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: Background - Minimal Residual Disease (MRD) assessed by Multi-parameter Flow Cytometry (MFC) has not been extensively evaluated as a predictor of outcome in younger patients with acute myeloid leukemia (AML) receiving ara-C plus anthracycline induction Methods - We examined the predictive value of MRD assessment by MFC in mainly younger patients with newly diagnosed AML who were treated with intermediate dose cytarabine (total of ≥ 6 g/m2) and idarubicin based induction chemotherapy. Among 280 patients treated with clofarabine, idarubicin plus ara-C (CIA), fludarabine, idarubicin plus ara-C (FIA), fludarabine, ara-C, GCSF plus idarubicin (FLAG-Ida), cladribine, idarubicin, plus ara-C (CLIA) who achieved complete remission (CR), CR without platelet recovery (CRp), or CR with incomplete count recovery (CRi) 186 had at least one available MRD data and are the subject of this analysis. MRD by MFC was assessed using an 8-color panel containing 19 distinct markers, on bone marrow specimens obtained at the time of achievement of CR/CRi/CRp (approximately 1-2 months post induction), during consolidation (approximately 3-7 months post-induction) and at completion of therapy (≥ 8 months post induction). Residual leukemic blasts were identified based on phenotypic differences from normal myelomonocytic precursors. Sensitivity was estimated at 0.1% in most cases, with maximum achievable sensitivity of 0.01%, depending on the leukemic phenotype. Results - Median age of the patients was 51 years (Range, 17 - 77 years). 6 patients were older than 65 (all with ELN favorable disease). Median WBC at presentation was 4.7 x 109/L (Range, 0.5 - 103 x 109/L). Cytogenetics was favorable risk in 34 (18%), intermediate risk in 115 (62%) and adverse in 27 (15%) and was not available in 10 (5%) Treatment included CIA in 102 (55%), FIA in 34 (18%), FLAG-Ida in 34 (18%) and CLIA in 16 (9%). 166 patients had available samples at 1-2 months post induction and 131 (79%) became MRD negative. Achieving MRD negative status at response was associated with a statistically significant improvement in relapse free survival (RFS) (p= 0.001) and overall survival (OS) (p= 0.003) (Figure 1). 116 patients were evaluated for MRD status during consolidation and 100 (86%) became negative. Achieving a negative MRD status during consolidation was associated with a significant improvement in RFS (p˂0.001) and OS (p˂0.001)(Figure 2). 69 patients were evaluated for MRD status after completion of all therapy and 58 (84%) became negative. Achieving a negative MRD status at completion of therapy was associated with improvement in RFS (P˂0.001) and OS (P˂0.001) (Figure 3). On multivariate analysis including age ˂40 years vs. ≥ 40, WBC at presentation ˂or ≥ 10 x 109/L, cytogenetics (favorable, intermediate, adverse), achieving CR vs. CRp/CRi, and treatment with CIA, FIA, CLIA, or FLAG-Ida, achieving MRD negative status was the only independent predictor of RFS and OS at response (P=0.03 and P=0.005, respectively), during consolidation (p˂0.001 for both), or at completion of therapy (p˂0.001 for both). Conclusion - Achieving MRD negative status by MFC at response, during consolidation therapy and after completion of therapy is associated with a highly significant improvement in the outcome of younger patients with AML receiving ara-C plus idarubicin-based regimens. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures Jabbour: Pfizer: Consultancy, Research Funding. Faderl:Astellas: Research Funding; Celator: Research Funding; JW Pharma: Consultancy; Seattle Genetics, Inc.: Research Funding; Karyopharm: Consultancy, Research Funding; Pfizer: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Speakers Bureau; Ambit: Research Funding; BMS: Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. Cortes:BerGenBio AS: Research Funding; Teva: Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

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: HMAs improve survival of pts with higher-risk MDS; however, the role of HMAs is less clear in pts with lower-risk MDS. These pts have a heterogeneous prognosis, and some may benefit from early HMA therapy. To test the hypothesis that low-dose HMA therapy would be safe and effective in pts with lower-risk MDS, we treated pts with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS with low-dose HMA regimens using 3 days of either 5-azacytidine (AZA) or decitabine (DAC). Methods: Adult pts with de novo or secondary low- or intermediate-1-risk MDS, CMML or MDS/MPN were eligible for this study. Pts were treated with AZA 75 mg/m2 IV/SC daily or DAC 20 mg/m2 IV daily for 3 consecutive days on a 28-day cycle. The primary efficacy outcome was the overall improvement rate (OIR) defined as the composite of complete remission (CR), CR with insufficient hematologic recovery (CRi) and hematologic improvement (HI). Secondary outcomes included safety profile, duration of response, conversion to transfusion independence, event-free survival (EFS), and overall survival (OS). EFS was defined as the time to HMA failure, progressive disease, transformation to acute myelogenous leukemia (AML) or death from any cause. Chi-square test was performed to evaluate differences in response rates. EFS and OS were calculated using Kaplan-Meier estimates and compared using the log-rank test. Results: Between 11/2012 and 6/2015, 88 pts with lower-risk MDS were treated; 83 of them are currently evaluable for response assessment (65 MDS, 15 CMML and 3 MDS/MPN). Thirty pts received AZA (36%) and 53 pts (64%) received DAC. Median time from diagnosis to treatment was 5 weeks (range 1-272 weeks). Median age was 71 years (range 44-85 years). Sixteen pts (19%) had therapy-related MDS. Thirty-eight pts (46%) were transfusion-dependent for RBCs and/or platelets at baseline, and 17 pts (20%) had received prior growth factor support with erythropoietin-stimulating agents or G-CSF. By IPSS, 13 pts (16%) had low-risk and 70 pts (84%) had intermediate-1-risk disease. By the MDACC lower-risk scoring system, 38 pts (46%) had high-risk, 38 pts (46%) had intermediate-risk and 7 pts (8%) had low-risk disease. Twenty-seven pts (33%) had ≥5% bone marrow blasts. By IPSS, cytogenetics were good-risk in 55 pts (66%), intermediate-risk in 20 pts (24%) and poor-risk in 8 pts (10%). Mutation analysis was performed in 76 pts at the time of enrollment, 43 (57%) of whom had at least one molecular mutation. TET2 mutation was identified in 17 pts (22%), RUNX1 in 8 pts (11%), TP53 in 6 pts (8%), ASXL1 in 5 pts (7%), IDH1/2 in 5 pts (7%) and DNMT3A in 4 pts (5%). The median follow-up was 13 months (range 2-30 months) and median number of cycles received was 9 (range 2-29 cycles). The OIR for the entire cohort was 61%; 32 pts (39%) achieved CR, 11 (13%) achieved CRi and 8 (10%) achieved HI. Of the 38 transfusion-dependent pts at baseline, 9 (24%) became transfusion-independent. The median time to best response was 2.2 months (range 0.8 to 19.6 months). Median duration of response has not been reached with 71% of responders still on study. Low-dose HMA therapy was well-tolerated with only 6 pts (7%) requiring dose reduction and 19 pts (23%) requiring dose delay. AML developed in 4 pts (5%), and 17 pts (20%) have died. For the entire cohort, the 1-year EFS rate was 67%, and the 1-year OS rate was 86%. The median EFS and OS have not been reached. When stratified by IPSS and the MDACC lower-risk scoring systems, there was not a significant difference in OIR, EFS or OS among various risk groups (Table 1). Conclusions: Among pts with low- and intermediate-1-risk MDS, low-dose HMA therapy was well-tolerated and resulted in an OIR of 61%. Response rates, EFS and OS did not differ when pts were stratified by IPSS or the MDACC lower-risk scoring system. A randomized trial of low-dose AZA vs. DAC vs. best supportive care in lower-risk MDS is ongoing. Table 1. Response and survival rates by risk stratification Risk Stratification Risk Group N OIR (%) P (OIR) 1-year EFS rate (%) P (EFS) 1-year survival rate (%) P (OS) IPSS Low 13 54 0.540 83 0.751 86 0.295 Intermediate-1 70 63 65 85 MDACC Lower-Risk Scoring System Low 7 71 0.851 67 0.925 100 0.179 Intermediate 38 61 77 92 High 38 61 58 78 All Patients 83 61 67 86 Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Steensma:Incyte: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Onconova: Consultancy. DiNardo:Novartis: Research Funding. Estrov:incyte: Consultancy, Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Verstovsek:Incyte Corporation: Research Funding.

Abstract: Introduction Tyrosine kinase inhibitors (TKIs) are effective treatments for chronic myeloid leukemia in chronic phase (CML-CP) in terms of response rates and clinical outcomes including overall survival (OS). The purpose of this study was to compare OS in each age group with newly diagnosed CML-CP compared to that of general population in the same age group in the era of multiple TKIs. Methods Response and survival data for 483 patients (pts) with newly diagnosed CML-CP who enrolled in five consecutive or parallel prospective clinical trials of imatinib at a dose of 400 mg or 800 mg daily, imatinib at a dose of 800 mg with pegylated interferon, dasatinib, or nilotinib were analyzed. The pts were divided into groups by age at diagnosis, as follows: 15-45 years; 45-65 years; 65-85 years; over 65 years. All pts, regardless of age, were divided into the following response groups within 1 year of treatment: complete cytogenetic response (CCyR); major molecular response (MMR); MR4.5 defined as more than or equal to 4.5 log reduction of BCR-ABL on the international scale; or complete molecular response (CMR). Pts also were assessed for OS, event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS). OS was dated from the start of therapy until death from any cause at any time. EFS was calculated from the start of therapy to loss of complete hematologic response, loss of major cytogenetic response, transformation to accelerated (AP) or blast phase (BP), or death from any cause during study therapy. TFS was calculated from the start of therapy to transformation to AP or BP, or death during study therapy. FFS was calculated from the start of imatinib, dasatinib or nilotinib to an event (as defined above), discontinuation for any reason, or death. The Kaplan-Meier method was used to calculate OS, EFS, TFS, and FFS. A log-rank test was used for univariate comparisons. Pvalues of less than 0.05 were considered statistically significant. Five-year relative survival rates were calculated from the five-year absolute OS divided by the estimated five-year OS in the general population. Estimated OS rates in the U.S. general population were obtained from national vital statistics reports for the year 2009. Results Of the 483 pts analyzed in the study, 271 were treated with imatinib, 101 with nilotinib, and 111 with dasatinib. The age breakdown was as follows: 15-45 years, 197 pts; 45-65 years, 222 pts; 65-85 years, 64 pts; over 65 years, 64 pts. No pts older than 85 years were enrolled in this study. Sokal risk score at diagnosis, and type of TKI treatment were analyzed by age group, cumulative best response, and five-year OS, EFS, TFS, and FFS, and the results are summarized in Table 1. Five-year OS in the general population, relative five-year OS in all age groups, and relative five-year OS by response group are also described in Table 1. As expected, 5-year OS decreased with increasing age groups, but for all age groups OS was similar to 5-year OS in the corresponding age group in the general population. 5-year OS in pts of ages 15-85 who achieved CCyR or better was similar to that in the general population. Conclusion In the era of TKIs, the OS rates in pts with newly diagnosed CML-CP in all age groups are only slightly lower to that of general population. However, the OS rates in pts who achieved CCyR or better within 1 year of treatment is similar to that of general population. Table 1. Patient Characteristics and Outcomes by Age Group Age 15-45 [n= 197] No. (%) Age 45-65 [n= 222] No. (%) Age 65-85 [n= 64] No. (%) P Sokal Risk Score .419 Low 129 (65) 158 (71) 48 (75) Intermediate 56 (28) 48 (22) 12 (19) High 12 (6) 16 (7) 4 (6) Type of TKIs .364 Imatinib 113 (57) 116 (52) 42 (66) Nilotinib 42 (21) 50 (23) 9 (14) Dasatinib 42 (21) 56 (25) 13 (20) Cumulative Best Response CMR 91 (46) 124 (56) 33 (52) .142 MR4.5 127 (64) 158 (71) 47 (73) .230 MMR 162 (82) 197 (89) 54 (84) .162 CCyR 171 (87) 208 (94) 59 (92) .048 5-y Outcome (%) FFS 77.9 74.5 60.6 .043 TFS 93.8 93.4 87.4 .224 EFS 81.0 89.2 78.9 .094 OS 96.2 93.5 80.1 〈 .001 5-y Absolute OS 5-y Relative OS 5-y OS in General Population Age Group (%) Ages 15-45 96.2 96.9 99.3 Ages 45-65 93.5 97.1 96.3 Ages 65-85 80.1 97.1 82.5 Ages 15-85 92.7 98.2 94.4 Ages 15-85 by Response (%) CCyR within 1 year 97.3 103.1 94.4 MMR within 1 year 97.9 103.7 94.4 MR4.5 within 1 year 97.1 102.9 94.4 CMR within 1 year 96.7 102.4 94.4 Disclosures Jabbour: Ariad, Novartis, BMS, Pfizer, and Teva : Consultancy. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding.

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.

Abstract: Introduction: Anemia is common in MPN-associated myelofibrosis (MF), and current therapies (e.g., erythropoiesis stimulating agents, androgens, danazol, immune modulatory drugs and corticosteroids) are unsatisfactory. Furthermore, anemia is not improved and initially worsened by ruxolitinib, an important MF therapy. New drugs with novel mechanisms of action are needed. Sotatercept is a first-in-class activin receptor type IIA (ActRIIA) ligand trap consisting of the extracellular domain of ActIIRA linked to the human IgG1 Fc domain. Sotatercept binds to and sequesters ligands of the transforming growth factor beta (TGF-ß) superfamily, thus relieving their blockade of terminal erythroid differentiation. Pre-clinically, sotatercept corrects ineffective erythropoiesis in ß-thalassemia (Dussiot, M. et al. Nat Med 2014) and its murine ortholog RAP-011 improves erythropoiesis in Diamond Blackfan anemia (Ear, J. et al. Blood 2015). Clinical trials in persons with lower risk myelodysplastic syndromes (Komrokji, R. et al. ASH 2014) and chemotherapy-induced anemia (Raftopoulos, H. et al. Support Care Cancer 2016) have shown promising results. Methods: This is an ongoing phase-2 study of sotatercept, 0.75 or 1 mg/kg subcutaneously every 3 weeks (1 cycle), in subjects with MF, whether primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF). Subjects must be RBC-transfusion-dependent (Gale, R.P. et al. Leuk Res 2011), have hemoglobin 〈 10 g/dL on every determination during the 84 days preceding study entry without RBC transfusions, or have hemoglobin 〈 10 g/dL despite intermittent RBC transfusions without fulfilling the criteria for transfusion dependence. Primary endpoints include anemia response and safety. Secondary endpoints include time to and duration of anemia response. Anemia response is a composite of RBC-transfusion-independence and hemoglobin response (increase of ≥1.5 g/dL from baseline on every determination consecutively over ≥84 days without RBC transfusions). Subjects must have received ≥5 cycles of sotatercept to be evaluable for response. Results: 18 subjects are enrolled to date. 1 subject received 6 cycles at a sub-therapeutic dose of 0.3 mg/kg and was not considered for efficacy evaluation, but was evaluable for safety. Of the remaining 17 subjects, 11 received 0.75 mg/kg and 6, 1 mg/kg. Median age was 67 years (range, 47-84 years); 10 were male and 7 female. 14 had PMF and 3, post-ET MF. 12 subjects had JAK2 V617F, 1 had MPLW515L and 2 had CALR exon 9 mutations. 1 subject was triple negative and 1 subject had no JAK2 or MPL mutation but was not tested for CALR mutations. All 17 subjects had intermediate-2 or high risk disease by the Dynamic International Prognostic Scoring System. Table 1 summarizes baseline variables for these 17 subjects. Median number of cycles of sotatercept received is 5 (range, 1-13). 14 of the 17 subjects received ≥5 cycles and were evaluable for response. The 3 other subjects received 1, 2 and 2 cycles and discontinued due to unrelated medical problems, hypertension and stem cell transplant (SCT), respectively. 5 of 14 (36%) evaluable subjects have responded; 4 of whom continue on study in ongoing response. All responders are female and all female subjects evaluable for response responded. Responses occurred across phenotypic driver mutation categories and in both transfusion-dependent (n=3) and -independent (n=2) subjects. 40% and 25% of evaluable patients responded in the 0.75 mg/kg and 1 mg/kg dose cohorts, respectively. Most adverse events (AEs) were grades 1 or 2. The only AEs possibly attributable to sotatercept include grade 3 hypertension leading to discontinuation, and grade 1 myalgia, bone pain, pain in extremity and injection site reaction. 5 subjects remain on study. 12 have discontinued because of no response (5), SCT (2), unrelated medical problems (1), hypertension (1), disease progression (1), transformation to AML (1) and withdrawal of consent (1). Conclusion: Sotatercept improves anemia and RBC-transfusion-dependence in persons with MF and is well-tolerated. Enrollment to the trial is ongoing; updated results will be presented. A separate cohort of subjects receiving ruxolitinib has been added and will also be discussed. Based on the preponderance of responses at the 0.75 mg/kg dose, this dose has been selected for the combination cohort. Disclosures Daver: Incyte: Consultancy, Other: Advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy.

Abstract: Background: Treatment with HMAs such as azacitidine and decitabine has changed the overall outcome of patients with MDS. Failure to respond to or relapse from HMA treatment is associated with poor prognosis without further approved therapy. Clofarabine is a second-generation nucleoside analog with single-agent activity in MDS. Aim: This is a phase II trial to evaluate the safety and activity of the combination of clofarabine and low-dose cytarabine in the treatment of patients with high-risk MDS who failed prior HMA therapy. Materials and Methods: Eligible patients were adults older than 18 years with MDS who had no response, progressed, or relapsed following at least 4 cycles of therapy with either azacitidine and/or decitabine and an ECOG performance status of ≤ 2 at the time of study entry. Responses were defined according to IWG 2006 criteria. Induction therapy consisted of clofarabine 15 mg/m2 IV daily for 5 days (days 1-5) and cytarabine 20 mg SC twice daily for 7 days (days 1-7). Responding patients proceeded with consolidation therapy with clofarabine 15 mg/m2 IV daily for 3 days (days 1-3) and cytarabine 20 mg SC twice daily for 5 days (days 1-5) every 4 weeks for a maximum of 12 cycles. Overall survival (OS) was defined as the time between the date of the first dose of clofarabine and the date of death from any cause. Univariate (UVA) and multivariate analysis (MVA) related to response and survival were performed with Cox regression analysis. Results: Between January 2012 and December 2013, 56 patients were enrolled. Fifty-two patients were evaluable for response (4 patients had not been on-study long enough to evaluate). The median follow-up is 15.3 months (range, 1.2-27.7+), and the median age at enrollment was 71 years (31-83). Ten patients (19%) had prior chemotherapy and 12 (23%) had prior radiation therapy. Median bone marrow blast percentage was 15% (6-30%). Three patients (6%) had CMML-1, 4 (8%) had CMML-2, 7 (14%) had RAEB-1, 19 (37%) had RAEB-2, and 19 (37%) had RAEB-T. Eight (15%) patients had intermediate-1 risk, 23 (44%) had intermediate-2 risk, and 21 (40%) had poor risk by IPSS. By IPSS cytogenetic risk, 25 patients (48%) had low-risk cytogenetics, 15 (29%) had intermediate-risk, and 12 (23%) had high-risk. Mutational analysis detected 2 (4%) FLT3-ITD, 0 FLT3-D835, 7 (13%) RAS, 2 (4%) NPM1, and 2 (4%) JAK2 mutations. Thirty-nine patients (75%) received prior azacitidine therapy and 15 (29%) received prior decitabine therapy. The overall response rate (ORR) was 48% (9 [17%] achieved complete remission [CR] , 3 [6%] complete remission with incomplete platelet recovery [CRp] , 7 [13%] marrow CR, and 6 [12%] had stable disease with hematological improvement), and median duration of response was 12.0 months (range, 2.0-26.7+). Five patients (10%) went on to receive allogeneic stem cell transplantation. Of the 25 patients with low-risk cytogenetics, 16 (64%) achieved OIR, 5 (20%) CR, 3 (12%) CRp, 6 (24%) mCR, and 2 (8%) HI. Of the 15 patients with intermediate-risk cytogenetics, 5 (33%) had OIR, 4 (27%) CR, and 1 (4%) mCR. Of 12 patients with high-risk cytogenetics, 2 (17%) had OIR, 1 (8%), CR, and 1 (8%) HI. Median OS was 6.8 months (range, 0.4-27.7+). The median OS in patients with response and those without response was 〉 12.4 months (range, 3.5-27.7+) and 3.4 months (range, 0.4-16.1), respectively. Most toxicities were of grade ≤ 2 and included elevated liver enzymes in 41% of patients, elevated bilirubin in 38%, rash in 28%, nausea in 31%, headache in 24%, and febrile neutropenia in 28%. Grade ≥ 3 toxicities included elevated liver enzymes (3%) and elevated bilirubin (3%). 21 (40%) patients had clofarabine dose reduction after a median of 2 courses (range, 1-8). UVA and MVA for survival identified performance status ≥2 (p=0.002; HR, 4.860; 95%CI, 1.784-13.244), stable disease or progressive disease after clofarabine (p 〈 0.001; HR, 8.372; 95%CI, 3.233-21.677), thrombocytopenia 〈 30 (/109L) (p=0.001; HR, 3.659; 95%CI 1.682-7.958), and complex cytogenetics (UVA, p 〈 0.001; MVA, p= 0.110, HR, 2.329; 95%CI 0.826-6.564) as prognostic factors for poorer OS. Conclusion: The combination of clofarabine and low-dose cytarabine has an ORR of 48% in patients with MDS who failed prior therapy with HMA. The study continues to accrue, and updated results with longer follow up will be presented at the meeting. Disclosures Daver: Novartis: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria. Borthakur:Tetralogic Pharmaceuticals: Research Funding. O'Brien:Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Garcia-Manero:Epizyme, Inc: Research Funding.

Abstract: Background: Vosaroxin, is a first-in-class anti-cancer quinolone derived (AQD) DNA intercalator and topoisomerase II inhibitor, which is not a substrate for p53 or P-glycoprotein, and is currently under evaluation for the treatment of pts with AML and high-risk MDS. Methods: Pts are eligible if they have AML or high-risk MDS (defined as having 〉 /= 10% blasts), are 60 years of age or older, and have adequate performance status (ECOG 〈 /= 2) and organ function. 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 repeated in approximately 4 to 5 week intervals for up to 7 cycles. This dose was well tolerated in the 6 patients. However, due to occurrence of 8 episodes of grade 3/4 mucositis in 7 of the subsequent 16 patients the induction dose of vosaroxin was reduced to 70 mg/m2 with the vosaroxin dose maintained at 70 mg/m2 or reduced to 50 mg/m2 in consolidation cycles. 34 patients were treated at this modified dose regimen. 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, 56 pts (50 AML, 6 high-risk MDS) with a median age of 69 years (range, 60 - 78) have been enrolled. They included 19 (34%) pts with diploid cytogenetics, 21 (38%) with complex cytogenetic abnormalities including chromosome 5 and/or 7 abnormalities, and 16 (28%) with other miscellaneous abnormalities. Fourteen (25%) pts with AML had antecedent hematological disorders (AHD) including 7 with MDS, 4 with MPN, 2 with MDS/MPN, and 1 with CLL. Four pts with AHD had received prior therapy including 5-azacytidine (n=1), decitabine (n=1), ruxolitinib + 5-azacytidine (n=1), and lenalidomide (n=1). Additionally, 10 (18%) pts had therapy-related disease with prior exposure to chemotherapy or radiation therapy. Median bone marrow blast %, and median white blood cell, hemoglobin, & platelet counts were 40% (range, 11 - 97), 3.4 x 109/L (range, 0.4 - 57), 9.4 g/dL (range, 6.8 - 13.1), and 35 x 109/L (range, 7 - 333), respectively. All 56 pts have completed 〉 /=2 cycles of therapy and were evaluable for response; 30 (54%) achieved CR, 8 (14%) CRp, and 5 (9%) CRi for an overall response rate of 77%. Minimal residual disease (MRD) by 19 color flow-cytometry was evaluable in 35 of the 43 responders. MRD was not detectable in 24 of 35 (66%) evaluable responders. All 56 patients had baseline cytogenetics and clinically validated next generation sequencing-based analysis for the detection of somatic mutations in the coding sequence of 28 genes commonly mutated in myeloid neoplasms. Response by baseline characteristics is shown in table 1. The median number of cycles to response was 1 (1 - 4); 13 pts have required 〉 1 cycle to achieve response. Seven (13%) pts have proceeded to allogeneic stem cell transplant. The median follow-up is 4.7 months (1.3 - 20.8). The regimen was well tolerated with the main therapy related grade 〉 /= 3 toxicities were mucositis in 10 (18%) pts and liver enzyme elevation in 8 (14%). The median overall survival (OS) for all pts is 8.3 months. Four-week and 8-week mortality for all pts were 0 and 14%, respectively. The induction dose of vosaroxin was 90 mg/m2 in 22 pts and 70 mg/m2 in 34 pts. The lower induction dose of vosaroxin was associated with a reduced early mortality and an improved overall response rate and OS (Table 2 and Figure 1). Conclusion: Combination of vosaroxin and decitabine is effective in older pts with AML and high-risk MDS. Reponses were encouraging in the pts with TP53 and complex cytogenetics. The lower dose of vosaroxin 70 mg/m2 on days 1 and 4 is better tolerated and is associated with significantly improved outcomes. Table 1. Response by baseline characteristics Parameter Category N Overall response(CR, CRp, CRi) CR Age 60-74 44 80% 57% 〉 /=75 12 67% 42% Cytogenetics Diploid 19 86% 57% -5/-7/other adverse 21 68% 42% Miscellaneous 16 75% 63% MutationStatus IDH2 11 91% 73% IDH1 14 57% 43% TP53 11 73% 55% RAS 11 64% 28% Table 2. Outcomes by induction dose of vosaroxin Induction dose(vosaroxin) N Med OS 8-week mortality Overall Response CR Need 〉 1 cycle to response 90 mg/m2 22 5.5 mos 25% 73% 41% 23% 70 mg/m2 34 11.5 mos 6% 79% 62% 23% Figure 1. OS by induction dose of vosaroxin Figure 1. OS by induction dose of vosaroxin Disclosures Daver: ImmunoGen: Other: clinical trial, Research Funding. Off Label Use: Vosaroxin in the management of AML. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding. DiNardo:Novartis: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Craig:Sunesis: Employment, Equity Ownership.