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Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.

Objective : We describe the Mayo Clinic experience in 797 newly-diagnosed patients with acute myeloid leukemia (AML) serially treated with 7+3 induction chemotherapy that included 3 days of daunorubicin at a daily dose of 60 mg/m2 (dauno-60; n=239) or 90 mg/m2 (dauno-90; n=52), or idarubicin 12 mg/m2 (IDA-12; n=506). Our objective was to compare overall (OS) and relapse-free (RFS) survival outcome. Methods : Newly-diagnosed AML patients seen at our institution and received intensive induction chemotherapy were identified from the Mayo Clinic AML database. Treatment period spanned from January 2004 through May 2021. Follow-up information was updated as of June 2021. Conventional criteria were used to diagnose AML, assign cytogenetic risk category, and classify treatment response. Results : The study group included 797 patients (median age 60 years, range 18-88; 58% males): 506 (63%) patients received IDA-12, 239 (30%) dauno-60, and 52 (7%) dauno-90. The respective median (range) ages were 60 (18-88), 61 (19-82), and 53 (22-72) years (p=0.01) (Table). Primary, secondary, and therapy-related AML accounted for 65%, 25% and 10% of patients treated with IDA-12, 69%, 22%, and 9% of those treated with dauno-60, and 75%, 23% and 2% of patients treated with dauno-90, respectively (p=0.1). The corresponding frequencies of adverse karyotype were 34%, 25% and 25% (p=0.05). CR/CRi was documented in 78% (620/793) of all evaluable patients: IDA-12 80% (400/503), dauno-60 75% (175/238), and dauno-90 87% (45/52) (p=0.1). 210 (34%) patients underwent allogenic hematopoietic stem cell transplant (AHSCT), including 125 (25%), 59 (25%) and 26 (50%) patients, in the three treatment groups, respectively (p=0.0004). After a median (range) follow up 19 (0.2-203) months, 348 (54%) relapses and 518 (65%) deaths were documented. Median (range) survivals for IDA-12, dauno-60 and dauno-90 groups were 21 (0.3-243), 14.5 (0.45-198), and 27.7 (0.2-180) months (p=0.07; figure 1). The respective 1-, 3-, and 5-year OS rates were 67%, 42%, and 34% (IDA-12); 66%, 37%, and 30% (dauno-60); and 78%, 51%, and 49% (dauno-90), respectively; the trend favoring dauno-90 was no longer apparent during age-adjusted analysis (p=0.33). Multivariable analysis that accounted for age, cytogenetic risk category, FLT3-ITD/NPM1 status and AML subtype confirmed the lack of additional contribution from IDA-12 vs dauno-60 vs dauno-90 (p=0.2) while affirming the independent prognostic value of the other four variables; AHSCT carried an additional predictive value for superior survival without altering these results. A total of 348 (54%) relapses were documented: 228 (57%) in the IDA-12; 99 (57%) in the dauno-60; and 21 (47%) in the dauno-90 cohorts (p=0.7); RFS was similar in the three treatment groups (p=0.1; figure 2). Conclusion :In the current large single-institution study of consecutive adult patients with AML, neither the choice of anthracycline (idarubicin vs daunorubicin) or the dose of daunorubicin (60 vs 90 mg/m2) appeared to effect outcome in terms of remission rates or overall or relapse-free survival. The study otherwise confirms the independent favorable effect of younger age, non-adverse karyotype, FLT3-ITD-/NPM1+ status, and AHSCT. Figure 1 Figure 1. Disclosures Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Litzow: Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee; Omeros: Other: Advisory Board; AbbVie: Research Funding; Astellas: Research Funding.

Children with myeloid leukemia associated with Down syndrome (ML-DS) have superior outcome compared with non-DS patients, but suffer from higher constitutional cytotoxic drug susceptibility. We analyzed the outcome of 170 pediatric patients with ML-DS enrolled in the prospective, multicenter, open-label, nonrandomized ML-DS 2006 trial by Nordic Society for Pediatric Hematology and Oncology (NOPHO), Dutch Childhood Oncology Group (DCOG), and Acute Myeloid Leukemia-Berlin-Frankfurt-Münster (AML-BFM) study group. Compared with the historical control arm (reduced-intensity protocol for ML-DS patients from the AML-BFM 98 trial), treatment intensity was reduced by lowering the cumulative dose of etoposide (950 to 450 mg/m(2)) and intrathecal central nervous system prophylaxis while omitting maintenance therapy. Still, 5-year overall survival (89% ± 3% vs 90% ± 4%; Plog-rank = .64), event-free survival (EFS; 87% ± 3% vs 89% ± 4%; Plog-rank = .71), and cumulative incidence of relapse/nonresponse (CIR/NR; 6% ± 3% vs 6% ± 2%; PGray = .03) did not significantly differ between the ML-DS 2006 trial and the historical control arm. Poor early treatment response (5-year EFS, 58% ± 16% vs 88% ± 3%; Plog rank = .0008) and gain of chromosome 8 (CIR/NR, 16% ± 7% vs 3% ± 2%, PGray = .02; 5-year EFS, 73% ± 8% vs 91% ± 4%, Plog rank = .018) were identified as independent prognostic factors predicting a worse EFS. Five of 7 relapsed patients (71%) with cytogenetic data had trisomy 8. Our study reveals prognostic markers for children with ML-DS and illustrates that reducing therapy did not impair excellent outcome. The trial was registered at EudraCT as #2007-006219-2.

Introduction: Next-generation sequencing (NGS) has redefined the genetic landscape of acute myeloid leukemia (AML) and has prognostic and, potentially, therapeutic implications in AML.Advances in the biological understanding of AML pathogenesis have led to the approval of new targeted agents that increase the therapeutic options for the treatment of AML. Despite these approvals, induction chemotherapy is still widely used for the treatment of patients newly diagnosed with AML. Unfavorable risk cytogeneticand secondary AML have been associated with low responses to induction chemotherapy. In the current study, we investigated the predictive role of molecular abnormalities detected with NGS related to responses to induction chemotherapy in newly diagnosed AML patients. Methods:We used the Medical Archival Retrieval System to identify newly diagnosed AML patients who had NGS analysis performed at our institution.. Patients treated with induction chemotherapy at AML diagnosis were included in the analysis. Response to therapy was evaluated two weeks after therapy was initiated and at count recovery. The difference in distribution of each mutation between the patients who responded to chemotherapy after one or two courses of induction chemotherapy and non-responders was analyzed using Fisher's exact test and the Cochran-Armitage Trend test. Findings with an expected false discovery rate ≤ 10% were reported as positive. The study was approved by the University of Pittsburgh IRB committee. Results: One hundred twenty-seven newly diagnosed AML patients (median age 61 years, interquartile range 51-68 years) were treated with induction chemotherapy. Sixteen patients (13%) had favorable risk cytogenetics, 73 patients (58%) had intermediate risk cytogenetics, and 36 patients (29%) had unfavorable risk cytogenetics. The most common molecular event was an NPM1 (28%) mutation followed by DNMT3A (25%), FLT3-ITD (22%), NRAS (13%), ASXL1 (12%), TET2 (12%), and TP53 (11%) as shown in Figure 1. Eighty-five of 127 patients (67%) achieved CR after one course of chemotherapy with idarubicin and cytarabine (7+3) and 17 patients (13%) responded after a second course with mitoxantrone and etoposide. Twenty-five patients (20%) did not respond to one or two courses of induction chemotherapy. From the 102 patients that responded, measurable residual disease (MRD) data were available in 59 (58%) patients. 29% patients were MRD positive and 71% patients were MRD negative. Secondary AML and poor cytogenetics were associated with poor response. Among the 17 genes with at least 5% prevalence, only TP53 mutations were associated with worse response. TP53 mutations increased monotonically with worse outcomes; TP53 mutations were present in only 2% of those responding to one course of chemotherapy, in 18% responding to two courses, and in 38% with no response to either course (p < 0.0001). Ninety-three percent of patients (13 of 14 patients) with TP53 mutations had poor cytogenetics. After induction chemotherapy, 21% of patients with TP53 mutations achieved CR and 14% achieved morphologic leukemia-free state (MLFS); 2 patients achieved CR after one course and, after the second course, 1 patient achieved CR and 2 patients MLFS. From the 5 patients that responded, 4 had available MRD data; 2 patients were MRD positive and 2 patients were MRD negative. NPM1 mutations were associated with higher response rates to induction chemotherapy (p =0.002). Ninety-four percent of patients (32 of 34 patients) with NPM1 mutations had intermediate cytogenetics. After induction chemotherapy, 92% of patients with NPM1 mutations achieved CR and 3% achieved MLFS; 32 patients (89%) achieved CR after one course. Two patients received a second course; one patient achieved CR and one MLFS. From the 34 patients that responded, 20 patients had available MRD data; 9 patients were MRD positive and 11 patients were MRD negative. Conclusion: Among 17 gene mutations detected using NSG at AML diagnosis, only TP53 and NPMI mutations were associated with responses to induction chemotherapy. Patients with TP53 mutations at AML diagnosis were associated with lower response rates to induction chemotherapy, whereas NPM1 mutations were associated with improved response. Disclosures Raptis: INTEGRA: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; UPMC: Current Employment. Hou:Genentech: Consultancy, Other: PI; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Other: PI. Dorritie:Kite-Gilead: Research Funding; Juno Therapeutics: Research Funding. Sehgal:TP Therapeutics: Research Funding; Prothena: Research Funding; Gilead Sciences: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Juno Therapeutics: Research Funding.

Background: Midostaurin, a multikinase inhibitor that directly inhibits FLT3, is approved for the treatment of adult patients (pts) with newly diagnosed, FLT3-mutated AML. In the phase 3 RATIFY study (NCT00651261), younger adults (aged ≤ 60 y) who received midostaurin plus standard chemotherapy (CT) had significant improvements in survival compared with those that received placebo plus standard CT. To further evaluate the safety and efficacy of midostaurin in FLT3-mutated AML, a phase 3b (NCT03379727) study was initiated that allowed enrollment of younger and older (aged > 60 y) pts and variations in CT regimens, including idarubicin or daunorubicin for 7+3 or 5+2. Methods: This is an open-label, single-arm, multicenter study in adults fit for CT with newly diagnosed AML, ECOG performance status (PS) ≤ 2, and a documented FLT3 ITD or TKD mutation. Pts must start their first induction cycle with 7+3 (cytarabine [Ara-C] 100-200 mg/m2/d on days 1-7 + daunorubicin 60-90 mg/m2/d or idarubicin 12 mg/m2/d on days 1-3) or 5+2 (a reduced-dose regimen with these agents) per investigator's discretion and enroll by day 7 of the first induction cycle. Pts are assigned to the 7+3 group if their Ara-C duration is ≥ 7 days, independent of daunorubicin/idarubicin duration, and to the 5+2 group in other cases. Pts may not switch once started on 7+3 or 5+2. Pts receive Ara-C consolidation (dose per investigator's choice). Midostaurin 50 mg bid is administered on days 8-28 of each 28-day induction/consolidation cycle and daily for ≤ 12 cycles of maintenance. Pts are discontinued from the study if not in either complete remission (CR) or CR with incomplete hematologic recovery (CRi) at the end of induction, relapse during consolidation/maintenance, receive a stem cell transplant (SCT), or experience toxicities leading to discontinuation. The primary and secondary endpoints are safety and the proportion of pts achieving CR/CRi, respectively. Results: Pts were recruited throughout Europe; study enrollment was closed January 28th, 2020, with 318 pts screened and 17 screen failures. Safety and efficacy analyses focused on 301 pts who received treatment and 300 pts who met all study criteria, respectively. The median age (range) was 59 (19-85) y, and 47.2% were aged > 60 y. Most pts had a FLT3-ITD mutation (82.7%), with 17.6% having a FLT3-TKD mutation. At data cut-off on March 31st, 2020, 63 pts were still receiving treatment. All 301 pts entered induction, 69% entered consolidation, and 26% entered maintenance; 28.7% underwent SCT. The majority of pts (80.4%) were treated with midostaurin plus 7+3; 19.6% received 5+2. Approximately 55.1% received idarubicin and 44.9% received daunorubicin for induction. Pts who received daunorubicin for induction were younger (62.2% vs 45.2% were aged < 60 y) and had a lower frequency of ECOG PS=2 (10.4% vs 18.1%) vs those who received idarubicin. Overall, 242 pts achieved CR/CRi (80.7%). The CR/CRi rates in older vs younger pts, female vs male pts, and pts who received daunorubicin vs idarubicin for induction were similar (Table). The majority of SAEs occurred during induction (75, 24.9%) and consolidation (64, 30.6%); there were 5 (6.3%) SAEs during maintenance. The most common AEs were pyrexia, nausea, diarrhea, and febrile neutropenia. Compared with younger pts, older pts had a higher frequency of grade ≥ 3 AEs (78.6% vs 90.8%) and SAEs (35.8% vs 51.4%), AEs leading to dose adjustment/interruption (30.2% vs 43%), and treatment-related AEs (73.6% vs 78.2%), SAEs (15.7% vs 23.9%), and those leading to discontinuation (6.9% vs 11.3%). Compared with younger pts, older pts had a higher frequency of certain grade ≥3 AEs, including severe infections (31.4% vs 45.1%), leukopenia (40.9% vs 49.3%), QT prolongation (3.1% vs 7.7%) , and pulmonary toxicity (3.8% vs 7.7%). There were 30 deaths (10%) reported during the study (7 younger pts, 23 older pts). Of pts who died, 19 were treated with idarubicin (all were older pts) and 11 were treated with daunorubicin for induction. Conclusions: Midostaurin plus CT resulted in high response rates regardless of pt age, sex, induction drug, or alternative CT regimen. The majority of pts received a 7+3 regimen regardless of age. The safety profile of midostaurin plus idarubicin or daunorubicin for induction was generally similar. The safety profile in older and younger pts was consistent with what has been previously reported, with no new safety signals identified. Disclosures Sierra: Jazz Pharmaceuticals: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead-Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Griškevičius:Novartis: Research Funding. Cluzeau:Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy. Luppi:Gilead Sci: Consultancy, Speakers Bureau; Abbvie: Consultancy; Daiichi-Sankyo: Consultancy; MSD: Consultancy; Novartis: Consultancy, Speakers Bureau; Sanofi: Consultancy. Farkas:Abbvie: Honoraria; MSD: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Johnson & Johnson: Honoraria. Bengoudifa:Novartis: Current Employment. Gilotti:Novartis: Current Employment. Hodzic:Novartis: Current Employment. Rambaldi:Roche: Honoraria; MSD: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Omeros: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Venditti:Novartis: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Jazz: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Pfizer: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES (paid by any for-profit health care company).

Background:Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL), an orphan disease, is a sub-type of T-Cell Acute Lymphoblastic Leukemia (T-ALL) with very poor prognosis and limited therapy options. ETP-ALL is a heterogeneous disease with many distinct genomic profiles, often with more myeloid than lymphoid characteristics. However, standard of care (SOC) drugs for acute myeloid leukemia (AML) have shown limited efficacy for ETP-ALL (PMID: 32733662, 25435716). The genomic profiles of ETP-ALL patients have more complex cytogenetics and larger numbers of genomic aberrations when compared to non-ETP-ALL (T-ALL) profiles (PMID: 22237106, 30641417). We present an alternative multi-gene analysis approach using the Cellworks Omics Biology Model (CBM) workflow to identify unique, intersecting protein pathways in patient-specific disease profiles. The CBM predictive workflow was used to design novel personalized therapy options for an ETP-ALL representative PEER human lymphoid cell line in comparison to a T-ALL JURKAT cell line. The predicted combination therapies were then validated in a lab model. Methods:A PEER cell line was selected to represent ETP-ALL and a JURKAT cell line was selected as a representative for non-ETP T-ALL. Next Generation Sequencing (NGS) was performed for the PEER cell line. For the JURKAT cell line, publicly available NGS whole exome sequencing from cBioPortal and Sanger, along with array CGH from Agilent, were used. The genomic data for the PEER and JURKAT cell lines were used as inputs to the CBM to generate dynamic patient-specific disease protein network maps. Biomarkers and pathway characteristics unique to the PEER and JURKAT cell lines were identified. A digital drug library of targeted FDA-approved agents was simulated on the disease models using both single drug agents and drug combinations at varying doses. The treatment impact was assessed by quantitatively measuring drug effect on a cell growth score, which is a composite of the quantified values of cell proliferation, survival and apoptosis along with impact on the patient-specific disease biomarker score. Comparative dose response studies were run to assess IC50 differences for both cell lines. Cellworks VenturaTM predicted novel therapy combinations for the ETP-ALL representative PEER cell line, which were then prospectively validated by in vitro experiments. The same therapy options were predicted to be less effective in the T-ALL representative JURKAT cell line, which was also confirmed by in vitro studies. Results:The CBM predicted three novel combination therapies for the ETP-ALL representative PEER cell line: nilotinib + cytarabine, bortezomib + cytarabine and bortezomib + idarubicin. All three therapies were predicted to be less effective in JURKAT cells. In vitro, PEER cells were sensitive to all 3 combinations, as predicted by the CBM; whereas, JURKAT cell lines were not sensitive to the first 2 combinations (as predicted), but were sensitive to bortezomib + idarubicin. The CBM analysis is supported by scientific rationales for these combinations based on the genomics-driven disease characteristics of the cell-line. The reasons for drug sensitivity and resistance were determined. These combinations were then prospectively validated in vitro on both cell lines and the experimental responses matched the predicted outcomes. Conclusion:The Cellworks Omics Biology Model integrates the multiple genomic abnormalities in a patient to identify disease network characteristics unlike other NGS analytic tools that attempt to interpret the impact of each genomic alteration in isolation. CBM identified 3 novel therapy options for ETP-ALL that were validated in vitro, similar to anecdotal experience in vivo. This predictive technology can improve clinical decision-making and identify novel treatment options. Disclosures Howard: Cellworks:Consultancy;Servier:Consultancy, Other: Speaker;EUSA Pharma:Consultancy;Sanofi:Consultancy, Other: Speaker;Boston Scientific:Consultancy.Kumar:Cellworks Research India Private Limited:Current Employment.Pampana:Cellworks Research India Private Limited:Current Employment.Ullal:Cellworks Research India Private Limited:Current Employment.Tyagi:Cellworks Research India Private Limited:Current Employment.Lala:Cellworks Research India Private Limited:Current Employment.Kumari:Cellworks Research India Private Limited:Current Employment.Joseph:Cellworks Research India Private Limited:Current Employment.Raju:Cellworks Research India Private Limited:Current Employment.Balakrishnan:Cellworks Research India Private Limited:Current Employment.Mundkur:Cellworks Group Inc.:Current Employment.Macpherson:Cellworks Group Inc.:Current Employment.Nair:Cellworks Research India Private Limited:Current Employment.Kapoor:Cellworks Research India Private Limited:Current Employment.

Introduction: Myelodysplastic syndromes (MDS) comprise a varied group of clonal myeloid neoplasms characterized by cytopenias and an increased risk of progression to acute myeloid leukemia. Prognosis is variable, but little is known about the clinical features of MDS in the Colombian population. The diverseness of the disease and changes in standardized diagnostic criteria throughout the years have hinder accurate case detection and epidemiologic evaluation of MDS in our population. Objective: The aim of the present study was to determine the clinical characteristics and evaluate the overall survival (OS) of patients with MDS treated at two large referral centers in Colombia. Methods: An observational, retrospective study was conducted at two tertiary care centers in Colombia. Patients diagnosed with MDS at Clinica FOSCAL and Hospital San Jose between June 2013 and June 2019 were selected. Descriptive statistics were used to analyze baseline demographic characteristics and clinical data such as disease classification, risk stratification, and treatment. The Kaplan-Meier method was used to assess overall (OS) at 1, 3 and 5 years. Results: A total of 96 patients were included. Median age at diagnosis was 75 years (range 31-104). Fifty-two (54.2%) patients were male. According to the 2016 World Health Organization classification of MDS, the most commonly diagnosed subtype was MDS with multilineage dysplasia (31.2%), followed by MDS with excess blasts (13.5%); however, 35.4% of patients had an unclassifiable MDS sub-type. Twenty-nine (31.2%) patients were screened for cytogenetic abnormalities, the most common chromosomal abnormalities were deletion in the long arm of chromosome 5 (4.2%) and deletion of 7q (2.1%). Therapy related MDS was diagnosed in 13 (13.5%) patients and secondary MDS associated to pesticides exposure in 2 (2.1%) patients. After stratifying patients by the International Prognostic Scoring System (IPSS), the majority of patients were in the intermediate risk group, with 21 (34.4%) and 16 (26.2%) patients in the intermediate-1 and intermediate-2 categories respectively. Almost 80% of the patients presented one or more comorbidities, the most common was cardiac disease (30.5%). Supportive care with erythropoiesis-stimulating agents was the most common first-line treatment (61.4%), followed by iron chelation therapy (6.2%). Forty-eight (50%) patients were treated with hypomethylating agents (HMA), 43.7% receiving azacytidine and 6.3% decitabine. Among HMA-treated patients, 49.6% were in the intermediate-2 and high-risk IPSS groups. Two patients underwent allogeneic hematopoietic stem cell transplantation. Only patients treated with HMA and cytarabine/idarubicin chemotherapy achieved a complete response (11.5%). OS at one- and five-years post-diagnosis was 73.4% and 40.7% (95%CI 62.4-81.6 and 27.1-53.9) respectively. Patients in the intermediate-2 and high-risk IPSS groups had lower survival rates compared to those in the low and intermediate-1 risk groups. The OS for patients treated with azacytidine was 77.2% (95%CI 60.7-87.5%) at one-year, 43.2% (95%CI 23.9-61.1%) at three-years, and 37.8% (95%CI 19.0-56.5) at five-years after diagnosis. The most common cause of death was infection (51.3%), followed by disease progression (24.3%). Conclusions: The OS of patients with MDS in our study is similar to the reported in the existing literature. Knowing the epidemiology, clinical characteristics, risk stratification, and disease outcomes of MDS patients in our population is crucial to decide the best treatment strategies and improve the clinical outcomes of our patients. Disclosures Sossa: Roche: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Novo: Honoraria. Abello:Dr. Reddy's: Consultancy, Research Funding; Takeda: Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Research Funding. Peña:Roche: Honoraria. Salazar:Novartis: Honoraria; Janssen: Honoraria. Sandoval-Sus:Celgene: Speakers Bureau; Massive Bio: Consultancy; Janssen: Consultancy; MorphoSys US: Consultancy.

Study Background: The presence of minimal residual disease (MRD) after IC in AML patients is often a harbinger of relapse, and therapeutic targeting of MRD has emerged as an important strategy to improve long-term outcomes. The importance of the PD-1/PD-L1 pathway in immune evasion of AML has been demonstrated in murine AML models whereby PD-L1 and PD-1 were upregulated in leukemia cells, and PD-1 blockade suppresses invivo leukemia cell proliferation and improved survival in AML bearing mice (Zhang et al., 2009; Zhou et al., 2010). Combining IC with immune checkpoint inhibition (ICPI) has resulted in a significant clinical activity in some advanced solid malignancies including non-small-cell lung cancer. A recent single-arm phase 2 study combining IC with nivolumab showed the combination was feasible and resulted in undetectable MRD in 53% of patients with Complete response (CR)/CR with incomplete count recovery (CRi) (Ravandi et al, 2019). Here we report on the design of the first randomized multi-center clinical trial of IC+ICPI in fit AML patients. Methods: The primary objective of this investigator-initiated Cancer Therapy Evaluation Program (CTEP)-sponsored multi-institutional, randomized phase II study (NCT04214249) is to assess the percentage of patients with MRD negative CR (MRD- CR) as measured by flow cytometry at the end of first cycle of consolidation therapy with IC+ pembrolizumab and compare between the two study arms (Figure 1). Secondary objectives include rates of CR/CRi, complete remission with partial recovery count (CRh) and hematologic improvement (HI) to red blood cells and platelets, MRD negativity at Day 14, MRD-negative CR at end of induction therapy and MRD negative CR after last consolidation cycle, event free survival (EFS), relapse free survival (RFS), duration of response (DOR), and overall survival (OS), and proportion of patients who develop severe toxicity. Important exploratory objectives include MRD assessment by duplex sequencing (DS) and comparing DS and multiparameter flow cytometry for MRD detection. The study will consist of an induction, consolidation, and maintenance phase of therapy. A total of 124 patients will be included (62 patients in the intervention arm and 62 patients in the control arm). Planned stratification factors include 1) age (younger than 65 vs. 65 and older), 2) cytogenetics by FISH or metaphase karyotype (presence vs. absence of core binding factor inversions and translocations), and 3) t-AML or AML arising from prior/antecedent MDS. All patients will receive cytarabine at 100 mg/m2/day continuous infusion on Days 1-7 and either idarubicin 12 mg/m2/day IV on Days 1-3 or daunorubicin 60 mg/m2/day IV on Days 1-3. on Day 8 of the induction chemotherapy, half of the patients will receive pembrolizumab IV (intervention arm), and continue Q3 weeks throughout Induction/Consolidation, and thereafter for up to 2 years from the start of maintenance. The other half will not receive pembrolizumab (control arm). After 31 efficacy-evaluable patients (patients who had a bone marrow biopsy done after the first consolidation cycle) in each of the two study arms have had their primary endpoint results available, a formal futility and toxicity analysis will be conducted. Follow up will continue up to 2 years after the last patient is randomized. Eligible patients are aged ≥18 and ≤75 years with newly diagnosed and pathologically-confirmed AML, including secondary AML arising from prior MDS and therapy-related AML. Patients with FLT3-mutated AML are excluded as well as those with prior allogeneic stem cell transplant, active infection requiring systemic therapy, and requiring use of high dose corticosteroids. Responses in AML patients will be assessed using European Leukemia Net 2017 response criteria. EFS will be calculated as the time from initial treatment to either disease relapse or death. OS will be calculated from time from initial treatment to death. Biomarker analyses will include an extensive array of immunologic and correlative studies that will evaluate PD-1 and PD-L1 expression, immune cell subset analysis, leukemia specific T-cell response, cytokine level, T-cell receptor (TCR) repertoire, as well as RNA-seq, gut microbiome characterization and metabolomics, and whole exome sequencing for tumor and germline DNA. Figure 1 Disclosures Zeidan: Epizyme: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Cardinal Health: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; Leukemia and Lymphoma Society: Other; Jazz: Consultancy, Honoraria; Celgene / BMS: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; BeyondSpring: Consultancy, Honoraria; Cardiff Oncology: Consultancy, Honoraria, Other; Takeda: Consultancy, Honoraria, Research Funding; Ionis: Consultancy, Honoraria; MedImmune/Astrazeneca: Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Aprea: Research Funding; ADC Therapeutics: Research Funding; Astex: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Taiho: Consultancy, Honoraria; CCITLA: Other; Novartis: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria. Radich:Amgen: Consultancy; Bristol-Myers Squibb: Consultancy; Jazz: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding.

Background: Acute myeloid leukemia (AML),which is the most common type of acute leukemia, is a clonal malignant hematological disease originated from hematopoietic stem cells, characterized with blocked differentiation, excessive proliferation, organs infiltration. "3+7" regimen [anthracyclines + cytarabine (Ara-c)] is the first choice of induction chemotherapy in young adult de novo AML, and cytarabine is always given by continuous intravenous infusion. It has been reported the concentration of Ara-CTP (active metabolite with anti-leukemia effect) was higher after subcutaneous injection than during continuous intravenous infusion for about 5 hours [Liliemark JO, Semin Oncol], and the subcutaneous injection is much more convenient and inexpensive for patients comparing to continuous intravenous infusion. However, no prospective, multicenter clinical evidenceto evaluate the efficacy and safety of subcutaneous injection administration compared with intravenous infusion of cytarabine. Objective: To evaluated whether subcutaneous injection of cytarabine is noninferior to intravenous infusion of cytarabine in "3+7" induction regimen for young adult patients with de novo AML. Design, setting and participants: Open-label, prospective, multicenter, noninferior, randomized clinical trial conducted in 10 hematological centers in China. Eligible patients (n=240) with de novo AML (exclude acute promyelocytic leukemia) has been enrolled. Patients were recruited between March 2015 and August 2017, with final follow-up in June 2020. Interventions: Patients were randomized to receive idarubicin 10 mg/m2 for 3 days and cytarabine 100 mg/m2/d by continuous intravenous infusion daily for 7 days (n=120) or idarubicin 10 mg/m2 for 3 days and cytarabine 100mg/m2/d subcutaneous injection every 12 hours for 7 days (n=120). Main outcomes and measures: The primary end point was the percentage of patients who achieved complete remission (CR). The noninferiority margin for the difference in CR was -15%. Secondary end points included overall survival (OS), event-free survival (EFS) and adverse events. Results: Among 240 randomized patients, the baseline characteristics including sex, age, ECOG, white blood cell, blasts percentage, FAB subtype, karyotype and NPM1, FLTS-ITD, c-kit, CEBPA, DNMT3A, IDH1 and IDH2 mutations were similar between two groups. CR was achieved by 86 of 120 (71.7%) patients in subcutaneous injection group vs 85/120(70.8%) in intravenous injection (difference, 0.9%[1-sided 95% CI, -8.8% to ∞]); p value for noninferiority=0.003) after first cycle of induction therapy. CR was achieved by 93 of 120 (77.5%) patients in subcutaneous injection group vs 91/120(75.8%) in intravenous injection group (difference, 1.7% [1-sided 95% CI, -7.3% to ∞]); p value for noninferiority=0.001) after first two cycles of induction therapy. 3-year OS were 60% [95% CI:50%-69%]in subcutaneous injection group vs 58% [95% CI:49%-67%] in intravenous injection group (Figure 1A). After adjustment for sex, age, region, white blood cell, ECOG, platelet, FAB subtype, integrated risk and transplantation, the adjusted hazard ratio (AHR) of OS for subcutaneous vs intravenous was 0.95 [95% CI:0.62-1.47]. 3-year EFS were 49% [95% CI:39%-58%]in subcutaneous injection group vs 44% [95% CI:35%-53%] in intravenous injection group (Figure 1B). After adjustment for sex, age, region, white blood cell, ECOG, platelet, FAB subtype, integrated risk and transplantation, the HAR of EFS for subcutaneous vs intravenous was 0.84[95% CI:0.58-1.22]. No differences of hematologic toxicity, non-hematologic toxicity and early death rate were observed between two groups. Conclusions: The efficacy of subcutaneous injection of cytarabine was non inferior to continuous intravenous infusion of cytarabine for the standard induction therapy in young adult de novo AML. The toxicity is equivalent between two groups. Subcutaneous injection of cytarabine offers a convenient and inexpensive alternative therapy to young adult de novo AML. Trial registration: The trial was registered in the Chinese Clinical Trial Register, number ChiCTR-IPR-17012643. Figure 1 Disclosures No relevant conflicts of interest to declare.

Background: The present standard induction treatment for newly diagnosed acute myeloid leukemia (ND AML) is three days' daunorubicin or idarubicin plus seven days' cytarabine chemotherapy (3+7). Venetoclax plus azacytidine or low dose cytarabine is effective and better than azacitidine or low dose cytarabine alone for ND AML in VIALE A and VIALE C trials, respectively and the outcome by Venetoclax dose levels was not different between 400 mg, 800 mg, or 1200 mg a day. As a strong CYP3A inhibitor, posaconazole can increase serum level of Venetoclax and the dosage could be reduced to 75~100mg a day. Method: We treat ND AML patients with uninterrupted Venetoclax 100 mg plus posaconazole 300 mg daily and 7 days' standard dose of cytarabine (100 mg/m2/day) or 7 days' azacitidine (75 mg/m2/d), followed by 5 days' consolidation cytarabine (100 mg/m2/d) or another 7 days' azacitidine, and then followed by allogeneic hematopoietic stem cell transplantation. Results: Eight patients have enrolled the treatment including 7 underwent venetoclax/posaconazole/cytarabine and one venetoclax/posaconazole/azacitidine patients and four patients are secondary AML (one myeloma, one MDS, and 2 breast cancer patients). All patients were hematologic complete remission achieved in one month and 6 patients underwent allogeneic hematopoietic stem cell transplantation including one from matched sibling, two from matched unrelated, and three from haplo-identical donors (sons). Febrile neutropenia rates were similar to 3+7 treatment patients on historical comparison but shorter period of febrile illness. There was no grade II or higher adverse effect of oral mucosa and gastrointestinal tract as compared with conventional 3+7 therapy. Two out of six allo-transplant patients got leukemia relapse then salvage treatment ensued and the other 2 non-transplant and 4 allo-transplant patients are persisted in complete remission. Conclusion: Venetoclax plus posaconazole and standard dose cytarabine is a feasible choice of induction therapy in ND AML and high CR rate and transplant rate achieved and there was no detrimental effect upon the hematopoietic recovery during induction and transplant therapy. Figure Disclosures No relevant conflicts of interest to declare.

High-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (ASCT) is still a consolidation treatment choice for relapsed/refractory (R/R) B-cell Non-Hodgkin's lymphoma (NHL) patients and some aggressive B-cell NHL as frontline therapy. Due to the shortage of carmustine, we switched to idarubicin-substituted BEAC (IEAC). We compared the outcomes of 72 B-cell NHL patients treated with IEAC or BEAC regimens followed by ASCT. The median time to neutrophil and platelet reconstitution showed no difference between IEAC and BEAC groups. IEAC regimen was well tolerated without increase of adverse events. Transplant-related mortality didn't occur. The overall survival (OS) and progression-free survival (PFS) of IEAC group were a little longer than that of BEAC group. 2-year OS and PFS rate were higher in IEAC group compared to BEAC group. Multivariate analysis showed that AnnArbor staging, IPI score, lactate dehydrogenase (LDH) level, remission of disease, modified regimen were related with the prognosis. In conclusion, IEAC regimen was well tolerated and replacement with idarubicin could effectively prolong the survival of patients. Disclosures No relevant conflicts of interest to declare.

[Figure][1] A 31-year-old white man presented with a 6-week history of symptoms of anemia, progressive hearing loss, and periorbital edema. Clinical examination revealed striking periorbital swelling (panels A-B) and periauricular edema with resultant tympanic membrane obstruction. No

Background Binding of E-selectin (E-sel) to sialyl Lex, the E-sel ligand, on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. Higher expression of E-sel ligand is associated with relapse and poor survival. Uproleselan (GMI-1271), a novel E-selectin antagonist, disrupts cell survival pathway activation, enhances chemotherapy response and protects from toxicity such as mucositis with improved survival in vivo. Preclinical data support combination of uproleselan with chemotherapy improves response without additional toxicity. A phase 1/2 study (NCT02306291) of uproleselan added to chemotherapy (mitoxantrone, etoposide, cytarabine, MEC) in R/R AML showed promising outcomes at the recommended phase 2 dose (RP2D), including a CR/CRi rate of 41% and median OS of 8.8 m (95% CI 5.7-11.4). 11/16 (69%) evaluable patients were MRD negative (DeAngelo et al ASH 2018). Patients with sufficient expression of the appropriate E-selectin ligand (the target of the E-selectin inhibitor) exhibited higher CR/CRi rate and longer survival. Median OS for Leukemic blasts/E-sel ligand ≥10% vs leukemic blasts/E-sel ligand Study Design and Methods This study is a global, randomized, double-blind, placebo-controlled phase 3 registration trial. Major Eligibility Criteria ≥18 to ≤75 years old Primary refractory AML, first or second relapse of AML Prior transplant (HSCT) is allowed Must be medically eligible for chemotherapy ECOG performance status ≤2 Study treatment and endpoints Treatment is MEC or FAI (fludarabine, cytarabine, idarubicin) induction with blinded study drug (uproleselan/placebo at 1:1 ratio) administered 1 day prior (sentinel dose) and then BID through 2 days post chemotherapy. Consolidation (HiDAC/IDAC) with uproleselan/placebo (same assignment) up to 3 cycles is allowed. The primary endpoint is overall survival; key secondary endpoints include the incidence of severe oral mucositis during induction and CR/CRh rate. Measurable residual disease, event free survival, safety, and pharmacokinetics will also be evaluated. In addition, the relationship between E-sel ligand expression on leukemic cells in the bone marrow and clinical outcomes in AML will be determined. Statistical methods The phase III primary endpoint will compare overall survival between the treatment arms using a stratified log-rank test. Stratification factors will be age group, disease status, backbone chemotherapy and prior transplant status. Median time to event values will be estimated using the Kaplan-Meier method. The study is powered to detect an improvement in median OS using a log-rank test (HR= 0.68, one-sided 0.025 type I error rate). A hierarchical testing procedure will be used to assess the statistical significance of the key secondary analyses, incidence of severe oral mucositis and remission rate (CR/CRh, CR). Study status This trial is expected to enroll 380 patients across approximately 9 countries in North America, Europe, and Australia. The first patient was enrolled in November 2018. Disclosures DeAngelo: Novartis: Consultancy, Patents & Royalties: Royalty, Research Funding; Takeda Pharmaceuticals: Consultancy; Jazz Pharmaceuticals Inc: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Abbvie: Research Funding; GlycoMimetics: Research Funding; Celgene: Consultancy; Blue Print Medicines: Consultancy, Research Funding; Shire: Consultancy. Erba:Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Amgen: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; ImmunoGen: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding. Jonas:AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. O'Dwyer:AbbVie: Consultancy; GlycoMimetics Inc: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Onkimmune: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marlton:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Liesveld:Abbvie: Membership on an entity's Board of Directors or advisory committees; Onconova: Other: Data safety monitoring board. Bhatnagar:Novartis and Astellas: Consultancy, Honoraria; Cell Therapeutics, Inc.: Other: Research support; Karyopharm Therapeutics: Other: Research support. Uy:Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Cull:Amgen: Other: Travel, accommodation ; AbbVie: Other: Travel, accommodation; Glycomimetics: Other: Travel, accommodation. Armstrong:GlycoMimetics: Consultancy. Fogler:GlycoMimetics Inc: Employment, Equity Ownership. Chen:GlycoMimetics: Employment. Magnani:GlycoMimetics Inc: Employment, Equity Ownership. Thackray:GlycoMimetics Inc: Employment. Feldman:GlycoMimetics Inc: Employment. Advani:Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding. Becker:Accordant Health Services/Caremark: Consultancy; AbbVie, Amgen, Bristol-Myers Squibb, Glycomimetics, Invivoscribe, JW Pharmaceuticals, Novartis, Trovagene: Research Funding; The France Foundation: Honoraria.

KEY WORDS: Acute Promyelocytic Leukemia, oral Arsenic Trioxide, ATRA, Front Line Therapy. CONTEXT: Studies showed the combination of all-trans-retinoic acid (ATRA) with Arsenic trioxide (ATO) as an effective treatment of patients with newly diagnosed Acute Promyelocytic Leukemia (APL), permitting a chemotherapy-free treatment approach. Oral formulations of ATO were developed with similar efficacy compared to the IV formulation, and a slightly safer profile. OBJECTIVE:To determine the effectiveness and safety of a locally produced oral ATO with ATRA as a first line therapy in APL. DESIGN:We designed the LPCR05 protocol based on established treatment protocols. Treatment regimen: Induction phase: all patients received ATRA (45 mg/m2 daily) and an locally produced oral formulation of ATO (10 mg daily), with a dose of Idarubicin (12 mg/m2 on days 1,3,5 and 7, if older than 60 years only given on day 1) added only to the high-risk patients. Consolidation Phase: 3 cycles of ATO + ATRA for 30days every 6 weeks. Maintenance Phase: 4 Cycles of ATRA+ATO daily for 15 days every 3 months. Oral formulation for ATO is prepared by the Laboratory of Pharmaceutical Products from our Social Security System according to the literature and approved by local health and pharmaceutical regulators. RESULTS: We report data on our first 26 APL patients enrolled on the LPCR05 protocol. Six patients were classified as high risk, eighteen intermediate and two low risk (Table 1). One high risk patient discontinued after first consolidation because of lost follow up. The median follow up is 12.5 months. Hematological complete remission was obtained after 30 days of treatment in all 26 patients. Molecular complete remission in 22 evaluated patients after first and third consolidation was achieved in 95% and 100% respectively (Table 2). None of the patients have relapsed. There were no withdrawals of the protocol because of side effects and no induction deaths because of coagulopathy. No severe cardiac or neurological toxicity was found. Grade 3 hepatic toxicity was seen in two patients, in both cases, temporary discontinuation of ATRA and ATO resolved the side effect. One patient developed non treatment related grade 3 renal toxicity and other one developed a probably related grade 3 skin toxicity. Severe infectious complications were seen in three patients, two had pneumoniae (one death) and one enteritis (Table 3). Patients are managed in the ambulatory setting, with fewer hospitalizations (mean hospitalization days per patient of 38,1 with ATRA + chemotherapy vs 14,1 with oral ATO and ATRA), and therefore the cost is three times lower (US$65 208 vs US$24 195) than our previous approach with ATRA + chemotherapy protocol. CONCLUSION: Our data demonstrate both efficacy and safety of oral ATO with ATRA as front line therapy in all risk groups. This strategy also demonstrated lower operational costs, fewer hospitalization days, and improved convenience for patients. We expect longer follow-up will confirm that treatment with oral ATO and ATRA is a curative therapeutic strategy for patients with APL that is particularly attractive for use in low and medium income countries. Disclosures No relevant conflicts of interest to declare.

Background: For patients (pts) with AML undergoing induction chemotherapy (IC), incomplete platelet (plt) recovery can lead to an increased risk of bleeding, prolonged dependence on plt transfusions, plt alloimmunization, as well as delay in post-remission therapy. Eltrombopag is a thrombopoietin receptor agonist that stimulates megakaryopoiesis and has anti-leukemic effects. Herein, we present the final results of a phase 2 trial evaluating the efficacy of eltrombopag in accelerating plt count recovery in older AML pts receiving IC (NCT02071901). Methods: All newly diagnosed FLT3-negative AML pts > 60 years (yrs) with ECOG scores of 0-2, no active second malignancy, and no evidence of marrow fibrosis at the time of AML diagnosis were included. Acute promyelocytic (AML-M3), megakaryocytic (AML-M7), and AML arising from myeloproliferative neoplasms were excluded. Pts with any arterial or venous thrombotic event (excluding line thrombosis) within the past 12 months were excluded. IC consisted of an anthracycline (daunorubicin at 45 mg/m2 x 3 days) and infusional cytarabine (100 mg/m2 x 7 days). Eltrombopag was administered starting day 15 (range, day 15-18) of IC in pts who had marrow blasts 50000/µL by day 24 of IC. In a historical cohort of 220 older AML pts (excluding APL and AML-M7) treated with IC between 2004 and 2011 at Cleveland Clinic, 60% achieved a plt count > 50,000/µL by day 24. Eltrombopag was administered at a dose of 200 mg with a one-time maximal dose escalation to 300 mg daily if plts remained < 50,000/µL after 2 weeks on treatment. Eltrombopag was discontinued once plts exceeded 100,000/µL. Informed consent was obtained prior to start of IC, and eligibility was determined on day 14. Results: Between 9-2014 and 9-2018, 93 pts were consented, of whom 31 met the eligibility criteria. Sixty seven percent of pts were ineligible as they had >5% blasts on day 14 marrow and the remaining met one or more of the following exclusion criteria: acute clinical worsening; use of supraphysiologic dose of steroids (n=1); marrow fibrosis (n=1); active second malignancy (n=1); elevated transaminases (n=5), and elevated serum creatinine (n=1). Median age was 67 years (range, 60-78), 38% were female, and 81% had a good ECOG status (ECOG 0 or 1). Most pts (84%) had de novo AML, 16% had secondary AML. By CALGB/Alliance criteria, 82% had intermediate cytogenetics, 9% had adverse karyotype and in 9% cytogenetic analysis was unsuccessful. The median eltrombopag treatment duration was 10 days (range, 8-11 d), and no dose escalations were required. Trends in the levels of plt count over time are shown in Figure 1. Median times from the start date of eltrombopag to plt >50,000/µL, and >100,000/µL were 7 d (range, 6-8) and 10 d (range, 8-11), respectively (Figure 2). By day 24 of IC, 30 of 31pts (97%) had plt >50,000/µL. The median peak plt count reached on eltrombopag was 606,000/µL (range, 280- 1,935,000/µL). The median time to reach peak plt count from start date of eltrombopag was 14 d (range, 13-36). Pts received a median of 4 units of plt transfusions (range, 3-11) in the first 14 days of induction (1 unit every 3.6 days), while during the eltrombopag treatment period, the median requirement decreased to 2 units (range, 0-6) or 1 unit every 4.8 d (P=.04). Ninety percent of pts achieved complete remission at a median time of 30 d [95% confidence interval (CI), 25-34d] from IC. No death occurred during treatment. The most common any grade toxicities (incidence > 15%) were maculopapular rash (28%), nausea (24%), increased alkaline phosphatase (24%), anorexia (20%), headache (20%), increased aspartate aminotransferase (16%), hypocalcemia (16%), and hypokalemia (16%). Grade 3/4 toxicities were reported at 4% (n=1) for febrile neutropenia, fever, pain, decreased white blood cell count, hypocalcemia, hypokalemia, generalized muscle weakness, maculopapular rash, and thromboembolic event. Median overall survival time from IC was 11.2 months (95% CI, 1.9, 14.8 m). Conclusion: In this study, eltrombopag appeared to hasten plt recovery and reduce plt transfusions without increasing rates of refractory disease in older FLT3-negative AML pts undergoing IC, without any limiting toxicities. Additional analyses are currently underway to evaluate durability of platelet responses, responses in other cell lineages and survival. Disclosures Mukherjee: Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; McGraw Hill Hematology Oncology Board Review: Other: Editor; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Gerds:Celgene Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Sierra Oncology: Research Funding; Roche: Research Funding; Imago Biosciences: Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding. Advani:Abbvie: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Saunthararajah:EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties; Novo Nordisk: Consultancy. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees.

Purpose: Classical introduction therapy of etoposide combined with cytarabine and daunorubicin (DAE) is commonly applied in childhood acute myeloid leukemia (AML), but etoposide has an increasing risk of secondary cancer. In this study the non-inferiority effect of homoharringtonine (H) versus Etoposide was compared in induction phase for Chinese childhood AML treated by CCLG-AML 2015 protocol. Patients and Methods: The total of 818 childhood AML patients (median age of 80 months; range from 1 to 193 months) from CCLG-AML 2015 study group (40 centers) were randomly allocated to two induction arms of DAE and DAH. During the course of induction I, 467 patients in DAE group received daunorubicin and cytarabine (DA) plus etoposide (D: 40 mg/m2 per day on days 1, 3 and 5; A: 100 mg/m2 every 12 hours from day 1 to 7; E: 100 mg/m2 per day from days 1 to 5), and 351 patients in DAH group received the same DA does plus homoharringtonine ( H: 3 mg/m2 per day from days 1 to 5). During the course of induction II, Idarubicin (10 mg/m2 per day on days 1, 3 and 5) was used to instead of daunorubicin, and patients accepted corresponding IAE or IAH treatment. All patients were divided into standard, intermediate or high risk group (SR, IR or HR group) according to CCLG-AML 2015 regimen (table 1). They were assessed by bone marrow (BM) aspiration and morphologically defined complete remission (CR: blasts ≤5%), partial remission (PR: blasts between 6~19%), or non-remission (NR: blasts ≥20%) on days 28 of induction. Results: DAH/IAH group showed non-inferiority for remission rates both in induction Ⅰ (DAE 70.2% vs DAH 76.6%, P = 0.041) and induction Ⅱ (IAE 79.4% vs IAH 87.7%, P = 0.016). Total CR rate at end of induction Ⅰ reached 73.0% and it didn't differ between DAE and DAH group for IR or HR group (IR group: DAE, 73.9% vs. DAH, 77.3%, P = 0.529; HR group: DAE, 53.9% vs. DAH, 62.6%, P = 0.128). But for SR group, CR rate of DAH group is significantly higher than DAE group (DAE, 85.1% vs. DAH, 95.1%, P = 0.013). It has similar results after induction Ⅱ. Total CR rate reached 83.1% and all patients has almost gained CR/PR for SR or IR group, only 2 patients still couldn't obtain remission. There was no significant difference in SR or IR group between two arms, but for HR group, CR rate significantly increased in those who accepted IAH chemotherapy (SR group: IAE, 91.2% vs. IAH, 95.0%, P = 0.398; IR group: IAE, 87.1% vs. IAH, 92.5%, P = 0.275; HR group: IAE, 66.1% vs. IAH, 78.8%, P = 0.050). Conclusion: Homoharringtonine is an effective cytotoxic drug and DAH regimen showed non-inferiority induction effect compared with classical DAE regimen in childhood AML, especially for patients of standard risk group. Disclosures No relevant conflicts of interest to declare.

High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) has become a standard consolidation treatment for patients with invasive lymphoma. The combination of cyclophosphamide, carmustine, and etoposide (CBV) is a commonly used conditioning regimen prior to auto-HSCT for patients with invasive lymphoma. Many modifications of the CBV regimen, including the addition of idarubicin, have been employed, with varying results. We retrospectively analyzed the clinical characteristics and treatment outcomes of 36 patients with invasive B-cell non-Hodgkin lymphoma treated with a conditioning regimen prior to auto-HSCT between January 2015 and June 2018. For our analysis, the patients were divided into two groups: one group received the classic CBV conditioning regimen and the other group received idarubicin at a dose of 8 mg/m2 for 3 days in addition to the CBV regimen. Overall survival (OS), median progression-free survival (PFS), adverse reactions, and hematopoietic reconstitution time were compared between the two groups. OS and PFS were analyzed using the Kaplan-Meier method, and the log-rank test was used for comparison between groups. Cox regression was used for multivariable analysis of other clinical factors. The median follow-up time was 29 months. Among the 36 patients in the cohort, 19 were male and 17 were female, with a male-to-female ratio of 1.12 to 1. The median age of onset was 39.5 years; 18 patients were older than 40 years and 18 were younger than 40 years. Twenty-six patients (72%) had an international prognostic index score of 0-2 and 10 patients (28%) had a score of 3-5. According to Ann Arbor staging criteria, 9 patients (25%) had stage I-II disease and 27 patients (75%) had stage III-IV disease. A total of 21 patients achieved complete remission and 15 patients achieved partial remission before transplantation. There were no significant differences between the groups in terms of neutrophil counts (P = 0.795) or platelet reconstitution time (P = 0.551). Also, there was no difference in adverse reactions between the two groups, suggesting that the addition of idarubicin to the conditioning regimen did not aggravate adverse reactions. OS and PFS were significantly longer in the idarubicin group than among patients who did not receive idarubicin. In the multivariable analysis, the use of idarubicin and complete remission state before auto-HSCT were associated with improved prognosis. These results indicate that the use of idarubicin with the CBV conditioning regimen prior to auto-HSCT is a safe and effective choice for patients with invasive B-cell non-Hodgkin lymphoma. Keywords: B-cell non-Hodgkin lymphoma; conditioning regimen; autologous hematopoietic stem cell transplantation; idarubicin Disclosures No relevant conflicts of interest to declare.

Background: Since FLT3-ITD is a poor prognostic factor for acute myeloid leukemia (AML), allogeneic hematopoietic stem cell transplantation (allo-HSCT) is practically performed. However, clinical usefulness of allo-HSCT at the first remission (CR1) has not been fully evaluated by the prospective study. To prospectively elucidate the role of allo-HSCT at CR1 in younger adult patients with FLT3-ITD positive AML and explore the prognostic impacts of clinical and genetic features, we conducted a phase II multicenter study (JALSG AML209-FLT3-SCT, UMIN Clinical Trials Registry UMIN000003433, http://www.umin.ac.jp/ctr/). Methods: A total of 49 patients 16 to 49 years of age with newly diagnosed de novo AML were enrolled in this study if they had a FLT3-ITD mutation and achieved complete remission within 2 courses of the standard induction therapies consisting of cytarabine and either daunorubicin or idarubicin. All patients were to be received allo-HSCT as soon as possible while continuing 4 courses of consolidation therapy combining cytarabine plus mitoxantrone, daunorubicin, aclarubicin or etoposide, vincristine, and vindesine. Patients received no further chemotherapy until allo-HSCT or relapse. Conditioning was selected according to each institutional standard from myeloablative regimens except for reduced intensity conditioning only in patients older than 40 years old or with higher HCT-CI than 1 point. GvHD prophylaxis was according to each institutional standard based on cyclosporine A or tacrolimus combined with short-term MTX. Targeted sequencing of 57 genes frequently identified in myeloid malignancies were analyzed using the preserved DNA extracted from AML cells at diagnosis. FLT3-ITD allelic ratio (AR) was quantified using DNA fragment analysis. Primary endpoint was 3-year disease-free survival (DFS). Results: Among 48 eligible patients with the median age of 38.5 (range, 17-49) years, 36 (75%) maintained CR1 to receive allo-HSCT at the median of 108 (range, 54-228) days after the achievement of CR1. Median follow-up was 1,726 (range, 983-2,974) days. The 3-year DFS rate was 43.8% (95% confidence interval [CI], 30-57%, Figure 1). The lower limit of 95% CI exceeded threshold response rate of 20%, concluding the treatment was effective. The 3-year overall survival, post-transplant DFS and non-relapse mortality rates were 54.2% (95%CI, 39-67%), 58.3 % (95%CI, 41-72%) and 25.0% (95%CI, 12-40%), respectively. There was no significant difference in DFS post allo-HSCT according to donor sources (related BM 64.6% vs. related PB 50.0% vs. unrelated BM 63.6% vs. UCB 60.0% at 3 years, P= .881). Neutrophil recovery was achieved in 94.3%. Cumulative incidences of grade II to IV and III to IV acute GvHD at day 100 were 21.2% (95%CI, 9-37%) and 9.1% (95%CI, 2-22%), respectively. Cumulative incidence of chronic GvHD at 1 year was 25.0% (95%CI, 12-40%). Mutations in NPM1 gene (65%) and genes associated with DNA methylation were frequently identified including DNMT3A (36%), IDH1 (6%), IDH2 (17%) and TET2 (17%, Figure 2). Median ITD AR was 0.344 (range, 0.006-4.099). There was no significant overlap of genetic alterations with high ITD-AR (≥ 0.5). No significant impact on DFS was observed by high ITD AR (≥0.5) (Hazard ratio [HR], 1.53; 95%CI, 0.58-4.06; P= .39) or other co-occurring genetic alterations including NPM1 mutations (HR, 0.78; 95%CI, 0.28-2.20; P= .64). Conclusions: This prospective study demonstrated the efficacy and safety of proceeding faster to allo-HSCT in CR1 for younger adult patients with FLT3-ITD positive AML, whose graft sources were not limited to HLA identical donors and the first available donor should be considered. Beyond FLT3-ITD mutations, no significant prognostic factor was identified in their genetic background or high ITD AR. Further study is required to improve the prognosis of AML patients with FLT3-ITD by establishment of an adequate therapeutic strategy using FLT3 inhibitors and allo-HSCT. Disclosures Atsuta: Kyowa Kirin Co., Ltd: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Sawa:Asahi-Kasei: Honoraria; Celgene: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Honoraria; Mochida: Honoraria; Ono Pharmaceutical Co., Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Kyowa-Hakko Kirin: Honoraria; Nippon Shinyaku: Honoraria; Pfizer Japan Inc.: Honoraria; Novartis: Honoraria; Eisai: Honoraria; Otsuka Pharmaceutical: Honoraria; Shire: Honoraria; Mundi Pharma: Honoraria. Ozawa:Kyowa-Hakko Kirin: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Astellas Pharma Inc.: Honoraria. Tomita:Taiho Pharma: Research Funding; Kyowa Kirin: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding. Maeda:Nippon Shinyaku Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K..: Honoraria. Usuki:Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Astellas Pharma Inc: Research Funding, Speakers Bureau. Matsuoka:Takeda Pharmaceutical: Research Funding; Novartis: Research Funding; Astellas Amgen Biopharma: Consultancy. Asou:SRL Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharm Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Asahi Kasei Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd: Research Funding; Novartis Pharmaceuticals: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding. Matsumura:Otsuka Pharmaceutical: Consultancy, Research Funding; Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau. Miyazaki:Kyowa-Kirin: Honoraria; Dainippon-Sumitomo: Honoraria; Chugai: Research Funding; Nippon-Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria. Kiyoi:Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria; Zenyaku Kogyo Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Perseus Proteomics Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM Corporation: Research Funding.

INTRODUCTION: In AML, the ability to target disease-related mutations is an important therapeutic innovation. FMS-like tyrosine kinase 3 (FLT3) mutations (FLT3mut+) are common in AML and confer a negative impact on prognosis. Since FLT3 mutational status can change over the course of the disease and FLT3-targeting therapies may benefit FLT3mut+ patients (pts), FLT3 mutational testing is recommended for R/R AML pts, even if testing was performed at initial diagnosis. As the landscape of FLT3mut+ R/R AML evolves, it is important to understand how the utilization/sequencing of therapies and application of FLT3 mutational testing impacts pts in real-world settings. The objective of this analysis was to examine real-world data from a large, multicenter, collaborative EMR database to learn more about treatment and FLT3 testing patterns in pts with FLT3mut+ R/R AML. METHODS: This retrospective, longitudinal, observational cohort study was designed to describe treatment FLT3 testing patterns in adult (≥18 years) pts in the USA with FLT3mut+ R/R AML. For this analysis, initial diagnosis of R/R AML must have occurred between January 1, 2015 and November 30, 2018. This study focuses on data collected prior to the date of approval of gilteritinib for treatment of FLT3mut+ R/R AML (November 28, 2018). Patients were identified by confirmation of diagnosis of AML, followed by confirmation of FLT3mut+ disease, and then ≥1 R/R event. Data were derived from a consolidated EMR database, which combined data from CancerLinQ and Vector Oncology. Data were extracted through an SQL query and abstracted by clinical research nurses. Descriptive statistics were used to examine potential differences among subsets of pts. RESULTS: In the initial phase, data from 99 pts (52.5% male; n=52) with FLT3mut+ R/R AML were evaluated. The majority of pts were Caucasian (72.7%; n=72) with a median age of 62 years (range: 20-86) at first R/R episode. At the first R/R event, treatment regimens were diverse; a total of 89/99 (89.9%) pts underwent 44 different anticancer therapies and only 10.1% (n=10/99) of pts received best supportive care (BSC). At first R/R, the most common anticancer treatments were cytarabine + fludarabine + idarubicin (29.4%; n=10/34) for pts undergoing high-intensity chemotherapy (HIC) and decitabine (45.4%; n=5/11) for pts undergoing low-intensity chemotherapy (LIC). The percentage of pts receiving FLT3 inhibitors, either as single agent or in combination with chemotherapy, was 33.3% (n=33/99) of the total population (Table). Among pts aged CONCLUSIONS: During the study period, there was substantial heterogeneity regarding the management of FLT3mut+ R/R AML. A total of 89 pts received 44 different anticancer therapies and approximately one-third of pts received a FLT3 inhibitor (alone or in combination) at first R/R. However, during the study period, approved agents for treatment of FLT3mut+ R/R AML were not available. Despite NCCN guidelines, at first R/R, FLT3 retesting was not often performed. With recent approval of FLT3-targeted therapies, it is important to measure rates of retesting in the R/R setting to better understand how elements of pt care, such as monitoring changes in FLT3 mutational status, may impact pt outcomes. Disclosures Zeidan: Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Medimmune/AstraZeneca: Research Funding; ADC Therapeutics: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding. Gilligan:Astellas: Other: Project. Gautam:Astellas: Other: Project. Hu:Astellas: Other: Project. Grinblatt:Abbvie: Consultancy; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Pandya:Astellas Pharmaceuticals: Employment.

Introduction: The combination treatment of venetoclax (VEN) with both low-dose cytarabine (LDAC) and hypomethylating agents (HMA) in untreated primarily elderly AML patients yielded promising response rates leading to its approval for newly diagnosed AML patients who are 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Prolonged cytopenias are of potential concern in venetoclax treated patients, especially in patients who underwent allogeneic hematopoietic cell transplantation (alloHCT) prior venetoclax treatment. Objective: To compare hematologic recovery in patients treated with VEN in combination with intensive and non-intensive chemotherapy regimens for the treatment of relapsed or refractory (R/R) acute myeloid leukemia (AML) depending on the pretreatment status for alloHCT. Methods: In this retrospective controlled study (www.clinicaltrials.gov NCT03662724), we included patients aged 18 years or older with R/R acute leukemia previously treated with VEN (days 1-7) combined with intensive salvage chemotherapy (fludarabine, cytarabine, idarubicin - FLAVIDA) or VEN combined with non-intensive regimens, namely HMA or LDAC. Eighty-one patients who were treated with FLA-IDA for R/R AML served as control for the intensively treated patients included in this analysis. Responses were evaluated per revised International Working Group criteria for AML. Main outcome measure was the rate of objective response (complete remission [CR] + CR with incomplete blood count recovery [CRi] + partial remission [PR] + morphologic leukemia-free state (MLFS; defined as less than 5% blasts in an aspirate sample). Safety and efficacy analyses included all patients who received at least one cycle of VEN combination treatment. This study was approved by the local Ethics Review Committee in accordance with the Declaration of Helsinki. Results: Between January 2017 and May 2019 49 patients with a median age of 59 years (range 18-80) received VEN with either FLA-IDA (n=14), HMA (n=31) or LDAC (n=4) and had safety and efficacy outcomes reported. The patient cohort was a high-risk cohort of relapsed (n=24) and refractory (n=25) patients. The analysis included 24 patients (49%) with secondary AML and two patients with biphenotypic acute leukemia (BAL). Twenty-two patients (45%) had received prior alloHCT and 7 (14%) had relapsed For intensively treated patients the ORR was 79% (n=11) with 9 CR/CRis (64%), one MLFS, and one PR compared to an ORR of 47% in the FLA-IDA control cohort. Median time to neutrophil (≥1.0x109/L) and platelet recovery (≥100x109/L) in intensively treated responding patients were 34 and 36 days compared to 39 and 41 days in the control cohort. Median recovery times in patients with and without prior alloHCT were similar (FLAVIDA: 34 vs. 33 days for neutrophil recovery; 36 vs. 36 days for platelet recovery, Fig. 1 C-D; FLA-IDA control: 41 vs. 38 days for neutrophil recovery; 70 vs. 38 days for platelet recovery, Fig. 1 E-F). After a median follow-up of 10.5 months the median overall survival (OS) was 8 months in non-intensively treated patients. After a median follow-up of 9.9 months the median OS was not reached in intensively treated patients. Median event-free survival was 5.8 months in non-intensively treated patients and was not reached in intensively treated patients. Conclusions: Venetoclax in combination with intensive chemotherapy as well as non-intensive regimens showed promising response rates for treatment of relapsed or refractory AML with good tolerability and acceptable duration of cytopenias with no differences in recovery times in patients with and without prior alloHCT. Disclosures Koenecke: Novartis: Other: none. Heuser:Bayer Pharma AG, Berlin: Research Funding; Synimmune: Research Funding.

Background: DNA methyltransferase inhibitors sensitize leukemia cells to chemotherapeutics. Previous studies have indicated decitabine sequentially combined with idarubicin was an effective treatment for myeloid neoplasms. We therefore conducted a phase 2 study of combination of decitabine followed by low-dose idarubicin plus cytarabine in acute myeloid leukemia (AML) evolving from myelodysplastic syndrome (MDS) and higher risk MDS. Methods: The study was a single-arm, prospective, multicenter study. Patients with AML evolving from MDS and refractory anemia with excess blasts (RAEB-2) high-risk MDS based on the 2008 WHO classification were included. The treatment plan consisted of decitabine 20 mg/m2 daily for 3 consecutive days on days 1-3, followed by idarubicin 6mg/m2 for 3 consecutive days on days 4-6, and cytarabine 25mg/m2 every 12 hours for 5 days on days 4-8. Granulocyte colony stimulating factor ( G-CSF) was given from day 4 and discontinued when neutrophil count increased to 1.0 × 109/L. In case remission was achieved after the first course, a similar second remission-induction course was given, to be followed by either an allogeneic hematopoietic stem cell transplantation (allo-HSCT) or subsequent consolidation courses, which was at the investigator's discretion. Results: A total of 71 patients were enrolled and treated, among whom 44 (62.0%) had AML evolving from MDS, 55 (77.5%) were previously untreated, 12 (16.9%) had an adverse karyotype, and 6 (10.0%) had TP53 mutations. 40 (56.3%) patients achieved a major response, including 20 (28.2%) patients with complete remission (CR) and 20 (28.2%) patients with complete remission with incomplete blood count recovery (CRi). The major response (CR+CRi) rate was 63.6% in AML patients and 44.4% in MDS patients (p=0.142). The median overall survival (OS) was 22.4 months (95% confidence interval (CI) ,17.8-27.0). The median OS was 24.2 months (95% CI 18.0-30.4) and 20.0 months (95% CI 11.2-28.7) for patients with AML and MDS (p=0.347), respectively. The median progress free survival (PFS) for the entire cohort was 12.1 months (95% CI 3.9-20.4). The median PFS was 17.6 months ( 95% CI 13.3-22.0) and 6.8 months (95% CI 0.1-13.6) for patients with AML and MDS (p=0.151), respectively. Patients who achieved CR/CRi had superior OS: 26.4 months ( 95% CI 17.6-35.2) vs. 20.0 months (95% CI 6.2-33.8) in non CR/CRi patients (p=0.042). Also patients who achieved CR/CRi had prolonged PFS: 17.8 months (95% CI 8.6-27.0) vs. 8.6 months (95% CI 3.5-13.8) in those not achieving CR. Patients with platelet doubling achieved significantly higher CR/CRi rate (24/24(100%) vs. 16/47(34.0%), p50×109/L of 25 days (range: 8-41). Conclusions: The regimen of decitabine priming followed by low-dose idarubicin plus cytarabine appears to be highly effective and has an acceptable safety profile in patients with AML evolving from MDS or RAEB-2. Further controlled studies are needed to confirm the activity of this regimen, and could help to provide an alternative option for induction therapy in this population. Disclosures No relevant conflicts of interest to declare.

Introduction: FLT3 is a frequently mutated gene in approximately one-third of AML cases and is associated with a poor prognosis. Few effective therapeutic options exist for patients with R/R FLT3mut+ AML. In 2018, gilteritinib was approved in the US as the first targeted therapy indicated for R/R FLT3mut+ AML. The efficacy of gilteritinib was established in the ADMIRAL trial, a phase 3 randomized trial, in comparison with SC (i.e., low-dose cyctarbine [LDAC], azacitidine, mitoxantrone + etoposide + cytarabine [MEC], and fludarabine + cytarabine + granulocyte colony stimulating factor + idarubicin [FLAG-IDA]). The results from the trial indicated that gilteritinib significantly improved overall survival (OS) compared to SC with 1-year survival rates of 37% vs. 17%. To inform the value of gilteritinib, this study aimed to assess the cost-effectiveness of gilteritinib for the treatment of R/R FLT3mut+ AML from a US third-party payer's perspective. Methods: A cost-effectiveness analysis (CEA) model was developed using monthly cycles and a 3% discount rate to assess the incremental cost effectiveness of gilteritinib compared to SC over a lifetime horizon. The model structure comprised a decision tree followed by two three-state partitioned survival models. The decision tree component stratified patients based on whether they received allogeneic hematopoietic stem cell transplantation (HSCT) following treatment initiation. The partitioned survival components included three health states: event-free survival (EFS), alive and post-event, and death. The selected model structure was chosen because HSCT is a key clinical event that has a significant impact on treatment outcomes for the target population. The efficacy inputs (OS and EFS) varied by HSCT status. The efficacy inputs for OS and EFS without HSCT were estimated based on the ADMIRAL trial. The efficacy inputs for OS and EFS with HSCT were assumed to be the same for both gilteritinib and SC and were based on available literature (Evers 2018). Parametric survival models or HRs were used to predict probabilities of being in different health states until year 3. Afterwards, all patients who remained alive were considered long-term survivors and their mortality risk was twice that of the general population based on literature. Treatment costs (drug, administration, and hospitalization), adverse event (AE) costs, subsequent HSCT costs, medical costs for each health state, FLT3 mutation testing, post-progression treatment, and terminal care costs were obtained from public databases and literature. For SC, the same regimen composition (i.e., LDAC, azacitidine, MEC, and FLAG-IDA) as the ADMIRAL trial was considered to estimate the treatment costs. All costs were inflated to 2018 US dollar (USD). Utilities for each health state were derived from the ADMIRAL trial and disutilities for AEs were derived from the literature. Total incremental costs, total incremental LYs, and total incremental QALYs were calculated. Incremental cost-effectiveness ratios (ICERs), defined as the incremental cost per additional gain in health effect (i.e., LY and QALY), were used to assess the economic value of gilteritinib relative to SC. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analyses (PSA) were also performed to test the robustness of the base-case results. Results: Over a lifetime horizon, the base-case model estimated that treatment with gilteritinib led to an increase of 1.55 discounted LYs and an increase of 1.29 discounted QALYs at an additional cost of $141,097 relative to SC; the corresponding incremental cost per LY gained was $90,761, and incremental cost per QALY gained was $109,741. Cost-effectiveness was most sensitive to gilteritinib cost, HSCT rate, and discount rate. In the PSA, the estimated probability that gilteritinib is cost-effective was 93.5% at an acceptable willingness-to-pay threshold of $150,000/QALY. Conclusions: Gilteritinib demonstrated greater LY and QALY improvements compared with SC. With an ICER of $109,741/QALY, gilteritinib is a cost-effective strategy from a US third-party payer's perspective, based on the $150,000/QALY threshold recommended by the US Institute for Clinical and Economic Review. Compared to SC, gilteritinib represents a new active treatment option for R/R FLT3mut+ AML patients that provides better health outcomes with a favorable cost-effectiveness profile. Disclosures Zeidan: Trovagene: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Ariad: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria; Incyte: Consultancy, Honoraria, Research Funding; Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Agios: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria. Qi:Astellas: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Astellas for the conduct of this study; Analysis Group, Inc.: Employment. Pandya:Astellas Pharmaceuticals: Employment. Garnham:Astellas: Employment. Yang:Analysis Group, Inc.: Employment; Astellas: Other: I am an employee of Analysis Group, Inc., which provided paid consulting services to Astellas for the conduct of this study. Shah:Astellas: Employment.

Introduction CALGB study in 1994 reported improved leukemia free survival (LFS) with sequential courses of high dose cytarabine (HIDAC- 3 gm/m2, q12h on days 1, 3 and 5) compared to lower doses of 100 mg/m2 and 400 mg/m2 per day. Following this study, HIDAC has been commonly used for chemotherapy consolidation in AML patients 60 years or younger. More recently, several groups investigated the role of intermediate dose cytarabine (IDAC-1.5 gm/m2 q12h D 1, 3 and 5 or D 1-3) in this population and reported equivalent outcomes for IDAC compared to HIDAC (Table 1). ELN guidelines published in January 2017 recommend IDAC for consolidation therapy in young ( Methods Patients 60 years or younger with ELN favorable risk AML between 2004 and 2015 at SGH and between September 2015 and March 2018 at UMMC, who underwent induction therapy with 7+3 regimen (idarubicin 12 mg/m2 D1-3 or daunorubicin 60 - 90 mg/m2 and cytarabine 100 mg/m2 continuous infusion from D1-7) and consolidation with cytarabine monotherapy were identified. These dates were chosen to allow reasonably equal time distribution before and after change in our practice. We extracted relevant outcomes data using chart review. We used Chi-square testing and applied Kaplan-Meier survival analysis to detect differences in relapse and survival outcomes. Results Of 67 ELN favorable risk patients 60 years or younger, 42 received HIDAC and 25 received IDAC. Median age was 39 years (range 16-59). 64 patients received 1 induction cycle and 3 patients received 2 induction cycles to achieve complete remission. Median LFS and overall survival (OS) with HIDAC vs IDAC were not-reached (NR, median time for follow up = 6.9 years) vs 1.35 years (p=0.004) and NR vs 2.27 years (p=0.001) respectively (Figure 1). Cumulative incidence of relapse at 2 years was 23.8% for HIDAC and 60% for IDAC groups (p=0.003). 3-year LFS and OS for HIDAC vs IDAC groups were 71% vs 36% (p=0.06) and 90% vs 48% (p=0.002). Discussion Historical data suggests chemotherapy consolidation with 3-4 cycles of HIDAC achieves long-term LFS of 60 - 70 % in young favorable risk AML patients. While the outcomes in HIDAC group in this study are comparable to historical data with good outcomes, a significantly larger proportion of patients in the IDAC group had early relapse (60%) and death. A major difference between the patients in this study and the other studies which showed similar outcomes with HIDAC and IDAC is the mode of induction. Data from large randomized studies in AML (Table 1) that suggest similar efficacy of IDAC compared to HIDAC used higher intensity induction regimens (frequently double induction therapy) compared to 7+3 and/or used other agents in combination with Ara-C for consolidation. These data are not broadly applicable in patients who receive a single cycle of 7+3 for induction, when selecting dose of Ara-C as monotherapy for consolidation. Furthermore, studies that used 7+3 for induction therapy showed benefit for HIDAC compared with multi-agent chemotherapy that included IDAC (Table 1). Conclusion Using single agent IDAC for post remission therapy is associated with higher rates of relapse and poor overall survival compared to HIDAC among young, ELN favorable risk AML patients who achieve complete remission following 7+3. The large randomized studies that suggested equivalency of IDAC to HIDAC for post remission therapy in AML patients, either used more than one cycle of intensive induction regimen and/or used cytarabine in combination with an anthracycline for consolidation. Hence, ELN guidelines should be cautiously interpreted given the above limitations in generalizability. Our study suggests that HIDAC, rather than IDAC, is the preferred chemotherapy consolidation regimen in young, favorable risk AML patients following standard 7+3 induction. Foot note: BK & NAAH contributed equally. FH & ZL contributed equally. Disclosures Kolla: Amgen: Equity Ownership. Weisdorf:Pharmacyclics: Consultancy; Incyte: Research Funding; Fate Therapeutics: Consultancy.

Introduction: The prognosis of older patients treated for acute myeloid leukemia (AML) relies on cytogenetic/molecular classifications as well as their ability to tolerate intensive induction therapy for which comorbidities have an important impact. A prognostic model has been elaborated to incorporate these two variables, cytogenetic/molecular risk and comorbidities evaluated by the Hematopoietic Cell Transplantation - Comorbidity Index (HCT-CI) (Sorror et al. 2017). The AML-composite model (AML-CM), which also incorporates hypoalbuminemia and high LDH levels at diagnosis, has been recently updated to incorporate the new European LeukemiaNet (ELN) 2017 classification (Sorror et al. 2019). In this study, we aimed to confirm the predictive impact of the revised AML-CM in an independent cohort and to explore which parameters were the most relevant for predicting early mortality and relapse. Patients and Methods: All patients (pts) older than 60 years diagnosed with AML who received intensive induction therapy in our department between 2004 and 2017 were included. Patients with acute promyelocytic leukemia were excluded. They received induction therapy with idarubicin 8 mg/m2 for 5 days and cytarabine 100 mg/m2 for 7 days with or without lomustine 200 mg/m2 on day 1. Patients in first complete remission (CR1) were to receive six consolidation courses with idarubicin 8 mg/m2 for one day and cytarabine 100 mg/m2 for 5 days and maintenance therapy with oral methotrexate and mercaptopurine. The HCT-CI and the revised AML-CM were calculated as previously described (Sorror et al. 2005; Sorror et al. 2019) using individual patient medical records. Early mortality was defined as death within one month after the start of induction therapy. The ELN 2017 classification, the HCT-CI, and the revised AML-CM were considered to determine which parameters - comorbidities or cytogenetic/molecular risk - were associated with each outcome. Results: Ninety-nine pts were included in the study with a median age of 66 years-old (range: 60 - 82). Twenty-seven pts (27%) had secondary AML (prior solid tumor requiring chemotherapy and/or radiation therapy in 11 pts and prior hematological malignancy in 16 patients). According to the ELN 2017 classification, 24 (24%) were favorable, 53 (54%) were intermediate, and 22 (22%) were adverse. The most frequent comorbidities included liver disease (30 pts, low/moderate, 5 pts, severe), previous cancer (22 pts), and arrythmia (22 pts). Thus, 13 (13%), 25 (25%), 44 (45%), and 17 (17%) pts had a revised AML-CM score of 1-4, 5-6, 7-9, and >10, respectively. 78 pts (79%) achieved CR1, with 10 early deaths (10%) due to toxicity (early mortality) and 11 induction failures (11%). Fifteen pts received allogeneic SCT. 54 (55%) relapsed, and 72 (73%) died with a median follow-up of 18 months (range: 0 - 167). Both the HCT-CI and the AML-CM were associated with increased early mortality (OR: 1.4, 95% CI: 1 - 1.8, p=0.03 for HCT-CI and OR: 1.3, 95% CI: 1-1.7, p=0.03 for AML-CM) whereas the ELN 2017 classification had no impact. The predictive value of the AML-CM for early mortality was not superior to the HCT-CI (area under the curve - AUC: 0.76, p=0.01, and 0.76, p=0.01, respectively). The risk of relapse was only associated with an unfavorable ELN 2017 classification (OR: 8.8, 95% CI: 1.1 - 70, p=0.04). It was the most predictive parameter for relapse, in comparison to the HCT-CI and the revised AML-CM, but this did not reach statistical significance (AUC: 0.62, p=0.08). The AML-CM clearly distinguishes 4 groups with different prognosis (Figure, p 10, respectively (OR: 1.4, 95% CI: 1.2 - 1.8, p Conclusion: The revised AML-CM is an effective tool for predicting overall survival in older pts with AML receiving intensive induction therapy. It is a better prognostic system compared to the HCT-CI and the ELN 2017 classification as it combines the evaluation of comorbidities, which predicts early mortality, and cytogenetic/molecular risk, which predicts relapse. Figure Disclosures Orvain: Novartis: Honoraria; Incyte: Honoraria.

BACKGROUND: Acute myeloid leukemia (AML) patients who failed the first course of standard induction chemotherapy remain a challenge owing to poor response to the second induction regimen. We retrospectively compared the efficacy and safety of DAC+CAG regimen with non-DAC regimen in AML patients who failed the first course of standard induction regimen. MATERIALS AND METHODS: The three regimens consisted of (1) DAC combined with CAG regimen (decitabine, cytarabine, aclarubicin and granulocyte colony stimulating factor, n=25) ; (2) the repeated first course (IA 3+7, n=30); (3) Intermediate-dose AraC -based chemotherapy including IA 3+3 (idarubicin, Ara-C n=14) or CLAG (cladribine, aclarubicin and granulocyte colony stimulating factor, n=15). RESULTS: Our data indicate that after the second course, the overall response (OR, complete remission [CR]+partial remission [PR]) rates in DAC+CAG group was higher than the Intermediate-dose AraC -based group (80% vs 48.3%, P= 0.049), whereas the CR rates among 3 groups were not statistically different (P = 0.09). The overall survival (OS) of DAC+CAG group is longer than IA 3+7 group and Intermediate-dose AraC -based group with significance (21 months VS 18.5 months, P=0.038 and 21 months VS 10 months, P=0.023, respectively), the relapse-free survival (RFS) of DAC+CAG group is longer than Intermediate-dose AraC-based group (16 months VS 8.5 months, P=0.016), though there was no significant difference in overall survival (OS) of the transplanted patients among the 3 groups (P = 0.064). The median duration of thrombocytopenia in the DAC+CAG group is shorter than IA 3+7 group and Intermediate-dose AraC-based group (10 days vs 12 days, P CONCLUSION: Our data indicate that DAC combined with CAG regimen may represent a better alternative option with good response and safety for AML patients who failed the first course of standard induction chemotherapy. Disclosures No relevant conflicts of interest to declare.

We have previously reported that cytarabine/daunorubicin as well cytarabine/idarubicin can be safely combined with crenolanib at the full monotherapy dose (100mg TID) and administered throughout induction, consolidation and maintenance in newly diagnosed FLT3-mutated AML (Walter et al., EHA 2018). We hypothesize that crenolanib plasma levels might correlate with long term outcome in these patients. Methods: Twenty-seven newly diagnosed AML patients with FLT3 mutations, aged 18-60 years old enrolled in a phase II study of crenolanib combined with chemotherapy (NCT02283177) were included in this analysis. Patients received 7+3 induction with cytarabine 100 mg/m2 for 7 days and either daunorubicin 90 mg/m2 (n=16) or idarubicin 12 mg/m2 (n=11) for 3 days. Crenolanib 100 mg TID was administered continuously starting 24-48 hours after induction until 72 hours prior to the next chemotherapy cycle. Consolidation could consist of up to four cycles of high-dose cytarabine (HiDAC): 3 g/m2 for < 60 years and 1 g/m2 for 60 years) q12 hours on days 1, 3, and 5 with crenolanib starting 24 hours after the final HiDAC dose in each cycle. Eligible patients proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Maintenance crenolanib at 100mg TID was started after HiDAC or 30-90 days after HSCT for up to 12 cycles. Crenolanib levels (total and free) were measured 2-4 hours following the first dose of crenolanib and after two weeks of continuous crenolanib administration. Crenolanib levels were also measured on first day of crenolanib treatment following HiDAC consolidation. Free crenolanib was measured by rapid equilibrium dialysis. Durability of clinical remissions were documented by routine follow up every 3-4 months (as per institutional practice). Results: As of July 2019, all patients have completed all protocol therapy (one patient has continued crenolanib maintenance for 25 months per patient request). Twenty-three of 27 patients (85%) achieved complete remission, all of whom required only 1 cycle of induction chemotherapy. Nineteen of 27 patients remain alive and free of disease with a median follow-up of 29.3 months (Figure 1). Three relapses have occurred, all within the first year of treatment and no relapses have occurred in patients who completed at least 1 cycle of crenolanib maintenance. Seven patients received HiDAC consolidation along with crenolanib but did not receive HSCT. Six of these patients remain in long term remission. While the number of patients is small, we observed similar overall survival and cumulative incidence of relapse in patients who underwent HSCT as compared to those who did not (Figure2). Pharmacokinetic studies demonstrate that despite increases in acute phase reactants and AGP levels, both total and free crenolanib rapidly achieve sufficient levels to provide the continuous inhibition required to eradicate FLT3-ITD, FLT3-D835, and other FLT3 mutations including FLT3-N841, A680, V592, V491, and D839. Total levels of crenolanib exceeded 500 nM at steady state, and the majority of patients showed clearance of FLT3 mutations after combination therapy. Summary/Conclusion: These pharmacokinetic data show that crenolanib when given with chemotherapy can achieve sufficient levels to inhibit multiple FLT3 mutations, despite rises in FLT3 ligand and acute phase reactants. These clinical data suggest that this combination might improve outcomes in younger patients with newly diagnosed FLT3-mutant AML. With 29 months median follow up, median overall survival (OS), event-free survival (EFS), and cumulative incidence of relapse (CIR) have not been reached. No relapses have been observed in patients after completing crenolanib maintenance. A phase III randomized multicenter trial has been initiated to compare the efficacy of crenolanib versus midostaurin combined with standard chemotherapy for newly diagnosed patients with FLT3-mutant AML (NCT03258931). Figure Disclosures Goldberg: Abbvie: Research Funding; ADC Therapeutics: Research Funding; American Society of Clinical Oncology: Research Funding; American Society of Hematology: Research Funding; Arog Pharmaceuticals: Research Funding; Daiichi-Sankyo: Consultancy, Research Funding; Pfizer: Research Funding; DAVA Oncology: Honoraria; Abbvie: Consultancy; Celgene: Consultancy. Coombs:Abbvie: Consultancy; Covance: Consultancy; Dedham Group: Consultancy; H3 Biomedicine: Honoraria; Cowen & Co.: Consultancy; Octopharma: Honoraria; Pharmacyclics: Honoraria; Loxo: Honoraria; Medscape: Honoraria. Wang:Kite: Other: Advisory role; Abbvie: Other: Advisory role; celyad: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; Jazz: Other: Advisory role; Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Walter:Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding. Messahel:Arog Pharmaceuticals: Employment. Stone:Astellas: Consultancy; Biolinerx: Consultancy; Arog: Consultancy, Research Funding; Trovagene: Consultancy; Macrogenics: Consultancy; Argenix: Other: DSMB; Argenix: Other: DSMB; Otsuka: Consultancy; Takeda: Other: DSMB; Trovagene: Consultancy; Biolinerx: Consultancy; Daiichi-Sankyo: Consultancy; Celgene: Consultancy, Other: DSMB; Pfizer: Consultancy; Jazz: Consultancy; Roche: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Stemline: Consultancy; Biolinerx: Consultancy; Pfizer: Consultancy; Astra-Zeneca: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Actinium: Membership on an entity's Board of Directors or advisory committees; Biosight: Consultancy; Arog: Consultancy, Research Funding; Otsuka: Consultancy; Abbvie: Consultancy, Research Funding; Astra-Zeneca: Consultancy; Roche: Consultancy; Argenix: Other: DSMB; Macrogenics: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Biosight: Consultancy; Otsuka: Consultancy; Agios: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Takeda: Other: DSMB; Astellas: Consultancy; Agios: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Trovagene: Consultancy; Celgene: Consultancy, Other: DSMB; Stemline: Consultancy.

Background: The outcome of patients with blast phase chronic myeloid leukaemia (CML) remains extremely poor despite the advent of tyrosine kinase inhibitors (TKIs), and the majority of blast phase patients have already failed the currently licensed TKIs during the chronic phase. Currently there is no standard therapy for patients with blast phase CML, but most will receive 2 or 3 courses of chemotherapy or a TKI, followed by stem cell transplantation (alloSCT). In the PACE clinical trial of ponatinib, 23% of patients with blast phase CML achieved major cytogenetic response, with overall survival of 20% at 12 months. To date, there has been no prospective evaluation of salvage chemotherapy in combination with ponatinib. Methods: MATCHPOINT is a seamless Phase I/II trial to determine the optimal dose of ponatinib in combination with conventional chemotherapy (fludarabine, cytarabine, idarubicin and G-CSF; FLAG-IDA) for the treatment of CML in blast phase. An efficient Bayesian design, EffTox, which utilises both efficacy and toxicity to select desirable doses for subsequent patient cohorts, was used. Given the observed patient outcomes and the investigators' prior beliefs, the next cohort's dose is chosen adaptively to optimize the risk-benefit trade-off between efficacy and toxicity. The initial ponatinib dose was 30mg daily, commenced on day 1 of FLAG-IDA chemotherapy. Where possible, ponatinib was given continuously during the remission-induction phase, but ponatinib therapy was interrupted from day 28 of each cycle if haematologic recovery had not occurred. Patients received one or two cycles of FLAG-IDA chemotherapy plus ponatinib at the allocated dose level, and then proceeded to alloSCT followed by ponatinib maintenance. The co-primary outcome measured toxicity (dose-limiting toxicity; DLT) during the first therapy cycle and efficacy (clinical response; haematologic or cytogenetic) after the first cycle. Results: A total of 17 patients were recruited between March 2015 and May 2018. Eight presented with de-novo blast phase CML and 9 had progressed on TKI. Eight patients had additional cytogenetic abnormalities and 3 had BCR-ABL kinase domain mutations (E255K x2 and T315I x1) at study entry. Nine and 8 patients commenced 1 or 2 cycles of FLAG-IDA + ponatinib, respectively. Of these, 16 patients were evaluable for the primary analysis. Treatment-related mortality (TRM) occurred in 3 patients during remission-induction (cardiomyopathy x1, pulmonary haemorrhage x1 and marrow aplasia x1). During cycle 1, 4/16 patients experienced a DLT (raised ALT x1, fulminant cardiomyopathy x1, cerebral sinus vein thrombosis x1, elevated amylase x1). Eleven of 16 (69%) patients achieved a clinical response, defined as either complete haematologic (3 patients) or cytogenetic response (1 minor and 9 major [2 partial and 7 complete]). Five patients achieved major molecular remission after cycle 1. All patients were recommended to be dosed at the 30mg dose, which was defined as the optimal dose for ponatinib with FLAG-IDA. Nine patients proceeded to alloSCT (7 myeloablative and 2 reduced intensity). Four patients developed acute GvHD (grades 2-4) and 3 had CMV reactivation. Four patients re-started ponatinib maintenance post alloSCT, and de-escalated to 15mg if major molecular remission was maintained. Overall 1-year survival was 45.8% (95% CI 26.9-77.7%), estimated using Kaplan Meier. Summary/Conclusion: We report the first prospective trial of ponatinib and conventional chemotherapy for blast phase CML. The EffTox model combined Phase I and II, and delivered efficiency in determining the trial's optimal dose. This innovative statistical model has the potential to be applied in other rare malignancies. We confirm that FLAG-IDA + ponatinib 30mg, is a tolerable combination in blast phase CML, with promising response and survival. Post-transplant ponatinib was well tolerated and no excess toxicity was observed when ponatinib was used both pre- and post alloSCT. The combination of ponatinib and FLAG-IDA represents a potentially important advance in the treatment of blast phase CML, a rare complication which currently has a very poor outcome. Disclosures Copland: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Honoraria, Speakers Bureau; Cyclacel: Research Funding. Byrne:Ariad/Incyte: Honoraria, Speakers Bureau. Brock:Astrazeneca: Equity Ownership, Honoraria. De Lavallade:Incyte biosciences: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Clark:Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad/Incyte: Honoraria; Jazz Pharmaceuticals: Honoraria; AbbVie: Honoraria. Milojkovic:Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Yap:Celgene: Honoraria; Faron Pharmaceuticals: Other: Consultancy. OffLabel Disclosure: Ponatinib is a tyrosine kinase inhibitor (TKI). It is licensed to treat: - chronic myeloid leukaemia where the leukaemic cells have gene change (mutation) called T315I - acute lymphoblastic leukaemia that has an abnormal chromosome called the Philadelphia chromosome, or has the T315I mutation

Introduction: Outcome of patients (pts) with refractory AML or following relapse is considered dismal and usually reported as refractory/relapsed. Here we analyzed long term outcome of refractory and relapsing pts separately over a 10 year (y) period from two prospective, non-age-limited, adult AML studies. Results have been published or presented previously as part of the German AML Intergroup studies1,2. However, incidence, characteristics, treatment and outcome of refractory and relapsed pts have not been evaluated. Patients and Methods: A total of 1621 pts from the OSHO 2002 ≤60 y (n=740) and 2004 >60 y (n=881) with newly diagnosed AML (except acute promyelocytic leukemia) and eligible for chemotherapy were analyzed. The gender was male in 51.7% of pts. AML type was de novo in 66.6%, followed by secondary AML in 25.8% and therapy related in 7.6%. Cytogenetic risk status was normal in 47.9%, intermediate in 16.3%, unfavorable in 15.3%, monosomal in 12.6% and favorable in 7.9%. Molecular analysis revealed wildtype (wt) FLT3 in 80.9% and FLT3 ITD mutated (mut) in 19.1% of pts. NPM was mutated in 30.2% of 1124 pts. In the AML 2002 and 2004 studies (NCT 01414231; NCT 01497002; NCT00266136), pts were randomly (9:1) assigned to remission induction by cytarabine (1 g/m2 bid d 1, 3, 5, 7) and Idarubicin (AML 2002) 12 mg/m2/d d 1-31 or mitoxantrone (AML 2004) 10 mg/m2/d iv d 1 - 32 or to a common arm consisting of a 3+7 scheme 3. Pts in complete remission (CR) received consolidation and stem cell transplantation (HSCT) according to cytogenetic risk and donor availability1,2. Pts with partial remission (PR) or non-response (NR) to two induction cycles were considered refractory. Pts achieving CR and relapsing thereafter were considered relapses and treated with MitoFlag or Flag-Ida4. Results: The majority of pts [median age 62 (range 17-87) y] entered CR or CRi after one or two induction cycles (n=1144; 70.6%). OS was 31.9 (29.5-34.4) % @5y and 26.0 (23.4-28.9) % @10y. Results were age dependent and superior in younger pts with an OS of 46.8 (43.1-50.7) % @5y compared to 19.3 (16.7-22.4) % @ 5y in elderly. Age, cytogenetics and NPM1 were determinants for CR and WBC (p A total of 238 (14.7%) of 1621 pts, 23.5% in the younger and 76.5% in the elderly study, were refractory (PR 60.1%, NR 39.9%). Pts had a median age of 66 (range 23-83)y. OS of refractory pts was 11.4 (7.9-16.6)% @5y, and dependent upon PR [(13.1 (8.1-21.1) % @10y] and NR [5.2 (2.1-12.6) % @5y; p=0.0003]. Intensive chemotherapy ± HSCT and hypomethylating agents (HMA) were able to induce CR in 24.8% of pts. CR and non-CR pts had an OS of 42.7 (31.4-58.2) % @5y and an OS of 3.7 (1.7-8.0) % @2y, respectively. Risk factors for OS in refractory pts were age and type of therapy (p Of the 1144 CR/CRi pts, 582 relapsed 1-121 months (mts) after CR. Relapse occurred in 34.0% ≤6 mts, in 38,8% between 7-18 mts and in 12,2% >18 mts. Age, cytogenetic risk, type of AML, interval CR to relapse and HSCT were the dominant factors for relapse. CR2 was achieved after intensive chemotherapy ± HSCT, ± DLI and HMA in 227 pts (39.0%), 54.5% in the AML 2002 and 28.4% in the AML 2004. OS of relapsed pts was 13.8 (11.1 - 17.3) % @5y and 10.9 (7.4 - 16.2) % @10y and was higher in the younger with 23.4 (18.2-29.9) % @5y as compared to elderly pts 6.9 (4.4 - 11.0) % @5y. Pts with CR2 had a LFS of 24.9 (19.5-31.7) % @5y and was highest in patients Conclusions Outcome of pts with refractory and relapsed AML is unsatisfactory but consistent >10% @5y. A differential response is observed in refractory and relapsed pts and is dependent upon PR, NR and the achievement of CR. Increase of CR rate in younger but especially in elderly pts with second generation TKI, reduction of TRM using FLT3-inhibitor monotherapy and the option to treat pts ineligible to chemotherapy promise better outcome in refractory and relapsed AML. 1Büchner et al. JCO 2012; 2Niederwieser et al Blood 2016; 3Mayer et al. NEJM 1994; 4Thiel et al. Ann Oncology 2015 Disclosures Niederwieser: Daichii: Speakers Bureau; Cellectis: Consultancy. Scholl:Gilead: Other: Project funding; Daiichi Sankyo: Other: Advisory boards; AbbVie: Other: Advisory boards; Pfizer: Other: Advisory boards; Novartis: Other: Project funding. Zojer:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sayer:Novartis: Other: none. Schwind:Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Hochhaus:Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Al-Ali:Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; CTI: Honoraria.

Background: The presence of FLT3 "internal tandem duplication" (FLT3-ITD) mutation is associated with poor prognosis in acute myeloid leukemia (AML). However, the concomitant presence of NPM1 mutation (NPM1-mut) partially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild-type allelic ratio. NPM1 and FLT3 mutational status assessment is strongly recommended for risk stratificationat diagnosis by the last European Leukemia Net (ELN) guidelines. Aims: To investigate the efficacy of an intensive fludarabine-containing induction regimen (FLAI) for fit, de novo AML patients according to NPM1 and FLT3-ITD mutational status. Methods: One-hundred and sixteen consecutive AML patients, treated in 3 Hematology Italian centers from January 2008 to January 2018, were included in this analysis. Twenty five patients showed isolated FLT3-ITD, 39 concomitant FLT3-ITD and NPM1-mutation and 52 isolated NPM-1-mutation.Median age was 52 yrs (range: 18-65 years). All patients received fludarabine, high dose cytarabine-based induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm ondays 1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5). For patients achieving CR fludarabine was omitted on II induction course and idarubicin dose was increased to 12 mg/sqm. Before2017 patients with isolated FLT3-ITD mutation were scheduled to receive allogeneic bone marrow transplantation (BMT) in first complete remission regardless of allelic burden whereas after 2017 only patients with high allelic burden received BMT in 1st CR. Minimal residual disease was evaluated on marrow samples using multicolor flow-cytometry (MFC)or NPM1 expression levels. Negative MFC-MRD wasdefined by the presence of less than 25 clustered leukemic cells/105 total events (threshold of 0.025% residual leukemic cells, Minetto et. al, BJH 2019). NPM1mutation (NPM1-A, B and D) was measured using Muta Quant Kit Ipsogen from Qiagen. FLT3-ITD allelic burden was available in31/64 of FLT3-ITD patients. Results: Overall 60-days mortality was 4%. After two induction cycles, 101 patients achieved CR (87%). Thirty-three/101 (33%) CR patients underwent BMT in first CR. After a median follow up of 61 months, 3-year overall survival (OS) was 56.8% (median not reached). In univariate analysis OS duration was favorably affected by age Conclusion: Despite the potential bias due to the retrospective nature of the analysis, our data indicate that intensive fludarabine-high dose cytarabine-based induction exerts a strong anti-leukemic efficacy in younger AML patients carrying NPM1 mutation irrespectively of FLT3 mutational status.Thus, the synergism of fludarabine and cytarabine seems to affect the intrinsic chemosensitivity of NPM1-mut leukemic cells, overcoming the negative impact of FLT3-ITD. Moreover, our data suggest the strong prognostic impact on survival of MRD clearance and question the role of BMT in I CR in this setting of patients. Figure 1 Disclosures Candoni: Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Merck SD: Honoraria, Speakers Bureau. Bocchia:Incyte: Honoraria; Novartis: Honoraria; BMS: Honoraria.

INTRODUCTION AML is the most common malignant myeloid disorder in adults. Relapses are initiated by chemoresistant leukemic cells. DNA damage and repair mechanisms influence not only the genetic predisposition to leukemia but are also very important for refractoriness to treatment. The aim of this study was to investigate the possible alterations in the gene expression profile in DNA damage signaling pathways in two leukemic cell lines following their exposure to chemotherapeutic agents and verify the findings in AML patients. METHODS Kasumi-1 and MV4-11 AML cells were treated with either idarubicin (0.1μΜ) for 6h or cytarabine (1μΜ) for 48h. Dead cells were eliminated from drug-treated cells using the appropriate commercial kit. Gene expression profiling through PCR arrays analysis (RT2Profiler, Qiagen) was performed after RNA extraction from untreated, drug-treated and chemoresistant (live) cells following their exposure to cytotoxic agents. Human DNA Damage Signaling pathway related genes' expression was evaluated and analyzed through RT2Profiler PCR Array data analysis tool. Following our initial results, two genes were selected for further analysis: PPP1R15A and HUS-1 genes' relative expression was evaluated by qRT-PCR analysis with QuantiTect Primer Assays kit (Qiagen) using the 2^-∆∆Ct method. The analysis included 28 de novo AML patients before the onset of the 7+3 combination chemotherapy and 16 healthy donors. Eighteen cases had normal karyotype including 7 with flt3 mutation, 1 case had inv(16) and 9 cases intermediate risk karyotype. Statistics were performed through One Way Anova analysis. RESULTS PCR Array analysis after idarubicin and cytarabine treatment of Kasumi-1 cells revealed a significant up-regulation of genes involved in apoptosis, cell cycle, DNA damage and repair, and ATM/ATR signaling. Significant differences in their gene expression patterns were observed between cytarabine-treated Kasumi-1 cells and chemoresistant ones. HUS-1 gene (DSB) was 3x fold up-regulated in cytarabine-treated cells and 0.7x fold down-regulated in chemoresistant cells compared to untreated cells. Cytarabine and idarubicin treatment of MV4-11 cells led to an up-regulation of genes involved in cell cycle, DNA damage repair, including DSB repair and NER mechanisms. Most importantly, PPP1R15A gene's expression in both cytarabine and idarubicin chemoresistant MV4-11 cells was significantly 4.2x and 2.7x fold up-regulated compared to drug treated cells. Following these results the expression level of genes PPP1R15A and HUS1 was examined in the bone marrow cells of AML patients in order to verify their association with chemoresistance. PPP1R15A gene's relative expression was significantly up-regulated in non-responding to induction chemotherapy AML patients compared to responding (median: 2.705 vs. 0.73, p HUS1 gene's relative expression was remarkably down-regulated in AML patients compared to controls (median: 1.585 vs. 7.74, p CONCLUSIONS The up-regulation of PPP1R15A gene in chemoresistant MV4-11 cells after treatment with cytotoxic agents is justified since this gene participates in growth arrest and apoptosis in response to DNA damage, negative growth signals and protein malfolding by binding to protein phosphatase PP1, and attenuating the translational elongation of key transcription factors through dephoshorylation of eukaryotic initiation factor 2a(eIF2a). Most importantly the significant increased baseline expression of PPP1R15A in AML chemoresistant patients indicates its involvement in chemoresistance mechanisms and paves the way for targeted treatment. HUS1 gene's expression was remarkably depressed in de novo AML samples. This gene is required for the optimal ATM/ATR signaling response to DSBs and replication stress forming part of the RAD9A-RAD1-HUS1 (9-1-1) complex functioning as a damage sensor in checkpoint pathway. Therefore the described above reduced expression in AML samples indicates reduced ATM-ATR response to DSBs associated with genetic instability and offers new options for synthetic lethality treatment strategies Disclosures Symeonidis: Tekeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Pappa:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Novartis: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding; Celgene / GenesisPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Introduction: Venetoclax (VEN) is a potent and selective inhibitor of BCL-2. It has demonstrated activity in adults with acute myeloid leukemia (AML) in combination with low-dose cytarabine ( Methods: VEN was given daily for 28 days and chemotherapy was started on day 8, or earlier in cases of disease progression. Dosages of VEN and chemotherapy were escalated separately using a rolling-six design. Response to the VEN window was determined using total peripheral blood blast count or, in a subset of patients, bone marrow blast percentage as determined by flow-cytometry based minimal residual disease (MRD). Pharmacokinetics of VEN both as a single agent and in combination with chemotherapy were measured in a subset of patients treated at the maximum tolerated combination dose of VEN. Response to therapy was determined using bone marrow evaluation between days 29-50 of therapy. All patients received antimicrobial prophylaxis, typically with levofloxacin and micafungin. Azoles were prohibited during VEN administration. Results: Thirty-six patients aged 2-22 years were enrolled. All dose levels were tolerated. The recommended phase 2 dose of VEN in combination with high-dose cytarabine with or without idarubicin was 360 mg/m2 daily (max 600mg). One patient (treated with 240mg/m2 of VEN and intermediate-dose cytarabine) experienced a dose-limiting toxicity due to delayed count recovery and one patient died of recurrent colitis (at dose level 3) which first occurred during prior therapy and was deemed unrelated to VEN. Patients experienced a mean of 2.4 non-hematologic grade 3+ toxicities, with infections including culture-negative febrile neutropenia, sepsis, and colitis the most common toxicities. Patient-reported quality of life was similar at study entry and at the completion of cycle 1 and was within normal limits in most patients. Among 22 patients receiving VEN with high-dose cytarabine ± idarubicin, 14 (64%) achieved a complete response (CR) or complete response with incomplete count recovery (CRi). Response to the VEN window was associated with end of cycle 1 response; 13/15 (87%) patients with a greater than 80% reduction in peripheral blasts achieved a partial response (PR; 3) or CR/CRi (10). In contrast, only 8/15 (53%) patients with less than an 80% reduction in blasts responded to combination therapy (7 CR, 1 PR). Window response to VEN was associated with BH3 dependence as determined by cytochrome c release from leukemia cells in a flow-cytometry based assay. 5 of the 6 (83%) patients with primary BCL-2 dependence had a >80% reduction in blasts; the single patient with a poor response had a change to BCL-XL dependence at the end of cycle 1. In contrast, 4 of the 6 (66%) patients with primary BCL-XL dependence had a 90% reduction had secondary BCL-2 dependence. None of the 4 patients with FLT3-ITD or point mutations responded as determined by end of cycle 1 marrow. VEN levels were consistent across weights and ages and similar to levels seen in adults. The levels were similar between patients who did and did not receive idarubicin (mean AUC24 38.3 ± 32.7 vs. 47.3 ± 22.9 μg•h/mL). Conclusion: VEN combined with high-dose cytarabine or high-dose cytarabine and idarubicin was well tolerated and effective in children and young adults with relapsed or refractory AML. Enrollment continues to refine estimates of response rate. VEN window response is associated with BH3 dependence and end of cycle 1 response rates. Targeting BCL-XL or FLT3 may improve response to combination therapy. Table Disclosures Karol: Abbvie: Other: Unrelated to this study, St. Jude has received a charitable contribution from AbbVie, Inc. The charitable contribution is not being used for clinical or research activities, including any activities related to this study.. Alexander:AbbVie: Other: travel funding. Salem:AbbVie: Employment, Other: Stock/stock options. Palenski:Abbvie: Employment, Other: Stock/ stock options. Opferman:AbbVie: Research Funding. Rubnitz:AbbVie: Research Funding.

Background: Older AML patients often present with comorbidities and may have a compromised ability to tolerate intensive chemotherapy. These patients are more likely to have AML secondary to MDS/MPN and are considered to have a biologically distinct disease compared to their younger counterparts, with more frequent occurrence of adverse-risk cytogenetic abnormalities and mutations in genes regulating epigenetic modifications. In addition, the heterogeneity of driver mutations within a single patient contributes to limited responses to standard induction chemotherapy. While FLT3 mutations occur in this population, they are often subclonal, adding to the challenge of eradicating AML in older adult patients. Studies combining sorafenib or midostaurin with standard induction chemotherapy have shown relatively modest improvements in response rates and survival, and relapses, both early and late, remain a major concern. There is a major unmet need for optimizing chemotherapy and TKI treatment in this medically fragile population. We here report the safety and efficacy results in newly diagnosed older patients with FLT3 mutant AML treated with crenolanib, a type I FLT3 inhibitor, in combination with intensive induction and consolidation chemotherapy (NCT02283177). Methods: Fifteen consecutively treated patients, aged 61-75 (median age: 68), at four academic cancer centers were included in this analysis. Patients received 7+3 induction with cytarabine 100 mg/m2 for 7 days and either daunorubicin 60 mg/m2 or idarubicin 12 mg/m2 for 3 days. Crenolanib 100 mg TID was administered continuously starting 24 hours after chemotherapy until 72 hours prior to the next chemotherapy cycle. Consolidation consisted of up to 4 cycles of high-dose cytarabine (HiDAC: 1 g/m2) q12h on days 1, 3, and 5 with crenolanib starting 24 hours after the final HiDAC dose. Eligible patients proceeded to allogeneic hematopoietic stem cell transplant (HSCT). Maintenance with crenolanib at 100mg TID was started after HiDAC or 30-90 days after HSCT for up to 12 cycles. Results: Fourteen patients completed induction chemotherapy (one patient withdrew consent at day 19). Crenolanib could be safely combined with either daunorubicin or idarubicin based induction chemotherapy. The most common adverse events (grade ≥3) were diarrhea, nausea, and febrile neutropenia. Ten of 14 patients were able to receive full doses of crenolanib during induction. The major reason for dose reduction was edema in 3 patients and GI bleeding in 1 patient. There was one treatment-related death, with 93% survival at 30 and 60 days and 87% survival at 100 days. Complete remissions with full count recovery (CR) were achieved in 10 of 15 patients after just one cycle of induction chemotherapy. Two patients achieved a complete remission after reinduction for an overall CR rate of 86%. Of the 12 patients who achieved CR, 10 patients received HiDAC consolidation, with two patients unable to receive consolidation therapy on study. Three patients received crenolanib maintenance after multiple cycles of HiDAC consolidation. Six patients underwent HSCT and 3 received crenolanib maintenance. As of July 2019, median OS for the intent to treat population is 20.2 months. One-year survival was 67% and 5 patients remain alive and in remission. All 5 long term survivors were ≤70 years old. All surviving patients received either multiple cycles of HiDAC or HiDAC plus transplant, and 4/5 underwent crenolanib maintenance. The patient who did not receive transplant completed 3 cycles of HiDAC consolidation and a full year of crenolanib maintenance. Summary/Conclusion: This safety study shows that crenolanib can be combined at full doses (100mg TID) for the duration of 7+3 induction, consolidation, and maintenance in older patients with FLT3 mutant AML. Therapy was relatively well tolerated, with less than one third of patients requiring dose reductions. Long-term survival rates are encouraging in this high-risk population, but additional studies are needed to confirm the efficacy of this combination older adults. Figure 1 Disclosures Wang: Pfizer: Other: Advisory role, Speakers Bureau; Stemline: Other: Advisory role, Speakers Bureau; Abbvie: Other: Advisory role; Kite: Other: Advisory role; Jazz: Other: Advisory role; Astellas: Other: Advisory role, Speakers Bureau; celyad: Other: Advisory role; Daiichi: Other: Advisory role; Amgen: Other: Advisory role; Agios: Other: Advisory role. Griffiths:Abbvie, Inc.: Consultancy; Genentech, Inc.: Research Funding; Celgene, Inc: Consultancy, Research Funding; Onconova Therapeutics: Other: PI on a clinical trial; Novartis Inc.: Consultancy; Appelis Pharmaceuticals: Other: PI on a clinical trial; Onconova Therapeutics: Other: PI on a clinical trial; Appelis Pharmaceuticals: Other: PI on a clinical trial; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Genentech, Inc.: Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Astex Phramaceuticals/Otsuka Pharmaceuticals: Consultancy, Research Funding; Abbvie, Inc.: Consultancy, PI on a clinical trial; Celgene, Inc: Consultancy, Research Funding; Boston Scientific: Consultancy; Boston Scientific: Consultancy; Persimmune: Consultancy; Persimmune: Consultancy; New Link Genetics: Consultancy; Partner Therapeutics: Consultancy; Novartis Inc.: Consultancy. Walter:Jazz Pharmaceuticals: Consultancy; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; Seattle Genetics: Research Funding; Boston Biomedical: Consultancy; Covagen: Consultancy; BiVictriX: Consultancy; Daiichi Sankyo: Consultancy; Boehringer Ingelheim: Consultancy. Tallman:Hematology Oncology of Indiana: Honoraria; Salzberg Weill Cornall MSKCC Seminar in Hematologic Malignancies: Honoraria; University of Oklahoma Medical Center: Honoraria; Bioline: Membership on an entity's Board of Directors or advisory committees, Research Funding; BioSight: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Nohla: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Cellerant Therapeutics: Research Funding; Orsenix: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Mayo Clinic: Honoraria; New Orleans Summer Cancer Conference: Honoraria; Indy Hematology Review: Honoraria; Amgen: Consultancy; 14th Annual Miami Cancer Meeting: Honoraria; Danbury Hospital Tumor Board: Honoraria; International Conference in Leukemia: Honoraria. Goldberg:ADC Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; American Society of Clinical Oncology: Research Funding; American Society of Hematology: Research Funding; Celgene: Consultancy; Abbvie: Research Funding; Pfizer: Research Funding; Abbvie: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding; DAVA Oncology: Honoraria. Messahel:Arog Pharmaceuticals: Employment. Stone:Pfizer: Consultancy; Stemline: Consultancy; Astra-Zeneca: Consultancy; Argenix: Other: DSMB; Otsuka: Consultancy; Astellas: Consultancy; Argenix: Other: DSMB; Celgene: Consultancy, Other: DSMB; Stemline: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Biolinerx: Consultancy; Biosight: Consultancy; Trovagene: Consultancy; Arog: Consultancy, Research Funding; Takeda: Other: DSMB; Novartis: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy; Celgene: Consultancy, Other: DSMB; Abbvie: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Takeda: Other: DSMB; Biolinerx: Consultancy; Daiichi-Sankyo: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Jazz: Consultancy; Trovagene: Consultancy; Astra-Zeneca: Consultancy; Novartis: Consultancy, Research Funding; Roche: Consultancy; Macrogenics: Consultancy; Agios: Consultancy, Research Funding; Biosight: Consultancy; Abbvie: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Pfizer: Consultancy; Trovagene: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Arog: Consultancy, Research Funding; Macrogenics: Consultancy; Otsuka: Consultancy; Argenix: Other: DSMB; Astellas: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy; Biolinerx: Consultancy.

Background: The addition of the anti-CD33 targeting antibody Mylotarg (MY) to conventional "3+7" induction has been shown to improve the outcome of patients affected by acute myeloid leukemia (AML) without adverse cytogenetic alterations. Early reports suggested that MY was particularly effective among low risk patients, such as core binding factor AML, particularly if included in a high dose cytarabine-based induction therapy. The role of MY for intermediate risk patients appears to be less clear. Cytogenetically defined intermediate risk patients may be further stratified considering two frequent molecular aberrations: FLT3 "internal tandem duplication" (FLT3-ITD) mutation, associated with poor prognosis and NPM1 mutation (NPM1-mut), associated with a good prognosis. The concomitant presence of NPM1-mutpartially overcomes the negative prognostic impact of FLT3-ITD, which is also modulated by FLT3-ITD/wild type allelic ratio. NPM1 and FLT3 mutational status assessment is strongly recommended for risk stratification at diagnosis by the last ELN 2017 guidelines. Aims: To investigate the efficacy of MY added to an intensive fludarabine, high dose cytarabine and Idarubicin-based induction regimen (FLAI) as frontline treatment for younger ( Methods:One-hundred and forty eight consecutive AML patients, treated in 3 Italian Hematology centersbetween 2008 and 2018and harboring at least one molecular alteration among NPM1-mut and FLT3-ITD, were included in the analysis. Thirty three patients carried isolated FLT3-ITD, 50patients showed concomitant FLT3-ITD and NPM1-mut and 65 isolated mutated NPM-1.Median age was 50 years(range: 18-65). All patients received FLAI induction (fludarabine 30 mg/sqm and ARA-C 2g/sqm on days1 to 5 plus idarubicin 10 mg/sqm on days 1-3-5), with or without low dose MY(3 mg/sqm, added in 42 patients), followed by a second induction without fludarabine and with idarubicin at the increased dose of 12 mg/sqm. Before 2017, patients with isolated FLT3-ITD mutation were scheduled for allogeneic stem cell transplantation (HSCT), if an HLA-matched sibling donor was available, whereas after 2017 only patients with high allelic burden isolated FLT3-ITD mutation received HSCT in first CR. The other patients received conventional high dose cytarabine consolidation for a total of 3 cycles. Results: Overall, 60-days mortality was 3%, and was not significantly influenced by receiving or not MY during induction. After one induction cycle, 126 patients achieved CR (85%) with no difference between patients receiving or not MY. After a median follow up of 70months, 3-year overall survival (OS) was 59.5% (median not reached). OS duration was significantly longer in NPM1 mutated patients (p Conclusions: Despite the potential bias due to the retrospective nature of the analysis, our data seem to indicate that Mylotarg, added to an intensive fludarabine/high dose cytarabine-based induction, provides a significant improvement in anti-leukemic efficacy in patients carrying FLT3-ITD mutation, especially if concomitant NPM1 mutation is not present. Disclosures Candoni: Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Merck SD: Honoraria, Speakers Bureau. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria.

Introduction Venetoclax (VEN), a potent BCL2 inhibitor, demonstrated favorable outcomes combined with hypomethylating agents and low dose cytarabine (AraC) in elderly patients (pts) newly diagnosed (ND) with acute myeloid leukemia (AML). In order to improve both remission rates and survival in fit AML pts, we evaluated the combination of VEN with FLAG-IDA regimen in fit pts with ND or relapsed/refractory (R/R) AML. Objectives This phase (Ph) Ib/II single center clinical trial has dual primary objectives: (1) Safety and tolerability of the combination for pts with R/R AML (Ph Ib), and (2) Overall response rate (ORR) by modified IWG AML criteria in pts ND or R/R AML (Ph II). Secondary analyses include duration of response (DOR) and overall survival (OS). Methods Eligibility includes medically fit, ND or R/R AML pts of any age with adequate organ function, PS ≤ 2, and WBC < 25x109/L. Only R/R AML pts were eligible for Ph Ib dose escalation. Pts receive FLAG-IDA induction/consolidation (ind/cons), with VEN orally daily. The original FLAG-IDA ind consisted of fludarabine 30 mg/m2 IV D2-6, AraC 2 g/m2 IV D2-6, idarubicin 6 mg/m2 IV D4-6 (8 mg/m2 IV D4-6 for ND pts), and filgrastim 5 mcg/kg daily D1-7 (or pegfilgrastim 6 mg after day 5 to replace remaining injections). The 3+3 algorithm was applied for dose escalation. The first cohort (dose -1, n=8) received FLAG-IDA with VEN 200 mg on days 1-21 of ind, incorporating a 2-day VEN dose ramp up. After the observation of gram negative bacteremia and/or sepsis in 5 of 6 pts during cycle 1 nadir, an amended dose level -1 ind was designed with reduced AraC 1.5 g/m², with VEN 200 mg on D1-14 and dose level 0 with VEN 400mg on D1-14. After completion of ind/cons, single agent VEN at 400 mg continuously is provided as maintenance for pts not proceeding to alloSCT. The data cutoff was 6.10.2019. Results At data cutoff, 34 pts with a median age of 47 yrs (range, 21-72) have been enrolled: 16 pts in the Ph Ib, and 18 pts in Ph II (11 in ND, and 7 in R/R cohort). 23 pts had R/R AML with a median of 2 (range, 1-4) prior therapies, and 10 (43%) pts had received prior alloSCT. Additional demographics including molecular profile at study enrollment are provided in Table 1. The median number of cycles received is 2 (range, 1-4). VEN 400 mg on D1-14 was considered safe for Ph II dose expansion. Serious adverse events regardless of causality were infections (n=26), bacteremia (n=12), sepsis (n=5), hypotension (n=4) and typhlitis (n=3). No tumor lysis syndrome was identified. 30-day mortality was 0%, 60-day mortality was 0% in ND cohort and 13% in R/R cohort (2 pts died from progression and 1 pt from fungal pneumonia). All enrolled pts were evaluable for response. Of 23 R/R pts, 17 pts (74%) achieved a best response of CR/CRi (12 CR, 5 CRi: 3 CRh + 2 CRp). 12 (52%) pts attained MRD negative status by flow cytometry. 15 pts attained a best response after one cycle, and two attained blast reduction after cycle 1 followed by CR after re-induction. Among responders, 9 pts proceeded to alloSCT, 2 remain on study, 3 pts relapsed, and 3 pts died in CR at 1.7, 3.4 and 4.6 months on treatment. Median time to ANC recovery > 500/ul and platelet recovery > 50K in responders was 27 days (range, 20-90) and 33 days (range, 20-54) respectively. With a median follow-up of 5 months, median DOR is not reached and OS is 7.1 months. Median OS for pts in salvage 1, 2, and ≥ 3 is 9.4, 10, and 4.9 months, respectively. Of 11 ND pts, 10 pts (91%) achieved ORR (9 CR, 1 CRh) and all 10 pts became MRD negative by flow cytometry: 3 pts proceeded to alloSCT, and 7 pts remain on active treatment. Median time to ANC and platelet recovery with induction was 23 days (range, 19-31) and 25 days (range, 18-31) respectively. Both DOR and OS are not estimable. Of interest, responding pts demonstrated higher apoptosis priming, as shown by depolarization in response to Bid, PUMA and Bim peptides by BH3 profiling (Fig 1). Conclusions FLAG-IDA with VEN demonstrates notable activity in both R/R and ND medically fit pts. Improved safety and tolerability without decreasing efficacy was achieved by decreasing AraC to 1.5 g/m2, and administering VEN for 14 days in ind, and 7 days in cons cycles. Neither prolonged cytopenias nor early mortality were observed. Ph II portion for R/R and ND pts is ongoing. Correlative studies with genomic annotation, CyTOF analysis and BH3 profiling are being analyzed, with higher apoptosis priming identified in responding pts. Longer follow-up is necessary to establish long term survival benefit. Table 1 Disclosures Konopleva: Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Calithera: Research Funding; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding. Kadia:Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioline RX: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Garcia-Manero:Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; Amphivena: Consultancy, Research Funding. Ravandi:Xencor: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Daiichi: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Biopath: Consultancy; BiolineRx: Consultancy, Research Funding; Merus: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz: Consultancy, Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Novartis: Research Funding; Ariad: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Astex: Research Funding. DiNardo:celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; syros: Honoraria; abbvie: Consultancy, Honoraria; medimmune: Honoraria; jazz: Honoraria.

In this "real-life" retrospective study, we assessed outcome after a "personalized" treatment strategy for patients with acute myeloid leukemia (AML) in a tertiary care center. Our strategy consisted of induction therapy adjusted to age, comorbidities and molecular abnormalities, as well as allogeneic stem cell transplantation (allo-SCT) in first complete remission (CR1), whenever possible, for patients with European Leukemia Net 2017 (ELN) intermediate or high-risk patients. Allo-SCT was followed by post-transplant maintenance consisting of 5-azacytidine (AZA) for most patients, or sorafenib for patients with FLT-3 ITD. We included 99 consecutive patients (65% male). The median age at diagnosis was 49 years (range, 18-88) with 28 patients older than 60. Karyotype was normal in 59 patients. Molecular analysis revealed core binding factor (CBF) mutation in 13 patients (13%), NPM1 mutation in 26 patients (26%), FLT3-ITD and FLT3-TKD mutation in 15 (15%) and 1 (1%) patient, respectively. According to the ELN 2017 classification, 24, 48 and 27 patients belonged to the low, intermediate and high-risk groups, respectively. Patients aged 60. Of those 26 transplanted patients, 24 received post-allo-SCT maintenance consisting of AZA in 18 patients (69%) or sorafenib in 6 patients (23%). Allo-SCT was performed in 20 additional patients at time of relapsed and/or refractory disease, with 14 of them receiving post-transplant maintenance. The median follow-up for alive patients was 35 months. For the whole cohort, the 3-year overall survival (OS) was 54%. In patients aged These results indicate an improved outcome for AML patients who receive a treatment strategy tailored to age, comorbidities, and disease risk with an overall 76% CR rate and a relatively low rate of mortality during induction (7%). The use of allo-SCT in CR1 followed by post-transplant maintenance significantly improved outcome of young patients ( Disclosures No relevant conflicts of interest to declare.

Introduction: There is no consensus regarding the best salvage regimen for refractory or relapsed acute myeloid leukemia (r/rAML), with classic regimens traditionally based on high-dose cytarabine in a changeable combination with anthracyclines, purine analogs, and etoposide. Outcomes of r/rAML patients in developing countries are underreported, even though the same regimens are widely used. Methods: This is a retrospective single-center study, conducted in an academic center in Brazil. Local research ethics committee approved this analysis. All patients above 16 years of age who received MEC (mitoxantrone, etoposide and cytarabine) or FLAG-IDA (fludarabine, cytarabine, filgrastim and idarubicin) as originally reported (Amadori, S. et al. and Steinmetz, H. T. et al.) for r/rAML between December/2009 and January/2019 were included. Only patients with refractory or relapsed disease following standard upfront therapy ("7+3" regimen) were included in this analysis, being divided among refractory (less than partial response after one cycle of "7+3"), early relapsed (relapse within one year from first complete response [CR]) and late relapsed (relapse after one year of CR). Only the first salvage was considered for this study. Results: Sixty patients were included in the final analysis, with a median age of 45 years (range, 17 - 69). There were no cases of therapy-related AML. Four AML cases (7%) were secondary to myeloproliferative neoplasm (MPN) or myelodysplastic syndrome (MDS). All FLT3-ITD positive cases had an associated NPM1 mutation. Two patients had chronic human immunodeficiency virus infection and received antiretroviral therapy. Baseline characteristics of the whole cohort are summarized in Table 1. Three patients had undergone SCT in first CR and were post-SCT relapses. Twenty-eight patients received MEC and 32 received FLAG-IDA. By comparing the baseline characteristics of both groups, no difference statistically significant was found except for the indication for salvage treatment, in which there were more refractory cases in FLAG-IDA group (56 vs. 28%, p=0.029) (Table 2). Overall, 17/60 achieved CR and 12/60 CRi, with a total CR rate (CR+CRi) of 48.3% (95% confidence interval [CI], 35.4 - 61.5). Sixteen patients (27%) early died before a response assessment. By univariate analysis, only age affected the CR rate (p=0.045). No difference in CR rate was found between the two protocols (MEC 53.5 vs. FLAG-IDA 43.7%, p=0.447). Looking into this data, it can be seen that there were more refractory patients in FLAG-IDA arm (37.5 vs. 4%, p=0.02) but more patients early-died in MEC arm (35.7 vs. 18.7%, p=0.137), even though the latter was not statistically significant. After correcting the initial differences between the two groups regarding indication for salvage through a propensity score calculation, a post-matching cohort with 44 subjects was found. In this cohort, no difference in refractoriness rate could be detected (p=0.077). In the whole cohort, 17 patients proceeded to allogeneic SCT - 15 in CR/CRi and 2 with active disease, with no difference in SCT execution rate between the two groups (p=0.470). 4/17 transplanted patients were alive. Median follow-up was 48 months. Median survival for total cohort was 4 months (95% CI, 2.7 - 9.2), with a 3-year OS of 9.7% (95% CI, 4 - 23.7) and a 3-year EFS of 7.5% (95% CI, 2.5 - 22.4). In the univariate analysis for OS, age (p=0.04), FLT3 status (p Conclusion: In this analysis, there was no difference concerning the chosen regimen for r/rAML, even though a possible higher refractoriness rate could be seen in FLAG-IDA arm. High early toxicity was found, emphasizing the role of supportive care and judicious selection of patients to intensive salvage therapy in our setting. FLT3-ITD mutation and SCT remained as significant factors for survival in a multivariable analysis, which is in line with previous studies. Disclosures No relevant conflicts of interest to declare.

Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease with varied outcomes dependent on patient cytogenetic and mutational status. Thirty percent of adults with newly diagnosed AML have a mutation in the fms-related tyrosine kinase 3 (FLT3) gene. Midostaurin is a small molecule inhibitor that acts on multiple receptor tyrosine kinases, including FLT3. The RATIFY trial showed improved overall survival (OS) and event-free survival in patients treated with daunorubicin and cytarabine (7+3) plus midostaurin (Stone et al, NEJM 2017). In this trial, a dose of daunorubicin 60 mg/m2 was administered. High dose (HD) 90 mg/m2 daunorubicin significantly improved the rate of complete remission and overall survival, including in patients with FLT3-ITD (Luskin et al, Blood 2016). HD daunorubicin has also been shown to be more effective than idarubicin in patients with FLT3-ITD AML (Lee et al, J Clin Oncol 2017). This data raises the question of whether the combination of midostaurin and HD daunorubicin would further improve outcomes of FLT3 mutated AML patients, while maintaining a tolerable safety profile. The objective of this study is to describe the safety and efficacy endpoints of FLT3 mutated AML patients treated with HD daunorubicin plus midostaurin as part of induction therapy. Methods: We retrospectively reviewed clinical and molecular data of patients at Memorial Healthcare System, Moffitt Cancer Center, and Sylvester Cancer Center with newly diagnosed FLT3 mutated AML treated from May 1st, 2017 to July 1st, 2019. Clinical data was abstracted in accordance with institutional review board approved protocol. All patients were induced with HD daunorubicin 90 mg/m2 on days 1-3, cytarabine 100 mg/m2 on days 1-7, and midostaurin 50 mg PO twice daily on days 8-21. Growth factor and antimicrobial support were used per institutional guidelines. Demographics were analyzed using descriptive statistics. OS was analyzed using Kaplan Meier method. Other efficacy outcomes were CR, CRi (assessed according to the European Leukemia Network Criteria for AML), proportion of patients needing re-induction, and proportion of patients who underwent hematopoietic stem cell transplant (HSCT). Safety outcomes were adverse events (AEs) and early (30- and 60-day) mortality. Results: Twenty-six patients were included in the final analysis. Patient characteristics are outlined in TABLE 1. All patients were FLT3 mutated, as confirmed with molecular studies. The FLT3 subtype was ITD (high) in 3 patients, ITD (low) in 16 patients, TKD in 5 patients, and both in 2 patients. Seventy-seven percent of patients achieved a CR/CRi after one induction cycle, and 96.2% attained CR after two induction cycles. Median time to ANC and platelet recovery was 28 and 26 days, respectively. One patient died during the first 60 days, due to Enterococcus sepsis. The most common non-hematological AEs were nausea (77%), diarrhea (62%), mucositis (58%), rash (54%), and increased ALT (54%). Cumulative incidence of relapse in the cohort was 28% (n=7). Four patients relapsed pre-transplant and achieved CR2 with additional therapy. All 7 of these patients had co-occurring mutations of various types. Of the 20 patients who were considered transplant eligible, 13 (65%) underwent HSCT and 4 (20%) are pending transplant. Of the 13 transplanted patients, 3 experienced relapse post-transplant. After a median follow up of 14.5 months, median OS has not been reached. Conclusion: In our multi-center experience, induction with HD daunorubicin, cytarabine, and midostaurin is clinically effective and seems to be well tolerated. Short term mortality was low and AEs were manageable, with no unexpected safety signals. Also, CR/CRi rates were higher than previously reported, suggesting that the combination of HD daunorubicin and midostaurin may improve the outcomes of patients with FLT3 mutated AML. Future analyses with larger patient samples and longer follow up are warranted to further evaluate long-term safety and efficacy for this regimen. Figure Disclosures Sandoval-Sus: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Bradley:AbbVie: Other: Advisory Board. Talati:Agios: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Astellas: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria, Speakers Bureau. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Sallman:Abbvie: Speakers Bureau; Novartis: Speakers Bureau; Jazz: Research Funding; Incyte: Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Sweet:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; Novartis: 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; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees. Lancet:Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services ; Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding.

In acute myeloid leukemia (AML), new strategies assess the potential benefit of genetically targeted therapy at diagnosis. This implies waiting for laboratory tests and therefore a delay in initiation of chemotherapy. We studied the impact of time from diagnosis to treatment (TDT) on overall survival, early death, and response rate in a retrospective series of 599 newly diagnosed AML patients treated by induction chemotherapy between 2000 and 2009. The effect of TDT was assessed using multivariate analysis. TDT was analyzed as a continuous variable using a specific polynomial function to model the shape and form of the relationship. The median TDT was 8 days (interquartile range, 4-16) and was significantly longer in patients with a white blood cell count (WBC)50 Giga per liter (G/L) (P.0001) and in older patients (P = .0004). In multivariate analysis, TDT had no impact on overall survival (P = .4095) compared with age60 years, secondary AML, WBC50 G/L, European LeukemiaNet risk groups, and Eastern Cooperative Oncology Group performance status. Furthermore, TDT was not associated with response rate and early death. Thus, waiting a short period of time for laboratory tests to characterize leukemias better and design adapted therapeutic strategies at diagnosis seems possible.

Acute promyelocytic leukemia (APL) is commonly complicated by a complex coagulopathy. Uncertainty remains as to which markers of bleeding risk are independent predictors. Drawing from 5 large clinical trials that included all-trans retinoic acid (ATRA) as part of induction, we assessed known determinants of bleeding at baseline and evaluated them as potential predictors of hemorrhagic death (HD) in the first 30 days of treatment. The studies included were ALLG APML3 (single arm of ATRA + idarubicin ± prednisone), ALLG APML4 (single arm of ATRA + idarubicin + arsenic trioxide + prednisone), CALGB C9710 (single arm of ATRA + cytarabine + daunorubicin), Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) E2491 (intergroup I0129, consisting of daunorubicin + cytarabine vs ATRA), and SWOG S0521 (single-arm induction of ATRA + cytarabine + daunorubicin). A total of 1009 patients were included in the original trials, of which 995 had sufficient data to be included in our multivariate analysis. In this final cohort, there were 37 HD cases during the first 30 days following induction, for an estimated cumulative incidence of 3.7% (95% confidence interval [CI], 2.6% to 5.0%). Using multivariate Cox proportional hazards regression, the hazard ratio of HD in the first 30 days was 2.17 (95% CI, 0.84-5.62) for an ECOG performance status of 3-4 vs 0-2 and 5.20 (95% CI, 2.70-10.02) for a white blood cell count of ≥20 000/μL vs

Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a noninvasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrate that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in marrow, decreased with response to treatment. 2-HG decrease was more rapid with induction chemotherapy compared with DNA-methyltransferase inhibitor therapy. Our data suggest that serum or urine 2-HG may serve as noninvasive biomarkers of disease activity for IDH-mutant AML.

We investigated whether body mass index (BMI) correlates with distinct outcomes in newly diagnosed acute promyelocytic leukemia (APL). The study population included 144 patients with newly diagnosed and genetically confirmed APL consecutively treated at a single institution. All patients received All-trans retinoic acid and idarubicin according to the GIMEMA protocols AIDA-0493 and AIDA-2000. Outcome estimates according to the BMI were carried out together with multivariable analysis for the risk of relapse and differentiation syndrome. Fifty-four (37.5%) were under/normal weight (BMI < 25), whereas 90 (62.5%) patients were overweight/obese (BMI ≥ 25). An increased BMI was associated with older age (P < .0001) and male sex (P = .02). BMI was the most powerful predictor of differentiation syndrome in multivariable analysis (odds ratio = 7.24; 95% CI, 1.50-34; P = .014). After a median follow-up of 6 years, the estimated cumulative incidence of relapse at 5 years was 31.6% (95% CI, 22.7%-43.8%) in overweight/obese and 11.2% (95% CI, 5.3%-23.8%) in underweight/normal weight patients (P = .029). Multivariable analysis showed that BMI was an independent predictor of relapse (hazard ratio = 2.45, 95% CI, 1.00-5.99, in overweight/obese vs under/normal weight patients, P = .049). An increased BMI at diagnosis is associated with a higher risk of developing differentiation syndrome and disease relapse in APL patients treated with AIDA protocols.

Background: Treatment for acute myeloid leukemia (AML) has remained relatively unchanged over the past few decades. Standard-dose cytarabine and idarubicin (7+3 IA) or daunorubicin (7+3 DA) induction regimen have been recommended for AML induction therapy by global guidelines. Mitroxantrone, a type II topoisomerase inhibitor, disrupts DNA synthesis and DNA repair, has been recommended as a salvage treatment for refractory/relapsed AML or induction therapy for elderly patients. Objective: To compare the the clinical response and adverse events of Idarubicin regimen ( IA) with mitoxantrone and cytarabine (MA) in the treatment of newly acute myeloid leukemia (AML) . Methods: This retrospective study evaluated 164 patients with newly diagnosed AML who received either IA (idarubicin 10mg/M2, d1-3; cytarabine 200mg/d, d1-7) or MA regimen (mitoxantrone 10mg/M2, d1-d3; cytarabine 200mg/d, d1-7) as induction therapy from September 2010 to November 2017 at Guangdong General Hospital. The primary end point of this study was complete response and complete response with incomplete blood count recovery (CR/CRi), with secondary end points were adverse event rates and days of granulocyte and platelet recovery. Results: A total of 164 patients , 90 patients were males and 74 females, the median age was 41 (range:14~64) years old. There were 88 patients received IA regimen and 76 patients received MA regimen. There was no significant difference in clinical features and molecular biological characteristics in two groups (P>0.05). The CR/CRi rate was 72.3% and 64.0% (P=0.263) in IA and MA group after the first induction regimen, respectively. And the accumulated CR/CRi rate was 85.9% and 75.7% in two group, respectively (P=0.109). The common adverse reactions in the two groups were myelosuppression and infection , but with no statistical difference (P>0.05) in the incidence and grade of serious. The grade 4 and grade 5 neutropenia were 95.3% vs.98.7% and 4.7% vs. 1.3%, P>0.05 in IA and MA group respectively. And thrombocytpenia were 72.9% vs.63.2% and 4.7% vs. 1.3%, P>0.05. There was no significant difference in the incidence and severity of gastrointestinal, cardiovascular, respiratory, skin, liver and kidney injury between the two groups (P>0.05). The median days of intravenous antibiotics (including antifungal drugs), neutrophil recovery, platelet recovery and the units of platelet and red blood cell suspension transfusion had no statistical difference in two groups (P>0.05). Conclusion: This retrospective study implied mitoxantrone with standard-dose cytarabine (3+7 MA) regimen has similar efficacy and outcome to the idarubicin with standard-dose cytarabine (3+7 IA) regimen for newly diagnosed AML, without increasing the incidence of adverse event rates. Disclosures No relevant conflicts of interest to declare.

Background Successful allogeneic stem cell transplantation (HSCT) in treatment of patients (pts) with acute myeloid leukemia (AML) is dependent upon graft-versus-leukemia, suggesting that intact immune surveillance is essential for eradicating minimal residual disease. Myeloblast-induced T-cell tolerance through overexpression of indoleamine 2,3-dioxygenase (IDO) is thought to play a significant role in immune evasion through upregulation of tryptophan (Trp) catabolism and kynurenine production, resulting in a Trp-poor environment that leads to immune system suppression. Indoximod is a small-molecule inhibitor of the IDO pathway that acts directly on immune cells to reverse IDO pathway-mediated suppression. We are assessing the safety and preliminary efficacy of indoximod in combination with standard induction chemotherapy in patients (pts) with newly diagnosed AML. Methods In this open-label, multicenter, phase 1 study (NCT02835729), eligible pts with newly diagnosed AML were treated with indoximod in combination with induction chemotherapy (idarubicin 12 mg/m2/d x3 days with cytarabine 100 mg/m2/d x7 days). Using a "3+3" design, indoximod (600 mg [dose level 0], 1000 mg [dose level 1], 1200 mg [dose level 2]) was given orally every 8 hours (Q8h) starting on day 9 of induction. Regimen limiting toxicity (RLT) was defined as any ≥ grade 3 non-hematologic adverse event (AE) that was not incontrovertibly related to the underlying AML or cytarabine or idarubicin. After induction, pts received up to 4 cycles of high dose cytarabine (HiDAC) consolidation while continuing indoximod. Patients continued on maintenance indoximod for up to 6 months from completion of consolidation therapy. Indoximod was discontinued 4 weeks prior to HSCT in eligible patients and not restarted as maintenance post-HSCT. Results As of July 15, 2018, 31 pts were enrolled (median age 55 years, range 18-78; 77% male). Six patients did not proceed with study therapy due to a diagnosis of acute promyelocytic leukemia, issues with medical insurance coverage, consent withdrawal, critical illness, and intestinal myeloid sarcoma preventing oral intake. Pts who received ≥1 dose of indoximod were included in the intention-to-treat (ITT) analysis (n=25), and pts who received ≥80% of their scheduled indoximod doses were included in the per-protocol (PP) analysis (n=19). Reasons for not completing ≥80% of indoximod doses were: consent withdrawal (n=3), inability to swallow (n=2) and physician decision (n=1). Of the 19 PP patients, 16 (84%) had either unfavorable karyotype or adverse mutation profile and 3 (16%) had secondary AML (s-AML). Indoximod combined with induction chemotherapy was well tolerated; no RLT was observed. The most frequent grade ≥3 non-hematologic treatment-emergent AEs in the ITT population, regardless of attribution, were febrile neutropenia (60%), hypoxia (16%), atrial fibrillation (12%), pneumonia (12%), hypocalcemia (12%), and hypotension (12%). Among 25 ITT pts, 21 (84%) achieved a remission (CR/CRh/CRi/CRp), and 15 of 19 (79%) in the PP analysis achieved remission. Among 12 pts with measurable residual disease (MRD) available in remission, 10 (83%) had MRD Conclusions Indoximod is well tolerated in combination with standard AML induction therapy. Rates of morphologic response and of MRD-neg status are very promising. The recommended phase 2 dose (RP2D) was 1200 mg oral Q8h and a placebo-controlled randomized phase 2 study is under development. Disclosures Emadi: NewLink Genetics: Research Funding. Loken:Hematologics, Inc: Employment, Equity Ownership. Kennedy:NewLink Genetics: Employment, Equity Ownership. Link:NewLink Genetics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Munn:NewLink Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: Aurora kinases play essential roles in regulating cell division, and increased expression has been noted in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We previously conducted a phase I study of alisertib combined with "7+3" induction chemotherapy in untreated patients with AML, and found the combination to have an adverse event profile similar to 7+3 alone, with promising efficacy, particularly for patients with high-risk disease, such as those who were older, with high-risk molecular features, or with secondary AML. These patients collectively have a historically grim prognosis, with an approximate rate of remission, in trials, of 45%. CPX-351, a liposomal daunorubicin-cytarabine product, was recently approved for use in secondary AML after it was demonstrated to be superior to 7+3 induction, with a median survival of 9.6 months versus 5.9 months among older patients, in a phase 3 trial. We recently completed accrual to a phase II study of alisertib plus induction chemotherapy in patients with untreated, high-risk AML. Methods: Patients were eligible if they had AML defined by WHO 2016 and either an adverse-risk karyotype (European Leukemia Net Guidelines), secondary (post-MDS/MPN) AML, therapy-related AML, or age ≥ 65 vears. We used a Simon two-stage design, assuming a null composite remission rate (complete remission [CR] and CR with incomplete count recovery [CRi]) of 45%. Patients could be enrolled prior to cytogenetic classification, but those without adverse-risk karyotype who lacked other eligibility criteria were removed before day 8 and replaced. All patients received continuous infusion cytarabine 100mg/m2 on days 1-7 [D1-7] and idarubicin 12mg/m2 [or daunorubicin 60mg/m2] D1-3 (7+3). On D8 through D15, alisertib at 30mg BID orally (PO) was administered. All underwent a mid-induction marrow biopsy to assess for residual disease, which if present, was treated with 5+2 re-induction without alisertib. Following remission, patients could receive up to 4 consolidation cycles with cytarabine (3g/m2 BID D1,3,5 for age Results: 39 eligible patients were enrolled. The median age was 67 (range 33-83); 25 (64%) were male, and 33 (85%) were Caucasian. 22 patients (56%) had secondary AML (16 with antecedent MDS, 2 with antecedent CMML, 1 with antecedent MPN, and 3 with therapy-related AML). 13 (33%) exhibited adverse risk karyotype. FLT3 mutations were seen in 7 (18%), NPM1 in 7 (18%), IDH1 in 5 (13%), IDH2 in 5 (13%), CEBPA in 3 (8%), and TP53 mutations in 4 (10%) patients. 33 patients (85%) demonstrated an ablated marrow at mid-treatment, and six (15%) received re-induction at mid-treatment. 8 patients (21%) were refractory to induction, and five (13%) died prior to response assessment due to infection or bleeding. The 30-day and 60-day mortality rates were 8% and 13%, respectively. Patients experienced expected grade 4 toxicities of leukopenia, anemia, thrombocytopenia, and febrile neutropenia; no new attributable safety signals were detected. The CR+CRi rate was 64% (2-stage 95% CI 48-79%) with 20 patients (51%) achieving CR and 5 (13%) achieving Cri. The CR+CRi rate was 59% (13 of 22) in those with secondary AML, 67% (18 of 27) in those aged ≥ 65, 77% (10 of 13) in those with adverse risk karyotype, and 75% (3 of 4 patients) in patients with TP53 mutations. One (3%) patient achieved a partial remission. Based on the composite remission rate of 64%, the combination was deemed effective per study design. 5 patients have relapsed to date. 10 have received at least 1 cycle of consolidation, 16 patients (41%) have gone on to SCT. With a median follow-up of 14 months (Figure), the 12-month overall survival (OS) is 51% (37-65%). Although the data continues to mature, median OS is 12.2 months (90% CI 8.8-NA). In the subset of patients achieving a CR+CRi, the 12-month relapse-free survival was 52% (90% CI 34-67%). Conclusions: Alisertib, a novel aurora A kinase inhibitor, combined with conventional induction, is efficacious and demonstrates a promising rate of remission and survival among patients with previously untreated high-risk AML. Larger randomized studies are under consideration to better assess the promise of this novel combination. Figure. Figure. Disclosures Brunner: Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. DeAngelo:Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; BMS: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria; Shire: Honoraria; BMS: Consultancy; Amgen: Consultancy; Pfizer Inc: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; ARIAD: Consultancy, Research Funding; Amgen: Consultancy; Takeda: Honoraria; Blueprint Medicines: Honoraria, Research Funding. Amrein:Takeda: Research Funding. Steensma:Acceleron: Consultancy; Amphivena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; H3 Biosciences: Research Funding; Janssen: Consultancy, Research Funding; Kura: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Otsuka: Membership on an entity's Board of Directors or advisory committees; Syros: Research Funding; Takeda: Consultancy. Garcia:Celgene: Consultancy. Rosenblatt:Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees. Chen:Magenta Therapeutics: Consultancy; REGiMMUNE: Consultancy; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceuticals: Consultancy. Fathi:Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Boston Biomedical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Agios: Honoraria, Research Funding; Jazz: Honoraria.

Background: Measurable residual disease (MRD), as determined by quantitation of Nucleophosmin 1-mutated (NPM1mut) transcript levels (TL), provides significant prognostic information independent of other risk factors in patients (pts) with acute myeloid leukemia (AML). This is also addressed by the 2017 European LeukemiaNet (ELN) risk stratification system, which recommends taking into account results from MRD monitoring when selecting the appropriate post-remission therapy. Furthermore, MRD monitoring provides a powerful tool to evaluate treatment effects within clinical trials investigating novel therapies. Aims: To determine the impact of the anti-CD33 immunotoxin Gemtuzumab-Ozogamicin (GO) on kinetics of NPM1mut TL in pts with newly diagnosed NPM1mut AML [18 to 82 years (yrs), median age 58 yrs] enrolled in our randomized Phase III AMLSG 09-09 study (NCT00893399). In this study GO was randomized (1:1) to standard chemotherapy plus ATRA. Patients and Methods: In total, 588 evaluable pts were enrolled in the clinical AMLSG 09-09 study. Standard treatment comprised two cycles of induction therapy with A-ICE (ATRA, idarubicin, cytarabine, etoposide; arm A) followed by three consolidation cycles of high-dose cytarabine (n=371, 63%) or allogeneic hematopoietic cell transplantation (n=42, 8%). In the investigational arm (arm B), GO (3 mg/m²) was given at d1 of each induction and in the first consolidation cycle. 296 pts were randomized to arm A and 292 pts to arm B. For this correlative study, outcome analysis was restricted to the clinical endpoint cumulative incidence of relapse (CIR) due to study protocol requirements allowing overall survival analysis to be performed only two years after the last pt had been enrolled. MRD monitoring was performed in a total 503 pts for whom at least one bone marrow (BM) sample was available using RQ-PCR technique; the median follow-up (FU) of the 503 pts was 2.8 yrs. NPM1mut TL (ratio of NPM1mut/ABL1 transcripts x 104) were determined by RQ-PCR (sensitivity 10-5 to 10-6). Results: In total, 3711 BM samples were analyzed (at diagnosis, n=415; during treatment, n=1765; during FU, n=1531). Both study arms were well balanced with regard to pts characteristics and pretreatment NPM1mut TL. First, we evaluated the impact of GO on kinetics of NPM1mut TL during treatment. After the first induction cycle, median NPM1mut TL were significantly lower in the investigational arm (p=.001) and this was true for all subsequent treatment cycles [after induction II (p=.008), consolidation I (p Conclusion: In our randomized Phase III AMLSG 09-09 study, the addition of GO to intensive chemotherapy plus ATRA was associated with a significantly better reduction of NPM1mut TL after each treatment cycle. This better clearance translated into a significantly lower CIR in the investigational arm with GO. Disclosures Paschka: Otsuka: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Other: Travel support, Speakers Bureau; Jazz: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sunesis: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Travel support; Janssen: Other: Travel support; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Astex: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees, Travel support; Takeda: Other: Travel support. Krönke:Celgene: Honoraria. Fiedler:Amgen: Other: support for meetíng attendance; GSO: Other: support for meeting attendance; Teva: Other: support for meeting attendance; Gilead: Other: support for meeting attendance; JAZZ Pharmaceuticals: Other: support for meeting attendance; ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees, support for meeting attendance; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Pfizer: Research Funding; Amgen: Patents & Royalties; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Other: support for meeting attendance. Schroeder:Celgene: Consultancy, Honoraria, Research Funding. Lübbert:Janssen: Honoraria, Research Funding; TEVA: Other: Study drug; Cheplapharm: Other: Study drug; Celgene: Other: Travel Support. Götze:JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; Celgene: Honoraria, Research Funding. Schleicher:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Investigator; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Ipsen: Membership on an entity's Board of Directors or advisory committees; Eissai: Other: Investigator; Astra Zeneca: Other: Investigator; Pfizer: Speakers Bureau; Janssen: Speakers Bureau; Celgene: Speakers Bureau. Schlenk:Pfizer: Research Funding, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Amgen: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Agios: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Celator: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Bristol Myers Squibb: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Research Funding; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding.

Introduction: After establishing the diagnosis of acute myeloid leukemia (AML), remission induction chemotherapy is started with curative intent. Due to paucity of direct therapeutic comparison of induction regimens, relative efficacy of two drug standard regimens and three drug induction regimens among newly diagnosed young ( Methods: The literature search was performed on PubMed, EMBASE, Cochrane Central Register of Controlled Trials, Web of Science and Clinicaltrials.gov from each database's earliest inception through July 28th, 2018 without language restrictions. Included trials assessed CR after one cycle of induction chemotherapy in adults (17-60 years) diagnosed with AML. We excluded studies with patients ≥60 years, who received double induction chemotherapy or two drug regimens other than standard chemotherapy. Data extraction and quality assessment of trials using GRADE approach was done by two independent reviewers. Any discrepancy was resolved by consensus or consulting the primary investigators. A conventional NMA assuming random effects was fitted to evaluate the pooled effect of induction therapy on CR with standard chemotherapy as reference treatment. The model estimated relative efficacy for each direct and indirect comparison, measured as odds ratio (OR), with uncertainty captured as 95% confidence interval (CI). Chemotherapy regimens were ranked based on the surface under the cumulative ranking curve analysis (SUCRA) with higher values reflecting greater CR. All statistical analyses were conducted using STATA, version 15 (Stata Corp LP, College Station, TX). Results: Our analysis included 8 RCTs (n= 6830) including nine treatment regimens (7+3 or 7+3+X): cytarabine + daunorubicin (DA), cytarabine + idarubicin (IA), DA+ gemtuzumab ozogamicin (DAGo), DA+ 6-thioguanine (DAT), IA+ granulocyte colony stimulating factor (IAG), DA + midostaurin (DAM), DA + cladribine (DAC), DA + fludarabine (DAF), IA + cladribine (IAC). Average median age of included patients was 38.1 years (range = 45-60) and all patients had newly diagnosed primary AML. 10% had favorable cytogenetics, 62% intermediate and 27% had high risk cytogenetics. Through the network meta-analysis IA achieved highest CR rates [OR of 1.85 (95% C.I: 1.02-3.35)] compared to other included regimens (Figure 1). There was no statistically significant difference in achieving CR between anthracycline based standard chemotherapy versus three drug regimens [IAC = 0.85 (0.25-2.87), DAGo = 1.09 (0.75-1.59), DAF = 1.10 (0.73-1.63), DAT = 1.19 (0.78-1.82), DAM = 1.24 (0.88-1.77), DAC = 1.38 (1.00-1.90), AIG = 1.83 (0.90-3.75)] (Figure 2). A dose specific subgroup analysis of daunorubicin (60 mg/m2) containing regimens showed no statistical difference between different therapies [DAG = 1.09 (95% CI: 0.75-1.59), DAF = 1.10 (95% CI:0.73-1.63), DAM = 1.24 (0.88-1.77), DAC =1.38 (1.00-1.90)] (Figure 1). Conclusion: Our results demonstrate that combination of cytarabine with idarubicin achieved highest rates of CR after one cycle of induction therapy in newly diagnosed young AML patients. There was no statistical difference between the efficacy of other standard regimens and three drug regimens. Head-to-head trials are required to reliably demonstrate the relative efficacy of these regimens. Disclosures No relevant conflicts of interest to declare.

Introduction In acute myeloid leukemia (AML) older age is independently associated with poor outcome, due to patient- and disease-related factors. Different genetic profiles characterize AML patients and their frequency varies according to age. Their identification can improve early risk stratification to select the most appropriate therapy, including alternative, not chemotherapy based, treatment modalities, such as hypomethylating and targeted agents (Döhner H et al., Blood 2017). We analyzed the clinical outcome of AML patients aged ≥60 years who were enrolled in the randomized multicentric trial NILG 02/06, and were deeply genetically characterized (Clinical Trials.gov Identifier: NCT00495287). Patients and Methods Five hundred seventy-four newly diagnosed AML patients were enrolled into the study and 168 were aged ≥60 years; all patients were randomized to receive conventional induction chemotherapy with idarubicin, cytarabine and etoposide (ICE) or sequential high-dose cytarabine and idarubicin (sHD), followed by consolidation courses with high dose cytarabine (Bassan R et al., annual congress EHA. Jun 9, 2016, abstr S485). Genetic characterization at diagnosis was obtained by conventional cytogenetics and RT-PCR for 145 and 168 patients, respectively, while Next Generation Sequencing was performed for 51 patients with normal karyotype. Patients were re-classified as per the 2017 European Leukemia Net (ELN) guidelines (Döhner H et al., Blood 2017). A myelodysplastic/myeloproliferative (MDS/MPN) related genetic signature was defined according to cytogenetic WHO criteria and/or molecular abnormalities known to be associated with MDS/MPN (Bullinger L et al., J Clin Oncol 2017) and used for outcome correlation. Results The characteristics of patients are summarized in Table 1. According to the ELN risk stratification, patients were classified as favorable, intermediate or adverse risk (23%, 38% and 39% of patients, respectively). A genetic MDS/MPN signature was demonstrated in 42% of patients (63/149), which was a higher proportion compared to that of patients with a clinical diagnosis of an antecedent MDS/MPN (19% of patients, 32/168). No significant difference was observed between the induction regimens regarding the achievement of complete remission (CR) (71% for sHD and 61% for ICE, P=0.23) and early death rate (12% and 10.6%, P=0.96). After achieving CR, a median of 2 consolidation courses was administered (range 1-5) within both treatment arms. A limited proportion of patients with high-risk genetic or clinical features (14%) had the opportunity to undergo an allogeneic hematopoietic stem cell transplant (alloHSCT), the majority of them (63%) receiving a reduced intensity conditioning. By intention to treat, 5-years overall survival (OS) and disease- free survival (DFS) on the whole study population were 29% and 32% respectively, without significant differences between the remission induction treatment (for sHD and ICE, OS: 29% and 28%, P=0.88; DFS: 34% and 29%, P=0.90). According to the ELN risk stratification, 5-years OS was 68%, 25% and 7% for favorable, intermediate and adverse groups (P Conclusions Older AML patients with favorable risk features according to ELN benefit from standard chemotherapy. The definition of an adverse genetic risk profile and particularly of a MDS/MPN signature is crucial to identify patients who have a very dismal outcome. These patients should be considered for alternative, innovative treatment options. In high-risk, ≥60 years old AML patients with a good performance status, alloHSCT significantly improves both OS and DFS and should always be considered as the most effective post consolidation treatment. Disclosures Cattaneo: GILEAD: Other: Advisory Board. Cortelezzi:janssen: Consultancy; novartis: Consultancy; abbvie: Consultancy; roche: Consultancy. Rambaldi:Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Amgen Inc.: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy.

Secondary Acute Myeloid Leukemia (sAML) accounts for 10-30% of all AML. It arises from a preexisting clonal disorder of hematopoiesis, such as myelodysplastic syndromes (MDS) or chronic myeloproliferative neoplasia (cMPN) in most cases (60-70%) or from exposure to a leukemogenic agent e.g. chemotherapy. sAML is generally considered to be of unfavorable prognosis, as treatment sensitivity is reduced, compared to de novo AML (dnAML) and overall survival is shortened. The incidence of AML associated NRAS are similar between sAML and dnAML (10 to 15%, Jelena D. Milosevic et al.). Prognostic impact of such mutations have been controversially discussed, but have been linked to favorable response to high dose cytarabine treatment in dnAML patients (Andreas Neubauer et al.), thus providing the first example of an oncogenic mutation impacting drug response in dnAML. This effect, however, has not yet been shown in sAML, therefore the aim of this work is to study the role of mutated NRAS in the response to chemotherapy and the hypomethylating agent (HMA) 5-azacitidine in sAML. We utilized two sAML cell lines SET-2 and HEL (both NRAS wildtype) in which we stably introduced the NRAS WT and the known activating hotspot mutation NRAS G12D using the sleeping Beauty technology. The dose-response assays of conventional chemotherapy and 5-azacitidine were carried out in the parental cell lines (SET-2/HEL) compared to NRAS WT (SET-2 NRAS WT/HEL NRAS WT) and NRAS G12D (SET-2 NRAS G12D/HEL NRAS G12D). In contrast to our expectations, both NRAS G12D mutation harboring cell lines, SET-2 and HEL developed resistance to cytarabine, idarubicin and 5-azacytidine, whereas the ones with wildtype NRAS remained susceptible to the drugs. To reverse the resistance we tested the MEK inhibitors Binimetinib and Trametinib in our SET-2 NRAS G12D cell line model according to recent reports about preclinical efficacy of MEK inhibition in NRAS mutant dnAML cells (Michael R. Burgess et al.). And in fact, single agent Binetimib and Trametinib treatments reduced cell viability by 20% at 48 hours. Strikingly, in combination with 5-azacitidine, Binimetinib and Trametinib treatments led to a viability reduction by 90%. Next we induced necroptosis in our NRAS mutant cell line models through the combination of Birinapant (SMAC mimetics) and Emricasan (Inhibitor of Caspase 8), as recently described by Brumatti et al. and were, in addition, able to reduce the cell viability by 60 %. In summary, we provide first evidence, that in contrast to dnAML, activating NRAS mutations may promote resistance to conventional chemotherapy and 5-azacitidine in sAML cell lines. Furthermore we were able to demonstrate, that the combination of MEK inhibitors (Binimetinib and Trametinib) and 5-azacitidine as well as the induction of necroptosis such as the combination birinapant and emricasan, may provide a potential strategy to overcome the resistance. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Introduction Patients with relapsed/refractory acute myeloid leukemia (AML) have a dismal prognosis. Achieving a remission with high-dose chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) remains the only curative approach. However, providing intensive salvage chemotherapy in order to obtain complete remission (CR) before alloHCT may be associated with significant morbidity that may preclude alloHCT. Furthermore, the lag period between the end of salvage chemotherapy and hematologic recovery may allow concomitant leukemic blast cell recovery. In attempt to solve this dilemma, Schmid et al. introduced in 2005 for the first time the sequential conditioning concept consisting of short course of chemotherapy to reduce the leukemic burden, followed shortly by RIC regimen. Aim Assess the feasibility of a transplantation strategy consisting of sequential cytoreductive chemotherapy with fludarabine, cytarabine, and idarubicin (FLAG-IDA) followed sequentially by tailored conditioning regimen and alloHCT (FLAG-IDA HCT) Methods A retrospective analysis of patients treated with the sequential FLAG-IDA HCT strategy in a single center between 01/2014 and 12/2017. Salvage chemotherapy consisted of fludarabine 30mg/m2 (days 1-5), cytarabine 2g/m2 (days 1-5) and idarubicin 12mg/m2 (days 3-5; FLAG-IDA). Dose reduction for cytarabine (1g/m2) and idarubicin (8-10mg/m2) were allowed for older patients and those with cardiac dysfunction, respectively. FLAG-IDA was followed within 3 days by conditioning regimen tailored according to the patient's clinical condition and co-morbidities. Graft versus host (GVHD) prophylaxis consisted of cyclosporine and short course of methotrexate (MTX). In patients with liver toxicity, renal failure, or grade 3-4 mucositis, MTX was replaced by mycophenolate mofetil. Antithymocyte globulin (ATG, Fresenius) was given to patients transplanted from unrelated and mismatched donors. Results 27 patients [median age, 64 years (range, 23 to 73) (3 patients >70 years)] received the sequential FLAG-IDA HCT regimen. Most (n=24) patients had AML followed by acute lymphoblastic leukemia, mixed phenotype acute leukemia and myelodysplastic syndrome (1 patient each). 52% (n=14) had primary refractory disease, 37% (n=10) had relapsed disease and 11% (n=3) were treated upfront for adverse-risk AML. All patients had active disease upon treatment initiation and 22% had more than 50% blasts in bone marrow (Table 1). Dose reduction of cytarabine and idarubicin were applied in 48% (n=13) and 26% (n=7) of the patients, respectively. A myeloablative conditioning (MAC), busulfex-based (n=3) or treosulfan-based (n=22), was applied in 25 patients (92%), and 11 (41%) received in-vivo T-cell depletion. 24 patients were transplanted from a matched sibling (n=12) or unrelated (n=12) donor and 3 from a mismatched donor, all but one from peripheral blood stem cell grafts. Median time to neutrophil and platelet engraftment was 12 (range, 8 to 26) and 14 (range, 8 to 68) days, respectively. Six patients (22%) died by day +30, all from infectious complications. Among 21 evaluable patients by day +30, 20 (95%) were in CR with full donor chimerism. With a median follow up of 19 (range, 6 to 52) months, 6 patients are still alive and in CR. Median 1-year OS was 206 days (Figure 1). In total, 21 (77%) patients died: 9 (33%) from relapse, 7 (26%) from infectious complications and 5 (19%) from other causes (acute GVHD, n=3, sarcoma, n=1, late idiopathic neurotoxicity, n=1). Infectious complications were frequent; 32 episodes of clinically documented infections were noted in 18 (67%) patients. These included 25 blood stream infections in 16 patients: bacteremia (n=17) and candidemia (n=3). Grade 2-4 acute GVHD and grade 3-4 acute GVHD by day +100 were documented in 48% and 30% of the patients, respectively. CONCLUSIONS FLAG-IDA HCT is a feasible strategy for relapsed/refractory acute leukemia patients that would have otherwise an extremely dismal prognosis. Yet, this regimen is associated with high early non-relapse mortality. Modifications of this regimen are warranted in order to reduce non-relapse mortality, without compromising the anti-leukemic effect. Disclosures No relevant conflicts of interest to declare.