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In spite of CR rates of 75-80% currently achieved with anthracycline-cytarabine regimens in younger patients with favorable and intermediate-risk AML, relapse remains a major issue. The French AML intergroup launched the BIG-1 trial in 2015 in order to test different strategies aiming at reducing relapse rate and improving survival. All patients with previously untreated non-APL and non-CBF AML aged 18-60 years are eligible for trial participation which is still ongoing. The trial design includes several randomizations (R): Idarubicin vs daunorubicin for induction (R1), HDAC vs IDAC for consolidation (R2), post-transplant GVHD prophylaxis modalities (R3). R4 consists of nested randomized phase 2-3 trials testing the addition of new drugs to the IDAC or HDAC backbones during the consolidation phase. The protocol was designed to allow the sequential evaluation of several new agents over the trial period. Vosaroxin (VOS) has shown antileukemic activity (Advani, Clin Cancer Res 2010). The combination of VOS and IDAC showed higher CR rate and a non-significant OS benefit as compared to a placebo-IDAC arm in a large phase 3 trial in patients with refractory/relapsed AML (Ravandi Lancet Oncol 2015). We hypothesized that the addition of VOS to IDAC would improve LFS as compared to IDAC alone when given during the consolidation phase. Methods. Eligibility criteria in the BIG-1 trial include: previously untreated AML according to WHO 2016 classification (AML secondary to an untreated myelodysplastic syndrome allowed), age 18-60, ECOG PS 0-2, no cardiac contra-indication to anthracyclines. Patients with APL and patients with CBF-AML are excluded. Eligibility criteria for R4 randomization were: Patients in first CR/CRp/CRi following 1 or 2 courses of induction chemotherapy according to the BIG-1 protocol; ELN2010 favorable- and intermediate-risk groups; ECOG PS ≤ 3; Absence of severe uncontrolled infection. Patients were scheduled to receive Cytarabine: 1.5 gr/m² twice daily on D1, 3, 5 with or without Vosaroxin: 70 mg/m² on D1 and D4 per cycle for a maximum of three cycles at 4-6 weeks intervals. Patients scheduled for allo-SCT or those who had reached CR after 2 induction cycles were to receive only 2 cycles of VOS-IDAC/IDAC. R4-VOS sub-trial was designed to detect an increase of the 18-month LFS from 55% to 75% using a two-step phase 2-3 study. With type I and II errors set at 20% and using a one-sided test, 70 patients had to be randomized. If the predefined statistical objectives were met, study would resume recruiting 130 additional patients in the phase 3 part for a total of 200 patients. Results. 70 patients (35 in each arm), median age 47, ELN 2010 favorable and intermediate risk groups, have been included. 94% had de novo AML with NPM1 mutations in 46% and FLT3-ITD in 20%. As shown in the Table, patients and disease characteristics were not different between the 2 arms except for slightly more patients in CRi in the VOS-IDAC arm. Patients received a median of 4 chemotherapy cycle (including induction; range 3-4) without difference between the treatment arms. 13 patients (18.5%) received an alloSCT (VOS-IDAC: 5, IDAC: 8). Time between cycle 1 and cycle 2 was significantly longer in the VOS-IDAC arm (p= 0.017). Hematologic toxicity was higher in the VOS-IDAC group with a significantly longer neutropenia duration after each cycle, a greater number of RBC and Platelet transfusions, a significantly greater number of days with antibiotics and antifungal therapies and days with fever (during cycle 1). There were also significantly more cutaneous toxicity, mild nausea/vomiting and diarrhea in the VOS-IDAC arm. With a median follow-up of 19 months, 14 and 15 patients relapse in the VOS-IDAC vs IDAC arms respectively. The study primary endpoint has not been reached and LFS was not significantly higher in the VOS-IDAC arm (18-month LFS of 51% vs 46% for VOS-IDAC vs IDAC respectively; see Figure) even after accounting for allo-SCT as a time-dependent variable (p-value=.49). The 2-year CIR was 51% vs 46% (p=NS) and 2-year OS was 88% vs 68% (p=NS). Conclusion, the study's primary endpoint has not been met and results fail to show a significant improvement of 18-month LFS with the addition of VOS to IDAC consolidation of favorable/intermediate-risk AML in first CR. The phase 3 part of the trial will not open. The BIG-1 trial is still ongoing and uses the same design to tests addition of other drugs to the IDAC/HDAC consolidation backbone. Disclosures Guieze: abbvie: Honoraria, Other: advisory board, travel funds; janssen cilag: Honoraria, Other: advisory board, travel funds; roche: Other: travle funds; gilead: Honoraria, Other: travel funds; astrazanecka: Honoraria, Other: advisory board. Dombret:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Nova: Consultancy, Research Funding; Celgene: Consultancy; Jazz Pharma: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sunesis: Consultancy; Servier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Menarini: Consultancy; Janssen: Consultancy; Cellectis: Consultancy; Shire-Baxalta: Consultancy; Immunogen: Consultancy; Otsuka: Consultancy; Abbvie: Consultancy. Hunault:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Diachi: Membership on an entity's Board of Directors or advisory committees; Jansen: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

Background: AML is an aggressive malignancy with a median age of 67 yrs at diagnosis and an age-adjusted 5-yr survival of less than 25%. Most older patients (pts) with AML have poor risk cytogenetic/genetic features associated with suboptimal complete remission (CR) rates and overall survival (OS). Until recently, the anthracycline and cytarabine based induction remained unchanged for over 4 decades. Vosaroxin (Vos) is a first-in-class anticancer quinolone derivative which is thought to induce less cardiac toxicity than standard anthracycline therapy. Vos was previously administered in combination with intermediate dose cytarabine (IDAC) in relapsed/refractory (r/r) AML pts in a large randomized phase 3 trial (VALOR) and demonstrated significantly improved CR rates compared to IDAC alone but without improvement in OS. In the VITAL study, we investigated the combination of infusional cytarabine (iAC) with Vos ("7 + V") in newly diagnosed AML. Methods: VITAL (NCT02658487) is a single-arm, open-label, two-stage phase II study of 90 mg/m2, Vos on days 1 and 4 (reduced to 70 mg/m2, days 1 and 4 in the event of re-induction) and 100 mg/m2 continuous iAC on days 1-7. Oral cryotherapy was administered during Vos administration as prophylaxis for oral mucositis seen in prior studies. Enrollment in stage 1 was limited to 17 evaluable pts >55 yrs of any risk classification or pts 18-54 years with high-risk disease. The two-stage design required CR in more than 7 of the first 17 pts in order to proceed to stage 2. The operating characteristics of the study design provided a 64% probability of early termination if CR occurred in 7 or fewer pts suggesting that the true CR rate would be ≤ 40%. Stage 2 included an additional 24 pts (age 18-54 yrs with intermediate or high-risk disease, or 55 years or older with any risk disease). Response was assessed using the modified IWG-2003 criteria. Results: In total, 42 pts were enrolled and assessed for toxicity. One patient who achieved an aplastic marrow biopsy at day 14, succumbed to an AML-related sepsis event prior to formal response assessment was initially deemed unevaluable for response and replaced but was ultimately included in the response assessment. Baseline demographics of the 42 enrolled pts are seen in Table 1a. Median age was 63 yrs (range, 43-74) and 86% (36/42) were ≥ 55yrs at time of enrollment. Almost all, 40/42 (95%), had intermediate (11/40) or poor (29/40) risk AML. Adverse events (AEs) of special interest of any Grade (Gr) and Gr 3-5 AEs occurring in > 10% of pts are listed in Table 1b. Oral mucositis was observed in 16/42 (38%) pts with 12/42 (29%) having Gr 1-2 and only 4/42 (10%) having Gr 3 severity. Three Gr 5 events occurred (2-Infection/Sepsis; 1-neutropenic colitis). No acute cardiac toxicity was seen. CR was achieved in 20/42 (48%) pts, while 3 additional pts achieved CR with incomplete count recovery (CRi) for a CR/CRi rate of 55% (23/42). CR was observed in 100% (2/2) with favorable risk (both >65 yrs old). CR/CRi was seen in 73% (8/11) intermediate and 45% (13/29) poor risk pts. One poor risk pt with CRi converted to CR in the absence of additional therapy but did so outside of the protocol defined time period for response assessment (Day 57 +/- 3 days) and was recorded as CRi for this analysis. CR/CRi was noted in 40% (4/10) pts whose AML had TP53 mutations. Allogeneic hematopoietic stem cell transplant was performed in 45% (19/42) of pts. Progression-free survival was 43% and OS was 48% for all pts at 1-year of follow-up (Figure 1). Conclusion: The combination of Vos and iAC in newly diagnosed AML pts appears safe. Mucocutaneous complications were observed as noted in previous studies with Vos. Administration of oral cryotherapy during Vos administration appeared to reduce occurrence of oral mucositis during induction, but > Gr 3 neutropenic enterocolitis occurred in 7/42 (17%) pts. Still, the combination appears to be tolerable with an adverse event profile analogous to conventional induction regimens. While the VALOR trial observed Gr 3-5 cardiac AEs in < 1% of the 705 r/r AML pts with prior anthracycline exposure, no attributable cardiac events were seen within the VITAL trial population. Vosaroxin and infusional cytarabine is a clinically active induction regimen which warrants further investigation based on response rates and toxicity profile at least similar to current anthracycline based induction strategies with an apparent absence of cardiac toxicity. Disclosures Strickland: Astellas: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Sunesis: Research Funding; AbbVie: Consultancy. Podoltsev:Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Kartos Therapeutics: Research Funding; Astellas Pharma: Research Funding; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding. Zeidan:Acceleron Pharma: Consultancy, Honoraria, Research Funding; Celgene Corporation: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Otsuka: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Medimmune/AstraZeneca: Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Trovagene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Research Funding; Jazz: Honoraria; Ariad: Honoraria; Agios: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Daiichi Sankyo: Honoraria; Cardinal Health: Honoraria; Seattle Genetics: Honoraria; BeyondSpring: Honoraria. Byrne:Karyopharm: Research Funding. Gore:Celgene Corporation: Consultancy, Research Funding. Savona:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; AbbVie: Membership on an entity's Board of Directors or advisory committees; Sunesis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding.

The development of new treatments for older patients with acute myeloid leukemia is an active area, but has met with limited success. Vosaroxin, a quinolone-derived intercalating agent has several properties that could prove beneficial. Initial clinical studies showed it to be well-tolerated in older patients with relapsed/refractory disease. In vitro data suggested synergy with cytarabine (Ara-C). To evaluate vosaroxin, we performed 2 randomized comparisons within the “Pick a Winner” program. A total of 104 patients were randomized to vosaroxin vs low-dose Ara-C (LDAC) and 104 to vosaroxin + LDAC vs LDAC. When comparing vosaroxin with LDAC, neither response rate (complete recovery [CR]/complete recovery with incomplete count recovery [CRi], 26% vs 30%; odds ratio [OR], 1.16 (0.49-2.72); P = .7) nor 12-month survival (12% vs 31%; hazard ratio [HR], 1.94 [1.26-3.00]; P = .003) showed benefit for vosaroxin. Likewise, in the vosaroxin + LDAC vs LDAC comparison, neither response rate (CR/CRi, 38% vs 34%; OR, 0.83 [0.37-1.84]; P = .6) nor survival (33% vs 37%; HR, 1.30 [0.81-2.07]; P = .3) was improved. A major reason for this lack of benefit was excess early mortality in the vosaroxin + LDAC arm, most obviously in the second month following randomization. At its first interim analysis, the Data Monitoring and Ethics Committee recommended closure of the vosaroxin-containing trial arms because a clinically relevant benefit was unlikely.

Intermediate dose cytarabine (IDAC) defined by daily intravenous bolus of 1g/m² during 5 days has been recently defined as the standard control arm in phase 3 placebo-controlled randomized trials for patients with relapsed or refractory acute myeloid leukemia (R/R AML). In these trials assessing clofarabine/IDAC (CLASSIC-1 study, Faderl S et al., JCO 2012) or vosaroxin/IDAC (VALOR study, Ravandi F. et al., Lancet Oncol 2015) vs placebo/IDAC, complete remission rates and median overall survival with placebo/IDAC were 17.8%/18.9% and 6.3/6.1 months in the CLASSIC-1 and VALOR studies, respectively. However, the dose-intensity of this IDAC regimen remains questioned in routine practice since many centers still use higher doses of cytarabine often in combination with an anthracycline and a third drug including fludarabine, etoposide or gemtuzumab ozogamycin (FLAG-ida, MEC or MIDAM regimen for example) although these regimen have proved little efficacy and higher toxicity. We assessed the outcome of R/R AML patients that fulfilled main VALOR inclusion criteria consecutively treated in our center with intensive salvage regimen. All patients with a diagnosis of AML in first relapse or with refractory disease were eligible for this study. Acute promyelocytic leukemia were excluded. Relapse was defined as re-emergence of at least 5% leukemia blasts in bone marrow or at least 1% blasts in peripheral blood 90 days to 24 months after first complete remission or complete remission with incomplete platelet recovery. Refractory AML was defined as persistent disease at least 28 days after initiation of induction therapy, or relapse less than 90 days after first complete remission (CR) or CR with incomplete platelet recovery (CRi). All patients have received previous induction therapy with an anthracycline. Salvage regimen used were mainly cytarabine 3 g/m²/12h, d1-4 plus idarubicine 12 mg/m²/d, d1-3 or dauno 60 mg/m²/d, d1-2 or amsacrine 200 mg/m²/d, d1-3; less frequently MiDAM (mitoxantrone 12mg/m² d1-3, cytarabine1 g/m²/12h d1-5, GO 4-6mg/m², d4) or FLAG-Ida. Cytarabine dose for patients >60 was reduced to 1g/m²/12h, d1-5. We found, in our database, 151 R/R AML according to VALOR criteria treated between 2000 and 2013: 72 patients (48%) had refractory diseases (primary refractory: n=60, 40% and relapse less than 90 days after CR: n=12, 8.0%) and 79 (52%) had relapsed (early relapse more than 90 days after CR and less than one year: n=52, 66%; late relapse between one and two years: n=27, 34%). Patients characteristics were as follows: 85 (56%) were male, median age was 48 years (interquartile range [IQR], 36-60.5; 38 (27%) were 60 years or older). Cytogenetics at diagnosis was favorable in 18 (12%); intermediate in 93 (62%); adverse in 38 (25%) or unknown in 2 (1%) patients, respectively. They were treated as first line therapy with one (42%) or two cycles (58%). Early death rates at day 30 and day 60 were 7% and 17% in the whole cohort; 6% and 12% in younger patients and 12% and 29% in patients 60 years or older. Combined CR rate (defined as CR and CRi) was 53% for the whole cohort, and 57%/42%/56%/52%/63%/50% for Using VALOR inclusion criteria, age is the main factor that discriminate R/R AML patients selected for clinical trials using IDAC as control arm compared to patients of daily practice. Thus, those patient populations remain hardly comparable. However, as far as CR is concerned, IDAC seems suboptimal as compared to higher-intensity regimen used in daily practice. Yet, this higher CR rates do not translate into a significant gain in survival since median OS remains close to that of IDAC with the possible exception of refractory patients who seem to benefit from higher-intensity regimen. Thus, although unsatisfactory, IDAC could be considered as a fair control arm for overall survival endpoint especially in patients older than 60 year of age. Table Table. Disclosures Tavitian: Novartis: Membership on an entity's Board of Directors or advisory committees. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity's Board of Directors or advisory committees. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding.

Background: Prognosis for older patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) is poor, with lower response rates and shorter survival compared with younger patients. Vosaroxin is a first-in-class anticancer quinolone derivative that is active in AML, is minimally metabolized, evades P glycoprotein receptor-mediated efflux, and has activity independent of p53 status. In the phase 3 VALOR trial, overall survival (OS) was significantly improved with vosaroxin plus cytarabine vs placebo plus cytarabine in a prespecified analysis in patients ≥ 60 years of age (median OS: 7.1 mo vs 5.0 mo, respectively; HR = 0.75 [95% CI: 0.62-0.92]; P = 0.0030). At the time of the primary analysis (September 2014), patients had been followed for a median of 24.4 months (as estimated by the reverse Kaplan-Meier method). Here, after a median follow-up of 39.9 months, we provide updated survival information for patients ≥ 60 years treated in the VALOR trial. Methods: In VALOR, patients with refractory or first relapsed AML were randomized 1:1 to receive cytarabine (1 g/m2 IV over 2 h, d 1-5) plus either vosaroxin (90 mg/m2 IV over 10 min, d 1, 4; 70 mg/m2 in subsequent cycles) or placebo. Eligible patients had refractory disease (persistent disease after induction, or first complete remission [CR1] lasting < 90 d) or were in first relapse (early relapse: CR1 lasting 90 d to 12 mo; late relapse: CR1 lasting 12 mo to 24 mo). Randomization was stratified by age (< 60, ≥ 60 years), disease status (refractory, early relapse, late relapse), and geographic location (US, non-US). Patients were followed for survival until death. At the time of the primary analysis (September 2014), 63/451 (14%) patients ≥ 60 years were alive and in continued follow-up. Results:As of Jan 22, 2016, 33/451 patients ≥ 60 years treated in the VALOR trial were alive and in continued follow-up: 23/226 (10.2%) in the vosaroxin/cytarabine arm and 10/225 (4.4%) in the placebo/cytarabine arm. Updated OS data in patients ≥ 60 years of age was consistent with the primary analysis, demonstrating a significant improvement with the addition of vosaroxin (Figure; HR = 0.75 [95% CI: 0.62-0.91]; P = 0.0017). The survival benefit associated with vosaroxin/cytarabine was durable, as demonstrated by the separation of the survival curves through 48 mo. At 24 and 36 mo after randomization, the estimated survival rate was twice as high with vosaroxin/cytarabine as with placebo/cytarabine in patients ≥ 60 years (17.0% vs 8.5% and 12.8% vs 6.0%, respectively). The OS benefit was consistent across various age subgroups in the population ≥ 60 years of age; in patients 60-64 years (n = 124), 65-74 years (n = 293), and 75-84 years (n = 34), vosaroxin/cytarabine treatment increased median survival by 2.9 mo (8.1 vs 5.2 mo; HR = 0.72 [95% CI: 0.49-1.06]), 2.0 mo (7.0 vs 5.0 mo; HR = 0.76 [95% CI: 0.60-0.97]), and 2.2 mo (5.5 vs 3.3 mo; HR = 0.72 [95% CI: 0.36-1.45]) over placebo/cytarabine treatment, respectively. An improvement in OS was observed among patients ≥ 60 years who received post-treatment transplantation (n = 91; 19.9 mo with vosaroxin/cytarabine vs 12.2 mo with placebo/cytarbine; HR = 0.70 [95% CI: 0.43-1.13]) and those who did not (n = 360; 5.3 mo vs 3.8 mo, respectively; HR = 0.75 [95% CI: 0.60-0.92]). When analyzed by disease status, the greatest OS benefit was observed in patients ≥ 60 years with refractory disease (n = 210; 6.7 mo with vosaroxin/cytarabine vs 3.8 mo with placebo/cytarabine; HR = 0.75 [95% CI: 0.57-1.00]) and those with early relapse (n = 154; 6.5 mo vs 3.9 mo, respectively; HR = 0.62 [95% CI: 0.44-0.87]). In patients ≥ 60 years with late relapse (n = 87), median OS was similar in both treatment arms (9.2 mo with vosaroxin/cytarabine vs 9.8 mo with placebo/cytarabine; HR = 1.06 [95% CI: 0.68-1.66]). Conclusions: After a median of 39.9 months of follow-up in the VALOR trial, the OS observed in patients ≥ 60 years of age treated with vosaroxin/cytarabine remains significantly improved versus placebo/cytarabine, with a separation of the survival curves through 48 months. The OS benefit is consistent among all older patients, even those ≥ 75 years of age, and is seen in patients with and without post-treatment transplantation. The updated survival data from VALOR continue to support the use of vosaroxin/cytarabine as a treatment option in patients ≥ 60 years of age with R/R AML. Disclosures Ravandi: BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Ritchie:Novartis: Honoraria, Research Funding; Celgene: Speakers Bureau; Incyte: Speakers Bureau; Pfizer: Honoraria; Arian: Speakers Bureau. Vey:Sunesis: Honoraria. Strickland:Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding. Schiller:Incyte Corporation: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Erba:Ariad: Consultancy; Millennium Pharmaceuticals, Inc.: Research Funding; Celator: Research Funding; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Juno: Research Funding; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Jannsen: Consultancy, Research Funding. Pigneux:Agios: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria. Horst:Amgen, Novartis, Pfizer, Gilead, Agios: Consultancy; Amgen, Regeneron: Research Funding; Celgene: Honoraria. Recher:Celgene, Sunesis, Amgen, Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene, Sunesis, Amgen, Novartis, Chugai: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding. Craig:Sunesis: Employment, Equity Ownership. Ward:Sunesis Pharmaceuticals: Consultancy, Employment. Smith:Sunesis: Employment, Equity Ownership. Stuart:Agios: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Incyte: Research Funding; Bayer: Research Funding; Celator: Research Funding; Astellas: Research Funding.

Background. AML blasts from different patients vary in the agents to which they are most responsive. With a plethora of novel agents to evaluate, there is a lack of predictive biomarkers to precisely assign targeted therapies to individual patients. Primary AML cells often survive poorly in vitro, thus confounding conventional cytotoxicity assays. Dynamic profiling, i.e. functional biomarker assays of responsiveness to chemotherapeutic agents, is an alternative approach to help further the move towards personalised therapy. The purpose of this work was to assess the potential of two same-day dynamic profiling assays in AML cell lines to predict response to chemotherapy. (i) Ribosomal protein S6 (rpS6) is a downstream substrate of PI3K/akt/mTOR/ p70S6 kinase and MAPK/p90S6 kinase pathways and is also dephosphorylated following DNA double strand breaks. It thus has the potential to function as a biomarker of responsiveness to several therapeutic agents. (ii) Cellular propensity for apoptosis can be interrogated via a functional assay termed BH3 profiling. Dynamic BH3 profiling can be used to predict cellular responses to therapy based on priming mitochondria with BH3 domain peptides and thus allowing early detection of pro-apoptotic drug effects on mitochondrial outer membrane permeabilisation. Methods.We measured effects of a short (four hour) incubation with drugs of interest on rpS6 phosphorylation and BH3 peptide-accelerated cytochrome C release by flow cytometry. Baseline rpS6 phosphorylation was determined by culture with the mTOR inhibitor Rapamycin and the MEK inhibitor U0126. BH3 profiling included permeabilisation with digitonin followed by mitochondrial exposure to PUMA BH3-derived peptide. To establish specificity for sensitive cells we also measured dose responses to the drugs in 12 diverse AML cell lines after 48 hours' culture. Results. RpS6 dephosphorylation at four hours closely predicted the 48 hour IC50 for FLT3 inhibitors, an hsp90 inhibitor and topoisomerase II inhibitors. ROC (predictive test) analysis of small molecule inhibitors showed that the assay was highly sensitive and specific with area under the curve (AUC) values of 1.0 (sorafenib), 1.0 (AC220) and 1.0 (17-AAG). RpS6 phosphorylation also predicted response to the double strand break inducing drugs, with AUC values of 1.0 (mylotarg), 0.83 (etoposide) and 0.82 (vosaroxin). In contrast, responses to cytarabine and ABT-199, likely independent of mTOR, MAPK or double strand break response pathways, are not predicted by rpS6 dephosphorylation. PUMA-BH3 peptide-induced cytochrome C release also closely predicted the 48 hour IC50 with AUC values for FLT3 inhibitors of 1.0 (sorafenib) and 1.0 (AC220), double strand break inducing drugs 1.0 (mylotarg), 1.0 (etoposide) and 1.0 (vosaroxin) and a Bcl-2 targeting agent 0.875 (ABT-199). Response to 17-AAG and cytarabine were not predicted by this assay. Preliminary analysis shows that differential responses within primary AML sample subsets can be interrogated with these methodologies. Conclusions. In conclusion, we have established that rpS6 dephosphorylation and/or PUMA-BH3 peptide-induced cytochrome C release predict chemoresponsiveness to tyrosine kinase inhibitors, topoisomerase II inhibitors, an hsp90 inhibitor and a Bcl-2 targeting agent in AML cell lines after short term culture. Both assays are sensitive, specific and amenable to leukaemic sub-population analysis and are thus suitable assays for further development towards use in a clinical setting. pRS6 can be performed on smaller samples and is less technically challenging than priming with PUMA-BH3 peptide, but does not take into account apoptosis resistance that may occur independently of pathways effecting pRS6 inhibition. Disclosures No relevant conflicts of interest to declare.

Background: Although hypomethylating agents are the mainstay of treatment for myelodysplastic syndromes (MDS), these agents produce remissions in a minority of patients and are not curative. Vosaroxin is a first-in-class quinolone derivative that intercalates DNA and inhibits topoisomerase II activity, which is active and tolerable in acute myeloid leukemia (AML). The novel combination of vosaroxin and azacitidine was found to be synergistic in primary myeloblasts. This phase I/cohort expansion trial was conducted to study the combination of vosaroxin and azacitidine for patients with MDS. Methods: Patients with MDS ≥ 18 years of age with cytopenias requiring transfusions, an IPSS score of intermediate-1 or greater, or CMML were eligible. The primary objective was to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of vosaroxin when given in combination with a fixed dose of azacitidine (75 mg/m2 /day). Vosaroxin was administered on days 1 and 4, and azacitidine on days 1-7 of a 28 day cycle, for up to 6 cycles in a 3+3 design. Results: Thirteen patients were enrolled in the dose escalation phase. No patients received prior hypomethylating therapy. The median age was 65 years (range 38-77) with IPSS scores of intermediate-1 (INT-1), (n=4); intermediate-2 (INT-2), (n=7); and high risk (HR), (n=2). At the initial dose of 50mg/m2 /day vosaroxin, 2 of 6 patients experienced a DLT (grade 4 hyperbilirubinemia, and grade 4 neutropenia >42 days). Additional incidences of ≥ grade 3 non-hematologic toxicity in this cohort included: febrile neutropenia (n=6), dysphagia (n=1), mucositis (n=3), infections (n=9), sepsis (n=3), and bleeding (n=3). The vosaroxin dose was de-escalated to 34 mg/m2 /day, resulting in 1 of 6 patients with a DLT (grade 4 mucositis). Incidences of ≥ grade 3 non-hematologic toxicity in this cohort included febrile neutropenia (n=4) and infection (n=4). No patients died within 30 days of treatment. Twelve patients completed at least one cycle and were evaluable for response, assessed by modified IWG criteria (Table). Best response for each patient was as follows: stable disease, n=3; stable disease with hematologic improvement (HI)-neutrophils, n=1; marrow complete remission (CR), n=3; marrow CR with HI-platelets; n=2; marrow CR with HI-neutrophils, n=1; marrow CR with HI-erythroid, n=1; and marrow CR with HI-platelets and neutrophils, n=1. Of these twelve patients, five (42%) have proceeded on to allogeneic stem cell transplantation. Conclusions: The MTD of vosaroxin in MDS patients was 34 mg/m2 /day when given on days 1 and 4 with a fixed dose of 75 mg/m2 of azacitidine on days 1-7. The major non-hematologic toxicities of febrile neutropenia, infections, and mucositis were expected based on the disease population and prior experiences with vosaroxin. The combination of vosaroxin and azacitidine showed promising activity with responses rates comparable or better than those generally observed with azacitidine alone. Additionally, the transplant rate observed was encouraging in this patient population with a median age of 65 years. A cohort expansion with plans to enroll an additional 20 patients at the MTD to further evaluate the tolerability and activity of the combination of vosaroxin and azacitidine in MDS patients is ongoing. In addition, correlative studies of the DNA damage response to the combination of vosaroxin and azacitidine from primary patient samples are in progress. Table 1.Best responsea, n (%)Evaluable patients (N=12)mCR/ mCR-HI8 (67)mCR3 (25)mCR-HI-erythroid1 (8)mCR-HI-neutrophils1 (8)mCR-HI-platelets2 (17)mCR-HI-neutrophil/platelets1 (8)Stable disease4 (33)mCR, marrow complete remission; HI, hematologic improvement.aResponse categories defined according to the modified IWG criteria (Cheson 2006). Disclosures Jacoby: Sunesis: Research Funding; Novo Nordisk: Consultancy. Off Label Use: Vosaroxin is currently under clinical development for the treatment of AML.. Abboud:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Teva Pharmaceuticals: Research Funding; Gerson Lehman Group: Consultancy. Uy:Novartis: Research Funding.

Introduction: The rate of early mortality in patients treated for acute myeloid leukemia (AML) reflects a balance of efficacy and safety outcomes. In the randomized phase 3 VALOR trial in patients with first relapsed or refractory AML, rates of 30-day (7.9% vs 6.6%, respectively) and 60-day (19.7% vs 19.4%, respectively) mortality were comparable between vosaroxin plus cytarabine and placebo plus cytarabine arms. The treatment-related mortality (TRM) score is a prognostic scoring system to predict risk of 30-day mortality with intensive treatment protocols in patients with newly diagnosed AML (Walter, 2011, J Clin Oncol 29:4417-4424). The "simplified TRM" score includes age, performance status (PS), platelet count, serum albumin, type of AML (secondary vs primary), white blood cell count, blast percentage in the peripheral blood, and serum creatinine. Here we present a multivariate analysis to identify baseline predictors of 30-day and 60-day mortality and a post hoc analysis of the 30-day mortality by TRM score to inform the assessment of treatment risk in VALOR patients. Methods: In VALOR, patients were randomized 1:1 to receive vosaroxin (90 mg/m2 intravenously [IV] over 10 min in cycle 1 and 70 mg/m2 in subsequent cycles, d 1 and 4) plus cytarabine (1 g/m2 IV, over 2 h, d 1-5) or placebo plus cytarabine. Baseline factors associated with 30-day mortality and 60-day mortality in patients treated with vosaroxin/cytarabine were identified from a univariate logistic regression analysis. Factors with significant associations (P < 0.10 by Type 3 P values) that were considered clinically and biologically relevant were included in a multivariate logistic regression model in the overall safety population. A stepwise selection procedure with entrance and retention criteria set to 0.05 was employed to reduce the risk factors to a parsimonious set. Simplified TRM scores were calculated retrospectively according to Walter 2011. Results: A total of 705 patients were included in the safety population (355 treated with vosaroxin/cytarabine and 350 treated with placebo/cytarabine). Based on multivariate analysis, vosaroxin/cytarabine treatment was not predictive for increased 30-day or 60-day mortality. Eastern Cooperative Oncology Group PS > 1 was predictive (P < 0.05) of 30-day mortality (odds ratio [OR] = 3.2) and 60-day mortality (OR = 2.1). Additional predictive factors identified for 30-day mortality were hemoglobin < 10 g/dL (OR = 3.8) and bilirubin > 1.0 mg/dL (OR = 3.3). For 60-day mortality, other predictive factors were albumin ≤ 3.6 g/dL (OR = 2.0), intermediate or high bone marrow blasts (10% to < 30% [OR = 2.6] or ≥ 30% [OR = 6.3]), prior myelodysplastic syndrome (OR = 2.2), and achievement of complete remission with first-line therapy (OR = 0.66). Age (< 65 y vs 65-69 y vs 70-74 y vs ≥ 75 y) was not a significant predictor of early mortality in the vosaroxin arm in the univariate logistic regression and therefore was not selected for multivariate analysis, although interestingly, age was predictive of 30-day mortality in the control arm. When added to the final multivariate model, age was of borderline significance (P = 0.0606). The median simplified TRM score at baseline was 2.6 (range 0-21) in the vosaroxin/cytarabine arm and 2.6 (range 0-33) in the placebo/cytarabine arm. Most patients (473/554, 85%) for whom a simplified TRM score could be calculated had a score < 8. Patients with lower TRM scores had lower rates of 30-day mortality (Table). Conclusions: Several individual baseline factors independently predicted risk of early mortality in patients with relapsed/refractory AML treated with vosaroxin or placebo plus cytarabine. In addition, the previously validated TRM score for predicting early mortality in newly diagnosed AML also predicted mortality in this relapsed/refractory population. In future studies of vosaroxin (and other intensive regimens), patient selection based upon these predictors of early mortality should be considered. Table. Thirty-Day Mortality by TRM Simplified Score TRM Simplified Score 30-Day Mortality, n/N (%) Pla/Cyt (n = 350) Vos/Cyt (n = 355) Total (N = 705) < 8 7/228 (3.1) 10/245 (4.1) 17/473 (3.6) 8 to < 16 6/31 (19.4) 5/31 (16.1) 11/62 (17.7) ≥ 16 3/10 (30.0) 5/9 (55.6) 8/19 (42.1) Missing 7/81 (8.6) 8/70 (11.4) 15/151 (9.9) Disclosures Lancet: Seattle Genetics: Consultancy; Kalo-Bios: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Boehringer-Ingelheim: Consultancy. Ritchie:Onyx: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Ariad: Other: Advisory Board; Celgene: Speakers Bureau. Strickland:Amgen: Other: Advisory Board Particpation; Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Boehringer-Ingelheim: Other: Advisory Board Particpation; Alexion Pharmaceuticals: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation. Schiller:Sunesis: Honoraria, Research Funding. Vey:Sunesis: Other: Steering Committee Member. Erba:Sunesis; Pfizer; Daiichi Sankyo; Ariad: Consultancy; GlycoMimetics; Janssen: Other: Data Safety & Monitoring Committees; Seattle Genetics; Amgen: Consultancy, Research Funding; Millennium/Takeda; Celator; Astellas: Research Funding; Novartis; Incyte; Celgene: Consultancy, Patents & Royalties. Recher:Celgene; Amgen; Chugai: Research Funding; Janssen; Novartis; Amgen: Other: Travel, accommodations, expenses; Sunesis; Celgene: Consultancy. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kell:Sunesis: Consultancy, Honoraria. Krug:Boehringer Ingelheim: Research Funding; Novartis; BMS; Roche; Boehringer Ingelheim; Bayer: Honoraria; Sunesis: Speakers Bureau; Sunesis; Clavis Pharma; usa Pharma, Catapult Cell Therapy, Gilead, Roche: Membership on an entity's Board of Directors or advisory committees. Page:Sunesis: Employment. DeVault:Sunesis: Consultancy. Hwang:Sunesis: Consultancy. Craig:Sunesis: Employment, Equity Ownership. Stuart:Sunesis: Honoraria, Other: Advisory Board, Research Funding; Astellas Pharma, Inc: Research Funding.

Background: Vosaroxin, is a first-in-class anti-cancer quinolone derived (AQD) DNA topoisomerase II inhibitor, which is not a substrate for p53 or P-glycoprotein, has limited toxicity, and is currently under evaluation for the treatment of pts with AML and high-risk MDS. Methods: Pts were eligible if they had AML or high-risk MDS (defined as having ³ 10% blasts in the bone marrow), were 60 years of age or older, and had adequate performance status (ECOG ² 2) and organ function. Pts younger than 60 who were unsuitable for standard chemotherapy were also eligible. In the phase I part of the study the first six pts received vosaroxin 90 mg/m2 daily on days 1 and 4 with decitabine 20 mg/m2 daily for 5 days. This dose was well tolerated with no dose limiting toxicity identified and pts were then enrolled on phase II at this dose and schedule. However, due to mucositis in a few subsequent pts, the induction dose of vosaroxin was reduced to 70 mg /m2, starting with pt #25. The vosaroxin dose could be maintained at 70 mg/m2 or reduced to 50 mg/m2 in consolidation cycles, which were repeated in approximately 4 to 5-week intervals for a total of up to 7 cycles. Dose adjustments and dose delays of one or both agents, were allowed based on toxicity. The primary endpoint was to determine the overall response rate including complete response (CR) + CR without platelet recovery (CRp) + CR with insufficient hematological recovery (CRi). Secondary endpoints were: CR duration, disease-free survival, overall survival, safety, and early mortality. Results: To date, 35 pts (32 AML, 3 high-risk MDS) with a median age of 71 years (range, 41-78) have been enrolled; 34 (97%) pts were older than 60 years. They included 15 (43%) pts with diploid cytogenetics, 12 (34%) with complex cytogenetic abnormalities including chromosome 5 and/or 7 abnormalities, and 8 (23%) with other miscellaneous abnormalities. 13 (37%) pts with AML had antecedent hematological disorders (AHD) including 7 (20%) with MDS, 4 (11%) with myeloproliferative neoplasm and 2 (6%) with MDS/MPN. Three pts with AHD had received prior therapy including 5-azacytidine (n=1), ruxolitinib + 5-azacytidine (n=1), and lenalidomide (n=1). Additionally, 5 (15%) pts had therapy-related disease with prior exposure to chemotherapy or radiation therapy. Median bone marrow blast %, median white blood cell, hemoglobin, & platelet counts were 40% (9-97), 4.1 x 109/L (0.4-57.0), 9.4 g/dL (6.8-11.5), and 40 x 109/L (7-333), respectively. 34 pts were evaluable for response; 17 (50%) achieved CR, 6 (18%) CRp, and 3 (9%) CRi for an overall response rate of 77%. One pt is too early for response assessment. Responses by age, cytogenetic and molecular characteristics are shown in table 1. The median follow-up is 5.1 months (range, 0.9-11.0). Pts have received a median of 2 (1-6) treatment cycles with the median number of cycles to response being 1 (1-4). Three pts have relapsed and the median duration of CR/CRp/CRi has not been reached (0.5-9.9+ months). Four (12%) pts have proceeded to allogeneic stem cell transplant (ASCT). 4-week and 8-week mortality were 0% and 14%, respectively. The regimen is well tolerated with the main grade ³ 3 toxicity being mucositis in 9 (26%) pts and liver enzyme elevation in 3 (9%). Conclusion: Combination of vosaroxin and decitabine is effective and feasible in older pts with AML and high-risk MDS. Enrollment is ongoing. Table 1: Response by baseline characteristics Parameter Category N Overall response Too early to evaluate Age* 60-70 16 14/16 (88%) 0 >70 18 12/17 (71%) 1 Cytogenetics Diploid 15 11/14 (79%) 1 -5/-7/other adverse 12 8/12 (67%) 0 Miscellaneous 8 5/8 (63%) 0 Mutation Status IDH2 7 7/7 (100%) 0 IDH1 5 1/4 (25%) 1 TP53 9 6/9 (67%) 0 RAS 9 4/9 (44%) 0 *1 pt below the age of 60 years was unsuitable for standard chemotherapy and was enrolled on study. Disclosures Naval: Sunesis: Advisory board membership Other, Research Funding. Off Label Use: Vosaroxin (Qinprezo) has not been approved for AML. In this clinical trial we are evaluating the efficacy and safety of vosaroxin (Qinprezo) in combination with decitabine in elderly patients with AML. . Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria. Borthakur:Tetralogic Pharmaceuticals: Research Funding. Jabbour:Ariad, Novartis, BMS, Pfizer, and Teva: Consultancy. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Craig:Sunesis: Employment. Ravandi:Sunesis: Advisory board membership Other, Research Funding.

Introduction: Despite 40 years of intense clinical research, there remain no new approved treatments or standard of care for patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). New safe and effective salvage treatments are urgently needed. Vosaroxin is a first-in-class anticancer quinolone derivative that is active in AML. Vosaroxin is minimally metabolized, evades P glycoprotein receptor–mediated efflux and has activity independent of p53 status. VALOR is a rigorously designed and conducted phase 3, adaptive design, randomized, double-blind, placebo-controlled trial evaluating vosaroxin plus cytarabine (vos/cyt) vs placebo plus cytarabine (pla/cyt) in patients with R/R AML (NCT01191801). Methods: Patients were randomized 1:1 to receive cytarabine (1 g/m2 IV over 2 hr, d 1-5) plus either vosaroxin (90 mg/m2 IV over 10 min d 1 and 4; 70 mg/m2 in subsequent cycles) or placebo. Up to 2 induction and 2 consolidation cycles were administered. Eligible patients had refractory disease (persistent disease after induction, or first complete remission [CR1] < 90 d) or were in first relapse (early relapse: CR1 of 90 d to 12 mo; late relapse: CR1 of 12 mo to 24 mo). Patients had received 1-2 cycles of prior induction chemotherapy including at least 1 cycle of anthracycline (or anthracenedione) and cytarabine. Randomization was stratified by disease status (refractory, early relapse, late relapse), age (< 60, ≥ 60 years), and geographic location (US, non-US). Primary efficacy and safety endpoints were overall survival (OS) and 30- and 60-day mortality; secondary endpoints were complete remission (CR) rate and incidence of adverse events (AEs). Results: Between Dec 2010 and Sept 2013, 711 patients were randomized to receive vos/cyt (n = 356) or pla/cyt (n = 355) at 124 sites; per the adaptive design, a prespecified 1-time sample size increase of 225 patients was implemented after the interim analysis. At the final analysis, median OS was 7.5 mo (95% CI: 6.4-8.5) with vos/cyt vs 6.1 mo (95% CI: 5.2-7.1) with pla/cyt (HR = 0.866 [95% CI: 0.73-1.02]; 2-sided unstratified log-rank P = 0.06) (Figure). The OS difference was statistically significant in a preplanned analysis accounting for the stratification factors at randomization (2-sided stratified log-rank P = 0.02). Overall, 29.5% of patients underwent allogeneic stem cell transplant (ASCT), including 45.8% of patients < 60 years and 20.2% of patients ≥ 60 years. Transplant rates were comparable between the 2 treatment arms (30.1% with vos/cyt and 29.0% with pla/cyt). In a predefined analysis censoring for subsequent ASCT, median OS was improved with vos/cyt (6.7 mo vs 5.3 mo with pla/cyt; HR = 0.81 [95% CI: 0.67-0.97]; P = 0.02; stratified P = 0.03) (Figure). In predefined subgroup analyses, OS benefit was greatest in patients aged ≥ 60 years (7.1 mo with vos/cyt vs 5.0 mo with pla/cyt; HR = 0.75; P = 0.003) (Figure) and those with early relapse (6.7 mo vs 5.2 mo; HR = 0.77; P = 0.04). OS with vos/cyt vs pla/cyt was 9.1 mo vs 7.9 mo in patients < 60 years (HR = 1.08; P = 0.60); 6.7 mo vs 5.0 mo in patients with refractory disease (HR = 0.87; P = 0.23); and 14.1 mo vs 12.3 mo in patients with late relapse (HR = 0.98; P = 0.96), respectively. A CR was achieved in 30.1% of patients treated with vos/cyt vs 16.3% treated with pla/cyt (P = 0.00001). Thirty-day and 60-day all-cause mortality was similar in the 2 arms (30-day: 7.9% vs 6.6%; 60-day: 19.7% vs 19.4% with vos/cyt vs pla/cyt, respectively). Most common serious AEs were febrile neutropenia (11.3% with vos/cyt vs 7.4% with pla/cyt), sepsis (8.7% vs 4.3%), pneumonia (7.6% vs 4.9%), bacteremia (8.5% vs 2.9%), and stomatitis (3.4% vs 1.4%). Serious and non-serious cardiac, renal, neurologic, and hepatic AEs were comparable between treatment groups. Conclusion: Vos/cyt demonstrated improved OS and higher CR rates in patients with R/R AML without increased early mortality. In the primary OS analysis, the overall clinical benefit associated with vosaroxin may be underestimated, particularly in younger patients, due to the confounding effect of high transplant rates, a methodological limitation of AML trials. Vosaroxin-containing therapy had acceptable tolerability. VALOR results represent one of the largest datasets available in this setting, and the OS benefit was confirmed by a robust sensitivity analysis. These data support the use of this combination as a new option for salvage therapy in patients with R/R AML. Figure 1 Figure 1. Disclosures Ravandi: Sunesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sayar:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Strickland:Sunesis: Membership on an entity's Board of Directors or advisory committees. Schiller:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Erba:Sunesis: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Pigneux:Sunesis: Consultancy. Horst:Sunesis: Research Funding. Recher:Sunesis: Consultancy; Celgene: Consultancy, Research Funding; Chugai: Research Funding. Klimek:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Craig:Sunesis: Equity Ownership. Fox:Sunesis: Consultancy, Equity Ownership. Ward:Sunesis: Employment, Equity Ownership. Smith:Sunesis: Employment, Equity Ownership. Acton:Sunesis: Consultancy. Mehta:Sunesis: Consultancy. Stuart:Sunesis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.