposure-response analyses from IMbark to further evaluate the benefit/risk profile and justify 9.4 mg/kg every 21 days as the optimal dosing regimen for the planned Phase 3 study of imetelstat in refractory MF. Methods: The average plasma concentration (Cavg) of imetelstat was used to define the exposure. The Cavg values of 107 patients (pts) were grouped into 4 quartiles (Q1-4) representing different levels of imetelstat exposure regardless of the protocol-specified dose arm assignment. Optimal PD effect of imetelstat was defined as ≥50% reduction in telomerase activity or human telomerase reverse transcriptase (hTERT) from baseline. The exposure-response relationships between exposure quartiles and PD effect, symptom response, OS, and laboratory safety parameters were assessed. Results: The association between the 4 exposure quartiles and dose levels showed that 89% of pts in Q1 (the lowest exposure quartile) were treated with 4.7 mg/kg, while 96% of pts in Q4 (the highest exposure quartile) were treated with 9.4 mg/kg. The pts in the 4.7 mg/kg arm who had higher exposure in Q3 and Q4 were mainly those with dose escalation to 9.4 mg/kg, and pts in the 9.4 mg/kg arm who had lower exposure in Q1-Q2 were mainly those with dose delay, reduction, or interruption. 51.9% of pts in Q1, 63% in Q2 (vs Q1, p=0.5826), 77.8% in Q3 (vs Q1, p=0.0861), and 80% in Q4 (vs Q1, p=0.0439) achieved the optimal PD effect, respectively, indicating exposure-dependent on-target activity of imetelstat. The symptom response rate for pts in exposure quartile Q1, Q2, Q3, and Q4 was 7.4%, 18.5% (vs Q1, p=0.4203), 18.5% (vs Q1, p=0.4203), and 38.5% (vs Q1, p=0.0091), respectively. Median OS was 18.9 mos in Q1, 23.6 mos in Q2 (hazard ratio [HR]=0.663; 95% CI: 0.350, 1.259; log-rank p=0.2097), 24.6 mos in Q3 (HR=0.656; 95% CI 0.348, 1.236; p=0.1920) and 30.6 mos in Q4 (HR=0.467; 95% CI: 0.236, 0.925; p=0.0260), respectively. The exposure-response analyses showed that pts in the highest exposure quartile were more likely to have better clinical outcome. The relationship between exposure quartiles and hematological and liver function safety parameters was assessed. There were no significant differences between each imetelstat exposure quartile group on the change from baseline in hemoglobin concentration, platelet count, and neutrophil counts; or in the rate of Grade 3+ neutropenia, thrombocytopenia, and elevations in alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, and bilirubin. Pts with higher imetelstat exposure had similar rates of Grade 3+ adverse events as pts with lower exposure, suggesting that the lower dose does not improve safety. Conclusions: In summary, the exposure-response analysis results indicated 9.4 mg/kg and 4.7 mg/kg covered the therapeutic window of imetelstat in MF pts. Imetelstat 9.4 mg/kg every 21 days treatment yielded higher exposure, leading to higher rate of pts achieving the optimal PD effect, consistently better clinical benefits, such as higher symptom response and significantly longer median OS, and had a similar safety profile as 4.7 mg/kg with regard to hematologic and liver function parameters. This exposure-response analysis of benefit/risk profile supports 9.4 mg/kg every 21 days as the optimal dosing regimen for the planned imetelstat Phase 3 study in refractory MF. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Komrokji:Acceleron: Honoraria; Agios: Honoraria, Speakers Bureau; AbbVie: Honoraria; JAZZ: Honoraria, Speakers Bureau; Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; Geron: Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Niederwieser:Amgen: Speakers Bureau; Novartis: Speakers Bureau; Daiichi: Research Funding; Cellectis: Membership on an entity's Board of Directors or advisory committees. Reiter:Gilead: Other: travel support ; Incyte: Consultancy, Other: travel support ; AOP: Consultancy, Other: travel support ; Celgene,: Consultancy, Other: travel support ; Abbvie: Consultancy, Other: travel support ; Deciphera: Consultancy, Other: travel support ; Blueprint: Consultancy, Other: travel support ; Novartis: Consultancy, Honoraria, Other: travel support , Research Funding. Scott:Agios, BMS: Honoraria; Alexion, Incyte, Novartis, Regeneron: Consultancy; BMS, Novartis: Research Funding. Baer:AbbVie: Other: Institutional research funding; Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding. Hoffman:Protagonist: Consultancy; Dompe: Research Funding; Forbius: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Odenike:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Other: Institutional research funding; Astra Zeneca: Research Funding; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company.

Background: The incidence of both myeloid malignancies and cardiovascular disease (CVD) increases with age, and cardiac disease is the most frequent cause of non-hematologic morbidity in patients with myelodysplastic syndrome (MDS). We aimed to study whether the presence of CVD is associated with worse outcomes in patients with myeloid malignancies. Methods: We retrospectively reviewed 295 patients diagnosed with acute myeloid leukemia (AML), MDS or MDS/myeloproliferative neoplasm (MDS/MPN). CVD included congestive heart failure (CHF), coronary artery disease (CAD), arrhythmia, peripheral vascular disease, congenital heart disease and/or cerebrovascular accident. Endpoints included overall response rate (ORR), overall survival (OS), cardiac events and death within 60 days of treatment initiation. Patient characteristics were compared between those with CVD vs. no-CVD using the Fisher's exact and t-tests. The Kaplan-Meier approach was used to estimate OS. The multivariate Cox regression model was utilized to identify predictors of OS. Results: Patient characteristics are summarized in Table 1. The study population included 92 patients (31%) with CVD and 203 (69%) without CVD, with a median age of 66 years (range 19-89) at diagnosis. Patients with CVD were older (p Among the 228 AML patients, 20% vs. 48% of patients in the CVD vs. no-CVD groups achieved complete remission (CR), 24% vs. 22% achieved CR with incomplete count recovery (CRi), 1% vs. 3% achieved partial remission (PR), 20% vs. 17% were primary refractory (p For AML patients, 1-, 2- and 3-year OS in CVD vs. no-CVD groups (Figure 1) was 46% vs. 70%; 34% vs. 53%; and 26% vs. 43%, respectively [HR 1.9, 95% CI = 1.35, 2.67]. For MDS patients it was 44% vs. 81%, 26% vs. 51%, and 26% vs. 49%, respectively [HR 2.52, 95% CI = 1.27, 5]. In a multivariable regression model accounting for age, performance status and karyotype, CVD was an independent prognostic factor for worse OS (Table 2). Smoking history (pack-years) did not impact OS. There was a trend toward fewer CVD than no-CVD patients undergoing allogeneic transplantation (17.4% vs. 27.6%, p=0.08). With a median follow-up of 15 months in both groups, 75% of AML and MDS patients with CVD were deceased, compared to 54% of no-CVD patients (p Cardiac adverse events were more frequent in CVD compared to no-CVD patients, including myocardial infarction/demand ischemia (13% vs 2%, p= 0.0003), arrhythmia (20% vs 10%, p= 0.01), and CHF exacerbations (27% vs 10%, p= 0.002). Conclusions: Our study demonstrated that presence of CVD is a very important predictor of survival outcomes of patients with AML and MDS. As the incidence of both CVD and myeloid malignancies increases with age, a better understanding of their association and shared complications can translate into better therapeutic options. Disclosures Emadi: Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; NewLink Genetics: Research Funding. Baer:Astellas: Other: Institutional research funding; AbbVie: Other: Institutional research funding; Incyte: Other: Institutional research funding; Forma: Other: Institutional research funding; Takeda: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding.

Background: Poly (ADP-ribose) polymerase (PARP) enzymes are involved in repair of single-strand DNA breaks through base excision repair pathways. Inhibitors of PARP are approved for the treatment of BRCA1/2-mutant malignancies where they result in compromise of dual DNA damage repair pathways, leading to induction of double-strand DNA breaks during replication and ultimately cell death. We have previously demonstrated (Portwood et al, ASH 2019 abstract) that PARP inhibitors can reduce in vitro acute myeloid leukemia (AML) growth and can synergistically enhance the anti-leukemic activity of antibody-drug conjugates containing DNA-damaging cytotoxic agents in preclinical human AML models. Talazoparib (Tala) is a novel selective PARP inhibitor which has been shown to exert more potent growth inhibitory effects across a panel of human AML cell lines than four other PARP inhibitors (veliparib, olaparib, rucaparib, niraparib). Gemtuzumab ozogamicin (GO) is an approved drug consisting of an antibody against human CD33 (gemtuzumab) linked to a cytotoxic component (calicheamicin). Hypothesis: We hypothesize that the combination of Tala + GO will be well tolerated and will result in improved clinical efficacy as compared with historical outcomes of GO monotherapy in patients with relapsed or refractory (R/R) AML. Objectives: The primary objectives of this study are (a) to determine the safety and tolerability of Tala + GO therapy in R/R AML; (b) to determine the overall response rate (ORR = complete remission (CR) + complete remission with incomplete hematologic recovery (CRi)) of combination therapy in patients with R/R AML. Additional anti-leukemic effects will be reported including complete remission rate, best response rate, duration of remission, leukemia-free survival, transfusion independence, and overall survival. Exploratory aims include measurable residual disease, evidence of PARP inhibition and DNA damage, feasibility of subsequent allogeneic stem cell transplant, and quality of life. Study Design: This open-label multi-center, Phase 1/1b trial is designed to determine whether the combination of Tala and GO represents a safe and effective approach for R/R AML. Eligible patients are adults aged ≥18 years with CD33-positive AML whose disease has failed to respond to and/or has recurred following at least one prior line of chemotherapy. There are two parts of the study: dose escalation and dose expansion. The dose escalation portion will establish the recommended Phase 2 dose (RP2D) of Tala in combination with GO. Cohorts of 3 subjects will be treated at one of three dose levels of Tala (0.5 mg, 0.75 mg, and 1 mg orally daily) in combination with fixed doses of GO (3 mg/m2/day on days 1,4, and 7, capped to one 4.5 mg vial) using a standard 3+3 subject cohort dose evaluation. Treatment will be given in 28-day cycles. The dose limiting toxicity (DLT) window will be Cycle 1 Day 1 to 28. Therapy may be given in the outpatient setting. Following determination of the RP2D, an expansion cohort of patients will be treated with the combination of Tala + GO for preliminary assessment of toxicities and anti-leukemic efficacy. Bone marrow assessment will be performed on Day 28 of Cycles 1 and 2. Safety and activity will be assessed using descriptive statistical analysis. If a patient achieves CR/CRi after cycles 1-2, the GO dose will be reduced to a maintenance dose of 2 mg/m2 on day 1 only of every subsequent cycle until disease progression or for a maximum of 6 total cycles of therapy. Patients not achieving a clinical response after 2 cycles will stop treatment. Treatment duration will be up to six months. This trial was activated in July 2020 and is registered at ClinicalTrials.gov (NCT04207190). Accrual is ongoing. Disclosures Griffiths: Novartis: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Boston Biomedical: Honoraria; Persimmune: Research Funding; AbbVie Inc: Honoraria; Genentech Inc: Research Funding; Astex Pharmceuticals: Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Emadi:Jazz Pharmaceuticals: Research Funding; NewLink Genetics: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor. Baer:AbbVie: Other: Institutional research funding; Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding. Wang:Stemline: Speakers Bureau; Astellas: Consultancy; PTC Therapeutics: Consultancy; Macrogenics: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Pfizer: Speakers Bureau.

Background: Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Both cytogenetic abnormalities and gene mutations in MF carry prognostic significance. Development of novel agents for treatment of MF to target the underlying malignant clones remains a significant area of unmet need. IMbark (MYF2001; NCT02426086) is a randomized Phase 2 study of imetelstat (9.4 mg/kg or 4.7 mg/kg) in intermediate-2/high-risk MF relapsed/refractory to prior Janus kinase inhibitor treatment. Comparing the 9.4 mg/kg arm to the 4.7 mg/kg arm, the rate of symptom response (total symptom score [TSS] reduction ≥50%) was 32.2% and 6.3%, respectively (Mascarenhas et al ASH 2018 #685), and median overall survival (OS) was 28.1 months (mos) (95% confidence interval [CI]: 22.8, 31.6) and 19.9 mos (95% CI: 17.1, 33.9) with an overall study follow up of 42 mos (Mascarenhas et al, EHA 2020, EP1107). Dose-dependent target inhibition as evaluated by reduction of telomerase activity and human telomerase reverse transcriptase level correlated with clinical responses and longer OS; also, reduction in variant allele frequency (VAF) of driver mutations by imetelstat was reported (Mascarenhas et al EHA 2020 #EP1098). Aims: To evaluate imetelstat activity on depletion of malignant cells (cytogenetically abnormal clones and mutation burden); to assess the relationships between baseline cytogenetic status and change in mutation VAF with clinical benefits such as spleen volume reduction, symptom response, bone marrow fibrosis improvement, and OS. Methods: Cytogenetic analyses were performed on bone marrow aspirates. Peripheral blood samples pre and post imetelstat administration were collected and granulocytes were isolated to analyze mutations and VAF by next-generation sequencing (NGS) using the Illumina TruSight Myeloid Sequencing Panel. Bone marrow fibrosis was assessed by a central pathologist. Results: 83 patients (pts) had baseline cytogenetic results available; 45 (54.2%) had an abnormal karyotype, including 32 (71.1%) with a sole abnormality, the most prevalent being deletions 13q- (24.4%) and 20q- (8.8%), and 5 (11.1%) with a complex karyotype. Spleen and symptom responses were observed in pts with or without abnormal karyotype. Of the 24 pts that had identified cytogenetic abnormalities at baseline and with matched post-treatment cytogenetic results available, 5 (20.8%) achieved ≥50% reduction in their cytogenetically abnormal clones, and interestingly they all had sole deletion 13q-. 49 pts had matched pre- and post-imetelstat treatment (3-14 mos) NGS data and had at least one mutation at baseline. 46.2% of pts (12/26) in the 9.4 mg/kg vs 17.4% (4/23) in the 4.7 mg/kg arm (p=0.0321) achieved ≥20% VAF reduction in any of the mutated genes present at baseline. In addition, pts who achieved ≥20% VAF reduction had higher rates of spleen response (12.5% vs 3%), symptom response (31.3% vs 24.2%) or bone marrow fibrosis improvement (54.4% vs 25%) compared to pts who did not have VAF reduction regardless of dose level (Fig. 1A). Furthermore, a prolonged median OS was seen (Fig. 1B) in pts who achieved ≥20% VAF reduction (31.6 mos, 95% CI: 21.5, NE) vs those with no VAF reduction (22.8 mos, 95% CI: 17.1, 31.6). The 3-year survival rate was 45.5% for pts who achieved ≥20% VAF reduction vs 14.9% for pts with no VAF reduction. Conclusions: Clinical responses to imetelstat treatment were observed regardless of baseline cytogenetic status, and a subset of pts achieved ≥50% reduction in cytogenetically abnormal clones. Significant dose-dependent reductions of mutation burden by imetelstat were noted and correlated with improved overall clinical benefits including higher rates of spleen and symptom responses, bone marrow fibrosis improvement, and prolonged OS. Together with the clinical data that suggest improvement in median OS in these pts, the data presented here further demonstrate that imetelstat has disease-modifying activity by targeting malignant cells, as evidenced by depletion of cytogenetically abnormal clones and reduction in mutation burden. These results will be confirmed in the planned Phase 3 study in refractory MF. Figure Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Komrokji:Novartis: Honoraria; BMS: Honoraria, Speakers Bureau; Agios: Honoraria, Speakers Bureau; JAZZ: Honoraria, Speakers Bureau; Acceleron: Honoraria; AbbVie: Honoraria; Geron: Honoraria; Incyte: Honoraria. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Niederwieser:Novartis: Speakers Bureau; Cellectis: Membership on an entity's Board of Directors or advisory committees; Amgen: Speakers Bureau; Daiichi: Research Funding. Reiter:Gilead: Other: travel support ; Incyte: Consultancy, Other: travel support ; AOP: Consultancy, Other: travel support ; Celgene,: Consultancy, Other: travel support ; Abbvie: Consultancy, Other: travel support ; Deciphera: Consultancy, Other: travel support ; Blueprint: Consultancy, Other: travel support ; Novartis: Consultancy, Honoraria, Other: travel support , Research Funding. Scott:Alexion, Incyte, Novartis, Regeneron: Consultancy; BMS, Novartis: Research Funding; Agios, BMS: Honoraria. Baer:Astellas: Other: Institutional research funding; Forma: Other: Institutional research funding; Incyte: Other: Institutional research funding; Kite: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Takeda: Other: Institutional research funding; AbbVie: Other: Institutional research funding. Hoffman:Protagonist: Consultancy; Forbius: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding. Odenike:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, NS Pharma, Gilead Sciences, Janssen Oncology, Oncotherapy, Agios, CTI/Baxalta, Aprea: Other: Institutional research funding; Astra Zeneca: Research Funding; Impact Biomedicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Other: Institutional research funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sherman:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Dougherty:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Feller:Geron Corp: Current Employment, Current equity holder in private company. Berry:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Sun:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Wan:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Rizo:Geron Corp: Current Employment, Current equity holder in publicly-traded company. Huang:Geron Corp: Current Employment, Current equity holder in publicly-traded company.

Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with features of both myeloproliferative neoplasm and myelodysplastic syndrome (MDS). CMML is characterized by persistent blood monocytosis >1 x 109/L, bone marrow dysplasia in one or more hematopoietic cell lines, and increased risk of transformation to acute myeloid leukemia (AML). Our review of SEER Medicare data (Haematologica 2013;98:584) demonstrated that, compared to MDS, CMML has shorter overall survival (OS) and more frequent progression to AML. Hypomethylating agents (HMAs) have become standard therapy for CMML, with reported response rates of 37-69%, but their impact on AML transformation and OS is unclear. Methods: We retrospectively reviewed CMML patients treated at the University of Maryland Greenebaum Comprehensive Cancer Center between January 2000 and December 2019. Clinical characteristics, treatments, AML progression, time to AML progression (TTP), and OS were recorded and analyzed. Descriptive statistics were used for baseline characteristics and Kaplan-Meier analysis was performed for time-to-event data. Statistical analyses were performed using GraphPad Prism 8®. Results: We identified 71 patients with CMML, 82% male and 73% white, with a median age of 69 (range 25 - 96) years; 51% had Forty-six patients received HMAs, with an overall response rate (ORR) of 54% (complete response or partial response), while 25 patients did not receive HMAs. Patient and disease characteristics were similar in HMA- and non-HMA-treated patients (Table 1). The estimated OS of HMA-treated patients was 20 months, compared to 14 months for non-HMA-treated patients (p =0.43) (Figure 1). AML transformation occurred in 52% of patients treated with HMAs, with TTP ranging from 3 to 65 months, and in 33% patients not treated with HMAs, with TTP ranging from 5 to 47 months. Most patients receiving HMAs (63%) received ≥ 6 cycles; 46% transformed to AML despite initial response, often in a sudden and unpredictable manner. HMAs were azacitidine in 13 patients, decitabine in 24, azacitidine followed by decitabine in 4, and decitabine followed by azacitidine in 5. Five CMML patients in our cohort underwent allogenic stem cell transplantation. Four of the five relapsed with transformation to AML post transplant, and only one patient remains in remission, 9 months post transplant. Conclusions: Despite a 54% ORR, HMA treatment did not have a significant impact on frequency of AML transformation, or OS in our cohort. Based on our data, favorable response rates previously reported with HMAs and also seen in our patients do not appear to translate into decreased frequency of AML transformation or prolonged OS. Though our study is a retrospective study with inherent selection bias, our results underscore the ongoing need for novel therapies and for clinical trials for CMML patients. Disclosures Niyongere: Kartos Therapeutics: Other: Received clinical trial research support with Kartos Therapeutics ; Forty Seven: Other: Received clinical trial research support with Forty Seven. Emadi:Amgen: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor; NewLink Genetics: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Research Funding. Doung:Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: clinical trial research support; Incyte: Other: clinical trial research support; Astex: Other: clinical trial research support; MedPacto: Other: clinical trial research support. Baer:Takeda: Other: Institutional research funding; Oscotec: Other: Institutional research funding; Kite: Other: Institutional research funding; Incyte: Other: Institutional research funding; Forma: Other: Institutional research funding; Astellas: Other: Institutional research funding; AbbVie: Other: Institutional research funding.

Background/Aims: Venetoclax (Ven), a selective oral BCL-2 inhibitor, has shown synergy with hypomethylating agents (HMAs) such as Azacitidine (Aza), in treatment of higher-risk myelodysplastic syndrome (HR)-MDS. We evaluate prognostic impact of cytogenetic categories of revised International Prognostic Scoring System (IPSS-R) among HR-MDS patients treated with Ven+Aza. Methods: This study enrolled patients age ≥ 18 yrs, untreated for MDS, with IPSS score of ≥1.5, bone marrow blasts Results: As of 8/21/2019, 57 patients (75% male, median age 71yrs) received Ven+Aza combination. According to IPSS-R classification, at baseline, 9 (16%) patients were at intermediate risk, 13 (24%) at high risk, and 33 (60%) at very high risk. Cytogenetic risk based on IPSS-R: 2 (4%) were very good, 18 (32%) good, 8 (15%) intermediate, 13 (23%) poor, and 15 (26%) very poor. Ten genes were mutated in >10% of patients, including poor prognosis conferring TP53, RUNX1, TET2, ASXL1, SRSF2, STAG2, and IDH1/2. Median follow-up time was 8.9 months. Complete remission (CR)+marrow CR (mCR) rates by IPSS-R cytogenetic risk were: very good 100% (2/2), good 94% (17/18), intermediate 63% (5/8), poor 62% (8/13), and very poor 73% (11/15). Median with 95% confidence interval (CI) in progression-free survival (PFS) was 6.7 (0.7–not estimable), 9.3 (3.2–not estimable), and 9.5 months (2.7–9.5) in the intermediate, poor, and very-poor risk groups, respectively, and not reached in the good and very-good risk groups. Median overall survival (OS) in patients with very poor risk was 16.2 months (2.0–16.2). The estimated 12-month OS were 53%, 88%, and 100% in the poor, intermediate, and good risk groups, respectively. Conclusion: This preliminary analysis shows promising efficacy of Ven+Aza combination treatment across all IPSS-R cytogenetic risk categories and suggests prognostic relevance of the IPSS-R cytogenetic scoring system. Abstract was previously published at EHA25.