ALBERT

Description: Background: Venetoclax (VEN) monotherapy in patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) has been efficacious with a complete remission rate of 16% and also durable with median time to progression of 33.2 months (Roberts et al., 2019). Despite these responses, many pts eventually relapse. To investigate possible mechanisms of resistance to VEN monotherapy, we performed a genome-wide CRISPR screen to identify genes whose loss of expression leads to reduction in drug sensitivity. To determine whether similar genomic alterations occur in pts treated with VEN, we analyzed the DNA and RNA of pre- and post-therapy specimens from CLL pts enrolled in two VEN monotherapy trials (NCT01328626 and NCT01889186). Methods: CRISPR screen was performed in lymphoma SUDHL4 cell line using Brunello library. Peripheral blood or bone marrow specimens were collected pre-dose and after VEN discontinuation; CLL cells were enriched via CD19-positive (CD19+) selection using magnetic beads. DNA from 43 pts was analyzed by whole exome and two targeted sequencing panels. RNA-seq analysis was performed on paired pre- and post-therapy CD19+ samples from 24 pts. Results: The CRISPR screen identified genes whose loss of expression led to resistance to VEN. Several members of the pro-apoptotic machinery were among the strongest hits, including BAX, BCL2L11 (BIM) and PMAIP1 (NOXA). Outside of the apoptotic pathway, loss of ID3 or NFKBIA also led to decreased VEN sensitivity, suggesting multiple possible mechanisms of resistance. To compare these results to the potential mechanisms of resistance in pts treated with VEN, we sequenced the DNA from CD19+ B cells extracted before treatment initiation or upon treatment discontinuation. Of the 37 pts with disease progression, 15 acquired mutations in BCL2 at progression (N=14 CLL, N=1 Richters); 6 pts had a single mutation and 9 pts acquired 2-4 distinct BCL2 mutations. The prevalence of mutations increased with time on VEN therapy; mutations were observed in 12 pts progressing between 22 and 59 months and in only 3 pts progressing between 6 and 16 months. BCL2 mutations at G101V and D103 (E/Y/V) as previously described (Blombery et al., 2019; Tausch et al., 2019) were identified in 13/15 pts. Additionally, our analysis identified 1 patient with a mutation at F104L and 3 pts with mutations at A113G. These F104L and A113G mutations were previously identified in a preclinical NHL model of VEN resistance (Tahir et al., 2017) and in DLBLCL pts, respectively, but have not been previously reported in CLL pts. Two novel mutations in BCL2: a 4 amino acid insertion at position 110 and a substitution at V156(D) were acquired at CLL progression in 3 and 4 pts, respectively. Most BCL-2 mutations were subclonal (VAF 10%. In accordance with the CRISPR screen, we identified mutations in other pro-apoptotic genes including PMAIP1 (N=4), BAX (N=2) and BAD (N=1). In contrast to the acquired BCL2 mutations, mutations in these BCL-2 family members occurred with high allelic frequency in 4 of the 7 pts (27-35%). Interestingly, 4 pts had a mutation in BCL2 in addition to another member of the apoptotic machinery. In each case, allele frequency suggested that the mutations were found in different clones. Comparison of mRNA expression pre- and post-VEN treatment demonstrated increased expression at the time of progression of key apoptotic genes BCL2L1 (BCL-XL), MCL1 and BCL2A1, all of which are known resistance factors to VEN. Concomitant decreases in BCL2 and HRK expression, and to a lesser extent PMAIP1, were also observed. The changes in gene expression were found irrespective of the presence of BCL2 mutations. Conclusions: Preclinical investigation into potential resistance mechanisms indicated that reduction in several genes confer resistance to VEN. Some of these alterations were observed in clinical samples, including several distinct mutations in BCL2 and other BCL-2 family members.Our data suggest that BCL2 mutations are subclonal and further data are needed to evaluate their role in resistance to VEN monotherapy. Additional ongoing analyses of genomic data may identify genomic alterations in other biological pathways that potentially convey VEN resistance. Emergence of resistance is likely multifactorial with modulation of the apoptotic family members via both acquired mutations and changes in gene expression pattern. Disclosures Chyla: Abbvie, Inc: Employment, Other: Stock or options. Popovic:AbbVie: Employment, Other: Stock or options. Lu:AbbVie: Employment, Other: Stock or options. Dunbar:AbbVie: Employment, Other: Stock or options. Quarless:AbbVie: Employment, Other: Stock or options. Robinson:AbbVie: Employment, Other: Stock or options. Warder:AbbVie: Employment, Other: Stock or options. Jacobson:AbbVie: Employment, Other: Stock or options. Zhou:AbbVie: Employment, Other: Stock or options. Souers:AbbVie: Employment, Other: Stock or options. Waring:AbbVie: Employment, Other: Stock or options. Bhathena:AbbVie: Employment, Other: Stock or options. Leverson:AbbVie Inc: Employment, Other: Stock or options. Kim:AbbVie: Employment, Other: Stock or options.

Description: BACKGROUND: The median age for diagnosis of acute myeloid leukemia (AML) is 68 years. Elderly patients are often ineligible for intensive chemotherapy and have limited treatment options. Venetoclax (Ven), an oral agent that targets the antiapoptotic protein, BCL-2, has demonstrated high rates of remission (〉60%) when administered in combination with low-dose cytarabine (LDAC), and could represent a potent therapeutic option for patients ineligible for intensive chemotherapy. METHODS: This open-label, phase 1/2 study (NCT02287233) evaluated the safety and efficacy of venetoclax in combination with LDAC in patients with previously untreated AML who were ineligible for intensive chemotherapy due to comorbidities or age. Patients had an Eastern Cooperative Oncology Group (ECOG) performance score of 0-2, had adequate hepatic and renal function, and were enrolled from December 2014 to May 2017. In the dose escalation portion of the study, 600 mg venetoclax was determined to be the recommended phase 2 dose (RPTD). Venetoclax was initiated at 50 or 100 mg daily and dose escalated over 4-5 days to reach the RPTD. In subsequent 28 day cycles, venetoclax was administered at 600 mg on all days. LDAC (20 mg/m2 daily) was subcutaneously administered on days 1-10 of each cycle. At the beginning of the study, concominant strong and moderate CYP3A inhibitor use was prohibited; however, as additional safety and pharmacokinetic data became available, their use was allowed with appropriate venetoclax dose adjustments. Time to first response, rates of complete remission (CR), CR with incomplete blood count recovery (CRi), CR with partial hematologic recovery (CRh), duration of response, achievement of transfusion independence, overall survival (OS) and adverse events (AEs) were evaluated. Minimal residual disease (MRD) was evaluated centrally by multicolor flow cytometry at a cutoff of 10-3 leukemic cells. RESULTS: Data cutoff was November 8, 2017. Of 82 patients treated with 600 mg of venetoclax, 65% were male, 95% white race, 60% had intermediate and 32% had poor cytogenetic risk, and 49% had secondary AML (of whom 60% had prior HMA exposure). Transfusion dependence for red blood cells (RBC) and platelets within 8 weeks prior to venetoclax treatment was 65% (53/82) and 28% (23/82) of patients, respectively. Most common grade ≥3 AEs across all patients were febrile neutropenia (43%), thrombocytopenia (38%), neutropenia (27%), and anemia (27%). Laboratory evidence of grade 3 tumor-lysis syndrome (TLS) was observed in two patients; both patients achieved the target dose of venetoclax. Forty seven percent of patients received moderate (40%) or strong (7%) CYP3A inhibitors for at least 7 days (predominantly azole antifungals); no relevant differences in serious adverse event rates were observed. Key efficacy results are shown in the Table. Median time to first response was 1.4 months, and 54% and 46% of patients achieved CR/CRi and CR/CRh, respectively. The rates of CR/CRi for patients with secondary and de novo AML were 35% and 71%, respectively; median DOR for those with secondary and de novo AML was 8.1 and 11.6 months, respectively. Patients with selected genetic mutations achieved the following rates of CR/CRi: TP53, 30%; IDH1/2, 72%; FLT3, 44%; NPM1, 89%. MRD response below 10-3 cutoff was achieved by 32% of patients with CR/CRi; median OS has not yet been reached for these patients. Among patients that were RBC or platelet transfusion dependent at baseline, 49% (26/53) and 65% (15/23), respectively, achieved transfusion independence while on venetoclax therapy. CONCLUSIONS: Venetoclax in combination with LDAC led to rapid, deep, and durable responses in patients with AML who were ineligible for intensive chemotherapy. Venetoclax plus LDAC demonstrated an improved CR rate (26% vs. 8%), CR/CRi rate (54% vs. 11%) and median overall survival (10 months vs. 5 months) compared to the historical rates with LDAC alone. Furthermore, a majority of patients achieved transfusion independence during venetoclax therapy. Strong and moderate CYP3A inhibitors, including azole antifungals, were safely coadministered with appropriate venetoclax dose adjustments. These results demonstrate that venetoclax, in combination with LDAC, represents an effective therapeutic option for patients with AML who are not suitable for standard induction therapy. Disclosures Wei: Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Strickland:Boehringer Ingelheim: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Consultancy; Baxalta: Consultancy, Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sunesis Pharmaceuticals: Consultancy, Research Funding. Fiedler:Amgen: Consultancy, Other: Meeting attendance, Patents & Royalties, Research Funding; ARIAD/Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Gilead: Other: Meeting attendance; GSO: Other: Meeting attendance; Teva: Other: Meeting attendance; JAZZ pharma: Other: Meeting attendance; Daiichi Sankyo: Other: Meeting attendance. Lin:Jazz Pharmaceuticals: Honoraria. Walter:Actinium Pharmaceuticals, Inc: Other: Clinical Trial support , Research Funding; Amgen Inc: Other: Clinical Trial Support, Research Funding; Amphivena Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Aptevo Therapeutics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Covagen AG: Consultancy, Other: Clinical Trial Support, Research Funding; Seattle Genetics, Inc: Consultancy, Other: Clinical Trial Support, Research Funding; Pfizer, Inc: Consultancy; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy. Hong:Genentech Inc/Roche: Employment, Other: Ownership interests PLC. Chyla:AbbVie, Inc: Employment, Equity Ownership. Popovic:AbbVie Inc: Employment, Equity Ownership. Fakouhi:AbbVie, Inc: Employment, Equity Ownership. Xu:AbbVie, Inc: Employment, Equity Ownership. Hayslip:AbbVie: Employment, Equity Ownership. Roboz:Bayer: Consultancy; Pfizer: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; AbbVie: Consultancy; Orsenix: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy; Astex Pharmaceuticals: Consultancy; Orsenix: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Eisai: Consultancy; Celgene Corporation: Consultancy; Sandoz: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Cellectis: Research Funding; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy; Celltrion: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; Celltrion: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Eisai: Consultancy.

Description: While treatment with tyrosine kinase inhibitors is highly successful for patients diagnosed in the chronic phase of chronic myeloid leukemia, these drugs are inefficient for BCR/ABL associated B-cell acute lymphocytic leukemia (B-ALL). Therefore, it is necessary to identify molecular targets downstream of BCR/ABL to develop additional therapeutic approaches. Cells transformed by BCR/ABL are resistant to a wide variety of apoptotic stimuli and therapeutic strategies aimed at reinstating the apoptotic pathway appear as an attractive concept. Bcl-xL is an antiapoptotic member of the Bcl-2 family of proteins and studies employing cell lines, as well as primary cells have linked BCR/ABL expression with increased levels of Bcl-xL, resulting in resistance to chemotherapeutic agents. To define the role of Bcl-xL in BCR/ABL associated B-ALL, we generated two inducible transgenic mouse models. In the first model, BCR/ABL and loss of Bcl-x expression are co-induced, and in the second model, leukemia is induced with expression of Bcl-xL protein well above the levels found in wildtype lymphoblasts. Surprisingly, we found that deletion of Bcl-xL did not inhibit leukemogenesis or affect apoptosis. Bcl-x deficient B-ALL mice rapidly succumbed to a B-ALL like disease with Bcl-x deficient B-ALL animals being moribund as early as 17 days after induction. By day 28, all mice (n=10) had died or had to be euthanized. Necropsy of animals suffering from Bcl-x deficient leukemia revealed massive lymphadenopathy, pleural effusion, and splenomegaly. While loss of Bcl-x in our B-ALL model led to a more severe phenotype with considerable tumor burden, no statistically significant difference was found between the survival time in Bcl-x deficient and wild type B-ALL animals due to development of pleural effusion in both models. The most prominent difference was the presence of mitotic figures in the peripheral blood, lymph node, and spleen of Bcl-x deficient B-ALL animals, suggestive of increased proliferation of Bcl-x deficient lymphoblasts. Cell cycle analysis of leukemic cells isolated from pleural effusion and spleen of Bcl-x deficient B-ALL mice demonstrated a significant increase of cells in S/G2/M phase (p ≤ 0.05) compared to wildtype lymphoblasts. Thus, loss of Bcl-xL results in increased passage through the cell cycle, while expression of the protein limits the proliferation rate. To test this hypothesis, we generated a second model in which Bcl-xL is expressed at higher levels than in wild type lymphoblasts. Overexpression of Bcl-xL in BCR/ABL positive mice led to reduced proliferation as significantly fewer leukemic cells were present in the S phase than in controls substantiating a role for in Bcl-xL proliferation of lymphoblasts. Initial studies performed to determine the mechanisms by which loss of Bcl-x leads to increased proliferation suggest that the protein may indirectly regulate stability of p27Kip1. Our data show that cells from Bcl-x deficient B-ALL mice in G1 and S phase contain less p27, as a consequence of proteosomal degradation. Clearly, our model systems demonstrate an unexpected and novel role for Bcl-xL in the context of BCR/ABL associated B-ALL. Ongoing studies are aimed at the identification of the mechanism and molecules through which Bcl-xL is linked to cell cycle and proliferation of BCR/ABL transformed lymphoblasts.

Description: Introduction: Multiple myeloma (MM) tumor cell survival is largely dependent on a complex network of interactions between pro-survival (BCL-2, BCL-XL, MCL-1) and pro-death (BIM, NOXA, BID, BAD, BAK, BAX) BCL-2 family members. Venetoclax (VEN) is a potent, selective, orally bioavailable small-molecule BCL-2 inhibitor. Bortezomib (BTZ) is a proteasome inhibitor that can impede MCL-1 activity by increasing the MCL-1 antagonist NOXA. The addition of VEN has been shown to enhance the activity of BTZ in MM cell line and xenograft models. Chromosomal abnormalities (immunoglobulin heavy chain translocations, amplification, deletions) can also influence sensitivity of MM cells to treatment. Results presented herein describe retrospective biomarker analysis in a subset of dose-escalation patients (pts) from an ongoing phase 1b study of VEN in combination with BTZ and dexamethasone in relapsed/refractory (R/R) MM. Methods: Exploratory objectives included evaluation of chromosomal abnormalities, BCL-2 family member gene expression levels, and ex vivosensitivity of pt MM tumor cells to VEN and/or BTZ. Interphase FISH analysis was performed on CD138-positively selected bone marrow mononuclear cells (BMMC) using probes for t(11;14), t(4;14), deletion 17p (17p-), deletion 13q (13q-), and amplification of chromosomes 5, 9, or 15 (denoted as hyperdiploid [HY]). Absolute quantitation of BCL-2 family members (BCL-2, BCL-XL, MCL-1, BCL-2A1, BIM, BID, BAD, BAX, and NOXA) was performed on CD138-selected BMMCs collected at baseline using TaqMan probe-based droplet digital polymerase chain reaction. Ex vivosensitivity of BMMCs collected at baseline to increasing doses of VEN and/or BTZ was determined by flow cytometry using a combined analysis for the loss of CD138 surface expression and the alteration of cellular morphology (lower FCS). Correlations between biomarkers and median best percentage change in M-protein were examined by Spearman test. Correlations between biomarkers and median time on study (mToS) were examined by log-rank and Wilcoxon tests for binary biomarkers, and by risk ratio from a Cox proportional hazard model for continuous biomarkers. No correction for multiple testing was performed. Results: Forty-one pts were enrolled as of 06/15/2015. The biomarker study subgroups were similar to the overall pt population with respect to demographics. Of the 37/41 (90%) pts assessed by FISH, 5 were t(11;14), 3 were t(4;14), 20 were 13q-, 10 were 17p-, and 15 were HY. In pts with HY, median best percentage change in M-protein was -79.4% compared to +101.65% in non-HY, while mToS was 309 days compared to 29 days in non-HY (p

Description: Introduction Although CLL minimal residual disease (MRD) status is used in contemporary clinical trials aimed at maximizing response or determining treatment duration, its role as a predictive factor for PFS has only been established following chemoimmunotherapy. In contrast, whether MRD is a valuable tool for treatment choice in the era of novel targeted agents for CLL is unknown. Unlike kinase inhibitors, the BCL2 inhibitor venetoclax does result in undetectable MRD (uMRD). MURANO demonstrated significant PFS benefit for venetoclax + rituximab (VenR) given for a fixed duration vs bendamustine + rituximab (BR) in relapsed/refractory (R/R) CLL. Here we present analysis of peripheral blood (PB) MRD kinetics in relation to PFS in MURANO with long follow up, when all pts have completed therapy. Methods Pts were randomized to VenR (Ven 400mg/d for 2 yrs + R for first 6 mo) or BR (6 mo). Response was assessed clinically using complete blood count and physical exam at follow-up visits. PB MRD was analysed centrally by ASO-PCR and/or flow cytometry at Cycle 4, end of combination therapy (EOCT; mo 9) and every 3 mo thereafter until 3 yrs, then every 6 mo. As strong concordance between PB and bone marrow (BM) MRD with VenR was previously shown (Hillmen et al. ASCO 2018), we focus on PB MRD. Pts were categorized into uMRD (

Description: Introduction: Undetectable minimal residual disease at

Description: BACKGROUND: Acute myeloid leukemia (AML) has a median age of diagnosis of 68 years; however, patients who are ineligible for intensive induction chemotherapy have limited therapeutic options. Venetoclax (Ven), an oral agent that targets the antiapoptotic protein, BCL-2, has shown synergistic antileukemic activity when combined with hypomethylating agents (HMA), decitabine (Dec) and azacitidine (Aza); this combination has resulted in high rates of durable remission, which are independent of cytogenetic and molecular characteristics. METHODS: This is an open-label, phase 1b, dose escalation and expansion trial (NCT02203773) studying the safety and efficacy of venetoclax in combination with decitabine or azacitidine. Patients had previously untreated AML and were ineligible for intensive chemotherapy due to comorbidities and age. Here, we present the data from the expansion cohort, where patients were treated with 400 mg venetoclax in combination with either HMA. Venetoclax was administered daily in a three day ramp-up from 100 to 200 to 400 mg and coadministered with either 20 mg/m2 of intravenous (IV) decitabine on days 1-5 or 75 mg/m2 of IV or subcutaneous azacitidine on days 1-7 within each 28 day cycle. Dose adjustments for venetoclax were implemented for concomitant medications routinely used for prophylaxis with known drug-drug interactions. Safety and efficacy were evaluated. Time to first response, complete remission (CR), CR with incomplete blood count recovery (CRi), CR with partial hematologic recovery, duration of response, achievement of transfusion independence, overall survival (OS) and adverse events (AEs) were assessed. Minimal residual disease (MRD) was evaluated centrally by multicolor flow cytometry at a cutoff of 10-3 leukemic cells. Enrollment of patients treated with Ven + Aza began December 2014 and the majority was enrolled between January 2017 and June 2017; enrollment of patients treated with Ven + Dec occurred between November 2014 and June 2016, resulting in significantly different median follow-up time for the two treatment arms. RESULTS: Data cutoff was December 22, 2017. Of 115 patients treated with the 400 mg dose of venetoclax, 84 were treated with Ven + Aza and 31 received Ven + Dec. The median ages for patients treated with Ven + Aza and Ven + Dec, respectively, were 75 (range: 61-90) and 72 (range: 65-86). Overall, 25% and 29% had secondary AML, and 39% and 48% had poor cytogenetic risk, in patients treated with Ven + Aza and Ven + Dec, respectively. Transfusion dependence for red blood cells (RBC) or platelets within 8 weeks prior to venetoclax treatment was 64% (54/81) and 74% (23/31) in patients treated with Ven + Aza and Ven + Dec, respectively. Key grade ≥3 AEs across all patients were febrile neutropenia (44%), anemia (28%), pneumonia (25%), thrombocytopenia (22%) and neutropenia (18%). Median time on study treatment was 6.4 and 5.7 months, and median follow up was 8.2 (range: 0.4-35.5) and 16.2 (range: 0.7-36.7) months for patients treated with Ven + Aza and Ven + Dec, respectively. Key efficacy results are shown in the Table. Seventy percent and 74% of patients achieved CR/CRi, and the median time to first response was 1.2 and 1.9 months for patients treated with Ven + Aza and Ven + Dec, respectively. The median overall survival was 14.9 months for patients treated with Ven + Aza and 16.2 months for those treated with Ven + Dec. Among patients transfusion dependent at baseline, 52% (40/77) achieved transfusion independence from both RBC and platelets, defined as not receiving RBC or platelet transfusion for ≥56 days. Across both treatment groups, among patients with CR/CRi, 45% achieved MRD response less than 10-3 leukemic cells. Patients who received venetoclax dose reduction for CYP3A inhibitors had similar responses compared to those without dose reduction. CONCLUSIONS: Venetoclax in combination with either azacitidine or decitabine led to high rates of rapid and deep responses that were durable in patients with AML ineligible for standard induction chemotherapy. A majority of patients who were transfusion dependent at baseline achieved transfusion independence after initiating venetoclax therapy. These results suggest that venetoclax, in combination with hypomethylating agents, may provide a potent therapeutic option for patients with AML who are not eligible for intensive chemotherapy. Disclosures Pollyea: 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; 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; AbbVie: Consultancy, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Curis: Membership on an entity's Board of Directors or advisory committees. Pratz:AbbVie: Consultancy, Research Funding; Agios: Research Funding; Astellas: Consultancy, Research Funding; Boston Scientific: Consultancy; Millenium/Takeda: Research Funding. Letai:AbbVie: Consultancy, Other: Lab research report; AstraZeneca: Consultancy, Other: Lab research report; Novartis: Consultancy, Other: Lab research report; Vivid Biosciences: Equity Ownership; Flash Therapeutics: Equity Ownership. Wei:Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Konopleva:Stemline Therapeutics: Research Funding. Frankfurt:AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene, Jazz, Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rizzieri:GlaxoSmithKline: Research Funding. Xu:AbbVie, Inc: Employment, Equity Ownership. Dail:Genentech: Employment, Equity Ownership. Chyla:AbbVie, Inc: Employment, Equity Ownership. Potluri:AbbVie: Employment, Equity Ownership. DiNardo:Celgene: Honoraria; Agios: Consultancy; Karyopharm: Honoraria; Abbvie: Honoraria; Medimmune: Honoraria; Bayer: Honoraria.