Citations

Abstract Background: We previously demonstrated that putative clinical epidemiologic exposures associated with leukemia risk are prevalent among AML patients, and some are associated with unique cytogenetic risk group and with clinical phenotype (Finn, Cancer Epidemiol, 2015). Herein, we studied genome-wide DNA methylation in a cohort of AML patients to evaluate the association of individual hyper- and hypo-methylated CpG sites with epidemiologic exposures and overall survival. Methods: The Mayo Clinic AML Epidemiology Cohort is a highly annotated retrospective case series of 295 consecutive patients (pts) with AML diagnosed and treated at Mayo Clinic Florida and Arizona, with central cytogenetics performed in all cases. The prevalence of clinical epidemiologic exposures, past medical and family history as well as medication use and lifestyle was systematically obtained. After IRB approval, we interrogated the cytogenetic database and successfully obtained leukemia DNA from available remnant diagnostic cytogenetic cell pellets in a cohort of 148 AML patients in the Mayo epidemiology case series and performed an assessment of genome-wide DNA methylation using the Infinium HumanMethylation450K BeadChip. Samples were processed using the R Bioconductor package 'minfi' using Subset Within Array Quantile Normalization (PMID: 22703947). Individual CpGs that did not reach a detection p-value of <0.05 were filtered out. An internal control was included on each array to control for significant batch effects. To determine differential methylation status of 473,864 individual CpG sites (after exclusion of 11,648 that did not pass detection p-value QC), CpG sites with low interpatient variability, a standard deviation <0.05 of methylation values, and an interquartile range <0.05 of methylation values and X/Y chromosome probes were excluded from analysis. Epidemiologic and important clinical variables occurring in at least 10 pts or previously-identified as of unique interest but in fewer than 10 pts were evaluated, including sex, BMI, performance status and comorbidities, tobacco and alcohol use, family history of hematologic malignancy, medications of interest, history of toxin exposure, and history of immunosuppression and/or solid organ transplant or of secondary and therapy-related AML (t-AML). Associations of differential hypo or hypermethylation at 281,259 CpG sites with epidemiologic exposures/clinical variables were evaluated using Spearman's test of correlation (continuous or ordinal exposures), a Wilcoxon rank sum test (dichotomous exposures), or a Kruskal-Wallis rank sum test (multi-category exposures). A Bonferroni correction was applied for multiple testing, after which p <1.8 x 10-7 was considered as significant. To reduce the likelihood of false-negative findings, we additionally considered p <5 x 10-6 as indicating suggestive evidence of an association. CpG sites and associated gene and function was determined using Illumina manifest file & www.ncbi.nlm.nih.gov/gene. Results: Statistically significant associations (p <1.8 x 10-7) with individual epidemiologic and clinical exposures were identified for 109 unique CpG sites, corresponding to differential methylation in the genes listed in Table. Specifically, obesity (predominantly hypomethylation), specific cytogenetic lesions and risk group, and gender were highly significantly associated with unique CpG methylation status, but not smoking, toxin exposure, family history, comorbidity or performance status, secondary or t-AML, immunosuppression, medication use, of family history in the analysis. A further 353 unique CpG sites had defined suggestive associations (ongoing analysis). We also identified 8 additional CpG sites where differential methylation was associated with overall survival (p <5 x 10-6, Table). Conclusion: Obesity, cytogenetic lesions, and sex are associated with differential methylation of unique CpG sites at AML diagnosis, using stringent univariate statistical criteria. Significant CpG sites were identified in genes previously linked to AML biology and prognosis (DOCK6, HOXB3, MIR10A, FOXN3/CHES1, GPX1, MYST2/KAT7, PTPRD), but some represent novel findings in AML. These preliminary results suggest an association of some AML risk factors and clinical variables with unique gene methylation and will undergo validation in a prospective AML epidemiology dataset. Disclosures Cerhan: Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding; Celgene: Research Funding. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding.

Abstract Background: Blasts and leukemic stem cells of acute myeloid leukemia (AML) as well as several other hematologic malignancies express CD123, potentially providing a target for novel therapies. XmAb14045 (also known as SQZ622) is a potent bispecific antibody targeting both CD123 and CD3 that stimulates targeted T cell-mediated killing of CD123-expressing cells, regardless of T cell antigen specificity. It is a full-length immunoglobulin molecule designed to be dosed intermittently, in contrast to smaller constructs that are referred to as "DART" or "BiTE" bispecific antibodies that require a continuous infusion. Methods: Patients with relapsed or refractory AML, B cell acute lymphoblastic leukemia (B-ALL), blast phase chronic myelogenous leukemia, or blastic plasmacytoid dendritic cell neoplasm were eligible to enroll on this first-in-human, multicenter, open-label phase 1 dose-escalation study (XmAb14045-01) with standard 3+3 design. The primary objective was to estimate the maximum tolerated dose (MTD) or recommended dose and schedule of XmAb14045. Secondary objectives included safety, preliminary antileukemic activity, and pharmacokinetics/pharmacodynamics of XmAb14045. Treatment was administered weekly in 28 day cycles, using a weight-based dose with a single dose level in Part A and, in Part B, an initial priming dose on Day 1 followed by an escalated dose on subsequent weeks. Premedication to prevent cytokine release syndrome (CRS) was instituted as needed and included a steroid, acetaminophen, and diphenhydramine. Patients were premedicated at all XmAb14045 doses ≥0.075 µg/kg. Therapy was continued for as long as tolerated and there was continuing evidence of therapeutic benefit in the opinion of the investigator. Treatment response was assessed by the 2017 European LeukemiaNet (ELN) criteria after Cycle 1 and after each odd-numbered cycle. CRS was graded using the CRS revised grading system (Lee et al., Blood, 2014). Results: At data cut-off, 64 patients have been treated to date, 63 with relapsed/refractory AML and 1 with B-ALL. Patients had a median age of 61 years and were heavily pretreated (median of 3 prior therapies [range 1-8], including 19 [30%] who had undergone prior allogeneic stem cell transplantation). The recommended dose for Part A was 1.3 µg/kg after a single dose-limiting toxicity of Grade 4 CRS at 2.3 µg/kg; no MTD has been identified. CRS or its component symptoms was the most common treatment-emergent adverse event (TEAE). CRS episodes began within approximately 1-4 hours of the start of drug infusion and occurred in 49 of 64 patients (77%). Seven patients (11%) developed Grade ≥3 CRS, the majority of these on the first dose. There were no CRS-related deaths. Excluding CRS-related events, additional TEAEs occurring in >10% of patients included fatigue (31%), febrile neutropenia (30%), peripheral edema (30%), cough (23%), elevated hepatic transaminases (19%; all recovered without sequelae), pneumonia (17%), stomatitis (14%), hyperglycemia (13%), and sepsis (11%). No myelosuppression requiring dose modification or evidence of tumor lysis syndrome was seen. In Part A, single agent antileukemic activity was documented with a best response of CR (2) or CRi (1) in 3/13 AML patients (CR/CRi rate 23%) treated at the two highest dose levels studied to date (1.3 and 2.3 µg/kg weekly); no CR, CRi, or morphologic leukemia-free state (MLFS) responses were seen at lower doses. Antileukemic activity occurred quickly; all responders had achieved at least an MLFS response after 4 doses (1 cycle). Two responders were bridged to stem cell transplantation, and the third was ineligible for medical reasons but remains in remission at 14+ weeks after initiating therapy. Conclusions: XmAb14045 demonstrated evidence of antileukemic activity in heavily pretreated patients with relapsed/refractory AML treated in Part A at the 1.3 and 2.3 µg/kg doses administered once weekly, with a 23% CR/CRi rate. CRS was the most common toxicity but was generally manageable with premedications. The study is ongoing with further optimization of dose, schedule, and premedication regimen for CRS anticipated during accrual to dose escalation cohorts in Part B. ClinicalTrials.gov Identifier: NCT02730312 Disclosures Ravandi: Xencor: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Jazz: Honoraria; Sunesis: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Bristol-Myers Squibb: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding. Foran:Xencor, Inc.: Research Funding; Agios: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Mawad:Swedish Cancer Institute: Employment. Blum:Astellas: Consultancy; Pfizer: Consultancy; Boehringer Ingelheim: Research Funding; Forma: Research Funding; Xencor: Research Funding; Tolero: Research Funding. Saville:Xencor, Inc.: Employment, Equity Ownership. Johnson:Xencor, Inc.: Employment, Equity Ownership. Vanasse:Novartis: Employment, Equity Ownership. Ly:Xencor, Inc.: Employment, Equity Ownership. Mims:Novartis: Consultancy; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: Primary refractory and early relapsed acute myeloid leukemia (RR-AML) continue to pose a therapeutic challenge. Salvage therapy treatment regimens for refractory and relapsed disease are not standardized but include the commonly-used mitoxantrone, etoposide, and cytarabine (MEC) and cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M). Previous studies have suggested a potential benefit of CLAG-M, and therefore we performed an analysis of consecutive patients selected to receive either CLAG-M or MEC as salvage therapy for RR-AML. Methods: The study included 150 consecutive patients with RR-AML who received either CLAG-M or MEC between 09/01/2009 and 12/31/2017. Patients were identified through a pharmacy database based on use of mitoxantrone. Baseline disease and patient-related characteristics and clinical outcomes including allogeneic transplantation (ASCT) were obtained by systematic review of EMR. Overall survival (OS) and progression free survival (PFS) were estimated according to the Kaplan Meier method and log-rank test was used to compare outcomes between patients who received either of the two regimens. Results: There were 150 consecutive treated patients with RR-AML included in this analysis, 34 patients received CLAG-M and 116 patients received MEC. The median age was 57 years (18-76), and, and 52% were male. Forty-seven (31%) were treated for early relapsed disease (<6 months after successful induction), 17% (>6 months after induction), and the remainder had primary refractory disease (mean number of induction regimens was 1.8, range 1-6). AML risk was defined by cytogenetic criteria. There were a predominance of intermediate-risk subtypes at 47% (71/150) and followed by high-risk at 37% (55/150). Overall CR/CRi rates for CLAG-M and MEC were 74% (23/31) and 58% (63/108) in patients eligible for analysis (p=0.18). The median follow-up from relapse was 23.5 months (1-76). The median OS was 9.5 months for CLAG-M and 10.0 months for MEC (HR=0.88, 95%CI=0.54-1.41, p=0.59). In total, 76 patients (51%) were able to proceed to ASCT following salvage therapy with either CLAG-M or MEC. Among transplant recipients 56% (19/34) and 49% (57/116) were treated with CLAG-M and MEC, respectively. Median OS after ASCT was 13.0 months for CLAG-M and 31.0 months for MEC (HR=1.76, 95%CI=0.87-3.56, p=0.12). The median OS for refractory AML was 13.0 and 66.0 months for CLAG-M and MEC recipients, respectively (HR=0.92, 95%CI=0.46-1.84, p=0.24). Median OS for those with early relapse was 12.0 months for CLAG-M and 10.0 months for MEC (HR=0.69, 95%CI=0.22-2.11, p=0.51). Lastly, among those who had late relapse, median OS was 9.0 and 48.0 months for CLAG-M and MEC, respectively (HR=17.6, 95%CI=1.57-198, p<0.001). A univariate analysis was performed to investigate the impact of factors associated with OS, including treatment, age, gender, whether they proceeded to ASCT, cytogenetic risk type, and donor source. ASCT was associated with significant improvement in both PFS (HR=0.24, 95%CI=0.16- 0.37, p<0.001) and OS (HR=0.26, 95%CI=0.17-0.40, p<0.001) in this cohort. Age greater than 65 was associated with worse PFS (HR=1.02, 95%CI=1.00-1.03, p=0.04) but not OS (HR=1.01, 95%CI=1.00-1.03, p=0.06) after controlling for other variables including the impact of ASCT. Discussion: Despite a lower 30-day induction mortality we did not identify significant differences in outcomes among patients selected to receive CLAG-M vs. MEC. There was a statistically significant improvement in survival in patients who had late relapses and were treated with MEC, and a trend towards improvement in OS of those treated with MEC who proceeded to ASCT. As expected, ASCT was associated with significant improvement in OS in this cohort, and our results strongly support the use of ASCT as consolidation of remission after relapse for AML. Our data suggests that MEC may be a superior regimen, in particular including those with late relapse. Figure. Figure. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Al-Kali:Novartis: Research Funding. Palmer:Novartis: Research Funding.

Abstract Introduction: The preferred post-remission therapy for older patients (pts) with AML remains uncertain. We compared outcomes for older AML pts in CR1 receiving HCT reported to the CIBMTR to older AML pts achieving CR1 on National Clinical Trials Network induction and non-HCT consolidation therapy (CT) trials. Methods: This study focused on pts 60-75 years of age treated between 2004 to 2013. CT pts (n=211) underwent induction and consolidation on Alliance for Clinical Trials in Oncology, ECOG-ACRIN or SWOG clinical trials for initial therapy for newly diagnosed AML; the CIBMTR provided data for HCT pts (n=431). CT patients received at least one cycle of CT on study and were excluded if HCT occurred at any time. Time to event started at CR1 and pts entered at CT or HCT, respectively, using left-truncation to account for differential entry times. Results: For the CT cohort, first consolidation included standard therapy (e.g., cytarabine or a hypomethylating agent) and additional study drug (e.g., bortezomib, dasatinib, sorafenib, and Zosuquidar, gemtuzumab) or tipifarnib alone. Among HCT pts, the donor was a HLA-matched sibling or unrelated donor (URD) in 66% and the others were partially HLA-matched/mismatched URD (10%) or cord blood (24%). HCT pts were younger and more frequently had high-risk AML (high WBC, secondary AML and unfavorable cytogenetics) (Table). The median time from CR1 to HCT and CT was 3.2 and 0.5 months, respectively. Allogeneic HCT showed worse overall survival (OS) (HR=1.52, p=0.02) prior to 9 months and better OS thereafter (HR= 0.53, p <0.0001) relative to CT (figure 1A). Treatment-related mortality (TRM) was worse after HCT in the first 9 months (HR=2.8, CI: 1.5 -5.2, p=.0009), while relapse was less frequent beyond 9 months after treatment (HR = 0.42, CI: 0.29 to 0.61, p<.0001). Despite higher early TRM, HCT recipients went on to manifest superior OS [5 year OS: HCT 29% (24-34%), CT 13.8% (9 -22%)] (Figure 1A). The benefit of HCT for survival after 9 months was more prominent in those with unfavorable cytogenetics (Figure 1B). Multivariate analysis for OS showed no statistically significant effect of age or performance status, while unfavorable cytogenetics were detrimental (HR=1.74, p<.0001). Conclusions. Allogeneic HCT led to heightened early risks from TRM, but resulted in superior long-term survival in older AML pts receiving HCT relative to CT by reducing relapse. Efforts to attenuate early TRM after allogeneic HCT may further improve HCT outcomes for older pts. Disclosures Ustun: novartis: Speakers Bureau. Attar:Agios: Employment, Equity Ownership. Larson:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding. Roboz:Roche/Genentech: Consultancy; Eisai: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; Daiichi Sankyo: Consultancy; Celltrion: Consultancy; Novartis: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; AbbVie: Consultancy. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Stone:Fujifilm: Consultancy; Ono: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Arog: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Sumitomo: Consultancy; Amgen: Consultancy; Cornerstone: Consultancy. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Weisdorf:Seattle Genetics: Consultancy; Equillium: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Pharmacyclics: Consultancy.

Abstract BACKGROUND: Recurrent mutations in isocitrate dehydrogenase 1 (IDH1) are observed in approximately 4% of patients with myelodysplastic syndrome (MDS) and have been linked with increased transformation to acute myeloid leukemia. Ivosidenib (AG-120), an oral, potent, targeted, small-molecule inhibitor of the mutant IDH1 protein (mIDH1), is a therapeutic candidate for the treatment of patients with mIDH1 MDS. Through inhibition of mIDH1, ivosidenib suppresses the production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from patients with relapsed or refractory (R/R) MDS enrolled in the first-in-human, phase 1, dose escalation and expansion study of ivosidenib in patients with mIDH1 advanced hematologic malignancies (NCT02074839). METHODS: This ongoing study is evaluating the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib. Trial enrollment was completed on 08May2017. In dose escalation, patients received single-agent ivosidenib orally once daily (QD) or twice daily in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the dose to be tested in expansion. Expansion Arm 3 enrolled patients with mIDH1 advanced hematologic malignancies, including MDS. The overall response rate (ORR) for MDS was defined as complete remission (CR) + partial remission + marrow CR. Exploratory biomarker assessments included baseline co-occurring mutations (next-generation sequencing panel for hematologic malignancies) and mIDH1 variant allele frequency (VAF) in bone marrow mononuclear cells (BEAMing Digital PCR; lower limit of detection for mIDH1, 0.02-0.04%). Here, we present safety and efficacy data for patients with MDS in expansion Arm 3 and in dose escalation whose starting dose was 500 mg QD. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) received ivosidenib, including 12 patients with MDS (9 from expansion and 3 from escalation) whose starting dose was 500 mg QD. Baseline characteristics for these 12 patients were: 9 men/3 women; median age, 72.5 years (range, 52-78) and 42% were ≥75 years of age; median number of prior therapies, 1 (range, 1-3). As of 10Nov2017, 7 of 12 (58.3%) patients remained on treatment and 5 (41.7%) had discontinued (one for allogeneic stem cell transplantation). The median duration of exposure to ivosidenib was 11.0 months (range, 3.3-31.1). The most common adverse events (AEs) of any grade, irrespective of causality, occurring in ≥20% of the 12 patients were back pain (n=4, 33.3%) and anemia, decreased appetite, diarrhea, dyspnea, fatigue, hypokalemia, pruritus, and rash (n=3, 25.0% each). The majority of these AEs were grade 1-2 and reported as unrelated to treatment. No AEs led to permanent discontinuation of treatment. IDH differentiation syndrome (IDH-DS) was observed in 2 of 12 (16.7%) patients; the events were grade 1 and 2, respectively. Of the 12 patients with MDS receiving ivosidenib 500 mg QD, 5 achieved CR (41.7%; 95% CI 15.2%, 72.3%) and 6 achieved marrow CR (50.0%), resulting in an ORR of 91.7% (95% CI 61.5%, 99.8%). The median durations of CR and overall response were not estimable at the time of the data cutoff. The percentages of patients who remained in CR and response at 12 months were 60.0% and 61.4%, respectively. Among 5 patients who were transfusion dependent at baseline, 4 became transfusion independent for at least 56 days on treatment. Baseline co-occurring mutations and changes in mIDH1 VAF levels on ivosidenib therapy will be presented. CONCLUSION: In patients with mIDH1 R/R MDS, ivosidenib monotherapy was well tolerated and induced durable remissions and transfusion independence. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 R/R MDS. Disclosures DiNardo: Karyopharm: Other: Advisory role; Medimmune: Other: Advisory role; Celgene: Other: Advisory role; Bayer: Other: Advisory role; Agios: Consultancy, Other: Advisory role; AbbVie: Consultancy, Other: Advisory role. Watts:Jazz Pharma: Consultancy, Speakers Bureau; Takeda: Research Funding. Stein:Celgene: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Novartis: Consultancy; Bayer: Consultancy. de Botton:Agios: Research Funding; Celgene: Honoraria, Research Funding. Fathi:Takeda: Consultancy, Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Seattle Genetics: Consultancy, Honoraria; Agios: Honoraria, Research Funding. Stein:Amgen: Speakers Bureau; Celgene: Speakers Bureau. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Stone:AbbVie: Consultancy; Agios: Consultancy, Research Funding; Cornerstone: Consultancy; Orsenix: Consultancy; Fujifilm: Consultancy; Sumitomo: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Ono: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Consultancy; Jazz: Consultancy; Merck: Consultancy; Astellas: Consultancy; Arog: Consultancy, Research Funding; Argenx: Other: Data and Safety Monitoring Board; Amgen: Consultancy. Patel:France Foundation: Honoraria; Dava Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Tallman:Cellerant: Research Funding; BioSight: Other: Advisory board; ADC Therapeutics: Research Funding; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding; Orsenix: Other: Advisory board. Choe:Agios: Employment, Equity Ownership. Wang:Agios: Employment, Equity Ownership. Zhang:Agios: Employment, Equity Ownership. Dai:Agios: Employment, Equity Ownership. Fan:Agios: Employment, Equity Ownership. Yen:Agios: Employment, Equity Ownership. Kapsalis:Agios: Employment, Equity Ownership. Hickman:Agios: Employment, Equity Ownership. Agresta:Agios: Employment, Equity Ownership. Liu:Agios: Employment, Equity Ownership. Wu:Agios: Employment, Equity Ownership, Patents & Royalties. Attar:Agios: Employment, Equity Ownership.

Abstract Abstract 4608 Background: FCR has been a preferred 1st line therapy approach in CLL for the past decade. However it is associated with substantial toxicity and not recommended in NCCN guidelines for patients over age 70. We studied the impact of age, co-morbidities, and tempo of disease on 1st line therapy prescribing preferences of American hematology-oncology physicians (AHOP) for patients with CLL. Methods: During Feb-March 2012, prescribing preferences of 325 individual AHOP were assessed using a proprietary, live, case-based market research tool (Challenging Cases™). A core case scenario was constructed with variations based on altered age, co-morbidities, and tempo of disease progression prior to initial therapy. Preference data were acquired using blinded audience response technology. Responses for each scenario were obtained prior to any display of participant selections. All sources of research support were blinded. Core scenario: 67y male; CD 38+, ZAP 70+, del 13q and del 11q CLL, adenopathy, lymphocytosis, splenomegaly, anemia (Hgb 9.5 gm) but no thrombocytopenia. Co-morbidities: medication-controlled hypertension, moderate restrictive airways disease, and type 2 diabetes managed with metformin. Modified scenario: same clinical presentation except the patient is 72 years of age. Slower tempo of disease scenario: age 68y, time frame of observation without treatment 3 years from diagnosis, now with disease progression, anemia 10.9 gms, FISH only del 13q. Results: A progressive decrease in preference for FCR and commensurate rise in preference for BR as first line therapy occurs as age increases and co-morbidities are present (p<0.001). See table 1 Conclusion: As age crosses the 70 year threshold and as co-morbidities complicate therapy, there is a statistically significant increase in preference among AHOPs for prescribing bendamustine-rituximab as initial management for patients with RAI stage III CLL. Disclosures: Green: Xcenda: Employment; Teva: Consultancy, ownes publically traded shares in Teva Pharmaceuticals through 3rd party investment advisors, ownes publically traded shares in Teva Pharmaceuticals through 3rd party investment advisors Other. Williams:Xcenda: Honoraria. Willey:Xcenda: Employment. Scharf:Xcenda: Employment. Neely:xcenda: Employment. Foran:Xcenda: Honoraria.

Abstract Background: Patients ≥55 years of age with active, relapsed or refractory acute myeloid leukemia (R/R AML) who have failed standard induction therapies most often receive salvage therapy with a wide variety of agents, but very few achieve remission. These patients do not routinely undergo allogeneic hematopoietic cell transplantation (HCT) due to lack of efficacy using a standard HCT approach. The SIERRA trial is a prospective, randomized, phase 3, open-label, ongoing multicenter trial designed to address this significant unmet need in R/R AML. This trial compares Iomab-B, an 131I-radiolabeled anti-CD45 antibody as targeted conditioning prior to HCT against standard conventional care therapies with an accrual goal of 150 patients. We have performed a preliminary safety analysis, validating the initial feasibility of this multi-center trial. Methods: Eligible patients are ≥ 55 years of age with active, R/R AML, adequate organ function, and related/unrelated matched donor. Patients are randomized (1:1 ratio) to receive dosimetry directed Iomab-B followed 12 days later by HCT with fludarabine 30 mg/m2 x 3 days and 2 Gy of total body irradiation as transplant conditioning, or to a Conventional Care (CC) arm. Patients randomized to CC, may receive investigator's choice of salvage induction chemotherapy including approved targeted agents as well as Venetoclax (in combination with a hypomethylating agent) and proceed to standard HCT if they achieve complete remission (CR). If patients do not achieve CR, the study allows optional cross-over to the Iomab-B arm, evaluated between days 28-42 after CC therapy. The primary efficacy endpoint for the study is durable complete remission (dCR) of 6 months. The secondary efficacy objective is to evaluate overall survival at 1 year. Results: Forty patients have been enrolled to date and data are available for 38 patients (19 = Iomab-B, 19 = CC) as of July 5th, 2018. The median age was 63 years (range: 55-76). All patients had active disease at the time of enrollment with median bone marrow (BM) blasts of 30% in the Iomab-B arm and 47% in the crossover arm prior to receiving Iomab-B (Table 1). Of the patients in the CC arm, 88% did not achieve a CR and 65% of those crossed-over to receive Iomab-B. The most common reason preventing crossover was declining performance status. Time to HCT was not increased in the crossover patients receiving Iomab-B compared to those that underwent a standard of care transplant after achieving CR (median 65 vs 75 days), while the Iomab-B arm patients were transplanted at a median of 27 days after randomization. Iomab-B therapy was well-tolerated with no grade 3 or 4 infusion-related reactions reported. The median activity of Iomab-B was 626 mCi (range: 397-1027). All patients randomized to Iomab-B (N=13) engrafted, with median days to engraftment of ANC at 13 (range: 9-22) and platelets at 17 (range: 13-26). All patients who received Iomab-B after crossover (N=9) also engrafted with time to engraftment similar to patients initially randomized to the Iomab-B arm (Table 1). Donor chimerism (≥95%), within 100 days after HCT, was found in 9 of 10 patients in the Iomab-B arm and 8 of 9 patients in those that crossed over to receive Iomab-B, with two patient exceptions having mixed donor chimerism at day 28. A preliminary safety analysis for all randomized patients on either study arm showed the most frequent non-hematologic adverse events ≥ grade 3 occurring in >10% patients were febrile neutropenia (34.2%), stomatitis (15.8%), malnutrition (13.2%), epistaxis, sepsis, hypotension, hypobilirubinemia and fatigue (all 10.5%). There were no Iomab-B-related deaths. Interpretation: Preliminary safety analysis demonstrates the feasibility of delivering targeted conditioning with Iomab- B for HCT in R/R AML patients who have active disease and a high BM blast burden (median: ≥ 30%) prior to transplantation. All patients who received Iomab-B, including those crossed over after failing to achieve CR on CC salvage therapy, engrafted ANC within 13 days, despite active disease prior to transplant. In addition, the time to HCT from randomization was not increased in patients receiving Iomab-B after cross-over compared to those who underwent standard of care HCT after achieving CR on the CC arm. This study is currently enrolling and for full study details see www.sierratrial.com or clinicaltrials.gov (NCT02665065). Disclosures Tomlinson: Foundation Medicine: Consultancy. Foran:Xencor, Inc.: Research Funding; Agios: Research Funding. Chen:Bellicum Pharmaceuticals: Research Funding. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Lazarus:Pluristem Ltd.: Consultancy. Berger:Actinium Pharmaceuticals: Employment, Equity Ownership. Reddy:Actinium Pharmaceuticals: Employment, Equity Ownership; Pharmacyclics: Employment. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

Abstract Background Activating mutations in FLT3 - and in particular FLT3-ITD (internal tandem duplication) - are common in younger patients with AML, and are associated with relapse and with inferior overall survival (OS), however their prevalence and impact in older adults remains uncertain. We performed an analysis of FLT3-ITD mutations in patients age ≥60 yrs in the large prospective multicenter ECOG-ACRIN (E-A) E2906 Phase III trial. Methods Eligible patients (pts) age ≥60 yrs (n=727) were randomized to 'Standard' therapy with 7&3 (Dauno 60mg/m2) induction, and 2 cycles of intermediate dose Ara-C (1.5g/m2 x 12 doses; 6 doses if age ≥70yrs) consolidation (Arm A); or single agent clofarabine (CLO) induction and consolidation (2 cycles) (Arm B). As previously reported (Foran et al, ASH #217a, 2015), there was superior overall survival (OS) with standard therapy. AML diagnostic samples collected prospectively in the central E-A Leukemia Translational Research Lab (LTL) were used to detect mutations in the FLT3 gene by PCR using cDNA from total RNA. LTL investigators were blinded to treatment assignment. Patients with no RNA available or blast count <10% (threshold of sensitivity for the PCR assay) on the submitted sample were excluded. Statistical analysis was performed using X2 (categories) and Wilcoxon rank sum (continuous) tests to compare baseline patient and disease characteristics. Log-rank tests and multivariate Cox models stratified by treatment arm and adjusted for patient and disease variable (including WBC, cytogenetics, sex, performance status, secondary AML) were used to examine FLT3-ITD effect on OS and disease-free survival [DFS; relapse or death after complete remission (CR)/CRi (CR with incomplete CBC recovery)]. Results In the first 231 pts tested, FLT3-ITD mutations were identified in 43 (18.6%) pts, and the remainder were FLT3-ITD-negative (i.e. non-ITD). The proportion with FLT3-ITD was the same for patients age 60-69 yrs (18.8%) vs. ≥70 yrs (18.3%). In comparison to non-ITD, FLT3-ITD+ pts had significantly higher WBC (median 18.1 vs. 6.3, p=0.002) and BM blasts (80% vs. 51.5%, p=0.0004) at AML diagnosis, and were more likely to have intermediate risk (79.1% vs. 59%) vs. unfavorable risk (7.0 % vs. 31.4%) cytogenetics (p=0.002). There was no difference in CR/CRi rate overall (p=0.40), however standard (Arm A) pts with FLT3-ITD had a significantly higher CR/CRi rate (78.9% vs. non-ITD 51.5%, p=0.04). With median follow-up 53.5 months, FLT3-ITD patients tended to have worse OS (HR 1.24, 95%CI 0.85-1.81) but this was not statistically significant (Figure 1, p=0.26), and results were similar for both Arms A/B. DFS similarly tended to be worse overall for FLT3-ITD (HR 1.44, 95%CI 0.65-2.43) (p=0.17), and DFS was significantly worse for FLT3-ITD+ Arm A/Standard pts (Figure 2, p=0.033), while Arm B/CLO pts had a worse DFS regardless of FLT3 mutation status (Arm B, FLT3-ITD vs. non-ITD, p=0.93). More patients with FLT3-ITD underwent allogeneic transplantation (25.6% vs. non-ITD 19.7%), although this was not significant (p=0.41). Conclusions FLT3-ITD mutations are prevalent in older and elderly (age ≥70 yrs) patients with AML, and while they occur at somewhat lower rates than reported for younger adults, FLT3-ITD+ AML in this population has a leukemia phenotype similar to that reported in younger patients. Despite significantly higher CR/CRi rates with Standard therapy, older pts with FLT3-ITD also have significantly worse DFS following intensified Ara-C consolidation therapy than non-ITD pts. These results support routine assessment of FLT3-ITD status in older AML patients, and the incorporation of novel post-remission treatment strategies to improve outcome in FLT3-ITD+ pts ≥60 yrs. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Lazarus:Pluristem Ltd.: Consultancy. Tallman:BioSight: Other: Advisory board; AbbVie: Research Funding; Daiichi-Sankyo: Other: Advisory board; Cellerant: Research Funding; Orsenix: Other: Advisory board; ADC Therapeutics: Research Funding; AROG: Research Funding.

Abstract Background Multiple myeloma (MM) is the second most common hematologic malignancy in the U.S. and is characterized by increased immunoglobulin production and infiltration of the bone marrow by malignant plasma cells. Myeloma cell growth is supported by both the elements present in the bone marrow microenvironment as well as deregulation of internal cellular systems associated with proliferation and apoptosis. Defective programmed cell death by BCL2 or MCL1 upregulation is observed in >80% of myeloma cases and is associated with an aggressive clinical course. Remarkably, there is no approved drug with the ability to target BCL2 or MCL1. Various strategies to mitigate the effects of increased BCL2 functionality, via small molecule inhibitors or BCL2-specific antisense oligonucleotides have been previously examined in MM. These studies revealed that 1) apart from BCL2, additional anti-apoptotic members belonging to the BCL2 family (i.e. MCL1, BCL-xL) play integral roles in maintenance of the myeloma cell phenotype, 2) drugs, which target only BCL2 offer limited therapeutic advantage and 3) given that survival factors engaged in MM are multifactorial, perhaps isolated targeting of the BCL2 pathways may not be sufficient. We therefore hypothesized that the clinical development of drugs that target various antiapoptotic BCL2 family members will require a partnership with established anti-MM regimens whose activity can potentially be further enhanced with correction of the apoptotic response system. Aim Since lenalidomide and dexamethasone (LD) is an established therapy for plasma cell cancers, we investigated if the pan-BCL2 inhibitor AT-101 (BH3 mimetic), which has high binding specificity for BCL2, MCL1 and BCL-xL, can be an effective therapeutic partner to enhance anti-MM effects of LD. Methods Human MM (KMS11, U266, OPM2) and WM (BCWM.1) cell lines along with their corresponding bortezomib resistant (BR) clones, (KMS11/BR, U266/BR, OPM2/BR and BCWM.1/BR) which were developed in our laboratory were used in this study. For gene expression profiling, the Illumina HumanHT-12 v3 whole-genome gene expression array and Nanostring nCounter mRNA quantification assays (NanoString, Seattle, WA) were utilized. Statistical analysis was conducted using R-based packages and the MeV software (TIGR). Apoptosis was measured by annexin-v/PI staining, and mitochondrial membrane permeability (MOMP) was assessed using TMRM followed by flow cytometry. Protein profiles were ascertained by western blot. Results Gene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of various BCL2 family members, notably MCL1 and BCL-xL. In a dose-dependent manner, AT-101 was able to downregulate BCL2 and MCL1 and induced apoptotic cell death in MM and WM cells in a dose dependent manner. Tumor cell death was associated with caspase and PARP-1 cleavage accompanied by an increase in MOMP. This cytotoxic effect and BCL2 downregulation were further potentiated when AT-101 was combined with lenalidomide/dexamethasone (LDA). Nanostring nCounter mRNA quantification and IPA analysis revealed differential changes in the CCNA, FRZB, FYN, IRF1, PTPN11 genes in LDA treated cells. IPA canonical pathway analysis demonstrated the p53 signaling and the cyclins and cell cycle regulation pathways to be the most significantly activated by LDA therapy. Summary In summary, we describe for the first time the cellular and molecular events associated with the use of AT-101 in combination with lenalidomide/dexamethasone in preclinical models of plasma cell malignancy. This study lays the rationale for engaging and handicapping the intrinsic apoptotic system through the pan-BCL2 targeting capabilities of AT-101; thus enhancing the anti-MM effects of lenalidomide/dexamethasone. Disclosures: Foran: Celgene: Research Funding.

Abstract Background: CXCR4 is a chemokine receptor over-expressed on > 75% of cancers, including myeloid leukemia blasts. Ulocuplumab (BMS- 936564) is a first in class, fully human IgG4 monoclonal antibody which inhibits the binding of CXCR4 to CXCL12, resulting in the mobilization of leukocytes from the bone marrow to the peripheral blood. Ulocuplumab also induces apoptosis of CXCR4+ cells in clinicial samples (i.e., leukemia blasts) and in in vitro experiments (e.g. in Tregs). It is thus hypothesized that Ulocuplumab may induce the mobilization and apoptosis of myeloid blasts & immunosuppressive cells which could improve the overall response rate to chemotherapy Objective: To conduct a first-in-man phase I dose escalation/ expansion trial to determine the safety, pharmacology, and clinical benefit of Ulocuplumab in relapsed/refractory AML Results: Seventy three subjects (median age, 58 yrs; range, 21-79 y) with relapsed/refractory AML were treated with Ulocuplumab and MEC [mitoxantrone, 8 mg/m2; etoposide , 100 mg/m2; and cytarabine, 1 g/ m2; i.v. d 1-5]. Thirty subjects in escalation received a single infusion of Ulocuplumab (doses of 0.3, 1, 3, or 10 mg/kg) one week prior to starting MEC and 3 additional weekly doses per MEC cycle thereafter (starting on Day 1). Ulocuplumab was escalated to a maximum of 10 mg/kg without any dose-limiting toxicity during monotherapy or in combination with MEC in the 1st cycle. In expansion phase, 43 patients were similarly treated with10 mg/kg Ulocuplumab and MEC. The overall complete remission and complete remission with incomplete blood count recovery rate (CR/CRi) was 51%. Subjects with first CR > 6 months had better ORR (16/23, 70%) than those with CR1 ≤6 months or primary induction failure (6/20, 30%). Of note, four subjects had CR/CRi after a single dose of Ulocuplumab monotherapy. Transient, mild/moderate thrombocytopenia was the only treatment-related AE documented with Ulocuplumab monotherapy. Only one subject presented a mild infusion reaction on Cycle 1 Day 1. The safety profile in combination with MEC was similar to MEC alone as was the 60 day all-cause mortality (16.3%). A median 2- and 5-fold mobilization of leukocytes and leukemic blasts into the peripheral circulation was reported at day 8, respectively. There was a trend demonstrating that higher CXCR4 expression on AML blasts correlated with a positive clinical response. Reversible and manageable hyperleukoctosis occurred in one subject. Conclusions: This study shows that the blockade of the CXCR4-CXCL12 axis with Ulocuplumab has antileukemic activity and safely improves the historic response rate achieved with MEC alone (i.e.,24-28%). Disclosures Becker: Bristol-Myers Squibb: Research Funding. Off Label Use: Etoposide is indicated in the management of refractory testicular tumors and small cell lung cancer. . Foran:Bristol-Myers Squibb: Research Funding. Altman:Bristol-Myers Squibb: Research Funding. Yacoub:Bristol-Myers Squibb: Research Funding. Castro:Bristol-Myers Squibb: Research Funding. Sabbatini:Bristol-Myers Squibb: Employment. Dilea:Bristol-Myers Squibb: Employment. Wade:Bristol-Myers Squibb: Employment. Xing:Bristol-Myers Squibb: Employment. Gutierrez:Bristol-Myers Squibb: Employment. Cohen:Bristol-Myers Squibb: Employment. Smith:Bristol-Myers Squibb: Research Funding.