Abstract: Introduction: Additional cytogenetic clonal evolution (CE) is a known risk factor for a poor prognosis in chronic myeloid leukemia (CML). However, its prognostic significance in the setting of new tyrosine kinase inhibitor (TKI) remains unclear. We sought to analyze the baseline characteristics and clinical outcome in chronic phase (CP) CML pts with or without CE treated on frontline TKI clinical trials in a single institution. Methods: Patients (pts) with Ph-positive CML in CP with or without CE at the time of diagnosis receiving initial therapy with imatinib 400 mg/d, imatinib 800 mg/d, dasatinib 100 mg/d, nilotinib 800 mg/d or ponatinib 30 or 45 mg/d in consecutive or parallel clinical trials at a single institution were analyzed. Overall survival (OS), transformation free survival (TFS), event free survival (EFS), failure free survival (FFS) were analyzed from the start of therapy by Kaplan-Meier method. Clonal evolution (CE) was defined by the presence of any cytogenetic abnormality other than a single Ph, variant Ph chromosome or loss of Y chromosome. Also we analyzed CML pts with CE with regard 'major route' abnormalities vs other. The major route abnormalities includes trisomy 8 (+8), trisomy 19 (+19), isochromosome 17q10 (i17q) and additional Ph chromosome. Results: A total of 603 pts were analyzed including 579 pts in CP without CE and 24 pts with CE. Pts in CP without CE received initial therapy with imatinib-400 (n=70), imatinib-800 (n=200), dasatinib (n=138), nilotinib (n=122), or ponatinib (n=49), and pts with CE received imatinib-400 (n=2), imatinib-800 (n=7), dasatinib (n=10), nilotinib (n=4), and ponatinib (n=1). Pts with CP were usually older, female and have a higher WBC (P 〈 0.001). There was a statistically significant higher Complete cytogenetic response (CCyR) at 6 mo in pts without CE (P = 0.012), however the cumulative and 3-month rates of complete hematologic response (CHR), and the cumulative rates of CCyR and MMR were not different (Table). Similarly, the rates of MR4.0 and MR4.5 were similar for the two groups. At 5 years, the presence of additional cytogenetic findings at diagnosis does not seem to affect the rate of transformation, failure-free, event-free and overall survival. Acknowledging the small sample size for subset analysis, response rates and survival outcomes were comparable in CP with CE irrespective of whether chromosomal abnormalities were 'major route' or other (n=12 in each arm). Conclusion: Additional cytogenetic CE at the time of diagnosis among patients with CML in CP is associated with a similar favorable outcome as those without CE when treated with TKI. The type of additional CE (major route vs other) does not seem to impact outcome. Patients with CML-CP with CE at the time of diagnosis can thus be treated with TKI as all other pts with CP with no need for consideration for SCT unless there is clear evidence of failure. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. DiNardo:Abbvie: Research Funding; Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding. Daver:Ariad: Research Funding; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Research Funding; Kiromic: Research Funding; Otsuka: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Abstract: Introduction: CMML is a clinically heterogeneous myeloid neoplasm hallmarked by the coexistence of dysplastic and proliferative patho-clinical features, which can include cytopenias, constitutional symptoms, splenomegaly, and leukocytosis. However, according to the FAB classification schema, CMML may be differentiated in dysplastic and proliferative subgroups only by the presence of leukocytosis in the latter (WBC ≥13 x 109/L). We hypothesize that incorporation of other clinically discriminating features may yield a more informative CMML stratification system. To address this, we propose three distinct CMML categories and explore their clinical relevance leveraging our existing international CMML database (Padron E et al. Blood Cancer J. 20151). Method: 1622 WHO-defined CMML cases diagnosed between 1973 and 2014 were collected from eight large cancer centres that include up to 80 discrete data elements as previously described1. Cases were placed into three clinically distinct groups and the Pearson Chi-Square test and the Kruskal-Wallis test were applied respectively to compare categorical and continuous characteristics. The Kaplan-Meier (KM) method was used to estimate median OS and the log rank test was used to compare survival curves.Cox models whereapplied to obtain univariate and adjusted hazard ratios. Identification of optimal cut-off values for continuous variable was supported by graphical inspection of martingale residuals from the null Cox model. Statistical analyses were done in SPSS v23 and R v.3.3.0. Results: We propose three categories to delineate clinically distinct CMML subtypes: (1) Myelodysplastic (MD)-CMML: WBC≤10 x 109/L, PB-immature myeloid cells (IMC) = 0%, no splenomegaly (2) MD/MP-CMML: WBC 10-20 x 109/L or WBC ≤10 x 109/L but PB-IMC 〉 0% and/or splenomegaly (3) Myeloproliferative (MP)-CMML: WBC 〉 20 x 109/L. A recursive partitioning approach was used to identify the WBC cut points, with splenomegaly and IMC added to more accurately depict the MPN aspect of CMML. Numbers of patients included in the MD-, MD/MP-, and MP-CMML subcategories were 319 (19.7%), 789 (48.6%) and 514 (31.7%), respectively (Table 1). According to the FAB criteria, the MD/MP group included 521 (66%) MD- (WBC ≤13 x 109/L) and 268 (34%) MP-CMML (WBC 〉 13 x 109/L) patients suggesting that the proposed classification clinically reclassifies FAB-defined CMML. Within the MD/MP group, 344 patients (21.2%) had a WBC 〈 10 x 109/L but with IMC 〉 0% and/or splenomegaly. Comparison of overall survival (OS) among proposed groups demonstrated that this classification schema was capable of discriminating the CMML natural history (Figure 1). In comparison to MD/MP-CMML, the unadjusted OS Hazard Ratio (HR) was 0.60 (95% CI 0.49-0.73) for MD-CMML and 1.57 (95% CI 1.36-1.81) for MP-CMML (p 〈 0.001 for both). This difference was retained after adjusting for BM-Blasts ( 〈 vs ≥5%), IPSS or CPSS cytogenetics (High-risk vsInterm/low-risk), and elevated levels of LDH (HR was 0.73 with 95% CI 0.57-0.93, p=0.011 for MD-CMML, and 1.33 with 95% CI 1.12-1.58, p=0.001 for MP-CMML, respectively). We next explored whether each proposed group may have distinct variables that uniquely govern its prognosis. Peripheral blood blasts 〉 5%, RBC- and PLT-transfusion-dependence predicted poor OS only in the MD and MD/MP-subcategories (p 〈 0.005), but had no impact in the MP-CMML. Male gender and elevated LDH were only significantly associated with prognosis in the MD/MP group (p 〈 0.05 and p 〈 0.005, respectively) while absolute lymphocyte count 〉 2.5 x 109/L and absolute monocyte count 〉 10 x109/L were uniquely predictive for shorter survival in the MP-CMML subcategory (p 〈 0.005). Notably, we additionally identified gene mutations that uniquely predicted prognosis in each proposed group (Table 2). Conclusions: We demonstrate that our proposed 3-group clinical classification schema is capable of independently stratifying prognosis. Further, our analysis identified clinical and genetic variables that uniquely govern each group's prognosis, suggesting independent clinical behaviour. Further investigations are warranted to validate these groups. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau.

Abstract: Background: The Philadelphia chromosome (Ph) is the hallmark of chronic myeloid leukemia (CML). However a few patients present without Ph by conventional G-banding but express the BCR/ABL1 rearrangement detectable by molecular FISH and/or PCR representing a cryptic Philadelphia chromosome (i.e., Ph-, BCR-ABL1+ CML). There is a paucity of data regarding the outcome this small but important subset of patients when treated with tyrosine kinase inhibitors (TKI). In this report, we report the clinical characteristics and treatment outcome of these patients. Methods: We reviewed the medical records of all 630 patients with CML in chronic phase treated at a single institution in consecutive or parallel clinical trials with TKI as initial therapy between 2000 and 2015. Nine patients with Ph-negative BCR-ABL1-positive disease were identified. We analyzed their clinical characteristics and clinical outcome. Results: Median age of this group of patients was 34 years (range, 23 to 69); only 1 patient was aged 〉 50 years. This is in contrast to the median age of 53 years for patients with standard Ph-positive CML. Male to female ratio was 1.2. Baseline cytogenetic characteristics are shown in Table-1. Transcript type was e14a2 in 4, e13a2 in 4, and both in 2. Eight patients presented with low risk Sokal score and one with high-risk score. Four patients received initial therapy with imatinib (400 mg daily in 1, 800 mg daily in 3), 2 with dasatinib, 2 with nilotinib and one with ponatinib. The cumulative response is presented in Table-2. All patients achieved complete hematological response (CHR) within 3 months. Eight patients achieved complete cytogenetic response (CCyR), 6 of them within 6 months from start of therapy; 7 patients achieved MMR within 12 months from the start of therapy. MR4.5 was achieved in 7, and it has been sustained for at least 2 years in 5 patients; no patient has electively discontinued therapy. After a median follow-up of 79 months from start of therapy, 5 patients remain on their original TKI (including the 2 patients who started on imatinib 800 but currently receiving imatinib 400 due to dose reduction) with the molecular response at last follow-up being undetectable BCR-ABL1 in 4 and MMR in 1. One patient transformed to blastic phase. Median overall survival (OS) of these patients was not reached (two patients died from unrelated causes: one from a car accident, the other, who had transformed to blastic phase, received therapy with clofarabine, idarubicin, ara-C then imatinib followed by SCT, and died from a fall); the other 7 patients are alive 13, 11,7.8, 6.5, 5, 4, and 3.4 years from diagnosis. Conclusion: Ph-negative BCR-ABL1-positive CML presents at a younger age than the average CML population, and usually presents with low-risk disease. These patients respond well to therapy with TKI and have a very favorable long-term outcome. *One patient did not have molecular response assessment since he PCR testing was not routinely done before CCyR in 2001 when the patient had the 3 month response assessment. Disclosures Kantarjian: Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. DiNardo:Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Abstract: Background: The combination of low intensity therapy with inotuzumab ozogamicin improved survival compared to intensive chemotherapy and to single agent inotuzumab ozogamicin in first salvage (Jabbour et al. Cancer. 2018 (in press)). The incidence of veno-occlusive disease (VOD) is minimized with weekly divided dosage and reduced dose of inotuzumab ozogamicin per cycle. Blinatumomab single agent improves survival in relapsed / refractory ALL compared to that of standard chemotherapy. The sequential addition of blinatumomab to mini-hyper-CVD + inotuzumab ozogamicin might further improve survival and minimize the risk of veno-occlusive disease (VOD) by allowing a reduction of inotuzumab dose and spacing allogeneic stem cell transplant (ASCT) from the last dose of inotuzumab. Methods: Patients with relapsed / refractory Philadelphia chromosome negative ALL were eligible. The mini-hyper-CVD (cycles 1, 3, 5, 7) comprised cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracycline. Even cycles (cycles 2, 4, 6, 8) comprised methotrexate (250 mg/m2 on day 1) and cytarabine (0.5 g/m2 given every 12 h on days 2 and 3). Rituximab and intrathecal chemotherapy were given for first 4 courses. Inotuzumab ozogamicin was originally given on day 3 of the first four cycles at the dose of 1.3-1.8 mg/m2 at cycle 1, followed by 1.0-1.3 mg/m2 in subsequent cycles. After 67 pts were treated, an amendment was made to incorporate 4 cycles of blinatumomab after 4 cycles of mini-hyper-CVD + inotuzumab ozogamicin. Inotuzumab ozogamicin was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 at cycle 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m2 at subsequent cycles; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles. The decision to proceed with ASCT was based on the discretion of the treating physician after discussion with the patient. Results: From 2/2013 to 5/2018, 84 patients were enrolled and treated including 17 patients with mini-hyper-CVD + inotuzumab + blinatumomab. The median follow-up is 31 months (range, 0.1-64.1). Patient characteristics and outcome are summarized in Table 1. The median age was 35 years (range, 9-87), and 23% of patients had received prior ASCT. The overall response rate was 80% (CR, 58%, CRp/CRi, 21%). These rates were 92% in S1 (primary refractory, 100%; CR1 duration 〈 12 months, 82%; CR1 duration 〉 12 months, 100%) and 56% in S2, and 60% in S3 or higher. Among 64 evaluable patients for minimal residual disease (MRD) assessment, 51 patients (80%) achieved negative MRD by 6-color flow cytometry with higher rates of negative MRD at 85% in salvage 1. Thirty four patients (40%) received ASCT. Three-year CR duration and overall survival (OS) rates were 49% and 33%, respectively (Figure 1). The median OS was 25 months, 6 months, and 7 months in salvage 1, salvage 2, and salvage 3 or more, respectively (p=0.001). Historical comparison showed median OS of 14 months and 6 months in hyper-CVD + inotuzumab ozogamicin +/- blinatumomab and inotuzumab ozogamicin single agent, respectively (p=0.001) (Figure 2). Among the 79 evaluable patients, VOD was observed in 9 (11%). The incidence of VOD was reduced from 9/61 (15%) with single dose of inotuzumab ozogamicin to 0/18 (0%) with weekly divided dose schedule. Of the 17 patients treated with mini-hyper-CVD + inotuzumab ozogamicin + blinatumomab, 3 patients underwent ASCT (2, haploidentical transplant; 1, cord blood transplant). Conclusion: The combination of inotuzumab ozogamicin plus/minus blinatumomab with low-intensity mini-hyper-CVD chemotherapy is effective and shows encouraging results in patients with relapsed/refractory ALL. The risk of VOD can be minimized with fractionated inotuzumab ozogamicin dosing. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Ravandi:Xencor: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Orsenix: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Macrogenix: Honoraria, Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Orsenix: Honoraria; Bristol-Myers Squibb: Research Funding. Short:Takeda Oncology: Consultancy. Jain:Verastem: Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Cellectis: Research Funding; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Genentech: Research Funding; Infinity: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Servier: 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Servier: Research Funding; Pharmacyclics: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Adaptive Biotechnologioes: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Servier: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Stemline Therapeutics: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Kadia:Pfizer: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy; Celgene: Research Funding; Abbvie: Consultancy; Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Celgene: Research Funding; BMS: Research Funding; Novartis: Consultancy. Cortes:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Pfizer: Consultancy, Research Funding.

Abstract: Background: Several validated prognostic models exist for patients (pts) with myelodysplastic syndromes (MDS), including the International Prognostic Scoring System (IPSS), the Revised IPSS (IPSS-R), the World Health Organization (WHO) classification-based Prognostic Scoring System (WPSS), and the MD Anderson Prognostic Scoring System (MDAPSS). All were developed in pts with newly diagnosed MDS, and their prognostic value in subsequent stages of disease, such as at the time of hypomethylating agents failure (HMAs, azacitidine (AZA) and decitabine (DAC), has not been established. Despite this, the IPSS and IPSS-R is often used to determine clinical trial eligibility for pts who fail HMA and has been used by the FDA for drug labeling in this setting. Here in we developed a new prognostic model that predicts outcome post HMAs failure (HMAF). Methods Included patients were diagnosed with higher-risk MDS (per 2008 WHO criteria, higher-risk defined as IPSS Intermediate-2/High) with clinical and pathologic data entered into the MDS Clinical Research Consortium database. The IPSS, IPSS-R, WPSS and MDAPSS were calculated at the time of diagnosis and HMAF. HMAF was defined as no response to AZA or DAC following 〉 4 cycles, loss of response, or progression to acute myeloid leukemia (AML) at any time after starting therapy. Responses were defined per International Working Group criteria (IWG 2006). Overall survival (OS) was calculated from the time of diagnosis to time of death or last follow up when the models were applied at diagnosis and from HMAF date to time of death or last follows up when the models were applied at the time of HMAF. Cox proportional hazard analysis within the multivariable model-building with fractional polynomials (MFP) approach, which automatically select from all factors at the time of HMAF, was used to build the new model. Akaike information criterion (AIC) was used to compare fits from Cox proportional hazards models. Results Of 450 higher-risk MDS pts who failed HMAs, 311 (69.1%) were treated with AZA and 139 (30.9%) with DAC. The median age at diagnosis was 70 years (range: 35-91). Best responses (BR) to HMA were: 96 (21.3%) with complete remission, 40 (8.9%) partial remission, 46 (10.2%) hematologic improvement, 180 (40.0%) stable disease, and 88 (19.6%) with progressive disease. The median number of cycles received during treatment was 6 (range, 2-51). With a median follow up of 17.4 months (IQ range, 16.1, 18.7), the median OS from diagnosis for the entire group was 18.5 months (IQ range, 17.2, 19.8). Median OS from diagnosis was similar for patients treated with AZA compared to DAC (18.0 months vs. 20.3 months, p = .36). The median OS after HMAF was 7.3 months (IQ range, 6.3, 8.4). Survival plots for each prognostic scoring system at diagnosis and HMAF are shown in Figure 1. Comparing the predictive power of these scoring systems at the time of HMAF, the AICc for each model was: MDASS (3541.1); IPSS-R (3562.0), IPSS (3570.0), and WPSS with AICc of (3572.2) (lower AICc indicates better fit of the model). Given the lower predictive power of the current prognostic models at the time of HMAF, we developed a new prognostic model specific for this patient population. Our MFP modeling approach selected 6 factors that have significant association with OS at the time of HMAF in the final Cox multivariate model (Table 1). The new model identified two risk groups: Low: score 〈 2.25, median OS 11.0 months (95% CI 8.8-13.6) and a high risk group with score of 〉 2.25 and median OS 4.5 months (95% CI 3.9-5.3). Using the internal model validation assessment, the estimated AICc for the new model was 3520.4 (lowest AICc). When the new model was applied at time of diagnosis, the AICc decreased to 3515.1, a much smaller decrease compared to the existing prognostic systems built at diagnosis: MDASS (3515.7), IPSS-R (3528.2), WPSS (3537.5) and IPSS (3537.7). Conclusion Currently available MDS prognostic scoring systems should be used cautiously in pts at the time of HMAF and, given their inconsistent reliability, should be avoided for clinical trial eligibility or drug labeling. A new prognostic model was developed specific for this patient population. Table 1. The Post-HMA model Table 1. The Post-HMA model Figure 1. Overall survival by scoring systems at diagnosis and at the time of HMA failure Figure 1. Overall survival by scoring systems at diagnosis and at the time of HMA failure Disclosures Komrokji: Celgene: Consultancy, Research Funding; Incite: Consultancy; Novartis: Speakers Bureau; GSK: Research Funding. Steensma:Celgene: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Onconova: Consultancy. Padron:Novartis: Speakers Bureau; Incyte: Research Funding. List:Celgene Corporation: Honoraria, Research Funding. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.

Abstract: Background Chemotherapy induced nausea and vomiting can be a significant problem for pts with acute myeloid leukemia (AML) receiving induction chemotherapy causing deterioration in quality of life. Cytarabine-containing regimens are the cornerstone for the management of AML and cytarabine is a moderate emetic risk chemotherapy agent. Combination of cytarabine with other chemotherapeutic agent can substantially worsen nausea and vomiting. Ondansetron has been used for nausea control in pts receiving chemotherapy. Aprepitant is a P/neurokinin-1 (NK1)-receptor antagonist approved for use in combination with a 5-HT3-receptor antagonist and dexamethasone for the prevention of acute and delayed chemotherapy-induced nausea and vomiting. We explored whether the combination of two drugs with different mechanisms of action may improve the control of nausea in pts with AML receiving cytarabine-based induction. Methods Pts with AML, high-risk MDS or CML blast phase receiving induction chemotherapy with cytarabine at a dose of ≥1 g/m2/day for at least 3 days were randomized to: Arm 1) Ondansetron 8mg IV 30 minutes before high dose cytarabine followed by ondansetron 24mg IV continuous infusion daily until 6-12 hours after the end of last chemotherapy infusion. Arm 2) Aprepitant 125mg PO plus ondansetron 8mg IV 30 minutes before high dose cytarabine followed by ondansetron 24mg IV continuous infusion daily until 6-12 hours after the end of last chemotherapy, plus aprepitant 80 mg PO daily and to continue for 1 day after last dose of chemotherapy. Pts were followed for 72 hrs post chemotherapy. A diary was used by the pts to record daily number of episodes of nausea and /or vomiting experienced during the study, as well as to record any need of extra medications for escape nausea. Complete response was defined as no emesis episodes and no use of rescue medication during the study period. Partial response was defined as ≤ 1 episode of emesis during the entire study period, no use of rescue medication during the study period, and no more than moderate nausea (NCI grade 2). Results Forty nine pts were enrolled in each arm. Fifty seven percent were men in arm 1 and 55% men in arm 2. The median age was 53yrs (ranges, 30-68) in arm 1 and 49yrs (ranges, 21-70) arm 2. Caucasians were 83% in arm 1 and 76% in arm 2. African American and Hispanics were 10 % and 6% respectively in arm 1 and 8% and 12% in arm 2. Among the population studied 96% were diagnosed with AML in each arm. MDS 2% in arm 1 and 4% in arm 2. Fourteen percent received Idarubicin with cytarabine (Ara-C) in each arm. Twenty percent in ondansetron (OND) arm and 16% in ondansetron plus aprepitant (OND+APREP) arm receive Ara-C combined with Fludarabin. Ara-C in combination with anthracycline plus nucleoside analogues was given to 49% of pts in each arm. Ten percent in arm 1 received Ara-C with anthracycline and targeted therapy, 8% in arm 2 receive similar combination. Forty two pts on OND arm and 41 pts in the OND+APREP arm were evaluable for efficacy. Patient in the OND+APREP arms achieved higher overall response rates (complete plus partial responses) as shown in Figure 1, but the difference was not statistically significant (OND 67%, OND+APREP 80%; P= 0.11). More than 75% of pts overall were free of nausea on Days 1 and 2. On days 6 and 7 higher proportion of pts in OND+APREP arm were free from nausea than OND arm. Overall 36% of pts required rescue medications, 38% in OND arm and 34% in OND+APREP arm. Among them 14% of pts required rescue more than once; 19% in the OND arm and 10% in OND+APREP arm, as shown in Figure 2. Requirement of rescue medications on Days 2 and 3 were fewer in OND+APREP arm 7% and 5% respectively compare to 21% and 16% in the ondansetron arm (P = 0.06 and P=0.07). Most common adverse events were headache and diarrhea. Twenty percent of pts in OND arm and 19% in OND+APREP arm reported to have NCI grade 2 headache (P= 0.56). Five percent of pts in ondansetron arm and 12% in ondansetron plus aprepitant arm had grade 2 diarrhea (P=0.19). Conclusions The daily assessment of emesis and nausea did not show statistically significant differences between the study arms but there was a clear trend towards better responses in ondansetron plus aprepitant arm with more overall response rates and lower use of rescue medications. Further larger studies are warranted to further define the benefits of this combination of antiemetic drugs. Disclosures: No relevant conflicts of interest to declare.

Abstract: Inosine 5'- monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme that catalyzes de novo synthesis of the guanine nucleotide and is overexpressed in both hematologic and solid tumors. FF-10501-01 is a potent new competitive IMPDH inhibitor. We investigated the anti-leukemia effect of FF-10501-01 in a Phase 1 clinical study in advanced AML and MDS, including HMA failures. Previous preclinical studies demonstrated potent anti-proliferative and apoptotic effects of FF-10501-01 on AML cell lines, including HMA-resistant derivatives, through inhibition of de novo guanine nucleotide synthesis. Therefore, we performed a standard 3+3 dose-escalation Phase 1 trial to access the safety and clinical activity of FF-10501-01 in patients with advanced AML, MDS and chronic myelomonocytic leukemia (CMML). Eligibility criteria: age ≥ 18 years, high risk MDS/CMML, AML with documented PD following previous therapy, AML ≥ 60 years of age and not a candidate for other therapy, adequate renal and hepatic function, and no known history of significant cardiac disease. A total of 29 patients, 15M and 14F (23 AML, 6 MDS) have been treated in 7 dose cohorts (50 - 500 mg/m2 PO BID) for 14 days on and 14 days off, and 400 mg/m2 for 21 days on and 7 days off, each 28-day cycle. Median (range) values: age 75 yrs (59 - 88); baseline bone marrow blast counts for AML 34% (12 - 82), for MDS 10% (5 - 16), and overall 30% (5 - 82); and prior treatment regimens 2 (1 - 7). All patients relapsed from, or progressed on, prior HMAs. At baseline, mutations in FLT3, NPM1, GATA2, TET2, ASXL1, DNMT3A, NOTCH1, JAK2, IDH2, PTPN11, KRA, TP53, RUNX1, EZH2 and/or MDM2 were present in 13 of 29 (45%) of patients. Atrial fibrillation (Gr 2) was reported in 2 subjects at a dose of 500 mg/m2 BID. This met the definition of dose-limiting toxicity (DLT) and no further enrollment was made at this dose level. The maximally tolerated dose (MTD) was declared at 1 dose level lower, 400 mg/m2 BID, and this cohort was expanded to 6 subjects. No DLTs have been observed in N=7 total subjects treated at 400 mg/m2 BID x 14 days. FF-10501-01 has been very well tolerated through 24 cycles. The most frequent drug-related AEs have been Gr 1-2 nausea, diarrhea and fatigue. Drug-related thrombocytopenia, neutropenia and bone marrow aplasia (all Gr 4) were reported in 1 patient at 200 mg/m2 BID. The median number of FF-10501-01 cycles received to date is 2 (range 1 - 24). Partial remissions have occurred in 2 AML patients (50 and 100 mg/m2 BID) after 3 cycles, lasting for 5 and 24 cycles, respectively, with the higher dose patient still on study after 24 cycles. A total of 8/23 (34.8%) AML patients, including the 2 PRs, have attained stable disease (SD) control with no disease progression over 3 - 24 cycles. Three AML patients remain on study through 3, 23 and 24 cycles, respectively. A bone marrow complete response was achieved in 1 MDS patient treated at 400 mg/m2 BID after 1 cycle. Although the bone marrow blast counts have increased since, this patient remains stable and is still on therapy through 14 cycles. Three of 6 MDS patients (50%), including the marrow CR, attained SD control with no disease progression over 3, 14 and 14 cycles, and 2 remain on study through 3 and 14 cycles, respectively. FF-10501-01 was rapidly absorbed with mean Tmax of 2.74 hours and mean t1/2 of 4.05 hours. Drug exposure (AUC0-24 and AUCcourse) increased with dose in a near linear manner. Potent suppression of circulating xanthine monophosphate (XMP), a marker of IMPDH activity, has been observed following FF-10501-01 administration on Day 1 of Cycles 1 and 2 at dose levels of 50 mg/m2 BID and above. FF-10501-01 is a promising new agent for the treatment of advanced AML and MDS in patients who have failed or progressed on HMAs and with one or more baseline mutations in pathways known to be affected in AML and MDS. Preclinical activity was seen in multiple leukemia cell lines, including HMA-resistant derivatives. In a Phase 1 trial, clinical activity with a marrow CR, PRs, long-term disease stabilization (≥ 5 cycles) and a highly tolerable safety profile were observed. The Phase 2a expansion phase of the study is soon to begin. Disclosures DiNardo: Agios: Research Funding; Daiichi Sankyo: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Daver:BMS: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Karyopharm: Honoraria, Research Funding; Sunesis: Consultancy, Research Funding. Denton:Westat Corporation: Employment. Smith:Westat Corporation: Employment. Tiefenwerth:Westat Corporation: Employment. Iwamura:FUJIFILM Corporation: Employment. Gipson:Strategia Therapeutics, Inc.: Employment. Rosner:Strategia Therapeutics, Inc.: Employment. Myers:Strategia Therapeutics, Inc.: Employment. Paradiso:Strategia Therapeutics, Inc.: Employment.

Abstract: Background: The incorporation of intensive chemotherapy, hematopoietic stem cell transplantation (HSCT), targeted therapies including rituximab and tyrosine kinase inhibitors contributes substantial improvement in the outcome of patients with ALL over decades. VAD was changed to hyper-CVAD in 1992; rituximab was added to hyper-CVAD for CD20 positive ALL in 1999/2000; inotuzumab ozogamicin in combination with low-intensity chemotherapy was offered to elderly patients starting in 2011. The aim of this study is to describe the outcome of patients with ALL over decades by age groups. Methods: From 1980 to 2016, patients with newly diagnosed ALL at our institution were analyzed. Burkitt leukemia was excluded from our analysis. Patients were divided into age groups as follows: age 15-39, age 40-60, and age 〉 60. Patients were subsequently divided into diagnostic year cohorts by decade: 1980-1989, 1990-1999, 2000-2009, and 2010-2016. Overall survival was defined as time interval from diagnosis to the date of death regardless of any cause. Kaplan-Meier method with a log-rank test was used for survival comparison between cohorts. Stepwise multivariate analysis with Cox proportional hazards model was used to evaluate the impact of diagnosis year on OS. P-values were two-sided, and a p-value less than 0.05 was considered statistically significant. Results: Overall, 972 patients were identified and analyzed in our study. Median age at diagnosis was 39.5 years (range, 16-92) with a median follow-up of 10.4 years (range, 0.0-31.3). Patients were divided into 486 patients (50%) in the age 15-39 category, 301 patients (31%) in the age 40-60 category, and 185 patients (19%) in the age over 60 category. Baseline patient characteristics are summarized in Table 1. Overall, the median OS durations were 4.5 years, 2.8 years, and 1.3 years in age 15-39, age 40-60, and age 〉 60, respectively (p 〈 0.001; p 〈 0.001). Of the 486 patients in age 15-39, the improvement in OS was observed from 1980-1989 to 1990-1999 (p 〈 0.001); of the 301 patients in age 40-60, from 1980-1989 to 1990-1999, and from 1990-1999 to 2000-2009 (p=0.042; p=0.003); of the 185 patients in age 〉 60, from 2000-2009 to 2010-2016 (p=0.039). Stepwise multivariate analysis identified leukocytosis, thrombocytopenia, hypoalbuminemia, elderly age, poor performance status, lack of complete response, and diagnostic year as adverse prognostic factors for OS. Each year since 1980 had an impact on OS with hazard ratio of 0.961 (95% confidence interval, 0.951-0.971; p 〈 0.001). Conclusion: Patients with ALL have significant improvement in OS throughout all ages over decades. However, the decade time points of improvement in OS were different between age cohorts. Different treatment strategy and clinical trial designs by each age group are needed for further improvement in patient's outcome. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Ravandi:BMS: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Pemmaraju:incyte: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; cellectis: Consultancy, Research Funding; affymetrix: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding. Jain:Genentech: Research Funding; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Servier: Consultancy, Honoraria; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Infinity: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Andreeff:Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: AZA is a DNA methyltransferase (DNMT) inhibitor with a modest response rate (20-25%) and duration (Å4 months) in MF. Ruxolitinib and azacytidine may target distinct clinical and pathological manifestations of myelofibrosis. Aim:To determinethe efficacy and safety of the combination in pts with MF requiring therapy(ClinicalTrials.gov Identifier: NCT01787487). Methods:A sequential approach with single-agent RUX 15 mg orally twice daily (if platelets 100-200) or 20 mg twice daily (if platelets 〉 200) continuously in 28-day cycles for the first 3 months followed by the addition of AZA 25 mg/m2 on days 1-5 of each 28-day cycle starting cycle 4 was adopted. The AZA dosage could be gradually increased to a maximum of 75 mg/m2. Pts would be treated on study for 15 months followed by continuation of the combination off-study at the discretion of the treating physician. Results: 41 pts were enrolled between March 1, 2013 and June 30, 2016. Baseline characteristics are shown in table 1. 23 (56%) had received a median of 2 (range, 1-3) prior therapies for MF. 27 pts remain alive after a med follow-up of 20.4+ months (range, 0.5-37.3+). 39 pts were enrolled before January 1 2016 and are evaluable for response. International Working Group for Myelofibrosis Research and Treatment 2013 (IWG-MRT)objective responses were noted in 27 (69%), including PR in 2 (5%), CI for spleen and total symptom score (TSS) in 7 (18%), CI for TSS and hemoglobin in 2 (5%), CI for spleen only in 7 (13%), and CI for TSS only in 9 (21%). Ten (26%) pts had no IWG response and 2 (5%) pts had progression to AML on therapy. Three ptshave achieved a complete cytogenetic remission (baseline cytogenetics were +8 in two and del 20q in one). Responses occurred in 14 of 23 (61%) previously treated patients and 13 of 16 (81%) untreated pts (P=0.57). Median time to all responses was 1.0 month (range, 0.7-19.3 months). Median time to CI in spleen size was 1.8 months (range, 0.9 - 16.8), to CI TSS was 1.8 months (range, 0.7-15.8), CI Hb was 5.8 months (range, 1.1-14.7), and cytogenetic remission was 5.5 months (5.4-5.5). 29 pts had a baseline spleen ³5 cm and 14 (48%) achieved 〉 50% palpable spleen length reduction at 24 weeks and 23 (79%) achieved 〉 50% palpable spleen reduction at any time on study. 6/23 (26%) of the 〉 50% palpable spleen reductions occurred after the addition of azacytidine. Among the 29 pts with baseline spleen ³5cm best spleen response included: 50-100% reduction in 23 (79%), 25-49% reduction in 4 (14%), no reduction in 2 (7%). Serial JAK2 allele burden assessment was available in 15 of 17 JAK2 mutated responders. A reduction in the baseline JAK2V617F allele burden was noted in 13 of 15 (87%) serially evaluable responders with a median V617F allele burden reduction of 21% (range, 1-82%). Serial evaluation of bone marrow fibrosis was available in all 27 responders and revealed a reduction in EUMNET fibrosis score in 11 (41%) responders, including ³2 grade reduction in 2 pts and 1 grade reduction in BM fibrosis in 9pts with a median time to fibrosis improvement of 13.2 months (range, 5.1-13.2). Three pts experienced grade 3/4 non-hematological toxicity including fatigue (n=2), nausea (n=1), and pneumonia (n=1). New onset grade 3/4 anemia and thrombocytopenia were seen in 25 pts [61%; of which 7 (17%) had a 2+ grade change] and 11 (27%) pts, respectively. The med overall survival is 38.7+ mos. The AZA was administered in 34 (83%)pts: as planned in cycle 4 in 28pts(63%), earlierdueto increased blasts in 1pt, and later in 5pts[cycle 5 (n=2), cycle 7 (n=2), cycle 9 (n=1)]. Twoptsprogressed before starting AZA and 3 never started AZA due to prohibitive cytopenia. Twoptsare too early to start AZA. Six of 34 (18%)ptswho started AZA have required discontinuation of AZA: low platelets (n=3), fatigue (n=2), and low ANC (n=1). Twenty fourpts remain on study. Reasons for discontinuation in 17 pts included stem cell transplant (n=6), lack of response (n=3), AML (n=2), toxicity (n=3), death (n=1), patient preference (n=2). Fourteen pts have died: AML (n=4), pneumonia (n=3), unknown cause (n=3), sepsis (n=2), post SCT complications (n=1), and other cancer (n=1). Conclusion: Concomitant RUX with AZA was feasible and resulted ina IWG-MRT response rate of 69%. The 〉 50% spleen length reduction at 24 weeks and at any time on study were superior to single agent RUX and 26% of the spleen reductions occurred after addition of AZA. This combination warrants further evaluation on a large scale. Disclosures Daver: Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria; Ariad: Research Funding; Sunesis: Consultancy, Research Funding; BMS: Research Funding; Kiromic: Research Funding; Pfizer: Consultancy, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Verstovsek:Celgene: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Seattle Genetics: Research Funding; Roche: Research Funding; Geron: Research Funding; NS Pharma: Research Funding; Bristol-Myers Squibb: Research Funding; Gilead: Research Funding; Lilly Oncology: Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

Abstract: Despite advances in understanding of the biology of acute myeloid leukemia (AML), cure remains elusive for the majority of patients. Pro-survival molecules of BCL-2 family play critical roles in leukemia transformation and chemoresistance. The anti-leukemia potency of selective BCL-2 inhibitor venetoclax (ABT-199/GDC-0199) has been demonstrated in AML models (Pan et al. Cancer Discovery 2014). However, venetoclax is often associated with resistance due to its poor inhibition of MCL-1. RAF/MEK/ERK (MAPK) pathway is commonly activated in AML, and can stabilize anti-apoptotic MCL-1 and inactivate the pro-apoptotic BIM. In this study, we evaluated the anti-leukemia effects of concomitant BCL-2 and MAPK blockade by venetoclax in combination with MEK1/2 inhibitor GDC-0973 (cobimetinib). First, anti-leukemia activity of cobimetinib and venetoclax was examined in 18 primary AML samples with diverse genetic alterations. The combination significantly enhanced cell death, as compared to the single agent treatment (Fig 1A). Cobimetinib inhibited cell proliferation in the majority of AML cases (34.2 ± 23.7%) and the cell growth suppression was more profound in the combination group (60.2 ± 28.8%, p 〈 0.001) (Fig 1A). The clonogenic potential of myeloid progenitors was significantly suppressed by the combination (82.5 ± 20.0%), as compared to cobimetinib (38.3 ± 14.6%, p=0.01) or venetoclax (41.9 ± 18.6%, p 〈 0.05). The normal progenitor function was minimally affected. We next investigated signaling patterns and BCL-2 family protein expression in AML stem/progenitor cells using a 34-antibody panel for CyTOF. In AML 4400240, we identified 10 distinct subpopulations based on cell surface marker expression that were used to build the SPADE tree. BCL-2 and MCL-1 were both enriched in progenitor populations phenotypically positive for CD34, CD38, CD123 and HLA-DR (A2-5 and A9-10, Fig 1B and 1C). G-CSF-induced p-ERK and SCF-induced p-S6 signaling pathways were efficiently suppressed by cobimetinib (Fig 1D). The inhibition of p-S6 may reflect the sensitivity to cobimetinib of this sample (IC50=1.68 nM); consistent with previous study that suppression of TORC1 predicted response to MEK inhibitor (Corcoran et al. Sci Transl Med 2013). We have previously reported activity of venetoclax/cobimetinib combination in a panel of myeloid leukemia cell lines and revealed distinct response patterns to single agents and combination (Han et al. ASH 2015). Functional proteomics RPPA data indicated that p-ERK, p-S6 and p-RSK pathways were significantly down-regulated in response to the combination in cells showing synergy. Western blotting was performed to validate the RPPA data in 4 cell lines representing different response patterns. Cobimetinib inhibited p-ERK when used at high dose (1 _M) in all cell lines. In turn, inhibition of p-S6 at both ser235/236 and ser240/244 sites occurred at low dose of cobimetinib in sensitive cell lines (OCI-AML3 and MV4-11) and required high dose in resistant lines. In OCI-AML3 cells that showed synergy to combination, elevated levels of cleaved PARP was observed in the combination group, which was likely due to suppression of both BCL2:BIM and MCL-1:BIM complex, followed by release of free BIM to induce cell death. To test the efficacy in vivo, we injected NSGS mice with genetically engineered MOLM3/Luc/GFP cells. Bioluminescent imaging demonstrated significantly reduced leukemia burden in treated groups compared to controls, more prominently in the venetoclax (100 mg/kg/d) group and in venetoclax plus cobimetinib (10 mg/kg/d) co-treated mice (Fig 1E and 1F). Human CD45 engraftment and cell counts in both bone marrow and spleen demonstrated a trend towards decreased tumor burden when venetoclax was combined with cobimetinib in vivo (Fig 1G and 1H). In summary, combinatorial blockade of MAPK and BCL-2 pathways promotes cell death and suppresses proliferation in the majority of primary AML cells. The anti-leukemia efficacy of combined blockade of signaling and pro-survival pathways is associated with downregulation of MCL-1, release of pro-death BIM and suppression of p-S6. Additional novel transcriptional biomarkers of response are now being analyzed and will be presented. Combined efficacy of these agents is under clinical investigation in a Phase I trial in elderly relapsed/refractory AML (NCT02670044). Figure 1. Figure 1. Disclosures Leverson: AbbVie: Employment, Other: Shareholder in AbbVie. Monique:Genentech: Employment. Phillips:AbbVie Inc.: Employment. Chen:AbbVie: Employment. Jin:AbbVie Inc.: Employment. Daver:Ariad: Research Funding; Sunesis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; BMS: Research Funding; Otsuka: Consultancy, Honoraria; Karyopharm: Honoraria, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Kantarjian:Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Sampath:Genentech: Employment. Konopleva:AbbVie: Research Funding; Genentech: Research Funding.