ALBERT

Description: Epidermal growth factor-like domain 7 (EGFL7) is a secreted protein and plays an important role in angiogenesis by regulating the growth, proliferation and migration of endothelial cells. Recent studies in solid tumors have shown that EGFL7 is overexpressed and is associated with a more aggressive disease phenotype. Whether EGFL7 plays a similar role in blood cancers such as acute myeloid leukemia (AML) however, has not been previously reported. To investigate the association of EGFL7 expression with outcome in AML, we measured EGFL7 mRNA expression in newly diagnosed older (≥60 years, n=126) CN-AML patients. In these patients, those with high EGFL7 expression were less likely to achieve CR (52% v 76%, P=.009). Patients with high EGFL7 expression status had shorter event-free survival (5-year rates: 6% v 13%, P=.03) and overall survival (5-year rates: 10% v 16%, P=.009) than patients with low EGFL7 expression status. To validate our clinical data we measured EGFL7 mRNA in primary AML blasts (n=11) compared to normal bone marrow (NBM) (n=5) using RT-PCR, and found a ~2.4 fold-increase in the AML samples, P

Description: Introduction: Children with Down syndrome (DS) have a 10-20 fold increased risk of acute lymphoblastic leukemia (ALL) and suffer significantly poorer outcomes due to increased relapse and treatment-related mortality. DS-ALL exhibits a distinct spectrum of cytogenetic alterations, with a lower incidence of common recurrent ALL alterations, a higher incidence of alterations involving CRLF2 and JAK2, and a higher proportion of cases lacking a known oncogenic driver compared to non-DS ALL. We hypothesized that identifying genetic drivers in DS-ALL will facilitate improved risk-based treatment stratification and lead to novel therapeutic targets that may be harnessed to improve outcomes in this vulnerable population. Methods: We interrogated diagnostic tumor (bone marrow or peripheral blood) and matched remission ("normal") blood samples from a cohort of 63 DS-ALL cases (65% male; median age 5 years, range 1-21 years) obtained from Texas Children's Cancer Center and the Children's Oncology Group. Samples were selected to include ~1/3 CRLF2-rearranged (CRLF2-R) and ~2/3 CRLF2-wild-type (CRLF2-WT) cases. Whole exome sequencing (WES) and copy number analysis using the OmniExpress array were performed on both tumor and normal DNA and transcriptome sequencing (RNAseq) was conducted on tumor RNA, all using the Illumina platform and existing informatic pipelines at the Baylor College of Medicine Human Genome Sequencing Center. A median of 〉97% of targeted bases with at least 20x coverage (range 93.5-98.1%) was observed for WES, and an average of 55.4 million paired reads were generated per RNAseq. Results: Analysis of RNAseq data (n=60) using deFuse and SOAPfuse algorithms revealed known ALL-associated gene rearrangements in 37/60 (62%) of cases, including CRLF2-R (21/60, 35%) involving P2RY8 (n=17) or IGH (n=4); ETV6-RUNX1 fusions (14/60, 23%) and TCF3 fusions (PBX1 x 2 and a novel in-frame fusion with FLI1 x 1). WES (n=62) identified a median of 19 nonsilent somatic mutations per case (range 6-228). We did not find evidence of somatic or germline mismatch repair gene mutations in the 3 cases with 〉50 somatic mutations. WES findings included recurrent activating hotspot mutations in JAK2 (predominantly p.R683G/S) in 14 cases (23%) and CRLF2 (p.F232C) in 2 cases, all of which also had CRLF2-R. Somatic RAS pathway mutations (13 KRAS, 7 NRAS, and 2 PTPN11) were found in 20/62 cases (32%), 4 CRLF2-R and 16 CRLF2-WT, including 2 cases also harboring JAK2 activating mutations. Recurrent mutations in epigenetic or chromatin remodeling genes (e.g. KMT2C, SETD2, KDM6A, WHSC1, DOT1L) were observed in ~25% of patients, as were mutations in other known ALL genes (e.g. FLT3, IL7R, IKZF1, PAX5). Interestingly, inactivating mutations in the deubiquitinase USP9X, also recently reported in acute promyelocytic leukemia, were identified in 5/62 (8%) cases. Evaluation for internal tandem duplications (ITDs) demonstrated typical in-frame events in FLT3 (n=2) and an out-of-frame ITD in SETD2. Copy number analysis revealed frequent losses in cell cycle genes (CDKN2A/B, BTG1, RB1) and other known B-cell development genes (IKZF1, PAX5). Other putative candidate alterations detected by RNAseq, WES, and array are currently being validated by orthogonal platforms. We observed multiple subclonal driver events in 〉10% of patients, including one case with CRLF2-R and mutations in CRLF2, JAK2, KRAS, and NRAS; and a second case with CRLF2 and ETV6-RUNX1 rearrangements and a PTPN11 hotspot mutation. Six cases exhibited 2 different JAK2, KRAS, or NRAS mutations: in all four cases where evaluation was feasible, these mutations were present on different sequencing reads, suggesting the existence of distinct subclones. Clinical features (gender, age, initial white blood count) did not appear to co-cluster with any of the recurrent alterations. Conclusions: These findings detail the landscape of genomic and transcriptomic alterations in the largest cohort of DS-ALL comprehensively characterized to date. Our data confirm the frequency and occasional polyclonal nature of JAK2 and RAS pathway mutations, and demonstrate that mutations in these pathways are not mutually exclusive. We also identified several novel, recurrent mutations and fusions. Future analyses of additional cohorts will be needed to assess recurrence frequency and prognostic impact of these alterations. Disclosures Schore: Baxalta: Honoraria; Millennium Pharmaceuticals, Inc: Research Funding; Onyx/Amgen: Research Funding; Merck: Research Funding.

Description: Acquired drug resistance is a major reason for relapse and death in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of acquired drug resistance is a potential solution. DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) have been shown to reverse drug resistance gene signatures and restore chemosensitivity in relapsed ALL. We report results investigating decitabine (DNMTi) (10-15 mg/m2/dose) and vorinostat (HDACi) (180 mg/m2/dose) with vincristine, dexamethasone, mitoxantrone and PEG-asparaginase (UKALL R3 backbone) for relapsed/refractory ALL. Twenty-three patients with refractory or ≥2nd relapse B-ALL were enrolled (Table 1). Median age was 12 (range, 1-21) years. Toxicity was graded according to CTCAE v4.0. The most common grade (Gr) 3-4 toxicities included hypokalemia (65%), anemia (61%), febrile neutropenia (57%), hypophosphatemia (43%), hyperbilirubinemia (39%), thrombocytopenia (39%), neutropenia (35%), sepsis (30%), lung infection (30%) and infection/infestations-other (30%). Non-hematologic dose limiting toxicity (DLT) was defined as any Gr 3 or 4 adverse event that was at least possibly attributed to decitabine and/or vorinostat with the exception of nausea (Gr 3), vomiting (Gr 3), transaminase elevation that returned to Gr ≤1 or baseline prior to the end of the course, fatigue, fever/infection, electrolyte abnormalities that were transient and not associated with clinical sequelae, albumin, alkaline phosphatase, GGT and anorexia. Hematologic DLT was defined as an absence of peripheral blood count recovery within 6 weeks of starting chemotherapy. Any patient who experienced a DLT after receiving at least 1 dose of decitabine or vorinostat was evaluable for DLT. Patients who did not experience a DLT had to receive a pre-determined amount of protocol therapy as outlined in the study to be evaluable for DLT. Seventeen of 23 patients were evaluable for DLT. Three patients experienced DLTs as follows: Gr 3 cholestasis, Gr 3 steatosis, Gr 4 hyperbilirubinemia (n=1); Gr 4 seizure, Gr 4 somnolence, Gr 3 delirium (n=1); and Gr 3 pneumonitis, Gr 3 hypoxia, Gr 3 hyperbilirubinemia (n=1). The study was suspended and amended after the first 5 patients enrolled (decitabine, 15mg/m2), due to significant infectious toxicities [4 of 5 patients reporting invasive fungal infections: C. kruseii (n=2), C. lusitaniae (n=1), and C. guillermondii (n=1)] and two DLTs (reported above). The treatment schema was modified to lower the dose of decitabine (10mg/m2/dose) and to reduce the duration from days 1-7/15-21 to 1-5/15-19. The duration of vorinostat was also reduced from days 3-10/17-24 to 2-7/16-21 (Figure 1). In addition, anti-fungal prophylaxis with either an echinocandin or amphotericin agent was required. Despite these dose modifications, infectious complications remained common with 17/23 (74%) patients reporting Gr ≥3 infections including invasive fungal disease in 35% (8/23). In analyzing all 23 patients, the complete response rate (CR + CR with incomplete blood count recovery) was 39% (9/23). Fourteen patients (61%) were able to complete full protocol therapy and evaluable for response. The remaining 9 patients did not complete therapy, primarily due to treatment-related toxicities, and were not evaluable. Nine of the 14 patients (64%) achieved a complete response with the remaining 5 reporting stable disease (36%). Minimal residual disease (MRD) testing via flow cytometry was performed on 7 of 9 patients who achieved a CR with a median level of 0.087% MRD (range, 0.00% to 1.6%) detected. Overall survival at 6 months was 35.1% (95% CI, 16.0 - 54.9) and 23.4% (95% CI, 7.8 - 43.6) at 1-year. Death was reported in 18/23 (78%) patients at a median of 10 weeks from study start (range, 3-138). Cause of death was attributed to refractory leukemia (n=8), treatment related toxicity (n=5), infection (n=3) and transplant-related toxicity (n=2). Despite encouraging response rates including low MRD, the combination of decitabine and vorinostat with intensive chemotherapy in this patient population was determined not to be feasible. A future follow-up study with a less intensive chemotherapy backbone is needed to determine if these two promising epigenetic agents can be successfully incorporated into the treatment of pediatric ALL. This study is registered at http://www.clinicaltrials.gov as NCT01483690. Disclosures Wayne: Kite Pharma: Honoraria, Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel Support; Medimmune: Honoraria, Other: Travel Support, Research Funding; NIH: Patents & Royalties.

Description: Introduction: Treatment patterns and clinical outcomes in elderly patients with DLBCL treated outside of clinical trials are poorly characterized. A previous report from Medicare Claims data found that 28% of patients above the age of 66 were treated with rituximab monotherapy or were not treated at all, with corresponding median survival of 18 and 2 months, respectively (Hamlin PA et al., Oncologist 2014; 19:1249-57). We conducted a retrospective chart review of diffuse large B cell lymphoma (DLBCL) patients diagnosed and managed within a community oncology practice network to evaluate treatment patterns and corresponding clinical outcomes. Methods: This was a retrospective observational chart review study of patients aged 60 years and over with newly diagnosed DLBCL. Eligibility criteria required a diagnosis between 1/1/2011 and 12/31/2012, with follow up through 12/31/14, plus no prior therapy for DLBCL. Data were obtained via programmatic query of the US Oncology Network/McKesson Specialty Health electronic health record database. Manual chart review was then performed on a subset of patients (n = 301) to confirm initial findings and gather additional information. Structured data elements were evaluated in univariate and multivariable logistic regression analysis in the subset of patients with stage 2 to 4 disease in order to determine factors associated with treatment with standard R-CHOP. Overall survival (OS) and progression free survival (PFS) were estimated from treatment initiation using the Kaplan Meier (KM) method. Results: 1151 patients who fit the eligibility criteria were identified. Age significantly influenced frontline treatment selection. Table 1 lists the percentage of patients with stage 2 to 4 disease treated with various regimens by age cohorts. "R-CHOP Alternative" was defined as one of the following: less than 6 cycles of R-CHOP, 〈 80% of full doses of agents in R-CHOP, or use of an alternative regimen like R-CVP, R-CEOP, or bendamustine-R. In multivariable analysis, age (OR=4.07 for age 65-79 and OR=7.98 for age 60-64; p

Description: Background: Rituximab (R) plus CHOP (R-CHOP) is standard-of-care treatment for previously untreated diffuse large B-cell lymphoma (DLBCL). Approximately 35-40% of patients (pts) will relapse following R-CHOP, and outcomes with salvage therapy remain poor. Obinutuzumab (GA101; GAZYVA/GAZYVARO; G) is a glycoengineered, type II anti-CD20 monoclonal antibody with greater direct cell death induction and antibody-dependent cellular cytotoxicity/phagocytosis activity than R. In the Phase 2 GATHER study (NCT01414855), G plus CHOP (G-CHOP) demonstrated manageable toxicity and promising efficacy in pts with advanced untreated DLBCL. GOYA (NCT01287741) is an open-label, multicenter, randomized Phase 3 study comparing the efficacy and safety of G-CHOP with R-CHOP in pts with previously untreated DLBCL. GOYA was sponsored by Roche with scientific support from the Fondazione Italiana Linfomi. Methods: Eligible pts were aged ≥18 years and had adequate hematologic function, ≥1 bi-dimensionally measurable lesion, an ECOG performance status (PS) of ≤2 and an International Prognostic Index (IPI) score of ≥2 (high, high-intermediate or low-intermediate risk). Low-risk pts with an IPI score of 1 (but not due to age alone) or with an IPI score of 0 with bulky disease (one lesion ≥7.5cm) were also eligible. Pts were randomized 1:1 to receive 8 (21-day) cycles of G (1000mg i.v. on Days [D] 1, 8, and 15, Cycle [C] 1 and D1, C2-8) or R (375mg/m2 i.v. on D1, C1-8) in combination with 6 or 8 cycles of CHOP (number of cycles preplanned in advance for all pts at each site). Preplanned radiotherapy was allowed for bulky or extranodal disease. The primary endpoint was investigator (INV)-assessed progression-free survival (PFS); for the target hazard ratio (HR) of 0.75, the 3-year PFS was expected to improve from 60% to 68%. Secondary endpoints included: PFS assessed by Independent Review Committee (IRC); overall survival (OS); complete response (CR) and overall response rate (ORR) with or without PET (assessed by INV or IRC according to modified Cheson 2007 criteria); and safety. Results: 1418 pts were randomized to study treatment: 706 to G-CHOP and 712 to R-CHOP. Baseline characteristics were well balanced between the G-CHOP and R-CHOP arms: mean age, 62.0 years in both arms; ECOG PS ≥2, 12% vs. 14%; IPI score ≥3, 47% vs. 43%; Ann Arbor stage III-IV, 76% in both arms. Cell-of-origin distribution, as assessed by gene-expression profiling (NanoString), was similar in both treatment groups (GCB: 58% [271/471] G-CHOP, 58% [269/462] R-CHOP; ABC: 27% [125/471] G-CHOP, 26% [118/462] R-CHOP; Unclassified: 15.9% [75/471] G-CHOP, 16.2% [75/462] R-CHOP). For the primary endpoint of INV-assessed PFS, there was no significant difference between G-CHOP and R-CHOP (3-year PFS, 69% vs. 66%; stratified HR, 0.92; 95% confidence interval [CI], 0.76, 1.12; p=0.3868; Table). Secondary endpoints, including PFS by IRC, OS, and end-of-treatment ORR/CR rate (with and without PET), were consistent with the primary endpoint, with no clinically meaningful differences observed between the treatment arms (Table). In a prespecified subgroup analysis of INV-assessed PFS, a stratified HR of 0.72 (95% CI, 0.50, 1.01) in favor of G-CHOP over R-CHOP was determined for pts with GCB DLBCL (3-year PFS, 79% vs. 70%). No new safety signals were identified. Grade ≥3 adverse events (AEs; 74% vs. 65%) and serious AEs (43% vs. 38%) were more common in the G-CHOP than in the R-CHOP arm. Grade ≥3 AEs of particular interest that were numerically more common with G-CHOP than R-CHOP included neutropenia (57% vs. 48%), infusion-related reactions (45% vs. 32%), infections (54% vs. 44%), and thrombocytopenia (8% vs. 3%). AEs resulting in withdrawal from treatment (12% [84/704] G-CHOP; 9% [60/703] R-CHOP) and AEs with fatal outcome (6% [41/704] G-CHOP; 4% [30/703] R-CHOP) were slightly more common with G-CHOP. The most common AEs leading to death were pneumonia (5 G-CHOP; 6 R-CHOP) and sepsis/septic shock (7 G-CHOP; 3 R-CHOP). Conclusions: The primary endpoint of this study was not met: G-CHOP did not significantly improve INV-assessed PFS compared with R-CHOP in previously untreated pts with DLBCL. No unexpected safety signals were identified. Further investigation of outcomes in subgroups is planned. Disclosures Vitolo: Gilead: Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Takeda: Other: Honoraria for lectures. Trněný:Roche, Celgene, Takeda, Janssen, Gilead, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche, Celgene: Research Funding. Belada:Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Chua:Roche: Consultancy, Research Funding; Gilead: Consultancy; Celgene: Consultancy; Seattle Genetics: Consultancy; Lundbeck: Consultancy. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Kim:Celltrion, Inc.: Consultancy, Honoraria. Pinto:Millennium: Research Funding; Takeda: Honoraria; Helssin: Honoraria; Roche: Honoraria; Celgene: Honoraria; Servier: Honoraria; Janssen: Honoraria. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Oestergaard:Roche: Employment. Wenger:Genentech: Employment. Fingerle-Rowson:F. Hoffmann-LaRoche: Employment. Catalani:Roche: Employment. Nielsen:Hoffmann-La Roche: Employment. Sehn:roche/genentech: Consultancy, Honoraria; amgen: Consultancy, Honoraria; seattle genetics: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; TG therapeutics: Consultancy, Honoraria; celgene: Consultancy, Honoraria; lundbeck: Consultancy, Honoraria; janssen: Consultancy, Honoraria.

Description: Sickle cell disease (SCD) is an autosomal recessive genetic disorder caused by a point mutation in the human β-globin gene. Patients harboring this mutation can exhibit long-chain polymers of hemoglobin and sickle-shaped red blood cells, and suffer from severe medical manifestations including hemolysis and vaso-occlusive crises. Multiple preclinical, clinical and epidemiologic studies have shown that the levels of unmutated fetal hemoglobin (HbF encoded by the γ-globin gene) correlate with less severe disease, validating HbF induction as a therapeutic approach in SCD. Treatment with hydroxyurea (HU), the only approved therapy for SCD, results in a variable induction of HbF and significant improvement in the frequency of pain crises. However, a significant percentage of patients treated with HU fail to exhibit durable benefit, necessitating the need for alternative therapeutic agents. The human γ-globin gene is repressed in the post-natal period by epigenetic mechanisms, and therefore may lend itself to pharmacological intervention aimed at derepressing gene expression. One of the most important of these epigenetic mechanisms is catalyzed by lysine-specific demethylase 1 (LSD1), a histone demethylase that removes mono-/dimethyl marks from the lysine 4 and 9 residues of histone H3 through an FAD-directed redox process. Here, we report the characterization of selective, potent, and orally bioavailable LSD1 inhibitors from two classes - FAD-directed inhibitors that achieve inhibitory activity through formation of covalent FAD-adducts and non-FAD-directed, reversible inhibitors - and demonstrate their ability to induce γ-globin gene expression in murine and primate preclinical models. In the Towne's SCD mouse model, oral administration of LSD1 inhibitors significantly increased HbF+ cell (F cell) production. Concurrent with the increase in F cells, sickle cell numbers, reticulocyte counts, and bilirubin levels were all markedly reduced, indicating an amelioration of several pathophysiological features of SCD. FAD- and non-FAD-directed LSD1 inhibitors were more effective than HU in increasing F cells production, and the combination of HU and suboptimal doses of LSD1 inhibitors resulted in a greater induction of F cells and more pronounced reductions in reticulocyte counts and bilirubin levels. In addition to the humanized SCD model, HbF induction in response to LSD1 inhibitor treatment was evaluated in non-anemic cynomolgus monkeys. Oral administration of LSD1 inhibitors significantly induced F cells and HbF in a dose-dependent manner and over a sustained period (〉50 days) following the discontinuation of treatment. The percentage of induced F cells in total RBCs was linearly correlated with the percentage of HbF protein induced by LSD1 inhibition. Taken together, these results support the potential utility of LSD1 inhibition as a novel therapeutic approach to increase HbF production. Disclosures Lee: Incyte Corporation: Employment, Other: Stock. Soloviev:Incyte Corporation: Employment, Other: Stock. Zhang:Incyte Corporation: Employment, Other: Stock. Roman:Incyte Corporation: Employment, Other: Stock. Yang:Incyte Corporation: Employment, Other: Stock. Bowman:Incyte Corporation: Employment, Other: Stock. Burke:Incyte Corporation: Employment, Other: Stock. Margulis:Incyte Corporation: Employment, Other: Stock. O'Connor:Incyte Corporation: Employment, Other: Stock. Yang:Incyte Corporation: Employment, Other: Stock. Wu:Incyte Corporation: Employment, Other: Stock. Wynn:Incyte Corporation: Employment, Other: Stock. Burn:Incyte Corporation: Employment, Other: Stock. Shuey:Incyte Corporation: Employment, Other: stock. Diamond:Incyte Corporation: Employment, Other: Stock. Yao:Incyte Corporation: Employment, Other: Stock. Hollis:Incyte Corporation: Employment, Other: Stock. Yeleswaram:Incyte Corporation: Employment, Other: Stocks. Roberts:Incyte Corporation: Employment, Other: Stock. Huber:Incyte Corporation: Employment, Other: Stock. Scherle:Incyte Corporation: Employment, Other: Stock. Ruggeri:Incyte Corporation: Employment, Other: Stock.

Description: Background Spleen tyrosine kinase (SYK) is a nonreceptor cytoplasmic protein kinase and a key mediator of immunoreceptor signaling that has been shown to play an important role in the pathogenesis of both B-cell and myeloid malignancies. SYK has also been shown to directly bind and activate FMS-like tyrosine kinase 3 (FLT-3), a Class III receptor tyrosine kinase that is commonly mutated in approximately 30% of pts with AML (Puissant et al. Cancer Cell 2014;25:226-42). TAK-659 is an investigational, reversible, and potent dual inhibitor of SYK and FLT-3. Preclinical studies with TAK-659 have demonstrated growth inhibition of cell lines and xenograft tumor models of B-cell lymphoma or AML origin. Moreover, TAK-659 has exhibited antitumor activity in lymphoma pts in an ongoing clinical trial (Petrich et al. Blood 2015;126:2693). The primary objectives of the phase 1b dose-finding portion of this study are to evaluate the safety, tolerability, and maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of TAK-659, as well as preliminary efficacy in the phase 2 expansion study. Secondary objectives include evaluation of TAK-659 pharmacokinetics (PK) in this pt population. Methods During dose escalation using a 3x3 schema, adult pts with R/R AML received oral TAK-659 daily (QD) in 28-d cycles (C) starting with a dose of 60 mg. Adverse events (AEs) were assessed per NCI-CTCAE v4.03. Response per IWG criteria for AML was assessed between d22 and d28 of C1, C2, and C4. Blood samples for plasma pharmacokinetic (PK) assessments were collected pre-dose and at multiple times post-dose on d1 and d15 of C1. The pharmacodynamic effect of TAK-659 was assessed at multiple time points by measuring the phosphorylation of ribosomal protein S6 (pS6) in peripheral AML blasts using flow cytometry. FLT-3 mutation status (wild type [FLT-3-WT], FLT-3-ITD, or point mutation [FLT-3-D835Y]) was assessed using a PCR-based assay at a central laboratory. The effect of TAK-659 treatment on FLT-3-ITD phosphorylation was evaluated using a plasma inhibitory assay (PIA) as previously described (Levis et al. Blood 2006;108:3477-83). Results At data cut-off (June 9, 2016), 15 pts had been enrolled at TAK-659 QD 60 mg (n=4), 100 mg (n=7), or 120 mg (n=4). No dose-limiting toxicity per protocol has been observed. Dose escalation is currently ongoing at 160 mg QD. In the safety population (n=13), median age was 67 yrs (range 25-86), 69% of pts were male, and 38% had received ≥4 prior lines of therapy. Baseline mutation data was available for 12 pts: 6 pts were FLT-3-WT, 3 pts had FLT-3-ITD, 1 pt had FLT-3-D835Y, and 2 pts had concurrent FLT-3-ITD/D835Y mutations. In the safety population, all-grade drug-related AEs occurred in 12 (92%) pts overall; the most common were elevated AST (31%), ALT (23%), and amylase levels (23%). Grade ≥3 drug-related AEs occurred in 7 (54%) pts including: increased ALT, AST, and amylase levels, cataract, positive fungal test, macular fibrosis, pancreatitis, pneumocystis jirovecii pneumonia, rash, and fungal sinusitis (each 1pt). Blood LDH levels were increased in almost all pts (significance unknown). Three pts discontinued TAK-659 due to AEs and 3 pts died on study; none of these events were considered related to the study drug. Preliminary plasma PK of TAK-659 (n=11, 60-100 mg) was characterized by rapid absorption (median Tmax of 2 hours), moderate variability in steady-state exposures (42% coefficient of variation for C1 d15 dose-normalized AUCtau), and mean accumulation of 2.1-fold after repeated QD dosing for 15 days. Of 9 pts evaluated to date, pS6 was detected at baseline and reduced after dosing in 4 pts (2 FLT-3-ITD; 2 FLT-3-WT). At 60 mg and 100 mg TAK-659, up to 70% inhibition of FLT-3-ITD phosphorylation was observed as assessed by PIA. Early signs of clinical activity were observed, with decreases in peripheral blood myeloblasts observed in some pts. Assessment is ongoing and preliminary efficacy data will be presented. Conclusions TAK-659 has a unique mechanism of action with dual inhibition of SYK and FLT-3. Dose escalation to determine the MTD/RP2D is ongoing. TAK-659 exhibits an acceptable PK profile in R/R AML pts, supporting continuous oral QD dosing. Disclosures Kaplan: Seattle Genetics: Research Funding; Janssen: Research Funding. Morris:Boehringer-Ingelheim: Speakers Bureau. Altman:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syros: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wise-Draper:Merck: Research Funding. Collins:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Kannan:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Wang:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faucette:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Lee:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Shou:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Levis:Millennium: Consultancy, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria.

Description: Introduction and Objective: GBT440 inhibits HbS polymerization and reduces hemolysis, and is a promising treatment for Sickle Cell Disease (SCD). The traditional clinical endpoint, vaso-occlusive crisis (VOC) requiring healthcare utilization, is not a sensitive measure of the daily burden of symptoms in patients (the "tip of the iceberg" of severe symptom exacerbations) and poses a barrier to development of new treatments for SCD. The objective was to develop a sensitive measure to detect treatment-related improvements in daily symptoms and exacerbations that define the disease. Existing SCD measures focus on distal impact, not on the core signs and symptoms of disease, and therefore not appropriate for meeting the regulatory standard to prove treatment benefit. Beginning with a hypothesized conceptual framework focused on pain and fatigue, rigorous qualitative and quantitative research was used to develop the content of the Sickle Cell Disease Severity Measure (SCDSM). Methods: The content of the new measure was derived from 1-on-1 open-ended concept elicitation interviews in 56 adults and 10 adolescents with SCD in the US and UK. Participants were aged 12-63 years, 64% female, 44% currently on hydroxyurea treatment, 86% had 1 to 42 VOC in the previous year requiring urgent care. During the interview, 74% reported having a typical or "good" day versus 26% having a crisis or "bad" day. Interview transcripts were coded to identify the most bothersome and frequently mentioned concepts related to both "good" and "bad" days. As hypothesized, patients reported having crisis days more frequently than those crises requiring healthcare utilization (traditional VOC endpoint). Interviews continued until saturation was demonstrated. How items worked individually and together were explored to quantify the full range of SCD severity. Both Classical Test Theory and Rasch Measurement Theory quantitative analyses supported the qualitative data to refine item content. To document content validity, the SCDSM content in its final electronic daily diary format will be evaluated in cognitive debriefing studies. Subsequently, longitudinal evaluation will occur in future clinical trials with GBT440. Translation and cultural adaptation is planned. Results: After eliciting an initial pool of items using open-ended interviews, the items were administered to a small cohort of SCD patients. After analyses of the response data and re-examination of the qualitative data, revisions were made. The revised set was re-administered to a cohort of 50 SCD patients. Qualitative and quantitative analyses provided evidence that a set of 10-items demonstrated content validity in adult and adolescent SCD patients to produce a score which can measure the full range of sickle cell disease severity. The mixed methods process enabled streamlined decision-making concerning measure content. The final content includes items specific to pain, fatigue, concentration and breathlessness. Evidence supports the derived estimate as a reliable and valid measure of SCD symptom severity covering a wide range of experience and providing the ability to differentiate baseline symptoms from severe symptoms. Patient responses to the 10 SCDSM items are combined to generate a single daily estimate of SCD symptom severity. Two "scores" can be computed: an ordinal-level total score can be computed by summing item scores; an interval-level (linear) measure can be derived from item responses using RMT analysis. Conclusions: SCD patients have a high burden of daily symptoms, with severe or "crisis" days occurring more frequently than traditionally defined VOC. The 10-item SCDSM is a promising new measure of daily SCD symptom severity developed to be fit for purpose in clinical trials to determine the treatment effect of new drugs on potential improvement in baseline symptoms and/or prevention of symptom exacerbations. SCDSM will soon be tested in a clinical trial setting to determine its longitudinal measurement characteristics, generate guidelines for measure interpretability, and to explore the clinical benefit of GBT440 in SCD. Qualitative and psychometric findings based on the SCD patient voice will be presented at the meeting to provide evidence of SCDSM validity, reliability, and usefulness in assessing symptom severity in a disease that has heretofore been poorly characterized on a daily basis. Disclosures Burke: Lora Group: Employment; Global Blood Therapeutics: Consultancy. Hobart:Lora Group: Research Funding. Fox:Lora Group: Research Funding. Lehrer-Graiwer:Global Blood Therapeutics: Employment, Equity Ownership. Bridges:Global Blood Therapetics: Employment, Equity Ownership. Kraus:Global Blood Therapeutics: Employment, Equity Ownership. Ramos:Global Blood Therapeutics: Employment, Equity Ownership.

Description: Background The incidence of and mortality from coronary heart disease (CHD) is significantly higher among African Americans (AAs) compared to Whites, even after adjusting for traditional CHD risk factors. Studies suggests that the unexplained excess risk might be the result of genetic modifiers associated with African ancestry conferring a higher risk of CHD. One such gene variant is the sickle cell mutation. The heterozygous state, or sickle cell trait (SCT), with a prevalence of 8 - 12% among AAs, was previously deemed clinically benign; however, recent evidence indicates that SCT is associated with increased risk of chronic kidney disease venous thromboembolism and sudden death following exertion. Individuals with SCT have higher circulating levels of C-reactive protein, fibrinogen, prothrombin fragment 1.2 and D-dimer. We hypothesized that AAs with SCT have a higher risk for myocardial infarction (MI) and coronary heart disease (CHD) than AAs who are homozygous for wild-type hemoglobin. Methods We obtained genotype and phenotype data from the Women's Health Initiative (WHI) REasonsfor Geographic and Racial Differences in Stroke (REGARDS), Multi-Ethnic Study of Atherosclerosis (MESA), Jackson Heart Study (JHS) and Atherosclerosis Risk In Communities (ARIC) cohorts. The outcomes were incident MI or CHD. Incident MI was defined as adjudicated non-fatal or fatal MI, while incident CHD was defined as 1) adjudicated non-fatal MI, 2) fatal MI, 3) documented coronary revascularization procedures or 4) non-MI CHD death. SCT status was determined by either direct genotyping or imputation for rs334 using the 1000Genome reference panel. Homozygous individuals and those with a prior history of CHD were excluded. Individuals with incident “micro MI”, only defined in REGARDS, were also excluded from the analysis. Analysis was performed separately in each cohort using a Cox proportional hazard models to estimate the hazard ratio (HR) for incident MI or CHD comparing SCT carriers to non-carriers. Models in each cohort were adjusted for age, sex, study site or region of residence, hypertension or systolic blood pressure, diabetes, serum LDL or HDL or total cholesterol, and population stratification (using principal components of global ancestry). The results from each cohorts were then meta-analyzed using a random effect model due to significant heterogeneity between studies (I2 = 39.1%, p = 0.02 for MI meta-analysis and I2 = 56%, p = 0.01 for CHD meta-analysis). Results A total of 20,053 African American men and women were included in the combined sample; 1503 with SCT (7.5% prevalence). Average ages in years at baseline were: 65.0±6.0 in WHI (N = 2248), 62.0 ± 9.2 in REGARDS (N = 10573); 62.2±10.2 in MESA (N = 1556); 50.0 ± 11.9 in JHS (N = 2133); and 54.0 ± 6.0 in ARIC (N = 3543). There were no statistically significant differences in the distribution of traditional cardiovascular risk factors by SCT status within cohorts, except that atrial fibrillation was more prevalent among REGARDS participants with SCT compared to those without SCT (9.9% vs. 7.8%, p = 0.03). The crude incidence rate of MI per 1000 person years in those with SCT compared to those without SCT was: 4.0 vs. 5.2 in WHI; 5.7 vs. 5.0 in REGARDS; 5.8 vs 4.3 in MESA, 2.0 vs 2.1 in JHS; and 4.1 vs 5.9 in ARIC. For CHD, the crude incidence rate was: 5.8 vs. 7.2 in WHI, 8.9 vs. 7.4 in REGARDS; 15.4 vs. 6.4 in MESA; 3.4 vs. 3.4 in JHS; and 10.5 vs. 9.5 in ARIC. The HR (95% CI) for MI was: 0.96 (0.49 - 1.89) in WHI; 1.27 (0.8 - 2.0) in REGARDS; 1.84 (0.74 - 4.60) in MESA; 1.24 (0.28 - 5.44) in JHS; and 0.68 (0.42 - 1.10) in ARIC. And that for CHD was: 1.05 (0.63 - 1.74) in WHI; 1.49 (1.01 - 2.18) in REGARDS; 2.82 (1.48 - 5.38) in MESA; 1.45 (0.50 - 4.19) in JHS; and 1.10 (0.80 - 1.50) in ARIC. Meta-analysis showed that, while SCT status was not significantly associated with incident MI (1.10 [0.73 - 1.64]), it was significantly associated with incident CHD (1.42 [1.02 - 1.98] Figures 1a and 1b). Conclusions This study showed a significant association between SCT and incident CHD, but not MI. Our conclusion is limited by the significant heterogeneity that existed between studies. Since SCT status was not associated with MI, but was associated with CHD, further work is needed to confirm these findings, determine which CHD component(s) explain the observed association and elucidate the possible mechanism(s) involved. Disclosures No relevant conflicts of interest to declare.

Description: Introduction DLBCL is the most common lymphoid neoplasm in adults (Swerdlow 2016). While durable CRs are achieved in approximately 70% of patients (pts) with frontline RCHOP therapy (Pfreundschuh 2008), pts with high-risk features often experience disease resistance or relapse. In Part 1 of an ongoing study, pts with high-intermediate or high risk DLBCL by international prognostic index (IPI) scores, regardless of CD30 expression by IHC, were treated with 1.2 or 1.8 mg/kg brentuximab vedotin (BV) combined with RCHOP. After 3 of the first 10 pts treated at 1.8 mg/kg BV+RCHOP developed Grade 3 peripheral neuropathy (per Standardized MedDRA Query [SMQ]), all pts enrolled subsequently received treatment with 1.2 mg/kg BV+RCHOP. Following completion of enrollment in Part 1, the protocol was amended to enroll a non-randomized portion of the study (Part 2) evaluating the safety and efficacy of 1.8 mg/kg BV+RCHP (Yasenchak 2015), followed by an open-label, randomized portion comparing BV+RCHP to RCHOP (Part 3). Initial results from Part 2 and updated results from Part 1 are reported here. Methods For Part 2 of the study, pts with CD30-expressing high-intermediate and high-risk DLBCL were treated with up to 6 cycles of 1.8 mg/kg BV+RCHP (NCT01925612). Key inclusion criteria were CD30 expression by IHC performed by a local pathology lab and standard IPI scores of 3-5 or age-adjusted IPI (aaIPI) scores of 2-3 (high-intermediate/high risk). CD30 expression was confirmed by a central pathology lab, although CD30 expression by local pathology lab was required for eligibility. Disease response was evaluated with PET/CT per Cheson 2007. Results At the time of analysis for this ongoing study, 11 pts in Part 2 were treated with BV+RCHP (7 male, 4 female; 22-78 yrs). Of these pts, 9 had high-intermediate risk (IPI 3, aaIPI 2) and 2 had high risk disease (IPI 4-5, aaIPI 3), 6 had Stage IV disease, and 6 had an ECOG score of 2. At the end of treatment, the overall response rate was 91% (9 CR, 1 PR); 1 pt had PD after Cycle 4. The most frequent (〉20%) treatment-emergent adverse events (AEs) were alopecia and nausea (73% each); fatigue (64%); constipation and peripheral sensory neuropathy (55% each); neutropenia and throat irritation (36% each); and chills, diarrhea, headache, and stomatitis (27% each). Grade 3 or 4 AEs occurred in 8 pts and 5 pts had serious AEs, which included febrile neutropenia, bacteremia, nausea, pneumocystis jiroveci pneumonia, pulmonary embolism, and vomiting. Peripheral sensory neuropathy occurred in 6 pts and all were Grade 1 or 2 events; no peripheral motor neuropathy AEs were reported. No AEs were fatal or led to discontinuation. One pt discontinued treatment after Cycle 4 due to disease progression. For the first 51 pts in Part 1, the progression-free survival (PFS) at 18 months for pts with CD30 expression (25 pts) or without detectable CD30 expression (24 pts) by IHC was 79% (95% CI: 57%, 91%) versus 58% (95% CI: 36%, 75%), respectively. Overall survival for pts was 92% (95% CI: 71%, 98%) versus 71% (95% CI: 48%, 85%), respectively. Ten pts had pre-existing peripheral neuropathy (per SMQ) at study entry. Treatment-emergent peripheral neuropathy (per SMQ) was observed in 75% of pts (38/51) who received BV+RCHOP; 55% of these pts (21/38) had resolution of all or some peripheral neuropathy events. Conclusions 1.8 mg/kg BV+RCHP is active as frontline treatment in CD30-expressing, high-intermediate/high risk DLBCL. When combined with RCHP, 1.8 mg/kg BV appears to be well-tolerated. The PFS and OS for pts with CD30-expression who received BV+RCHOP appear promising. The study is currently ongoing in pts with CD30-expressing high-intermediate/high risk DLBCL to assess the safety and activity of 1.8 mg/kg BV+RCHP versus standard RCHOP. Disclosures Halwani: Bristol Myers-Squibb: Research Funding; Kyowa Hakko Kirin: Research Funding; Takeda: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Other: Travel Expenses, Research Funding; Seattle Genetics: Consultancy, Research Funding; Immune Design: Research Funding; Miragen: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding. Yasenchak:Seattle Genetics: Research Funding. Farber:Seattle Genetics: Research Funding. Burke:Pfizer: Consultancy; Janssen: Consultancy; Incyte: Consultancy; TG Therapeutics: Other: Travel Expenses; Millenium: Consultancy. Fayad:Seattle Genetics: Consultancy, Research Funding. Holkova:Seattle Genetics: Research Funding. Knapp:Insys Therapeutics, Inc.: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Kolibaba:Gilead: Consultancy, Research Funding; Celgene: Research Funding; TG Therapeutics: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; janssen: Research Funding; GSK: Research Funding; Genentech: Research Funding; Acerta: Research Funding. Patel-Donnelly:Seattle Genetics: Research Funding. Yimer:Ariad Pharmaceuticals: Consultancy; Biotheranostics: Consultancy; Bluebird Bio: Equity Ownership; Kite Pharma: Equity Ownership; Clovis Oncology: Equity Ownership; Juno Therpeutics: Equity Ownership; Seattle Genetics: Research Funding. Smith:Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding. Levy:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics: Research Funding; Actinium Pharmaceuticals, Inc.: Research Funding. Seetharam:Seattle Genetics: Research Funding. Belada:Seattle Genetics: Research Funding. Brooks:Seattle Genetics: Research Funding. Kingsley:Gilead: Equity Ownership; Pharmacyclics LLC, an AbbVie Company: Equity Ownership. Wagner-Johnston:Seattle Genetics: Research Funding. Ruffner:Forma Therapeutics: Consultancy; Sydnax: Consultancy; Seattle Genetics: Employment, Equity Ownership; Array Biopharma: Employment; Medivation: Employment. Bartlett:Gilead: Consultancy.