ALBERT

Description: Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies.

Description: Activating mutations in FMS-like tyrosine kinase 3 (FLT3) are common in acute myeloid leukemia (AML) and drive leukemic cell growth and survival. Although FLT3 inhibitors have shown considerable promise for the treatment of AML, they ultimately fail to achieve long-term remissions as monotherapy. To identify genetic targets that can sensitize AML cells to killing by FLT3 inhibitors, we performed a genome-wide RNA interference (RNAi)-based screen that identified ATM (ataxia telangiectasia mutated) as being synthetic lethal with FLT3 inhibitor therapy. We found that inactivating ATM or its downstream effector glucose 6-phosphate dehydrogenase (G6PD) sensitizes AML cells to FLT3 inhibitor induced apoptosis. Examination of the cellular metabolome showed that FLT3 inhibition by itself causes profound alterations in central carbon metabolism, resulting in impaired production of the antioxidant factor glutathione, which was further impaired by ATM or G6PD inactivation. Moreover, FLT3 inhibition elicited severe mitochondrial oxidative stress that is causative in apoptosis and is exacerbated by ATM/G6PD inhibition. The use of an agent that intensifies mitochondrial oxidative stress in combination with a FLT3 inhibitor augmented elimination of AML cells in vitro and in vivo, revealing a therapeutic strategy for the improved treatment of FLT3 mutated AML.

Description: Chronic neutrophilic leukemia (CNL), atypical chronic myeloid leukemia (aCML), and myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN-U) are a group of rare and heterogeneous myeloid disorders. There is strong morphologic resemblance among these distinct diagnostic entities as well as a lack of specific molecular markers and limited understanding of disease pathogenesis, which has made diagnosis challenging in certain cases. The treatment has remained empirical, resulting in dismal outcomes. We, therefore, performed whole-exome and RNA sequencing of these rare hematologic malignancies and present the most complete survey of the genomic landscape of these diseases to date. We observed a diversity of combinatorial mutational patterns that generally do not cluster within any one diagnosis. Gene expression analysis reveals enrichment, but not cosegregation, of clinical and genetic disease features with transcriptional clusters. In conclusion, these groups of diseases represent a continuum of related diseases rather than discrete diagnostic entities.

Description: Two tools have recently been developed to predict allogeneic HCT tolerance: the HCT-comorbidity index (HCT-CI) (Sorror, Blood 2005) and “risk group” (Artz BBMT, 2006). The HCT-CI focuses on a comprehensive list of comorbidities whereas the “risk group” combines a simple comorbidity tool and performance status to identify patients at high risk for transplant-related mortality (TRM) and inferior survival. However, clinical parameters have limitations of reproducibility and accuracy. Biomarkers represent another promising method of risk stratification. Thus, we analyzed whether biomarkers independently predicted HCT tolerance. Among 112 consecutive transplants on a single protocol, 81 patients with pre-HCT cryopreserved sera underwent analysis of C-reactive protein (CRP) and 79 of interleukin-6 (IL-6) levels. AML and MDS represented the most common diagnosis (57%). All patients underwent HCT using fludarabine (125 mg/m2 IV total), melphalan (140 mg/m2 IV total) and alemtuzumab (100 mg IV total). The median age was 52 yrs and 46% had active disease at HCT. The median follow-up was 42 months. To determine tolerance, we evaluated initial hospital duration, aGVHD, and TRM. Median duration of initial hospitalization for HCT was 23 days and Grade II–IV aGVHD developed in 30 pts. Day 100 and day 180 TRM were 17% and 23% respectively. The median pre-HCT CRP level was 18.5 mg/L (mean, 40.5 mg/L; range, 0.17 to 180). The median IL-6 was 78.3 mg/L (range, 10 to 2258). CRP and IL-6 above the median were tested as adverse risk factors. High CRP was strongly associated with prolonged hospitalization (P=0.007) whereas increased IL-6 was not (P=0.30). HCT-comorbidity index (HCT-CI) ≥ 3(P=0.126) and “risk-group” (P=0.091) did not confer an increased risk of prolonged hospitalization. In univariate analysis, CRP above the median also predicted for grade II–IV aGVHD (P= 0.003). TRM was predicted by CRP (P=0.013) but not IL-6 (P=0.22). Multivariate analysis showed CRP retained independent predictive value for TRM when considering adverse risk factors of age ≥50, HCT-CI ≥ 3, active disease, or “risk group”. The impact of these biomarkers was limited to HCT tolerance as CRP and IL-6 did not predict for increased relapse (P=0.42 for both). Finally, inferior overall survival was associated with pre-HCT CRP (P= 0.029) but not IL-6 (P= 0.48). CRP holds promise as a reproducible biomarker to predict HCT related morbidity and mortality independent of standard measures. IL-6 may be less useful. These findings require validation, but because of the ready availability and reproducibility of CRP, this biomarker could be rapidly integrated into other HCT risk-assessment tools. P value for Transplant-Related Mortality Predictive Factor Univariate Multivariate HCT- CI-hematopoietic cell transplant comorbidity index Age 0.27 0.79 Disease 0.16 0.26 HCT-CI 0.79 0.98 Risk Group 0.11 0.061 C-reactive protein 0.013 0.047 Interleukin-6 0.22 -

Description: Introduction Effective therapies for R/R AML remain limited. MEK or MDM2 inhibition can downregulate MCL1, overcoming resistance to BCL2 inhibition. Preclinical synergy was seen when combining BCL2 inhibitor Ven with MEK inhibitor cobimetinib (cobi) or MDM2 inhibitor idasa (Han et al. ASH 2016; Pan et al. Cancer Cell 2017), supporting clinical evaluation in AML. Preliminary data in a Phase Ib dose-escalation study (NCT02670044) evaluating Ven+cobi/idasa in R/R AML suggested both combinations were tolerable (Daver et al. ASH 2017). However, Ven+cobi was closed due to limited clinical activity. Here we present data for additional pts, longer follow-up and biomarker analyses for Ven+idasa. Methods This ongoing, open-label, multicenter study evaluates safety, tolerability and efficacy of Ven+idasa in R/R AML or secondary AML previously treated for an antecedent hematologic disease. Pts 〉60 yrs of age and ineligible for cytotoxic therapy/allogeneic stem cell transplant were enrolled. A 2-dimensional dose escalation was used to establish the maximum tolerated dose: pts received doses of Ven orally (PO) daily (400mg or 600mg) + idasa PO daily on Days 1-5 (150mg, 200mg, or 400mg) in 28-day cycles. Plasma samples were taken for PK analysis at Cycles 1 and 2 Days 1 and 5, and Cycle 4 Day 1. BCL2, BCLxL and MCL1 status and minimal residual disease (MRD) were assayed centrally at Covance Laboratories using multicolor flow cytometry. Mutation (mut) sequencing was performed by Foundation Medicine using FoundationOne Heme at screening and from last bone marrow collected on study. Results As of April 6 2018, 34 pts received Ven+idasa across all dose cohorts (Table 1). Median age: 74 (range 64-93) yrs; median prior therapies: 1 (range 1-4); ECOG performance status 2: 18%; refractory: 56%; secondary AML: 53%; adverse cytogenetics: 27%. Pre-therapy mut data were available for 32 pts; most common muts were RUNX1 14 (41%), ASXL1 11 (32%), SRSF2 11 (32%). Other significant pre-therapy muts: TP53 6 (18%), IDH2 7 (21%), IDH1 1 (3%), FLT3 4 (13%). The most common adverse events (AEs) were diarrhea (88%) and nausea (71%); the most common grade (Gr) ≥3 AEs were neutropenia (32%), febrile neutropenia (32%), thrombocytopenia (29%; Table 2). After 2 cases of Gr 3 diarrhea in the Ven 600mg cohorts, mandatory prophylaxis was implemented; no further cases of Gr ≥3 diarrhea were seen in the following 10 pts. Laboratory tumor lysis syndrome occurred in 3 pts (9%); none required treatment discontinuation. There was no apparent PK drug-drug interaction between Ven and idasa. PK was dose-proportional over the ranges tested for Ven and idasa. The recommended Phase II dose (RP2D) has not been identified yet. Across all dose cohorts, 30/34 pts were response-evaluable; the remaining 4 were still on study treatment without post-baseline response assessment. The anti-leukemic response rate (CR+CRp+CRi+MLFS+PR) was 37% (11/30). Across the 2 Ven 600mg cohorts, which are being considered for RP2D, the anti-leukemic response rate was 9/18 (50%) (Table 1, Figure 1). MRD negativity (

Description: Introduction: IDH2 mutations (mIDH2) are recurrent in ~5% of patients (pts) with MDS and ~15% of pts with acute myeloid leukemia (AML). mIDH2 proteins have neomorphic enzymatic activity and are associated with DNA and histone hypermethylation, altered gene expression, and blocked differentiation of hematopoietic progenitor cells. Enasidenib (AG-221/CC-90007) is a small-molecule allosteric inhibitor of mIDH2 protein that induces hematological responses in pts with mIDH2 AML, including relapsed or refractory (R/R) AML (Stein, Clin Cancer Res, 2016). The current analysis is the first to evaluate the safety and clinical efficacy of enasidenib monotherapy in pts with mIDH2-positive MDS. Methods: This analysis includes pts ages ≥18 years with MDS and mIDH2 who participated in a phase 1 study with a dose-finding period followed by an expansion phase in which all pts received daily oral enasidenib 100 mg QD in 28-day cycles. Pts had R/R MDS or were not candidates for standard therapies. Response was measured using peripheral blood (PB) and bone marrow (BM) samples from days 15, 29, 57, and every 56 days thereafter, and by objective investigator report. Overall response rate (ORR) reflects the best response achieved by pts, and includes complete remission (CR), partial remission (PR), marrow CR (mCR), and any hematologic improvement (HI) (IWG 2006 MDS criteria). Evaluable pts required a response assessment at Cycle 2 Day 1 or later, or discontinued before assessment. Overall survival (OS) was estimated using Kaplan-Meier methods. Next-generation sequencing identified pre-existing co-occurring genomic alterations using the FoundationOne® Heme test on purified mononuclear cells from BM or PB, to assess relationships between co-mutational status and clinical response. Results: Of 16 pts with MDS in this study, 12 pts had discontinued and 4 pts continued to receive enasidenib at interim database lock (15 April 2016). Reasons for discontinuation included disease progression (n=1), adverse event (AE; n=1), death (n=4), investigator decision (n=2), and other (n=1); 3 pts proceeded to transplant. Median age was 67 years (range 45-78) (Table 1). R140 mutations were more common than R172 mutations (88% vs 12%). At entry, 3 pts (19%) had relapsed following allogeneic stem cell transplant and 11 (69%) had failed prior treatment (Tx) with a hypomethylating agent (HMA). Six pts (38%) had received ≥2 prior anticancer Tx for MDS. MDS pts in the dose-finding phase received daily enasidenib doses of 60 mg (n=1), 150 mg (1), 200 mg (3), or 300 mg (1); 10 pts received enasidenib 100 mg QD. Median number of Tx cycles was 3 (range 1-25); 5 pts (31%) received ≥6 enasidenib cycles and 4 pts (25%) received ≥12 cycles. Grade 3-4 Tx-emergent AEs (TEAEs) were reported for 13 pts (81%); the most frequent were hyperbilirubinemia (n=5, unconjugated), pneumonia (n=4), thrombocytopenia (n=3) and hypokalemia (n=3). Seven pts (44%) had a grade 3-4 drug-related TEAE. One pt was not evaluable for response. ORR was 53% (8/15), including 1 pt who achieved CR (Figure 1). Of 10 evaluable pts who had received prior HMA Tx, 5 (50%) had a response with enasidenib, including the pt in CR. Of the 4 pts with no prior MDS Tx, 2 responded (1 PR, 1 mCR). Median time to CR, PR, or mCR (sustained ≥4 weeks) was 24 days (range 17-87) from beginning enasidenib Tx, and to HI (sustained ≥8 weeks) was 11 days (11-60). Two pts experienced disease progression. Median OS was not reached after a median follow-up of 4.7 months. FoundationOne® data were available for 12 pts; the most frequently observed known somatic co-occurring mutations were ASXL1 and SRSF2 (Figure 2). Although trends between response and co-occurring ASXL1 and/or SRSF2 mutations were observed, the small number of pts tested prevents definitive conclusions. Discussion: Daily Tx with oral enasidenib monotherapy was well tolerated and induced responses in more than one-half of these MDS pts with mIDH2, 50% of whom had higher-risk disease, and two-thirds of whom had failed prior HMA Tx. Notably, one-half of evaluable MDS pts who had failed prior HMA Tx had a response, including a CR, with enasidenib monotherapy. Only 2 pts experienced disease progression during Tx. Mutational testing is rapidly becoming essential to diagnosis and prognostication in MDS, and assessment of IDH2 mutations can identify MDS pts who may benefit from targeted Tx with enasidenib. Disclosures Stein: Seattle Genetics: Research Funding; Agios Pharmaceuticals: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Novartis: Consultancy. Fathi:Merck: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Celgene: Consultancy, Research Funding; Bexalata: Other: Advisory Board participation. DiNardo:Novartis: Other: advisory board, Research Funding; Agios: Other: advisory board, Research Funding; Celgene: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Abbvie: Research Funding. Pollyea:Celgene: Other: advisory board, Research Funding; Ariad: Other: advisory board; Glycomimetics: Other: DSMB member; Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding. Roboz:Celgene: Consultancy; Astex: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Juno: Consultancy; Genoptix: Consultancy; Amgen: Consultancy; MEI Pharma: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; Onconova: Consultancy; Sunesis: Consultancy; Novartis: Consultancy; Roche/Genentech: Consultancy; MedImmune: Consultancy; Celator: Consultancy; Amphivena: Consultancy. Sekeres:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Stone:Pfizer: Consultancy; Sunesis Pharmaceuticals: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; Juno Therapeutics: Consultancy; ONO: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Roche: Consultancy; Xenetic Biosciences: Consultancy. Attar:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Tosolini:Celgene: Employment, Equity Ownership. Xu:Celgene: Employment, Equity Ownership. Amatangelo:Celgene: Employment, Equity Ownership. Gupta:Celgene: Employment, Equity Ownership. Knight:Celgene: Employment, Equity Ownership. De Botton:Agios, Celgene, Pfizer, Novartis, Pierre Fabre, Servier: Consultancy, Honoraria, Research Funding. Kantarjian:Amgen: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Description: Introduction: Patients (pts) with higher-risk myelodysplastic syndrome (HR-MDS) and those who fail to respond to or relapse/progress after treatment with hypomethylating agents (HMA) have limited therapeutic options and poor prognosis. PD-L1 expression is upregulated in HR-MDS pts (compared with lower-risk MDS pts) and in those who fail HMA therapy. Combining inhibition of the PD-L1/PD-1 pathway with azacitidine may improve outcomes in MDS. Methods: We conducted a Phase Ib trial of the anti-PD-L1 monoclonal antibody atezolizumab, with or without azacitidine, in HMA-failure and HMA-naive MDS pts (NCT02508870). The primary objective was to determine the safety and tolerability of atezolizumab as a single agent or in combination with azacitidine. An initial safety evaluation was performed in three cohorts. Cohort A1 (10 pts) consisted of HMA-failure HR-MDS pts treated with atezolizumab alone (1200mg IV q3w). Cohort B1 (11 pts) consisted of HMA-failure HR-MDS pts treated with atezolizumab (840mg IV q2w) in combination with azacitidine (75mg/m2 qd for 7 days q4w) for 6 cycles, followed by atezolizumab maintenance alone (1200mg IV q3w). Cohort C1 (6 pts) consisted of HMA-naive HR-MDS pts treated with atezolizumab (840mg IV q2w) in combination with azacitidine (75mg/m2 qd for 7 days q4w). If atezolizumab alone or in combination with azacitidine was deemed safe and tolerable in Cohorts A1 and B1, an additional 1:1 randomization into two cohorts of 30 pts each (Cohorts A2 and B2) was planned. If the combination of atezolizumab and azacitidine was found to be safe and tolerable in Cohort C1, an additional expansion cohort (Cohort C2) of 14 pts with HMA-naive HR-MDS was planned. Primary endpoints included determining the safety and tolerability of atezolizumab-based regimens in HR-MDS and defining the recommended Phase II dose for the combination. Results: As of January 2018, 42 HR-MDS pts had been treated with atezolizumab-based regimens: Cohort A, 10 pts; Cohort B, 11 pts; Cohort C, 21 pts. Median age for the entire pt cohort was 76 years (range: 63−89). Median treatment duration for Cohorts A, B, and C was 4.2, 5.5, and 5.8 months, respectively. The overall response rate for Cohorts A, B, and C was 0%, 9% (hematologic improvement [HI]: 9%), and 62% (CR, 14%; mCR, 19%; mCR + HI, 10%; HI, 19%), respectively. All pts in Cohorts A and B have discontinued therapy, with a median overall survival (OS) of 5.9 months and 10.7 months, respectively. For pts in Cohort C, 8/21 pts remain on therapy, and median OS has not been reached. Grade 3−5 adverse events (AEs) in 〉10% of pts were primarily hematologic; grade 3−5 febrile neutropenia occurred in 29% of all pts and was particularly common in pts receiving the atezolizumab-azacitidine combination (Cohorts B [36%] and C [33%] compared with Cohort A [10%]; Table 1). In Cohort A, 70% (7/10) of pts died, as did 64% (7/11) of pts in Cohort B and 29% (6/21) of pts in Cohort C. Median time to death was 160 days (Cohort A), 299 days (Cohort B), and 53 days (Cohort C). Timing and causes of death were different in the three cohorts. Causes of death were more commonly from disease progression in Cohorts A and B, while serious AEs accounted for all deaths in Cohort C (Table 2). In addition, deaths within 3 months occurred in 10%, 18%, and 29% of pts in Cohorts A, B, and C, respectively. The high early death rate compared with historical controls observed in HMA-naive HR-MDS patients (Cohort C) led to early termination of the study prior to completing recruitment. Biomarker assessment demonstrated PD-L1 expression on variable proportions of AML blasts in samples from all pts analyzed. However, PD-L1 expression was not associated with clinical response (Figure). Conclusions: Combination of atezolizumab plus azacitidine in HMA-naive HR-MDS pts had an unfavorable safety profile, which led to early termination. Limited responses were observed with atezo-based regimens (with or without azacitidine) in HMA-failure HR-MDS pts, without excessive or unexpected toxicity. Better understanding of the reasons associated with the differential toxicity profile observed between HMA-naive versus HMA-failure HR-MDS pts will be crucial for potential future developments of this combination. Disclosures Gerds: Incyte: Consultancy; Celgene: Consultancy; CTI Biopharma: Consultancy; Apexx Oncology: Consultancy. Khaled:Daiichi: Consultancy; Alexion: Consultancy, Speakers Bureau; Juno: Other: Travel Funding. Lin:Jazz Pharmaceuticals: Honoraria. Pollyea:AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees. Dail:Genentech: Employment, Equity Ownership. Green:Genentech: Employment. Ma:Genentech: Employment. Medeiros:Genentech: Employment, Equity Ownership. Phuong:Genentech Inc: Employment, Equity Ownership, Other: Ownership interests PLC. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Yan:Roche: Employment.

Description: Myelodysplastic syndrome (MDS) is a malignant disorder of myeloid hematopoietic cells, resulting in ineffective hematopoiesis leading to bone marrow dysfunction and failure, and frequently evolves to acute myelogenous leukemia (AML). While chemotherapy can on occasion induce transient remissions, the disease is typically progressive, with the vast majority dying of MDS complications or AML. While MDS is thought to arise from a malignant stem cell population, the properties of such cells are not well understood. Thus, we performed studies to better characterize candidate MDS stem cells and allow insights into the development of novel stem cell directed targeted therapies. One line of investigation examined the cytokine receptor CD123, which we have previously shown to be a marker of AML stem cells. Analysis of primary human specimens demonstrates that CD123 is not expressed in the normal stem cell population (phenotypically identified as CD34+/CD38-) or in stem cells(CD34+/CD38-) from low risk (5% blasts and/or ≥ high risk IPSS-R) as shown in figure 1. These data suggest that up-regulation of CD123 may be a hallmark of pathogenesis as MDS progresses toward AML. To better understand the properties of CD123+ vs. CD123- stem cells, we performed global expression studies (RNA-seq) on sorted primary cell populations derived from high-risk MDS patients. The data indicate strong up-regulation of protein synthesis machinery, which indicates a major change in underlying cellular physiology and metabolism. Increased protein synthesis in CD123+ MDS stem cells was verified using the fluorescent protein substrate OP-puro, which identifies newly synthesized polypeptides. We found a ~13 fold difference in OP-puro staining of the CD123+ MDS stem cells versus CD123- cells. Based on these findings, we pursued two related lines of investigation to develop targeted therapies against MDS stem cells. First, we tested the protein synthesis inhibitors anisomycin and homoharringtonine for their ability to target the candidate MDS stem cell population; both agents demonstrated highly selective eradication of CD123+ stem cells, with a significant differential toxicity observed in multiple samples (up to an 80-fold difference in viability after treatment) as shown in figure 2. Second, because protein synthesis inhibition is known to rapidly down-regulate Bcl-2, we tested a selective Bcl-2 inhibitor. This agent also selectively eradicated CD123+ MDS stem cells in 4 of 10 patient samples tested. Finally, analysis of protein synthesis inhibitors or a Bcl-2 inhibitor in combination with the hypomethylating agent 5-azacytidine demonstrated potent efficacy in targeting the CD123+ stem cell population with greater then additive toxicity when compared to single agent treatment. We found significant differential sensitivity in the CD123+ population to the Bcl-2 inhibitor + 5-azacytidine in 9 out of 10 in samples tested and found significant toxicity to the combination of anisomycin or homoharringtonine with 5-azacytidine in 4 out of 4 samples. Taken together, these data show that we have identified two novel pharmacological approaches that may effectively target the MDS stem cell population. Further, these agents may function well in conjunction with commonly used agents used in the treatment of MDS. Disclosures Pollyea: GlycoMimetics: Other: Member of data safety monitoring board; Pfizer: Consultancy; Ariad: Consultancy; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.