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We designed a prospective, observational study enrolling patients presenting for treatment of acute myeloid leukemia (AML) at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), and function in: the entire cohort, those aged ≥65 years, those with high comorbidity burden, intermediate cytogenetic risk, adverse cytogenetic risk, and first complete remission with or without measurable residual disease. Patient were assessed 8 times over 2 years. Time-dependent regression models were used. Among 692 patients that were evaluable, 46% received HCT with a 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in most subgroups. Although function, social life, performance status, and depressive symptoms were better for those selected for HCT, these health advantages were lost after receiving HCT. Recipients and nonrecipients of HCT similarly ranked and expected cure as main goal of therapy, whereas physicians had greater expectations for cure than the former. Accounting for health impairments negates survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is mostly owing to selection of the healthier candidates. Considering patients’ overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

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.

Introduction: Cytarabine is a backbone of intensive acute myeloid leukemia (AML) chemotherapy; yet it is associated with toxicity which precludes its use in older patients and in those with comorbidities. Aspacytarabine (BST-236) is a prodrug of cytarabine, which is inactive in its intact prodrug form until cytarabine is gradually released in the plasma and inside the cells. Due to the pharmacokinetics and metabolism of aspacytarabine, the peak toxic systemic exposure to cytarabine is decreased, resulting in reduced systemic toxicity with relative sparing of normal tissues, thus enabling delivery of high cytarabine doses to AML patients otherwise unfit to receive intensive cytarabine therapy. Presented herein are the data, including final primary endpoint analysis, from a phase 2b study that recently completed enrollment. Aims: To evaluate the efficacy and safety of aspacytarabine as a single agent for induction and consolidation therapy of newly diagnosed AML patients unfit for standard induction chemotherapy. Methods: Aspacytarabine was administered at 6-day courses of 4.5 g/m 2/d (equimolar to 3 g/m 2/d cytarabine) daily 1-hour intravenous infusions, for 1-2 induction and 1-3 consolidation courses, to AML patients age ≥75 years or otherwise unfit for intensive chemotherapy. Patients with secondary or therapy related AML, and patients who received prior hypomethylating agents (HMA) ± venetoclax therapy for a preceding condition were eligible. Primary endpoint is complete remission with complete hematological recovery (CR). Secondary and exploratory endpoints include safety, duration of response (DOR), overall survival (OS), and minimal residual disease (MRD). NCT03435848. Results: Enrollment into the study was completed in May 2021. Sixty-five newly diagnosed AML patients unfit for standard chemotherapy (median age 75 years, range 54-88 years) were treated with aspacytarabine and completed 1-4 courses (median 1 course) at doses of 4.5 g/m 2/d, including 39 patients (60%) with de novo AML and 26 patients (40%) with secondary AML. Eleven patients (17%) were previously treated for MDS/CMML with HMA (median 14 courses), including 1 patient (2%) with HMA + venetoclax. Thirty-two patients (49%) and 15 patients (23%) had adverse or intermediate European LeukemiaNet (ELN) scores, respectively. The baseline median bone marrow blasts was 43%, and 25 patients (38%) had ECOG PS 2 or 3 at enrollment (Table 1). Aspacytarabine was well-tolerated in repeated-course administration. Grade ≥3 drug-related adverse events included hematological events and infections, with, importantly, no severe gastrointestinal or neurological events. The 30-day all-cause mortality rate was 12.5% (95% CI, 5.9-23.7). Of the 65 intention-to-treat AML patients, 24 (37%) achieved a CR following 1 (17 patients) or 2 (7 patients) courses. The median time to complete neutrophil and platelet recovery were 27 days (range 11-39 days) and 26 days (range 18-40), respectively. The CR rates in de novo and secondary AML patients were 44% and 27%, respectively. Twenty-seven percent of the patients with prior HMA therapy achieved a CR, including the 1 patient with prior HMA + venetoclax treatment. The CR rates in patients at the age of ≥75 years and patients with adverse ELN scores were 35% and 34%, respectively. Of the 21 patients in CR evaluable to date for MRD analysis by multiparameter flow cytometry, 11 (52%) became MRD negative following aspacytarabine treatment. Follow up is ongoing, with a current median duration of follow up of 5.2 months. The median DOR has not yet been reached at 12 months, and median OS of responders not reached at 24 months (Figure 1). Conclusions: Aspacytarabine appears to be an effective regimen for AML with a considerable reduction of the attendant toxicities that typically are associated with standard intensive cytotoxic therapies. The results of the phase 2b study are consistent with the previously completed phase 1/2a study, which demonstrated safety and a 36% CR rate in a similar population, suggest that aspacytarabine, given as monotherapy, is generally safe and effective as a first-line therapy for AML patients who are unfit for intensive chemotherapy These data support a role for aspacytarabine as a new treatment option for older patients with AML. Furthermore, this agent may serve as a backbone for combination therapy with targeted or other chemotherapy agents, as well as in younger patients with AML. Figure 1 Figure 1. Disclosures Altman: Boehringer Ingelheim: Research Funding; BMS: Research Funding; Immunogen: Research Funding; Syros: Consultancy; GlycoMimetics: Other: Participation on an advisory board; Daiichi Sankyo: Consultancy; AbbVie: Consultancy, Other: Advisory Board, Research Funding; Fujifilm: Research Funding; Kura Oncology: Consultancy; Kartos: Research Funding; Biosight: Consultancy, Other: Travel fees, Research Funding; Astellas: Consultancy, Other: Advisory Board, Research Funding; ALZ Oncology: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Theradex: Consultancy, Other: Advisory boards; Kura: Research Funding. Koprivnikar: Bristol Myers Squibb: Speakers Bureau. McCloskey: Amgen: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; Incyte: Speakers Bureau; BMS: Honoraria, Speakers Bureau; COTA: Other: Equity Ownership. Kota: Pfizer: Consultancy; Novartis: Consultancy; Incyte: Research Funding. 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. Zuckerman: BioSight Ltd: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Orgenesis Inc.: Honoraria; Cellect Biotechnology: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau. Levy: Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; Dova: Consultancy, Other: Promotional speaker. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Wolach: Novartis: Consultancy; Amgen: Research Funding; Janssen: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Neopharm: Consultancy. Percival: AbbVie: Research Funding; Biosight: Research Funding; BMS/Celgene: Research Funding; Cardiff Oncology: Research Funding; Glycomimetics: Research Funding; Nohla therapeutics: Research Funding; Oscotec: Research Funding; Pfizer: Research Funding; Trillium: Research Funding. Roboz: Actinium: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Mesoblast: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Research Funding; Daiichi Sankyo: Consultancy; Blueprint Medicines: Consultancy; Bristol Myers Squibb: Consultancy; Helsinn: Consultancy; Jasper Therapeutics: Consultancy; Astellas: Consultancy; Astex: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy. Levi: AbbVie: Consultancy, Research Funding. Flaishon: BioSight Ltd.: Current Employment. Cohen: BioSight Ltd.: Current Employment. Tessler: BioSight Ltd.: Current Employment. Blumberg: BioSight Ltd.: Current Employment. Gengrinovitch: BioSight Ltd.: Current holder of individual stocks in a privately-held company. Ben Yakar: BioSight Ltd.: Current Employment. Rowe: Biosight Inc.: Consultancy.

Introduction: Cytogenetic analysis is important for stratifying patients with various myeloid neoplasms. It has been reported that whole-genome sequencing can be used as an alternative to cytogenetic analysis in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). With the increasing use of liquid biopsy in the diagnosis and monitoring of patients with various types of neoplasms, we explored the potential of using liquid biopsy and next generation sequencing (NGS) in detecting chromosomal structural abnormalities or copy number variation (CNV) in patients with myeloid neoplasms. For practical approach and for capturing single nucleotide variants (SNV) and to achieve enough depth in sequencing, we used targeted sequencing for determining the chromosomal structural abnormalities in cell-free DNA (cfDNA) in patients with myeloid neoplasms. Methods: Peripheral blood plasma samples from 144 patients with myeloid neoplasms were used to extract cfDNA for NGS testing. This included 49 patients with MDS, 31 with AML, and 64 patients with myeloproliferative neoplasms (MPN). The median age was 68.5 (range: 24-96); 56 (39%) were female. cfDNA was sequenced using 275 gene panel. The panel uses single primer extension (SPE) approach with UMI. Sequencing depth was increased to more than 1000X (after removing duplicates). CNVkit software was used for analyzing and visualizing copy number variations. All samples were confirmed to be diagnostic by showing mutations in diagnostic genes with variant allele frequency >20% or by showing diagnostic chromosomal structural abnormalities (e.g., 5q deletion in MDS, 5q- syndrome). Cytogenetic data on 35 corresponding bone marrow samples (18 AML and 17 MDS) were available for comparison. Results: Of the 144 samples, 47 (33%) showed chromosomal structural abnormalities. In the AML group, 20 of 31 (65%) showed cytogenetic abnormalities by cfDNA testing. Of these positive AML patients, 18 (90%) (58% of total AML) had poor-risk cytogenetics. Therefore, the AML patients with normal cytogenetics or cytogenetic abnormalities other than high-risk constituted 42% of total AML patients. Of the MDS group, 11 of 49 MDS patients (22%) showed cytogenetic abnormalities by cfDNA testing, 6 of whom (54.5%) had high-risk cytogenetics. Overall, 12% of all MDS had poor-risk cytogenetics by cfDNA testing. In the MPN group, 16 of 64 (25%) showed cytogenetic abnormalities, 2 of which (12.5%) had 7q deletion (3% of all MPN); the rest (87.5%) of cytogenetic-positive MPN (22% of total MPN) had other abnormalities including 20q-, +8, 12q, 17p-, 11q-, trisomy 9, trisomy 21 and others. To compare chromosomal abnormalities as detected by cfDNA NGS testing with conventional cytogenetic analysis of corresponding bone marrow samples, we classified cytogenetic findings based on risk stratification into either intermediate-risk or poor-risk. Of the 36 cases, there was 100% concordance between cfDNA data and cytogenetic data when findings were grouped based on risk classification. Two of the conventional cytogenetic samples showed no metaphases while one showed intermediate-risk abnormalities by cfDNA NGS analysis and the second showed poor-risk cytogenetic abnormalities by cfDNA NGS analysis. These 36 cases included 16 cases with normal cytogenetics. Simple abnormalities such as 5q-, 7q-, +8 were called in identical fashion, but some other abnormalities such as derivative chromosome and marker chromosome were resolved or interpreted differently by the cfDNA NGS analysis. The NGS panel design used in this study does not cover fusion genes or chromosomal translocation, and chromosomal translocations were missed at this time. Conclusions: This data shows that liquid biopsy using and targeted NGS is reliable in detecting chromosomal structural abnormalities in myeloid neoplasms and potentially can replace the need for conventional cytogenetic testing. While the current study was not designed to detect chromosomal translocations, a small, targeted panel of 275 genes is adequate for standard risk classification of myeloid neoplasms into intermediate or high-risk. Considering that in the same test complete mutation profiling can also be achieved along with chromosomal structural analysis, liquid biopsy in myeloid neoplasms might be considered as an efficient replacement to bone marrow biopsy in patients with myeloid neoplasms when fusion genes are not expected. Figure 1 Figure 1. Disclosures Goy: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Infinity/Verastem: Research Funding; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; OncLive Peer Exchange: Honoraria; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; LLC(Targeted Oncology): Consultancy; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Xcenda: Consultancy, Honoraria; Gilead: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Rosewell Park: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Honoraria, Other; Incyte: Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Celgene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Hoffman la Roche: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Michael J Hennessey Associates INC: Consultancy; Hoffman la Roche: Consultancy; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Medscape: Consultancy; Phamacyclics: Research Funding; Constellation: Research Funding; Xcenda: Consultancy; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Pecora: Genetic testing cooperative: Other: equity investor; Genetic testing cooperative: Membership on an entity's Board of Directors or advisory committees. Koprivnikar: Bristol Myers Squibb: Speakers Bureau. McCloskey: BMS: Honoraria, Speakers Bureau; COTA: Other: Equity Ownership; Takeda: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; Amgen: Speakers Bureau.

Introduction: BST-236 (aspacytarabine), a novel pyrimidine antagonist, is a cytarabine prodrug designed to deliver high cytarabine doses with reduced systemic toxicity. BST-236 pharmacokinetics and metabolism reduce peak systemic exposure to free cytarabine and enable intensive treatment to patients otherwise unfit for intensive therapy. An open label phase 2b study, following a completed phase 1/2a dose escalation study, is ongoing. Enrolled are newly-diagnosed acute myeloid leukemia (AML) patients unfit for standard therapy, including patients with treatment-related AML or AML secondary to myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA). Aims: To evaluate the efficacy and safety of BST-236 induction and consolidation in AML patients unfit for standard induction therapy. Methods: BST-236, at a dose of 4.5 g/m2/d (containing 3 g/m2/d of cytarabine), is evaluated as a first-line induction and consolidation therapy in newly-diagnosed AML patients unfit for standard chemotherapy. Patients with secondary AML, previously treated with HMA, as well as patients with therapy-related AML, are eligible. Each BST-236 induction and consolidation course consists of 6 daily 1-hour intravenous infusions. Results: To date, in the phase 1/2 and phase 2 studies, 42 AML patients were treated with BST-236, of whom 20 newly-diagnosed AML patients unfit for standard chemotherapy (median age 73 years) completed 1-4 courses of 4.5 g/m2/d BST-236. Of these, 40% had de novo AML and 60% had secondary AML. Thirty percent of patients were previously treated with HMA for MDS (median 10 courses), and 10% received prior chemo- or radiotherapy. The median baseline bone marrow blast percentage was 38 (range 13-94), and 35% and 53% of patients had intermediate or adverse European LeukemiaNet (ELN) score, respectively. BST-236 is safe and well-tolerated in repeated-course administration. Grade >2 adverse events include mainly hematological events and infections, with no other drug-related typical high-dose cytarabine events such as severe mucositis or cerebellar toxicity. Related serious adverse events include only cytopenia and pneumonia. The 30-day mortality rate is 7%. The complete remission (CR) rate in the evaluable patients to date who received 4.5 g/m2/d BST-236 is 50% in the de novo patients, 20% in secondary AML patients, and 20% in patients with prior HMA treatment. Forty-three percent of patients with adverse cytogenetics attained a CR, including 1 of 3 patients with a TP53 mutation. The median number of courses for reaching a CR is 1, and notably, all patients with bone marrow remission achieved complete hematological recovery within 36 days. BST-236 consolidation was well-tolerated and did not result in increased toxicity, enabling full count recovery. While none of the patients have undergone stem cell transplant, considered ineligible by the treating investigator, responses to BST-236 were durable and median overall survival (OS) for responders is not reached at 23 months (Figure 1A). Median OS for secondary AML patients was 6.8 months, and not reached for the de novo AML patients (Figure 1B). Follow up is ongoing with additional patients enrolling on study; updated analysis of response, minimal residual disease (MRD), duration of response, and OS will be presented at the meeting. Conclusions: The cumulative clinical data suggest that BST-236 as a single agent treatment is a safe and efficacious induction and consolidation therapy for patients who are unfit for standard intensive chemotherapy, including patients with adverse cytogenetics and prior exposure to HMA. The data may establish BST-236 as a new intensive therapy backbone of AML and may, for the first time, allow older adults deemed unfit for standard intensive induction and consolidation therapy, to benefit from an intensive treatment. Disclosures Altman: Genentech: Research Funding; Novartis: Consultancy; Syros: Consultancy; Theradex: Other: Advisory Board; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; AbbVie: Other: advisory board, Research Funding; Fujifilm: Research Funding; Kartos: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; ImmunoGen: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Amphivena: Research Funding; Janssen: Consultancy; Immune Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; ASH: Consultancy; Cancer Expert Now: Consultancy; PeerView: Consultancy; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; PrIME Oncology: Consultancy; France Foundation: Consultancy. Luger:Ariad: Research Funding; Biosight: Research Funding; Kura: Research Funding; Onconova: Research Funding; Agios: Honoraria; Acceleron: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Daiichi-Sankyo: Honoraria; Hoffman La Roche: Research Funding; Loxo Oncology: Honoraria. Koprivnikar:Amgen: Speakers Bureau; Novartis: Speakers Bureau; Alexion: Speakers Bureau; BMS: Speakers Bureau. Kota:Novartis: Consultancy, Honoraria; Incyte: Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Honoraria; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical, Company Ltd, Cambridge, MA, USA: Honoraria; Xcenda: Honoraria. 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. Bhatnagar:Novartis: 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; KITE: Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapuetics: Research Funding; Cell Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bixby:GlycoMimetics: Research Funding. Burch:Janssen: Other: paid speaker. Wolach:Amgen: Other: Fees for lectures and Consultancy; Janssen: Other: Fees for lectures and Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures and Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Astellas: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Pfizer: Consultancy, Honoraria. Levi:Abbvie Inc: Consultancy, Research Funding. Flaishon:BioSight Ltd.: Current Employment. Tessler:BioSight Ltd.: Current Employment. Gengrinovitch:BioSight Ltd.: Current Employment. Ben Yakar:BioSight Ltd.: Current Employment. Rowe:Pluristem ltd: Consultancy.

Background Patients with secondary acute myeloid leukemia (sAML) have poor outcomes compared to those with de novo AML. In 2017, liposomal daunorubicin and cytarabine (CPX-351) was FDA approved for the treatment of adults with newly diagnosed AML with myelodysplasia-related change (AML-MRC) or therapy-related AML (t-AML). In its landmark trial, CPX-351 has displayed significant improvement in overall survival (OS) compared to conventional 7+3 in patients 60-75 years of age with sAML. Gaps remain in the literature regarding the clinical use of CPX-351 in context of the FDA approved label. Here we evaluate real-world outcomes with disease response and molecular monitoring in patients treated with CPX-351. Methods Adults who received CPX-351 between September 2017 and December 2019 were identified. The primary endpoint was overall response rate (ORR), defined by complete remission (CR) and CR with incomplete hematologic recovery (CRi) according to the Revised IWG criteria. Additional outcomes of interest included molecular minimal residual disease (MRD) status post induction as measured by next-generation sequencing (NGS), ORR in patients with baseline TP53, and progression-free survival (PFS) in patients with CR/CRi, with and without MRD after induction. Mutations associated with clonal hematopoiesis (TET2, ASXL1, DNMT3A) were excluded from analysis of molecular MRD. Results Fifty-four patients were identified with baseline characteristics as shown in Table 1. Overall, the study population was elderly with the median age of 64 [IQR: 60-68], and 13 patients were younger than 60 years old. Six patients developed AML in the setting of a pre-existing myeloproliferative neoplasm (MPN). The most common indication for treatment with CPX-351 was antecedent MDS (42.6%), followed by de novo AML with MDS karyotype (24.1%), therapy-related AML (13%), and antecedent MPN (11.1%). NGS was performed prior to treatment with CPX-351 in all but one patient, and 88.7% had at least one molecular marker that is not identified as one of the mutations associated with clonal hematopoiesis. Most commonly identified molecular markers were TP53 (16/53, 30.2%), RUNX1 (10/53, 18.9%), SRSF2 (8/53, 15.1%), NRAS (7/53, 13.2%), and IDH2 and JAK2 (6/53, 11.3%, each). Most patients were hospitalized until hematologic recovery. However, 5 patients received induction in the outpatient setting, and an additional 6 patients were discharged early before hematologic recovery. Among the patients who were discharged early or underwent outpatient induction, 81.8% (9/11) were admitted for a complication. There were no deaths associated with outpatient induction. Overall, 46 patients (85.2%) experienced febrile neutropenia and 17 patients (31.5%) had bacteremia. Thirty-day and 60-day mortality were 9.3% and 14.8%, respectively. The ORR was 54%, and the response rates observed in patients who were younger vs older than 60 years were similar (41.7% vs. 57.9%, p=0.508). In patients who achieved a remission after induction, 56% (14/25) were MRD positive by NGS. Among those who had TP53 mutation at baseline, 14 were available for response assessment after induction. The ORR in this subgroup was 57% (8/14) and all but 3 (63%) were MRD negative by NGS. Consolidation with allogeneic transplant was performed in 18 patients (33%). Median OS was 10.4 mos. Median OS was similar for patients older or younger than 60 years (p=0.76). For patients achieving a CR/CRi, median OS had not been reached at the time of analysis but was significantly improved compared to those with refractory disease (6.1 mos, p=0.0007). Median OS or PFS did not differ significantly (p=0.68) based on MRD negativity (Figure 1). Conclusion This analysis demonstrates comparable response rates to the landmark trial (54% in our analysis vs. 47.7%). Outpatient induction and/or early discharge was safe and feasible in appropriately selected patients. While this analysis is limited by the small sample size, CPX-351 appeared effective in populations that were not included in the published randomized studies, such as patients below the age of 60 years old and those with antecedent MPN. Remission rates and MRD clearance was high among TP53 mutants. A considerable number of patients who achieved a remission remained MRD positive by NGS, but this did not impact PFS. Future studies should evaluate the impact of molecular MRD and allele frequency to further guide treatment. Disclosures Koprivnikar: Alexion: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Speakers Bureau. McCloskey:Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau.

Background: CC-90009 is a novel cereblon E3 ligase modulator (CELMoD), which is currently under investigation in a first-in-human, phase I study (CC-90009-AML-001; NCT02848001) in patients with R/R AML. In preclinical models, CC-90009 drives the binding of the target protein, translation termination factor G1 to S phase transition 1 (GSPT1), to cereblon and induces its ubiquitination and proteasome-dependent degradation. Loss of GSPT1 results in activation of the integrated stress response (ISR), inhibition of nonsense-mediated decay (NMD), and induction of apoptosis. Deep degradation of GSPT1, mediated by CC-90009, led to AML cell death in vitro and potent antitumor activity in patient-derived AML xenograft models. In the ongoing phase I study, CC-90009 has demonstrated antileukemic activity. Here, we characterize the pharmacodynamic responses using a suite of novel assays to support CC-90009 dose and schedule optimization. Methods: Adult patients with R/R AML received intravenous CC-90009 daily on Days 1-5 (D1-5 schedule) or on Days 1-3 and 8-10 (D1-3/8-10 schedule) of a 28-day cycle. Peripheral blood samples taken before, during, and after dosing in the first treatment cycle were analyzed. Levels of intracellular GSPT1 in blasts and normal blood cell types were quantitated by flow cytometry analysis. Transcript levels of ISR and NMD variants in peripheral blood mononuclear cells (PBMC) were measured by qPCR. Bone marrow (BM) core biopsies at screening, Cycle 1 Day 5 and 28, and Cycle 2 and 4 Day 28, were analyzed for GSPT1, cleaved caspase 3, and CD34 protein expression by immunohistochemistry. ATF3 and DDIT3 mRNA levels were assessed in BM samples by RNA in situ hybridization. Results: The rate and depth of GSPT1 loss in T cells and in circulating AML blasts increased with dose. A marked reduction in GSPT1 was observed in T cells and blast cells of most patients after the first dose of CC-90009 at all dose levels, and GSPT1 levels approached the assay floor between Days 2 and 5 at doses of 1.2 mg and higher on the D1-5 schedule. At 2.4 mg and higher on the D1-5 schedule, a reduction in GSPT1 levels of > 90% was observed in T cells (19 of 29 patients) and in blast cells (11 of 29 patients), with stronger GSPT1 reductions detected in AML blasts and normal T cells compared with B cells or granulocytes. In the 3 mg D1-5 cohort, patients with sustained GSPT1 reduction in peripheral blasts in the days following treatment had more persistent blast suppression compared with patients showing an earlier rebound of GSPT1. At 3 mg and 3.6 mg dose levels, continuous treatment (D1-5) resulted in slower kinetics of GSPT1 rebound and conferred superior antileukemic activity compared with the intermittent dosing schedule (D1-3/D8-10). In addition to measuring the direct target of CC-90009, GSPT1, we also investigated markers downstream of GSPT1 degradation. Several patients with deep and sustained GSPT1 loss in the high-dose cohorts (2.4 mg and above) showed increased levels of ISR-related transcripts (ATF3 and DDIT3) and NMD-associated splice variants (SRSF3 and SRSF6) in on-treatment PBMC samples. Similarly, in BM, deep GSPT1 loss coincided with induction of ATF3 and DDIT3 mRNA, increased cleaved caspase 3 expression, and reduced CD34+ blasts. These clinical findings are consistent with our preclinical studies in which GSPT1 loss culminated in apoptosis, which may be mediated through activation of ISR and inhibition of NMD pathways. Conclusions: CC-90009 is a novel CELMoD and a first-in-class GSPT1 degrader. A suite of novel pharmacodynamic assays performed on patient-derived peripheral blood cells and BM demonstrated a dose-dependent modulation of GSPT1, and showed that the preclinical mechanisms of ISR induction, NMD inhibition, and apoptosis can be confirmed in AML cells in patients. Deeper and more rapid GSPT1 degradation as well as delayed rebound were associated with more rapid, deeper, and more persistent blast reductions. Characterization of these pharmacodynamic responses in ongoing dose-schedule explorations will help identify the optimal scheme for the expansion phase and provide further insight into the mechanism of clinical response. Disclosures Fan: Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Yao:Celgene Corporation: Employment. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Zeidan:Pfizer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Montesinos:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees. DeAngelo:Jazz Pharmaceuticals, Inc.: Consultancy; Takeda Pharmaceuticals: Consultancy; Shire: Consultancy; GlycoMimetics: Research Funding; Pfizer, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy; Celgene Corporation: Consultancy; AbbVie, Inc.: Research Funding; Blue print Medicines: Consultancy, Research Funding; Amgen: Consultancy. Altman:Novartis: Consultancy; Cancer Expert Now: Consultancy; Biosight: Other: US Lead; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee. Koprivnikar:Amgen: Speakers Bureau; Abbvie: Speakers Bureau; Pfizer: Honoraria; Novartis: Speakers Bureau. Vyas:Astellas: Speakers Bureau; Pfizer: Speakers Bureau; Abbvie: Speakers Bureau; Daiichi Sankyo: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding. Fløisand:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Honoraria. Gjertsen:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; EU Horizon 2020: Research Funding; KinN Therapeutics AS: Equity Ownership; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; ERA PerMed: Research Funding; The Norwegian Cancer Society: Research Funding; Helse Vest Health Trust: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Research Council of Norway: Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ACTII AS: Equity Ownership. Buchholz:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Pierce:Celgene Corporation: Employment, Equity Ownership.

Background: CC-90009 is a cereblon (CRBN) E3 ligase modulator (CELMoD) and a first-in-class small molecule that drives the binding of a novel target protein, G1 to S phase transition 1 (GSPT1), to CRBN, resulting in the proteasome-dependent degradation of GSPT1. GSPT1 plays a central role in mRNA translation, and loss of GSPT1 activates an integrated stress response that leads to AML cell death (Matyskiela ME, et al. Nature. 2016;535:252-7; Zhouravleva G, et al. EBMO J. 1995;14:4065-72). In preclinical testing, CC-90009 is active across a range of AML cell lines and primary AML patient (pt) samples in vitro and in vivo and exerts its GSPT1- and CRBN-dependent effects through rapid induction of apoptosis. Here we share the first clinical results in pts with R/R AML. Methods: Adult pts with R/R AML enrolled in the dose-finding phase of this first-in-human, multicenter, open-label phase 1 study to evaluate tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of CC-90009; and to establish the recommended phase 2 dose and schedule (RP2D) (CC-90009-AML-001; NCT02848001). Dose escalation proceeded via a modified 3 + 3 design. Treatment was by daily intravenous administration on either Days 1-5 (D1-5) or Days 1-3 and 8-10 (D1-3/8-10) of a 28-day cycle. Treatment response was assessed after Cycles 1, 2, and 4 by modified International Working Group 2003 criteria. Safety and preliminary response data are presented for all treated pts. PK and PD were analyzed for evaluable pts. Results: As of May 15, 2019, 45 pts with R/R AML had been treated, including 35 pts on the D1-5 and 10 pts on the D1-3/D8-10 schedule. Median age was 66 years (range 27-81); 73% were male. Most pts (n = 36; 80%) were refractory to their last therapy and 17 pts (38%) were refractory to all prior therapy; 14 pts (31%) had secondary AML. Pts were treated at dose levels from 0.3 to 3.6 mg. Dose-limiting toxicities (DLTs) reported (only in dose levels from 2.4 to 3.6 mg) included hypotension, systemic inflammatory response syndrome (SIRS), hyperbilirubinemia, pneumonitis, and pericarditis with tamponade. Exploration of the 3.6 mg dose level is ongoing; the RP2D has not yet been determined. CC-90009-related grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 23 pts (51%); those occurring in >1 pt were hypocalcemia (22%); hypotension (13%); and hyperbilirubinemia, hyperglycemia, hypophosphatemia, pneumonitis, sepsis, thrombocytopenia, and tumor lysis syndrome (4%). Preclinically identified hypocalcemia was confirmed as a CC-90009 on-target toxicity in the clinic; it was reversible, manageable and did not lead to any treatment discontinuations. The majority of treated pts experienced ≥1 serious TEAE (80%); most were infections (47%). Two (4%) pts experienced TEAEs leading to permanent discontinuation of the study drug. Dose interruptions due to TEAEs occurred in 12 pts (27%) and dose reductions in 2 pts (4%). Of 40 pts who discontinued treatment, 24 (60%) discontinued due to progressive disease or lack of efficacy. Seven pts discontinued treatment due to death; 4 deaths were secondary to progression from AML, 2 due to sepsis and 1 due to hyperglycemic hyperosmolar nonketotic syndrome. Responses to single-agent treatment were observed in pts treated at 3.0 or 3.6 mg on the D1-5 schedule, with a best response of complete remission (CR; n = 1), morphologic CR with incomplete blood count recovery (CRi; n = 1) and morphologic leukemia-free state (MLFS; n = 1). A dose-dependent decrease in GSPT1 levels in peripheral blood blasts and T cells was observed, with a >90% decrease observed for higher dose levels. Evidence of antileukemic activity (decreases in bone marrow and/or peripheral blasts) was seen in pts treated with CC-90009 at 1.2 mg and above with a trend to more sustained reductions at the highest dose levels. Plasma PK analysis demonstrated dose-dependent exposure. Conclusions: In this phase 1 study of CC-90009, a first-in-class agent, evidence of deep GSPT1 degradation, on-target activity and promising antileukemic activity was observed. The observed TEAEs, in addition to those expected in this heavily pretreated R/R AML pt population, were generally well manageable. The study is ongoing with further optimization of dose, schedule and toxicity mitigation. Expansion cohorts in R/R AML and higher-risk myelodysplastic syndromes are planned. Disclosures Uy: GlycoMimetics: Consultancy; Curis: Consultancy; Astellas: Consultancy; Pfizer: Consultancy. Montesinos:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. DeAngelo:Blue print Medicines: Consultancy, Research Funding; Celgene Corporation: Consultancy; Shire: Consultancy; Pfizer, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Incyte Corporation: Consultancy; Jazz Pharmaceuticals, Inc.: Consultancy; GlycoMimetics: Research Funding; AbbVie, Inc.: Research Funding; Takeda Pharmaceuticals: Consultancy; Amgen: Consultancy. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; France Foundation: Speakers Bureau; PeerView: Speakers Bureau; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Cancer Expert Now: Consultancy; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; prIME Oncology: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Koprivnikar:Amgen: Speakers Bureau; Pfizer: Honoraria; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Vyas:Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Forty Seven, Inc.: Research Funding; Daiichi Sankyo: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Fløisand:Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria; Novartis: Honoraria. Gjertsen:BerGenBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; EU Horizon 2020: Research Funding; Daiichi Sankyo: 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; The Norwegian Cancer Society: Research Funding; KinN Therapeutics AS: Equity Ownership; ACTII AS: Equity Ownership; ERA PerMed: Research Funding; Helse Vest Health Trust: Research Funding; Research Council of Norway: Research Funding. Esteve:Astellas: Consultancy, Speakers Bureau; Amgen: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Pfizer: Consultancy. Buchholz:Celgene Corporation: Employment, Equity Ownership. Couto:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Fan:Celgene Corporation: Employment, Equity Ownership. Hanna:Celgene Corporation: Employment, Equity Ownership. Li:Celgene Corporation: Employment, Equity Ownership. Pierce:Celgene Corporation: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties; Mersana Therapuetics: Membership on an entity's Board of Directors or advisory committees; Society for Immunotherapy of Cancer: Membership on an entity's Board of Directors or advisory committees; Arcus Biosciences: Membership on an entity's Board of Directors or advisory committees. Pourdehnad:Celgene Corporation: Employment, Equity Ownership. Zeidan:Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Cardinal Health: Honoraria; Daiichi Sankyo: Honoraria; Novartis: Honoraria; Otsuka: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Astellas: Honoraria.

Background The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy improves the prognosis of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Single agent blinatumomab, a bi-specific T-cell engaging CD3-CD19 antibody construct, is more effective than multi-agent chemotherapy in relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) and successfully achieves minimal residual disease (MRD) negativity in MRD positive patients. Limited data is available on the safety and efficacy of these agents in combination and uncertainties remain regarding the optimal use of blinatumomab +TKIs. Dual therapy with blinatumomab and TKIs may offer a safe and effective treatment option for relapsed and refractory patients without the incorporation of chemotherapy. Patients and Methods We report our retrospective experience in 18 patients who received blinatumomab +TKI for relapsed/refractory (R/R) Ph+ ALL (n=14), MRD+ Ph+ ALL (n=2) and chronic myeloid leukemia in lymphoid blast crisis (CML-LBC) (n=2). Ten patients received ponatinib; 8 patients received second generation TKIs (dasatinib, n=5; nilotinib, n=2; bosutinib, n=1). Blinatumomab was administered according to the package insert and TKI was initiated on day 1. Median follow up was 15 months and median number of blinatumomab +TKI cycles was 2 (range, 1-5). The median age was 47 years (range, 22-77). The median number of prior therapies was 2 (range, 1-8) and the median number of prior TKIs was 2 (range 1-4). Preexisting T315I mutations were present in one third of patients and 5 patients had relapsed following allogeneic stem cell transplant (alloHSCT). Results Transient grade 2-3 transaminase elevation was observed in 3 patients (ponatinib=2, dasatinib=1). Cytokine Release syndrome was observed in 2 patients. Transient neurotoxicity was observed in 3 patients (1patient with grade 3). All grade 2 and 3 toxicities were observed during the first cycle and all patients were successfully able to complete induction with blinatumomab +TKI. One patient on dasatinib experienced a PICC-associated DVT. There were no other vascular events observed. For patients with r/r disease the CR rate was 88% (14/16) with most of these remissions being MRD negative by flow and PCR (12/14). Both of the patients treated for MRD positivity achieved an MRD negative response. Among T315I mutated patients, 5/6 achieved a CR and 4/5 were MRD negative. The median time to remission was 35 days. The 1 year survival was 80% and the median overall survival following blinatumomab therapy was 45 months. Among 16 pts who achieved an initial response to blinatumomab +TKI, six have expired at the time of this analysis. At the time of relapse on combination therapy, 3/8 pts exhibited new T315I mutations. Of note, all of these were treated with blinatumomab in combination with a second generation TKI. All patients maintained their CD19 positivity at the time of relapse. Both pts with CML-LBC were able to move to a transplant following therapy with blinatumomab +TKI and both attained MRD negative status as measured by Bcr/Abl PCR values. In total, 10 patients treated with blinatumomab +TKI proceeded to alloHSCT, 7 of these are still alive. Median duration of response (DOR) was 5.1 months with maximum DOR of 23.3 months. Discussion While limited due to its retrospective nature and relatively small sample size, this data set begins to answer important regarding the safety and efficacy of blinatumomab +TKI. Combination therapy was effective at achieving rapid and deep responses in this refractory patient population. The toxicities observed with blinatumomab +TKI were in keeping with those seen with blinatumomab alone. However, care should be taken in regard to potential overlapping toxicities of TKIs and blinatumomab, such as hepatotoxicity. The study also suggests a role for blinatumomab treatment in patients with CML-LBC, a rare and difficult disease state to treat. The identification of T315I mutation at relapse in 40% of patients on blinatumomab +second generation TKIs supports further prospective studies with ponatinib and blinatumomab in combination. Finally, loss of C19, which has relevance with regards to the potential benefit of subsequent CD19-directed therapies such as chimeric antigen receptor T-cell therapy was not seen in patients treated with blinatumomab +TKI. Disclosures McCloskey: Jazz: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Gagnon:Amgen: Speakers Bureau. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Pfizer: Honoraria; Novartis: Speakers Bureau; Abbvie: Speakers Bureau.

Background Hypomethylating agents (HMAs) are the current standard of care therapy in high-risk MDS. However, only ~50% of patients with MDS respond to HMAs and most responding patients eventually progress. Outcomes after HMA failure in patients with high-risk MDS are especially poor, with median survival of 4 to 6 months. Venetoclax in combination with HMAs led to deep and durable remissions in elderly patients with newly diagnosed AML with CR+CRi rate of 67% and median survival of 17.5 months.Here, we performed a multicenter retrospective analysis to determine outcomes in patients with MDS receiving HMA + venetoclax (off-label) and identified risk factors associated with response and survival. Methods After obtaining institutional review board approval(s), we retrospectively reviewed charts of patients receiving HMA and venetoclax between January 1, 2018 to July 15, 2019. Criteria for inclusion were a pathologically confirmed diagnosis of MDS and treatment with either decitabine or azacitidine in combination with venetoclax. Patients with progression to AML prior to treatment with HMA+ venetoclax were excluded. Bone marrow response assessments were evaluated per WHO 2006 criteria. For subjects who required a delay in study treatment for blood count recovery after bone marrow evaluation, hematology values for up to 2 weeks were used to determine response. When available, cytogenetics, next generation sequencing, and flow cytometry data were included for analysis. HMA failure was defined as progression to a higher IPSS-R risk MDS while on HMA or lack of response after 4 cycles of HMA treatment. On univariate analysis, Fisher's exact test and Student t tests were used for overall response and Kaplan-Meier estimates were used to summarize OS and RFS. Results 42 patients met criteria for inclusion. The patient population was predominantly male, elderly, R-IPSS very poor cytogenetics, R-IPSS very high risk, MDS-EB2, and with HMA failure prior to initiation of HMA + venetoclax (Table 1.) Median blast count was 13% (range 2-18%). MDS was classified as therapy-related (t-MN) in 13 (31%) patients. TP53 mutations with complex karyotype occurred in 9 out of 34 (26%) patients (Figure 2). Azacitidine was the most common HMA used in combination with venetoclax (63%). Median follow up from the start of the combination was 5.4 months. Out of 40 patients evaluable for response, the ORR and marrow CR rate was 55%, median RFS and OS were not reached. Patients who achieved a marrow CR had a significantly prolonged OS in comparison to non-responders (median OS not reached vs. 5.64 months, p= 0.002). Among HMA naïve patients, the marrow CR rate was 73%. Furthermore, the marrow CR rate was 47% for patients with HMA failure and there was no significant difference in response or survival based on HMA exposure (Table 2). Median time to initial response was 1.6 months. On univariate analysis, therapy related disease and very poor risk cytogenetics were significantly associated with decreased response and a delay in starting cycle 2 or 3 was associated with increased response. Female gender, t-MN, very poor risk cytogenetics and a TP53 mutation were significantly associated with inferior OS. Very poor risk cytogenetics, a TP53 mutation, and the decitabine combination was significantly associated with decreased RFS (Table 3). Of note, neither a dose delay of venetoclax > 7 days or Conclusion In summary, venetoclax in combination with HMAs led to high rates of marrow remission (55%) and hematologic improvement (38%) in a very high risk and heavily treated MDS population. The response rate was higher in HMA naïve patients but not significantly decreased among patients with HMA failure. Achievement of marrow CR led to significantly prolonged OS. HMA + venetoclax also led to allo-SCT in 59% of all responders and 56% of responders with HMA failure. Complex karyotypes and TP53 mutations were associated with worse response and survival. These results suggest that adding venetoclax may salvage patients failing to respond optimally to HMA, thus allowing more patients to proceed to allo- SCT, and likely warrant testing prospectively. Disclosures Stein: Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma US, Inc: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; PTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Bioline: Membership on an entity's Board of Directors or advisory committees. Tallman:ADC Therapeutics: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; UpToDate: Patents & Royalties; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; UpToDate: Patents & Royalties; Cellerant: Research Funding; Cellerant: Research Funding; Cellerant: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellerant: Research Funding; ADC Therapeutics: Research Funding; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biosight: Research Funding; Cellerant: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: 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; Cellerant: Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties. Gill:Novartis: Research Funding; Tmunity Therapeutics: Research Funding; Carisma Therapeutics: Research Funding; Amphivena: Consultancy; Aro: Consultancy; Intellia: Consultancy; Sensei Bio: Consultancy; Carisma Therapeutics: Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Pfizer: Honoraria; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Sallman:Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau; Jazz: Research Funding; Novartis: Speakers Bureau; Abbvie: Speakers Bureau. Goldberg:ADC Therapeutics: Research Funding; American Society of Clinical Oncology: Research Funding; American Society of Hematology: Research Funding; Celgene: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; Pfizer: Research Funding; DAVA Oncology: Honoraria; Abbvie: Research Funding; Arog Pharmaceuticals: Research Funding; Abbvie: Consultancy. Komrokji:Novartis: Speakers Bureau; pfizer: Consultancy; DSI: Consultancy; Incyte: Consultancy; Agios: Consultancy; JAZZ: Speakers Bureau; celgene: Consultancy; JAZZ: Consultancy. OffLabel Disclosure: We will describe outcomes for patients receiving venetoclax in combination with hypomethylating agents in MDS.

Background: AlloHCT is a potentially curative treatment for patients with acute myeloid leukemia (AML) and other myeloid malignancies (MM), however has a 40% relapse rate. The 2-year post-relapse survival rate is less than 20%; sustainable remissions are rare. Multiple strategies to mitigate relapse have been employed with variable degrees of success. An as yet untested approach involves manipulation of the T-cell milieu in the post-alloHCT setting using CI. Preclinical animal models of tumors have shown that blockade of PD-1 by monoclonal antibodies(mAbs) can enhance the anti-tumor immune response and result in tumor rejection, suggesting that host mechanisms limit the antitumor response. A murine model of an anti-PD-1 mAb given at the time of transplant showed that PD-1/PD-L1 interactions decrease acute GVHD, but increase chronic GVHD suggesting that PD-1 pathway modulation may provide unique opportunities for stimulating immune regulation post-alloHCT. Use of ipilimumab (I) to treat post-transplant MM resulted in a complete response rate of 42% and decreased the Treg/Tconv cell ratio, consistent with enhancement of the graft-versus-tumor effect. The CPIT-001 Trial demonstrated the feasibility and safety of combined CI with I and nivolumab (N) as consolidation following autologous stem cell transplantation (ASCT) for high-risk hematological malignancies as well as a 67% PFS rate at 18 months post-ASCT, a significant improvement as compared with historical data. Study Design: The study employs a 3x3 design with intrapatient dose escalation. Patients will alternately be assigned to receive either N or I as a single agent. If the safety endpoint is met for each group, enrollment to the combination CI group will open. See table 1 for dosing. For all Groups, intrapatient dose escalation will be utilized. If the patient tolerates 28 days of treatment, he/she will be escalated to the next dose level and the next patient will be enrolled. Enrollment must occur within 60 days prior to HCT conditioning to allow for collection of baseline samples. Patients will start CI therapy 60 to 100 days after stem cell infusion when acute GvHD is adequately controlled on a prednisone dose of 20 mg daily or less, organ function, and peripheral counts are adequate. Key inclusion criteria at study start up included patient age 75 years or less with high risk AML or MDS undergoing alloHCT with a matched-related or 10/10 unrelated donor who were receiving non-myeloablative conditioning. Bone marrow aspiration will be performed for response evaluation approximately every 3 months post CI initiation. The primary objective is to assess the safety of CI in this patient population. Secondary objectives include efficacy, assessment of blood immune reconstitution, phenotype and TCR repertoire by sequencing, assessment of tumor site immune phenotype, TCR repertoire and PD-L1/2 expression both prior to alloHCT conditioning and at relapse. The tertiary objective is to identify specific intestinal microbial strains associated with improved outcomes in alloHCT patients treated with CI. Microbial composition in stool samples of patients will be analyzed at screening, at engraftment, at various time points post-transplant, and at time of relapse, as it occurs. Study Experience Thus Far: The study opened to accrual in May of 2017. Four patients have signed informed consent. Two patients have been treated with CI. One patient withdrew consent prior to treatment and a second patient is currently status post alloHCT, but has not yet reached day 60. One patient received 2 doses of N and the second patient received 1 dose of I. Accrual to trial has been slower than anticipated. A detailed analysis of the patient screening log was completed. It was determined that 139 patients had been screened for trial. Major reasons for being ineligible included a diagnosis of ALL (34 patients; 24%), use of a haploidentical donor (30 patients; 22%), use of a full dose conditioning regimen (14 patients; 10%), diagnosis of CML (12 pateints; 10%), age greater than 75 (12 patients; 9%), diagnosis of CMML (12 patients; 9%). Following this analysis, an amendment was filed to include patients receiving haplo identical transplant and/or myeloablative conditioning, and to expand diagnosis to include all MM including CMML, CML blast crisis, and myelofibrosis. Disclosures Koprivnikar: Amgen: Speakers Bureau; Pfizer: Honoraria; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. McCloskey:Jazz: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Abbvie: Speakers Bureau; Novartis: Speakers Bureau. Rowley:Fate Therapeutics: Consultancy; Allergan: Equity Ownership. OffLabel Disclosure: Nivolumab - immunomodulation Ipilimumab - immunomodulation

Background: Blinatumumab (B), a bi-specific T-cell engaging CD3-CD19 antibody construct, has shown significant activity in patients (pts) with B-cell acute lymphoblastic leukemia (B-ALL). Despite this improvement, uncertainties remain regarding the optimal use of this drug. These include the efficacy in pts with extramedullary (EM) disease, rates of relapse with EM disease, the safety and efficacy of B therapy in combination with tyrosine kinase inhibitors (TKIs) and in pts with lymphoid blast crisis of chronic myeloid leukemia (CML), and the incidence of loss of expression of CD19 following B therapy. Results: We report our retrospective experience with 28 adult pts treated with B since its commercial release. The median age at diagnosis was 45.5 years of age. More than half of the pts (N=16; 57%) received B for relapsed disease, while a quarter of pts (N=7; 25%) received treatment for refractory disease. The remaining 5 (18%) were treated for minimal residual disease (MRD). The median number of prior therapies was 2. The CR rate was 71% with nearly half of pts (45%) achieving a MRD negative remission following cycle 1 of B. Of note, MRD data was not available for 8 pts. Median progression free survival (PFS) was 9.8 months with a 1-year PFS rate of 41.7%. The overall survival following B therapy was 10.1 months. Among 20 pts who achieved an initial response with B therapy, half have expired at the time of this analysis. Median duration of response (DOR) was 5.85 months with maximum DOR of up to 41.5 months. The median disease burden prior to treatment was 65% leukemic blasts in the bone marrow. There was no association between disease burden and response to B (P=0.523). There was also no association between line of therapy and response to B (P=0.782). Pts treated in the relapsed setting were more likely to respond than those treated in the refractory setting (43% versus 94% P=0.017). Five of 28 pts in our series had documented EM ALL prior to initiation of B therapy. Four of these 5 pts experienced a CR to treatment with B. An additional patient with a history of central nervous system (CNS) involvement by ALL demonstrated relapse of CNS disease while on B treatment while systemic disease remained under control. Of 11 pts with documented relapse following B therapy, the majority (7) of these pts had involvement of EM sites. Four of these 7 pts had documented EM disease prior to initiation of B therapy. CD19 status was available for 12 pts with a relapse of their ALL following B therapy. Of these 12 pts, 11 retained their CD19 positivity. Nine pts (32%) treated with B had t (9;22). Two of these pts had lymphoid blast crisis of CML while the remainder of the pts had Ph+ B-ALL. All but one of the pts tolerated concurrent TKI and B. TKIs administered in this series included ponatinib, bosutinib, nilotinib, and dasatinib. The sole patient who was not able to tolerate dual therapy was receiving ponatinib and developed transaminitis with AST/ALT in the 3000s during the first 3 days of B therapy, which likely was in part due to cytokine release syndrome. Both pts with blast crisis CML were able to move to a transplant following therapy with B and both attained MRD negative status as measured by Bcr/Abl PCR values suggesting a potential role for B for treatment of pts with lymphoid blast phase of CML. Discussion: While limited due to its retrospective nature and relatively small sample size, this data set begins to answer important questions often not addressed as part of clinical trials. Pts with EM disease did respond to treatment with B, however, most of these of these pts as well as others who relapsed following B had EM involvement, suggesting that B may not have long term efficacy for disease outside of the bone marrow and that systemic restaging studies should be considered for pts receiving B therapy. The safety of B given concurrently with TKI therapy is also supported by our results as is the need to be aware of potential overlapping toxicities between TKI and B, such as the hepatotoxicity seen in our patient. Our study demonstrates that response to B appears to be independent of disease burden and also suggests a role for B treatment in pts with lymphoid blast crisis of CML, a rare and difficult disease state to treat. Finally, we also demonstrate that loss of C19, which has relevance with regards to the potential benefit of subsequent CD19-directed therapies such as chimeric antigen receptor T-cell therapy is rare in pts treated with B. Disclosures Koprivnikar: Amgen Pharmaceuticals: Speakers Bureau; COTA: Equity Ownership; Otsuka Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Consultancy, Speakers Bureau. Stanislaus:Takeda Pharmacetucals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Speakers Bureau; Celgene Pharmaceuticals: Consultancy, Speakers Bureau. McCloskey:COTA: Equity Ownership; Amgen Pharmaceuticals: Speakers Bureau; Takeda Pharmaceuticals: Speakers Bureau; Jazz Pharmaeuticals: Speakers Bureau; Celgene Pharmaceuticals: Consultancy, Speakers Bureau.

Introduction: Survival rates continue to improve after allogeneic HCT (Gooley et al, NEJM, 2013). Population-based studies also indicate overall improvement in survival of older (60-80 years old) AML patients (pts) (Bower, Blood Cancer Journal, 2016). Yet, only a small minority (6%-8%) of them receive HCT (Medeiros, Ann Hematol. 2015). Given these potentially incongruent findings and the changing face of survival in AML, we designed the first prospective multi-center longitudinal study dating from first presentation of adults with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We compared survival according to whether or not pts received HCT at later time points. Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including activities of daily living (ADL); frailty; geriatric assessment including cognition; QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale, ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. We used time-dependent Cox regression analyses to identify baseline and time-dependent risk factors associated with mortality in the overall population. The factors identified as significantly associated with mortality (p Results: Median follow-up was 16.8 months (range 0.1-52.4). In the initial multivariate analyses, the following were identified as significantly associated with an increased risk of mortality (Table 2): HCT-CI scores ≥5 (p Survival after HCT was 58% at 2-years. Initial unadjusted analyses showed significantly lower risks of mortality in association with receiving allogeneic HCT (p=0.0003). These findings were similar in pts with intermediate (p=0.0005) or unfavorable (p However, in the adjusted models, the advantage of HCT in reducing mortality rates was lost both in the overall population (p=0.21, see figure) as well as in the other groups (p>0.54, 0.40, and 0.51, respectively, Table 3). Formal tests of interactions (Table 3) showed no statistically compelling evidence that the association of HCT and mortality varies with respect to the timing of mortality or to the underlying ELN risk. Conclusions: In a prospective observational study, adjusting for key AML-specific and pt-specific variables negated the observed benefit of HCT over non-HCT therapies in reducing mortality rates among AML pts. Our results might reflect 1) improvement in supportive care and non-HCT therapies, 2) a relatively high non-relapse mortality early after HCT and the need for longer follow-up to demonstrate an adjusted benefit of HCT, and 3) the high selectivity of the transplant eligibility process, as we accounted here for variables that are often ignored in "genetic assignment" randomized studies (i.e. comorbidities and function). New randomized trials are needed; however, these trials have to be more inclusive of vulnerable pts and measure pt-specific variables. Trials focusing on reducing burden of comorbidities, frailty and poor function are needed alongside trials to treat AML with or without HCT. Disclosures Gerds: Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy. Shami:JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy. Rizzieri:Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Alexion: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Otsuka: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding.

Background: Acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are heterogeneous groups of disorders with a spectrum of clinical presentations and outcomes. Prognosis depends on various factors including age, karyotype, performance status, previous treatments and mutation status. Genetic profiling with next generation sequencing (NGS) is increasingly being used at diagnosis to detect presence of somatic mutations for prognostic risk stratification, and identification of therapeutic targets. Here we seek to identify epidemiologic differences in genetic mutations based on population and demographic data in patients with a preliminary diagnosis of AML or MDS. Methods: NGS mutation data were collected for 62 genes related to AML/MDS on a total of 10,934 patient samples submitted for testing for suspected AML/MDS. Samples were run on either the 54-gene NeoType Myeloid Disorders Profile (Neogenomics) or the 37-gene OnkoSight Myeloid Malignancies Panel (Genpath). The frequency of gene mutations (i.e., the number of patient samples with mutations for each gene) was identified for 58 counties in the USA. Counties in which fewer than 50 patient samples were tested were excluded from the dataset to minimize sampling bias. The counties were then grouped into 3 categories ranging from most urban to most rural based on a modified version of the 2013 National Center for Health Statistics classification system G-1 - > 1,000,000 (N=34), G2 - 250,000 - 1,000,000 (N=16) and G3 < 250,000 (N=8). One-way ANOVA and subsequent T-tests were performed for all genes based on the 3 urban-rural groupings to determine if significant differences in frequency of mutations exist between the 3 groupings. Difference of proportions tests were performed to identify variations in the patterns of frequency between counties. Results: The top 10 most frequent mutations were TET2, ASXL1, DNMT3A, SRSF2, TP53, RUNX1, SF3B1, U2AF1, NRAS, and NPM1(highest to lowest). The three mutations with the widest range of variability across counties were DNMT3A, TET2, and ASXL1 (DTA mutations). The median age across all counties was 68 (range 44-77). The county with the youngest and highest median age was Montgomery, CA and Pinellas, FL, with ASXL1 and TET2 as the most frequent mutation, respectively. Sacramento, CA had an unusually high rate of ASXL1 mutations (> 24%). ASXL1 was also significantly higher than TET2 in Essex, NJ; Montgomery, MD; and Sacramento, CA. (p=0.0287, p < 0.0001, p < 0.0001, respectively). IDH1was higher than IDH2 for Martin, FL (p= 0.0481). The highest frequency of TP53 mutation (24%) was in Bexar, TX compared to Montgomery, MD which had the lowest (2%). When counties were grouped based on population density, the frequency of RUNX1 and SF3B1 were statistically different across the counties, highest in G2 compared to G1 and G3 (p= 0.0294 and 0.0010 respectively). Conclusion: Our retrospective observational study is the first of its kind to look at genetic mutations in AML/MDS patients across the United States using commercially available NGS platforms. In general, patients had analogous combinations and frequencies of mutations commonly seen in AML and MDS, and the wide variation in frequency of DTA mutations is consistent with information known about age-related clonal hematopoiesis. In counties that showed a higher rate of ASXL1 > TET2, there may be a potential environmental factor accounting for this difference as the reverse is more commonly seen. Likewise, IDH1 mutations are typically seen at a lower frequency compared to IDH2, and it is interesting to note the reverse in Martin, FL (G2) despite the mutation frequency of all other genes being similar compared to the median for all counties. Our data analysis also showed a significant difference in frequency of mutations for TP53, RUNX1 and SF3B1. These variations have important implications in regard to prognosis, and the approach to treatment. Our observations suggest further investigation is warranted to explore potential environmental exposures related to somatic mutational patterns in patients with AML and MDS. Disclosures McCloskey: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Celgene Pharmaceuticals: Honoraria, Speakers Bureau; Amgen Pharmaceuticals: Speakers Bureau; Pfizer: Consultancy; Takeda Pharmaceuticals: Consultancy, Speakers Bureau; COTA: Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Otsuka: Consultancy; Alexion: Consultancy, Speakers Bureau.

Introduction: Acute myeloid leukemia (AML) is most frequently diagnosed in older patients (pts), whose median survival is less than 1 year. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. However, older pts often have significant comorbidities and other geriatric health problems, and the effect of these on the probability of receiving HCT is unknown. To this end, we designed a prospective, multi-center, longitudinal, observational study dating from first presentation of adult pts with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We examined the effects of different variables (see methods) on the probability to 1) survive long enough to receive HCT and 2) to receive HCT if such survival occurred. Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including instrumental activities of daily living (IADL) and activities of daily living (ADL); frailty including walk test; geriatric assessment (GA) including cognition; Karnofsky performance status (KPS); QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale (EQ-5D), ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. High-risk myelodysplastic syndromes (MDS) receiving AML-like therapy were included. We used competing risk Cox regression analyses, treating HCT as the event of interest and death without HCT as a competing risk, with staggered entry (left truncation) at time of consent. Associations between variables were assessed both at enrollment and over time. Results: The overall rate of HCT at 9 months after enrollment was 43% (Figure 1) and 92% of pts who received HCT did so by the 9 month mark. In multivariate analyses, death without HCT (Table 2) was associated with augmented HCT-CI scores ≥5 (HR:2.11, p Among survivors (Table 3), low likelihood to receive HCT was associated with age ≥70 years (HR:0.40, p=0.0001), low ELN risk (HR:0.28, p Conclusions: In a prospective, observational, multi-center study, increasing age, comorbidity burden, ELN risk, low-intensity initial AML induction regimen, depression, and functional dependence increase risks of early mortality without HCT. In those who survived long enough to potentially receive HCT, age up to 69 years and/or multiple comorbidities were not found to be barriers to HCT, likely reflecting the widespread use of reduced-intensity conditioning regimens. However, the independent sharp decline in receipt of HCT in pts aged 70-80 years suggests continued bias, although pts in this age group have been shown to derive similar benefit from HCT as younger pts. Use of objective comorbidity and GA tools rather than age per se to decide on HCT is encouraged. The adverse impact of impairments in psychological health and function on survival and of impairments of cognition, geriatric health, and performance status on receipt of HCT emphasize the need for interventions that target these health limitations in conjunction with AML treatment to improve outcomes. Finally, the benefit of intensive vs. less-intensive induction therapies should be addressed with a randomized trial. Disclosures Gerds: Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Rizzieri:Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang:Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Otsuka: Consultancy; Alexion: Consultancy, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding.

Abstract Background: The development of tyrosine kinase inhibitors (TKIs) has dramatically changed the landscape of chronic myelogenous leukemia (CML) treatment. Dosing of TKIs is based on the phase of disease at presentation, but is not altered based on body surface area (BSA), gender, or other patient characteristics. Although TKIs are generally well tolerated, lower grade hematologic and non-hematologic toxicities are not infrequent. Inability to maintain dosing during the first year of therapy (missing as few as 10% of doses per month) has been associated with lower rates of major molecular response (MMR), which might have survival implications and/or prevent treatment-free remission attempts. While the package insert of three TKIs (imatinib, dasatinib, nilotinib) commonly used in first line therapy provides specific dose-reduction instructions for hematologic toxicity, only nilotinib has recommendations for non-hematologic toxicities. Long-term outcome data on the effects of dose-reduction of TKI therapy based on toxicity is lacking. Furthermore, there is little data on risk factors for TKI intolerance. Thus, we sought to identify characteristics of patients requiring dose reductions as a part of first-line TKI treatment for chronic phase CML who successfully achieved an MMR 4 or greater as well to determine the long-term outcome of these patients in a retrospective fashion. Methods: Using electronic medical records, we identified patients seen at the John Theurer Cancer Center for treatment of newly diagnosed chronic phase CML between November 1, 2012 and July 1, 2016 who had successfully achieved an MMR 4 or greater. These records were screened for individuals requiring chronic dose reductions as part of first-line treatment for chronic phase CML. We identified 35 consecutive patients that were able to tolerate full dose TKI therapy per package insert. This control group was used to determine risk factors for TKI intolerance compared to patients that required dose reduction. Results: A total of 20 patients were identified who achieved an MMR 4 or greater and required long-term dose reduction of first-line TKI therapy with a median follow up of 48.5 months (range 18.7-172.6). The median time on full dose therapy prior to dose reduction was 7.7 months (range 0-40.2). The median time spent on reduced dose therapy was 43.5 months (range 12.1-159.0). The time to MMR was 8.3 months (1.8-40.2). The majority of patients remained in MMR 4 despite maintenance on dose reduction. Median progression free survival (PFS), as defined by loss of MMR, of dose-reduced patients had not yet been reached. One, two, and three year PFS rates were 100%, 95.0%, and 88.7% respectively. When compared to the control group of patients tolerating front line therapy at full-dose, patients requiring dose reduction were more likely to be female: 80% vs 46% (P=0.028) and have a lower BSA: 1.78 versus 2.03 mg/m2 (P=0.0014). Other variables including age, TKI, Sokol score, and performance status were similar in both groups. Discussion: Among patients who achieved MMR4 or greater on first-line therapy, we noted that female sex and lower BSA were risk factors for TKI dose reduction. Based on the available control group, it cannot be determined if either of these are independent variables. This retrospective analysis demonstrates many patients are able to successfully achieve and maintain a deep molecular response with reduced doses of TKI therapy and perhaps provides justification for dose reduction to increase compliance and maximize treatment tolerability. The majority of patients remained in MMR4 despite dose reductions. Disclosures McCloskey: Celgene Pharmaceuticals: Consultancy, Speakers Bureau; Takeda Pharmaceuticals: Speakers Bureau; Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Amgen: Speakers Bureau; COTA: Equity Ownership. Stanislaus:Celgene Pharmaceuticals: Consultancy, Speakers Bureau; Takeda Pharmacetucals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Novartis Pharmaceuticals: Consultancy, Speakers Bureau. Koprivnikar:Otsuka Pharmaceuticals: Honoraria; Alexion Pharmaceuticals: Consultancy, Speakers Bureau; Amgen Pharmaceuticals: Speakers Bureau; COTA: Equity Ownership.

Background: Pts with AML-Mo, often present with leukocytosis and aggressive clinical features such as extramedullary involvement and coagulation abnormalities. Frequently the clinical presentation resembles a hyperinflammatory phenotype. This often leads to unfavorable outcomes compared to pts with other subtypes of AML regardless of pretreatment cytogenetic/molecular features. No large series have systematically assessed the characteristics of pts with AML-Mo following standard induction therapy. We conducted a retrospective case-control study of pts with AML-Mo to define disease characteristics and associate those with outcome. Methods: Sixty-one consecutive pts between January 2010 and March of 2016 with AML who met FAB criteria for acute myelomonocytic or acute monocytic leukemia or exhibited greater than 20% monocytic differentiation on flow cytometry were considered as AML-Mo, and were compared to a control cohort of 128 pts with AML without monocytic differentiation. All pts were newly diagnosed and treated on a standard intensive induction protocol. Pts were excluded for incomplete cytogenetic and molecular data. Results: There were no significant differences between the two groups with regard to age, sex, secondary AML, prior MDS, and ELN risk stratification. Pts with AML-Mo had higher median WBC (43,000/µ vs 7,000/µL, p With a median follow up of 10.7 months, 1 and 5-yr OS was 55% and 34% (AML-Mo) compared to 70% and 38% (AML) at 1 and 5 years, respectively (p=.0075, p=.034)(Figure 1). Allo HSCT in CR1 resulted in greater reduction in the risk of mortality for pts with AML-Mo compared to other AML pts (56% vs 11%, p=0.148) (Figure 2). This effect prevailed when considering ELN risk at diagnosis and HSCT into a multivariate model (p=0.032). Conclusions: Pts with AML-Mo experience higher rates of complications and death within 30 days of induction. Despite similar CR rates, overall survival was inferior. While allo HSCT benefited both pts with AML and AML-Mo, the benefit was greatest for AML-Mo pts. Besides allo HSCT in CR, other measures (eg reduction of inflammatory reactions by suppression of cytokines and other mediators) should be considered to decrease the high induction mortality and complication rate of these pts. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures McCloskey: Novartis: Speakers Bureau; Incyte: Consultancy; Ariad: Consultancy, Speakers Bureau; Amgen: Speakers Bureau. Depadova:Amgen: Speakers Bureau. Koprivnikar:Alexion: Consultancy, Speakers Bureau. Stanislaus:Novartis: Consultancy, Speakers Bureau. Goldberg:Neostem: Equity Ownership; Pfizer: Honoraria; Bristol Myers Squibb, Novartis: Speakers Bureau; Novartis: Consultancy; COTA Inc: Employment.

OBJECTIVE: According to standard protocol, the earliest post treatment marker of response following intensive induction therapy in patients with AML is a D14 marrow biopsy. Some controversy has surrounded this practice. This study aims to evaluate response to induction therapy based on D14 marrow assessment meeting genetic risk classifications as defined by the ELN. METHODS: In a single center, retrospective chart analysis subjects diagnosed with AML treated with 7+3 therapy were included if they had molecular and cytogenetic testing performed at baseline, day 14, and day 28. Baseline characteristics and treatment results at these time points were extracted. Sample demographics and treatment were described descriptively. Risk ratios were calculated to investigate the likelihood of achieving a chemo-ablated[1] bone marrow biopsy at Day 14 across the ELN risk classifications. All analyses were performed using SAS 9.4 (SAS Institute Inc., Cary, NC). RESULTS: One hundred thirty eight pts were included. The median age at diagnosis was 57 years (range 26 to 69). The median white blood cell count at diagnosis was 12,800 (range 0.1 to 122,000 per microliter). 6.5% of the pts had secondary AML and 8.7% had AML arising from an antecedent hematologic disorder. ELN risk classifications at diagnosis were 47.1%, 8.7%, 20.3% and 23.9% for favorable, intermediate-I, intermediate-II and adverse, respectively. Demographic variables and baseline characteristics did not differ across risk groups. The percentage of pts achieving a chemo-ablated marrow biopsy at Day 14 was 88%, 83%, 68% and 67% for the Favorable, Intermediate-I, Intermediate-II and Adverse group, respectively (Table 1, p=0.0385). Similarly, the percentage of patients achieving CR at Day 28 was highest for patients with a favorable ELN risk classification (92%) compared to intermediate-I (83%), intermediate-II (71%) and adverse (79%) (Table 2, p=0.0440). Re-induction rate was significantly different when stratified across ELN risk groups (p=0.0487). Risk ratio analysis showed a 26% increased likelihood of achieving a chemo-ablated marrow biopsy when comparing Favorable ELN risk pts to those to those in the non-favorable ELN risk group (RR:1.2552; 95% CI: 1.0526-1.468). A test of discordance comparing hypocellular/hypercellular results based on the Day 14 marrow biopsy with having CR/non CR at end of cycle 1 were not significant across the ELN risk classifications. CONCLUSION: With the advent of personalized therapy comes the potential to customize treatment and hope to optimize pt outcomes. Our results indicate that karyotype and a range of genetic mutations predict marrow morphology at Day 14. How these results predict long-term outcome needs to be further explored. [1] (defined as cellularity Disclosures Ray: Ipsen Biopharmaceuticals: Employment. Koprivnikar:Alexion: Consultancy, Speakers Bureau. McCloskey:Amgen: Speakers Bureau; Ariad: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Incyte: Consultancy. Stanislaus:Novartis: Consultancy, Speakers Bureau. Howlett:Pfizer: Honoraria; Sandoz: Honoraria; Teva: Speakers Bureau; Amgen: Honoraria; Eisai: Honoraria. Depadova:Amgen: Speakers Bureau. Goldberg:Novartis: Consultancy; Pfizer: Honoraria; Bristol Myers Squibb, Novartis: Speakers Bureau; Neostem: Equity Ownership; COTA Inc: Employment.

Background: Cytogenetic and molecular abnormalities are the backbone of risk stratification for pts with AML/MDS. Yet, the current stratification systems still fail to identify some pts at high risk for treatment failure. TP53 mutations have been linked to poor outcome and treatment resistance in many malignancies. We conducted a retrospective case-control study of pts with HRMDS and AML with TP53 mutations (TP53 m) to define disease characteristics, response, and outcome after transplant (HSCT). Methods: Twenty-one consecutive pts with HRMDS or AML were treated between January 2014 and March 2016 who wereTP53 m. The pts were compared to a control cohort of 46 pts with wild type TP53 (TP53 wt). Mutation analysis was performed using next generation sequencing. All AML pts were treated with a standard 3+7 induction protocol. Pts were excluded for incomplete cytogenetic and molecular data. Results: A total of 21 patients were identified with TP53 m (14 HRMDS, 11 AML). The median age of the 21 pts was 64 years (range 32-84). Pts with TP53 m were older (median age 64 vs 55 years, p=.0256) and exhibited a higher rate of adverse cytogenetics (71% vs 30.4%, p=.043) when compared to TP53 wt. Secondary AML was also more common with TP 53 m (57% vs 31%, p=.05). Pts with TP53 m were less likely to achieve CR (33% vs 74%, p=.009). Three pts with TP53 m proceeded to transplant (2 with HRMDS and 1 with AML). With a median follow up of 3.4 months (range 0.3-73) the estimated PFS and OS at 18 months was superior in TP 53 wt compared to TP 53 m (17% vs 69%, p=.037 and 17% vs 50%, p=.0095 respectively). HSCST was associated with a 70% reduction in mortality, but this was not statistically significant (p=.067). Conclusion: TP 53 mutations in pts with HRMDS and AML are associated with advanced age, high risk cytogenetic abnormalities, and secondary AML. Our findings demonstrate that TP53 m in HR MDS and AML is associated with poor clinical outcome including lower CR rates, and lower PFS and OS. Different treatment strategies need to be devised for these pts. Disclosures McCloskey: Incyte: Consultancy; Ariad: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau. Koprivnikar:Alexion: Consultancy, Speakers Bureau. Depadova:Amgen: Speakers Bureau. Stanislaus:Novartis: Consultancy, Speakers Bureau. Goldberg:COTA Inc: Employment; Bristol Myers Squibb, Novartis: Speakers Bureau; Neostem: Equity Ownership; Novartis: Consultancy; Pfizer: Honoraria. Faderl:Celgene: Consultancy, Research Funding; JW Pharma: Consultancy; BMS: Research Funding; Ambit Bioscience: Research Funding; Karyopharm: Consultancy, Research Funding; Celator Pharmaceuticals: Research Funding; Astellas: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Amgen: Speakers Bureau.

Background: Imatinib revolutionized the treatment of chronic myelogenous leukemia (CML) demonstrating improved survival and durable response to treatment. Earlier and deeper response rates were observed with dasatinib and nilotinib in the front line setting compared to imatinib. Multiple clinical trials have revealed that carefully selected patients may safely discontinue TKI therapy. However, lifelong TKI therapy remains the standard of care outside of clinical trial. Methods: We reviewed the charts of patients with chronic phase CML treated with imatinib, dasatinib or nilotinib for chronic phase CML between January 2010 and April 2015 and identified 29 patients that had discontinued therapy. We collected data on their treatment history, response to therapy, and outcomes following TKI withdrawal. Results: At the time of TKI cessation all the patients had achieved an MMR (MR4) for at least 2 years. The median time in MMR prior to treatment withdrawal was 64 months. Twelve patients (41%) were treated with imatinib, 7 (24%) were treated with dasatinib, and 10 (35%) were treated with nilotinib. More than half of the patients had received prior treatment with an alternative TKI. At the time of data collection, 16 patients (55%) remained in MMR off therapy. The median time off treatment was 7 months (range: 3-24 months). The median time to loss of MMR was 5 months (range: 2-11 months). No significant difference was observed between TKI and time to loss of MMR (Table 1). Of those patients who lost MRR while off therapy, all achieved a second MMR upon resuming TKI therapy. Based on the average wholesale price, $3,149,576 was saved by cessation of TKI therapy during the observed period. The required follow up and PCR testing accounted for an additional cost of $84,200 for a net savings of $3,065,376. Conclusions: TKI therapy can be safely discontinued in patients with an MMR duration more than two years with close follow up. While this is a small retrospective study, the results are in keeping with those observed in larger trials. With the life expectancy of patients with chronic phase CML now approaching that of the healthy population, lifelong use of TKI has important implications for patients in terms of medical costs and quality of life. Table 1. Comparison of Patient Characteristics and Outcomes Off Treatment Variable Imatinib (n=12) Dastanib (n=7) Nilotinib (n=10) P-Value Age (years) Median (IQR) 55.5 (53.0 - 61.5) 68.0 (50.0 -72.0) 63.5 (51.0 - 72.0) 0.3811 Range 42.0 - 75.0 48.0 - 72.0 42.0 - 76.0 Gender Male n= 6 (50.0) n= 4 (57.1) n= 2 (20.0) 0.2266 Female n= 6 (50.0) n= 3 (42.9) n= 8 (80.0) Time on treatment prior to discontinuation Median (IQR) 98.0 (64.0- 110.5) 49.0 (39.0 - 69.0) 37.5 (27.0 - 60.0) 0.0016 Range 52.0 - 155.0 33.0 - 115.0 6.0 - 92.0 Time in MMR prior to stopping TKI Median (IQR) 52.5 (39.0 - 96.0) 37.0 (30.0 - 92.0) 71.0 (56.0 - 91.0) 0.6707 Minimum - Maximum 8.0 - 126.0 17.0 - 109.0 19.0 - 108.0 Time off treatment Median (IQR) 7.5 (3.0 - 12.0) 5.0 (2.0 - 9.0) 10.0 (6.0 - 12.0) 0.1599 Range 2.0 - 24.0 2.0 - 11.0 2.0 - 16.0 MMR status off treatment Remain in MMR N= 5 (41.7) N= 4 (57.1) N= 4 (40.0) 0.7970 Loss of MMR N= 7 (58.3) N= 3 (42.9) N= 6 (60.0) Time measured in months. Unless specified otherwise, data are presented as counts (percentages). Categorical variables were examined using Pearson's Chi-square test or Fisher's exact test, as appropriate. Continuous variables were examined using Kruskal-Wallis test or Proc mixed for one-way models, as appropriate. Any P Disclosures McCloskey: Novartis: Consultancy; Pfizer: Consultancy. Koprivnikar:Alexion: Consultancy. Goldberg:Novartis: Research Funding, Speakers Bureau; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Pfizer: Research Funding; BMS: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau. Howlett:Teva: Speakers Bureau.

Background: The development of tyrosine kinase inhibitors (TKIs) has dramatically changed the landscape of chronic myelogenous leukemia (CML) treatment. Dosing of TKIs is standardized and is based on the phase of disease at presentation, but is not altered based on body surface area (BSA), sex, or other patient characteristics. These medications are generally well tolerated, however, hematologic and non-hematologic toxicities are not infrequent. While the package insert of all three TKIs (imatinib, dasatinib, nilotinib) commonly used in first line therapy provides specific dose-reduction instructions for hematologic toxicity, only nilotinib has a standard recommended dose for nonhematologic toxicity. Long-term data on the effects of dose-reduction of TKI therapy based on toxicity is lacking. Furthermore, there is little data on risk factors for TKI intolerance. Thus, we sought to identify characteristics of patients requiring dose reductions as a part of first-line TKI treatment for chronic phase CML as well to determine the long-term outcome of these patients in a retrospective fashion. Methods: Using billing records, we identified all patients seen at our institution for treatment of chronic phase CML between November 1, 2010 and July 16, 2015. We then reviewed the records of all such patients to identify individuals requiring chronic dose reductions of first-line treatments for chronic phase CML. We identified a control group of patients by capturing all patients tolerating full dose first-line TKI therapy during a pre-specified period. This control group was used to determine risk factors for TKI intolerance. Results: A total of 18 patients were identified who required long-term dose reduction of first-line TKI therapy with a median follow up time of 34.72 months (range 12.47-124.07). The mean time on full dose therapy prior to dose reduction was 7.08 months (range 0-37.27). The median time spent on reduced dose therapy was 26.37 months (range 4.90-118.93). Eighty-nine percent of patients remained in a major molecular response 4 (MR4) despite dose reduction. Median progression free survival (PFS), as defined by loss of MMR, of dose-reduced patients had not yet been reached. One, two, and three year PFS rates were 100%, 93.8%, and 85.2% respectively. When compared to the control group of patients tolerating front line therapy at full-dose, patients requiring dose reduction were more likely to be female: 78% vs 48% (P=0.045) and have a lower BSA: 1.77 versus 1.99 mg/m2 (P=0.010). Discussion: This small, retrospective analysis identifies several potential important risk factors for TKI dose reduction including female sex and lower BSA. Based on the available control group, it cannot be determined if either of these are independent variables. The majority of patients remained in MR4 despite dose reductions. Both of the 2 patients (12.5%) who did not were able to regain MR4 status after switching to an alternate TKI, suggesting that long-term treatment with reduced dose TKIs is reasonable so long as patients are closely monitored. Our data suggest the possible utility of dose adjustments based on BSA for patients who are intolerant of TKI therapy. Table 1. TKI administered degree of dose reduction. Patient Number TKI Dose 1 Dasatinib 20 mg QOD 2 Dasatinib 10 mg daily 3 Dasatinib 40 mg daily* 4 Imatinib 300 mg daily 5 Imatinib 200 mg alternating with 300 mg daily 6 Dasatinib 40 mg daily 7 Imatinib 300 mg daily* 8 Dasatinib 50 mg daily 9 Dasatinib 40 mg daily 10 Dasatinib 70 mg daily 11 Nilotinib 450 mg daily 12 Dasatinib 40 mg daily 13 Nilotinib 450 mg daily 14 Dasatinib 50 mg daily 15 Dasatinib 40 mg daily 16 Imatinib 300 mg daily 17 Dasatinib 35 mg daily 18 Dasatinib 70 mg daily *Indicates loss of MR4 while on therapy Table 2. Risk factors for TKI dose reduction. Full dose group Dose reduction group P value Number 29 18 Gender Male Female 1514 414 0.045 (chi-square) BSA 1.99±0.28 1.77±0.25 0.010 (t test) BMI 30.27±6.34 27.20±4.28 0.084 (t test) Figure 1. PFS as defined by loss of MMR for patients on chronically dose-reduced TKIs. Figure 1. PFS as defined by loss of MMR for patients on chronically dose-reduced TKIs. Disclosures Koprivnikar: Alexion: Consultancy. McCloskey:Novartis: Consultancy; Pfizer: Consultancy. Goldberg:Pfizer: Research Funding; COTA: Employment, Equity Ownership, Other: Leadership, Stock; Ariad: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Faderl:Celgene Corp.: Other: Advisory Board.