ALBERT

Description: Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after

Description: INTRODUCTION: Allogeneic stem cell transplant (ASCT) is currently the only curative therapy for myelofibrosis (MF). Ruxolitinib, an inhibitor of the JAK-STAT pathway, has been FDA-approved since November 2011 for the treatment of intermediate and high-risk myelofibrosis. Off-label, the medication has been administered prior to ASCT in an effort to reduce spleen size before conditioning and improve subsequent engraftment. In the published literature, there are mixed results for this strategy. Notably, French researchers announced preliminary results of a prospective study of 23 patients in December 2013. They reported several severe adverse events (SAE) following Ruxolitinib discontinuation, including two fatalities. These events included three cases of cardiogenic shock and three cases of tumor lysis syndrome (TLS). Since 2012, all patients with MF receiving ASCT at our institution have been pre-treated with Ruxolitinib until 48 hours prior to the start of conditioning. Herein, we report on outcomes of these patients. METHODS: After receiving approval by the Medical College of Wisconsin Institutional Review Board, we collected data on all patients who received Ruxolitinib prior to an ASCT. Our eligibility criteria included receipt of an HLA-matched sibling or unrelated ASCT for myelofibrosis at the Medical College of Wisconsin between Jan 2012 and March 2014 and treatment prior to transplantation with Ruxolitinib. Patient characteristics, drug-related adverse events including cardiac toxicity, and outcomes including response, relapse, graft-versus-host disease (GvHD), and overall survival were analyzed. RESULTS: Our cohort included ten patients with a median age of 56 years (range: 47-60 years) at the time of transplant. Four patients had de-novo disease and the remaining had myelofibrosis which had evolved from another myeloproliferative neoplasm. Four patients received one or more therapies for myelofibrosis prior to starting Ruxolitinib. One of the ten patients had undergone a splenectomy as part of prior treatment. The majority (6/10) had intermediate II-risk disease by the Dynamic International Prognostic Scoring System (DIPSS). Six of the ten patients received myeloablative conditioning. All ten patients received Ruxolitinib as pre-treatment prior to transplant and a standard taper schedule was employed starting six days prior to conditioning. Patients were slowly transitioned off the medication from a steady-state dose (maximum of 25 mg BID) to 5 mg once a day with the last dose taken 48 hours prior to conditioning. Two patients stopped taking their Ruxolitinib prior to the tapering protocol – one with progressive disease and one due to severe headache. Of the nine patients with splenomegaly, five had reduction of spleen size attributed to the medication. One of nine patients experienced rebound splenomegaly after discontinuation of Ruxolitinib. No patient experienced clinical symptoms of TLS. No patient experienced cardiac toxicity. After ASCT, acute GvHD occurred in two patients but was ≤ grade II in both. Chronic GvHD occurred in four patients, two were graded as mild and two were graded as moderate. After a median follow-up of 14.5 months (range: 5 – 23 months), all ten patients are alive. No patients require transfusions, one patient remains on intermittent granulocyte-colony stimulating factor. By International Working Group for Myelofibrosis Research and Treatment Criteria (IWG-MRT), four patients achieved complete remission, two achieved partial remission, one had clinical improvement and three had stable disease. No patient has experienced treatment-related mortality or graft failure. CONCLUSION: Administration of Ruxolitinib before ASCT has beneficial effects on spleen size and engraftment. We did not observe any serious adverse events with Ruxolitinib pre-treatment and no special safety concerns related to transplant. Table. Variable N=10 % Toxicities to Ruxolitinib Thrombocytopenia 3 30 Anemia 3 30 Headache 2 20 Arthralgia 1 10 Dizziness 1 10 Rebound Splenomegaly following discontinuation 1 10 Toxicities after ASCT Mucositis 2 20 Sinusitis with RSV 1 10 CMV Reactivation 1 10 Acute GvHD 2 20 Grade III/IV 0 Chronic GvHD 4 40 Mild 2 20 Moderate 2 20 Severe 0 Median time to Engraftment in days (range) 17 (13 – 22) Graft Failure 0 0 Disclosures Off Label Use: Ruxolitinib and myelofibrosis prior to transplant.

Description: Introduction: Acute promyelocytic leukemia (APL) is a medical emergency with a high incidence of early mortality, mainly due to hemorrhage induced by coagulopathy. Despite All-Trans Retinoic Acid (ATRA) and cytotoxic chemotherapy (CC) therapy that rapidly normalizes coagulopathyin APL, there is concern for worsening prior to this anticipated improvement. At our center, we have observed that patients who receive CC as part of their induction regimen often develop worsening coagulopathyresulting in clinically significant bleeding. Our impression was that this exceeds that seen in patients who receive ATRA without CC. We retrospectively reviewed patients with APL to identify a differential effect of CC on the coagulation system that could explain this excessive bleeding. Methods: Following IRB approval, the medical records of 27 consecutive newly diagnosed APL patients presenting between July 2007 and 2014 to Froedtert Hospital /Medical College of Wisconsin were reviewed. D-dimerlevels, fibrinogen and platelet counts before, during and after administration of systemic therapy were analyzed. Hemorrhage during induction was analyzed as occurring post-CC vs. ATRA with or without Arsenic Trioxide (ATO). This was correlated with any clinically significant bleeding and thrombosis. Results: Of the 27 patients identified, the median age was 50, and 13 were males. Ten patients(37%) were induced without CC. APL risk category did not differ between those induced with and without CC. Overall, nine (30%) patients had a bleeding complication and of those, seven (78%) received CC (Table 1). The two patients that did not receive CC had bleeding as their initial presentation. Of the seven that received CC and bled, only one had bleeding as the initial presentation and this patient did not bleed again after induction. Use of CC therapy did not statistically increase bleeding rates, but this was likely influenced by sample size (p=0.24, Fisher's exact). The D-dimer kinetics also differed between patients treated with and without CC (fig1&2). 26 of 27(96%) patients presented with high D-dimer levels initially. These levels improved over the next 72 hours after ATRA administration in patients without CC. A second rise in D-Dimer levels after CC was seen in 16 out of 17(94%) patients. This second spike correlated with clinically significant bleeding (per International Society of Thrombosis and Hemostasisdefinition) in 6 out of the 7 patients (85%). The platelet count, risk category or presence of clot did not seem to have a confounding effect on the risk of bleeding in these patients. Discussion: This is the first report of bimodal D-Dimer kinetics and associated bleeding diathesis in patients with APL whose induction therapy includes CC. Although the sample size is small, this increase in clinically significant bleeding risk among patients treated with ATRA + CC highlights the importance of close hemostatic monitoring after starting CC. If confirmed in larger studies, prophylactic hemostatic treatments like anti-fibrinolytic therapy could be considered in patients with second elevation in D-Dimer. 100% of the patients in the low risk group that received CC experienced hemorrhage. Hence, physicians should consider induction regimens for low risk APL that donot contain CC to limit the risk of hemorrhage given published trials that CC does not improve outcomes in low-risk disease over ATRA plus ATO. Table1: Difference in incidence of bleeding based on treatment type Bleeding (%) No bleeding (%) Total (%) Chemotherapy 7(41) 10(59) 17(100) No chemotherapy 2(20) 8(80) 10(100) Figure 1: D-dimer kinetics in a patient who received chemotherapy Figure 1:. D-dimer kinetics in a patient who received chemotherapy Figure 2: D-dimer kinetics in a patient who did not receive chemotherapy Figure 2:. D-dimer kinetics in a patient who did not receive chemotherapy Disclosures No relevant conflicts of interest to declare.

Description: Background: Less-fit patients with acute myeloid leukemia (AML) or high-risk myelodysplasia (MDS) age 60 years and older constitute the majority of patients with AML/MDS but are not well represented in clinical trials. DNA-methyltransferase inhibitor (HMA) monotherapy (e.g. azacitidine or decitabine) is usual. Overall response rates (ORR) are low; improvement in overall survival relative to supportive care alone is modest, highlighting the critical need for efficient identification of effective novel therapies. Blocking programed cell death protein-1 (PD-1) signaling with nivolumab may increase the sensitivity of AML cells to azacitidine and improve outcomes and is the focus of one arm of the S1612 trial. Signaling through PD-1 contributes to tumor immune evasion and growth in AML [Chen, Cancer Biol Ther 2008]. Increased expression of PD-1 (~40% of AML), is associated with poor HMA response [Ørskov, Oncotarget 2015]. A single center azacitidine/nivolumab non-randomized phase II study in relapsed/refractory AML reported ORR of 33% (23/70), including 22% complete remission/complete remission with incomplete hematologic recovery [Daver, Cancer Discovery 2018]. About 25% of the patients developed grade 2-4 immune toxicities; nivolumab immune-related adverse events led to treatment discontinuation in nearly 1 in 7 patients. Study Design and Methods:The S1612 trial [NCT03092674] is a platform randomized phase II/III clinical trial with a common azacitidine control arm (CA) and two currently active experimental arms (EA). Therapy is intended for community setting: azacitidine/nivolumab; and azacitidine/midostaurin. The innovative design utilizes a phase II go/no-go decision comparing each EA with the CA independently when there are 100 pts/arm and 104 deaths on the EA and CA combined. EAs will proceed to phase III if the null hypothesis (HR=1) is rejected in favor of the EA (15% one-sided alpha). When the two currently active EAs complete phase II accrual, a third EA (decitabine/cytarabine) will open. The CA stays open the entire length of the trial and only concurrently randomized patients will be compared across arms. If an EA proceeds to phase III, 200 additional patients (300 total patients) will be accrued. Phase III analysis occurs 1.5 years after accrual or at 414 deaths (in the respective EA and CA), whichever comes first. The phase III tests the null hypothesis with 4.5% two-sided alpha and 83% power for each EA to detect an improvement in median OS from 10.4 to 15.6 months. Eligible pts are age ≥60 years, newly diagnosed AML with ≥ 20% blasts or myelodysplastic syndrome with excess blasts-2 (MDS-EB-2); deemed by the treating physician unfit for standard cytotoxic chemotherapy; and no prior HMA permitted. Trial in Progress Issues:Between December 2017 and October 2018, 113 patients were screened and 78 randomized to study treatment (median/range age: 75/61-86 years; median/range performance status 1/0-3). Two concerns challenged this trial: 1) required administration of 7-day azacitidine at the enrolling sites created a burden for this population and 2) an early excess grade 5 toxicity signal in the azacitidine/nivolumab arm compared with the control arm. Without a control comparison, this safety signal likely would have been missed. Strategies to address these concerns were developed by the study team. Discussion with the sponsor and US Food and Drug Administration (FDA) focused on allowance of standard-of-care protocol-directed azacitidine administration in the patient's primary care doctor's office rather than at the oncology center. Because of the toxicity concern, the trial was placed on partial clinical hold for further evaluation and possible nivolumab-arm eligibility changes, along with new surveillance and pre-emptive action including prompt steroid initiation for suspected immune-related toxicities. The S1612 trial highlights special concerns when enrolling vulnerable populations onto leukemia clinical trials, and the importance of collaborative strategies including with the FDA to preserve clinical trial integrity for patient benefit. It also demonstrates the efficiency this novel platform design has for therapeutic investigation and, importantly, very early identification of serious toxicity. Updates on accrual and resolution and of these issues will be presented. Disclosures Hay: Kite: Research Funding; Gilead: Research Funding; AbbVie: Research Funding; Janssen: Research Funding; MorphoSys: Research Funding; Seattle Genetics: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Roche: Research Funding; Novartis: Research Funding. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria. Walter:Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy; New Link Genetics: Consultancy; Agios: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Seattle Genetics: Research Funding; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy. Foran:Agios: Honoraria, Research Funding. Radich:TwinStrand Biosciences: Research Funding; Novartis: Other: RNA Sequencing. Othus:Celgene: Other: Data Safety and Monitoring Committee; Glycomimetics: Other: Data Safety and Monitoring Committee. Erba:Astellas Pharma: Consultancy; Amgen: Consultancy; Amgen: Consultancy; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Pfizer: Consultancy; Pfizer: Consultancy; ImmunoGen: Consultancy, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Astellas Pharma: Consultancy; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Michaelis:Pfizer: Equity Ownership, Research Funding; Incyte: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; TG Therapeutics: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; BMS: Research Funding; Bioline: Research Funding; ASTEX: Research Funding; Janssen: Research Funding; Millenium: Research Funding; Macrogeneics: Research Funding. OffLabel Disclosure: Off label experimental combination therapies in newly diagnosed AML/MDS will be discussed, including nivolumab and azacitidine.

Description: Background: Familial MPNs are uncommon disorders that, like sporadic cases, are characterized by clonal hematopoiesis and presence of somatic mutations, e.g. JAK2, CALR, MPL and occasionally TET2. There is little information, however, about germ-line mutations in these families that may explain the low penetrance hereditary predisposition. Methods: We studied five families with MPNs, each with at least 2 affected members. After obtaining an informed consent, clinical data was obtained from the patients’ electronic medical records. Blood and buccal samples were collected from patients and unaffected relatives. Exome sequencing was performed on the blood DNA samples using Agilent SureSelect Human All Exon V5+UTRs exome capture kit followed by massively parallel sequencing with Illumina HiSeq 2000. Sanger sequencing was then done on both the blood and buccal swab DNA samples to validate selected gene variants and to differentiate the nature of those variants (germ line or somatic). Results: The 5 families participating in this study had the following diagnoses: 1. Mother: polycythemia vera (PV); son: essential thrombocythemia (ET), 2. Mother: primary myelofibrosis (MF); daughter: unclassifiable MPN (UMPN), 3. Father: PV; son: PV, 4. Sister: MF; sister: MF, 5. Two aunts: MF; niece; UMPN. Six patients were positive for JAK2, V617F mutation. Blood and buccal samples were collected from 5 patients and 4 relatives. In all 5 families, the pro-band was younger at the time of diagnosis than his/her affected relatives. The clinical course of the MPNs appeared to be similar to the sporadic form. Exome sequencing revealed TET2 mutations in 2 probands. In addition, novel non-synonymous mutations in several candidate genes, KMT2D, KMT2C, NBEAL1, NBEAL2, AHNAK2, RNF213, were identified in the blood samples from the patients but not their unaffected relatives. These include two novel KMT2D mutations in two unrelated families. These 2 mutations were also found in the matching buccal swab samples, indicating that they are germ line mutations. Discussion: KMT2D and KMT2C mutations have been previously identified as somatic mutations in lymphoid malignancies, including non-Hodgkin’s lymphomas (Morin 2011), and as germ line compound heterozygote mutations in infant MLL and ALL (Valentine 2014). About 32% of diffuse large cell lymphoma and 89% of follicular lymphoma have somatic mutations of KMT2D. NBEAL2 germ line mutations are associated with familial gray platelet syndrome, where some patients have myelofibrosis (Gunay-Aygun 2011). To our knowledge, this is the first report describing germ line mutations in familial MPNs. The possible role of these mutations in predisposition to MPN will be discussed. Studies on additional families with MPNs are planned. Disclosures No relevant conflicts of interest to declare.

Description: Background: Outcomes of patients with AML have remained poor despite the availability of cytotoxic chemotherapy, hypomethylating agents (HMAs) and targeted therapies. HMAs, such as azacitidine, in combination with Bcl-2 inhibitors like venetoclax have demonstrated response rates of 67% in newly diagnosed AML and 21% in relapsed/refractory (RR) AML (DiNardo et al. Blood 2019 and Am J Hematol 2018). While the combination of azacitidine and venetoclax is efficacious in AML, preclinical studies indicate potential mechanisms of drug resistance including overexpression of MCL-1, an anti-apoptotic protein (Konopleva et al. Cancer Cell. 2006). Pevonedistat is a first in class inhibitor of Nedd8 activating enzyme that has demonstrated activity against AML (Swords RT et al. Blood. 2010). Pevonedistat induces NOXA, a pro-apoptotic protein leading to neutralization of MCL-1 inducing apoptosis (Wang et al. Biochem Biophys Res Commun. 2017). Preclinical studies evaluating the combination of pevonedistat and venetoclax against AML cell lines have demonstrated synergistic effect (Knoor KL et al. Cell Death Differ. 2015). Hence, we hypothesize that the addition of pevonedistat to the combination of azacitidine and venetoclax would enhance the therapeutic efficacy by overcoming resistance to apoptosis. Study design and methods: This is an investigator-initiated phase Ib study evaluating the safety of pevonedistat, azacitidine and venetoclax. Patients aged 18 years or above with morphologically documented AML (de novo, secondary or therapy-related), ECOG performance status 0-2 and adequate organ function are eligible for the study. Major exclusion criteria are patients with isolated extramedullary relapse, hematopoietic cell transplantation (HCT) within 100 days of enrollment, active acute GVHD, veno-occlusive disease, acute promyelocytic leukemia, liver cirrhosis and severe liver impairment. While the dose escalation phase is available only for patients with RR-AML, the dose expansion phase can also include newly diagnosed AML patients who are ineligible for intensive induction. The study is planned to be conducted at Medical College of Wisconsin, Mayo Clinic and University of Pennsylvania. The primary endpoint is to determine the recommended phase 2 dose (RP2D) and toxicity profile of pevonedistat, azacitidine and venetoclax. The secondary endpoints include determination of response rates, duration of response, survival and pharmacokinetics. Exploratory endpoints include correlation of response rates with AML genomic profile, correlation of pretreatment levels of BCL2, BCLXL, MCL1, BAX or BAK with response, determination of changes in NOXA (PMAIP1) mRNA and protein expression pre-and post-pevonedistat treatment, evaluation of BH3 mimetic profiling on bone marrow samples by flow cytometry and assessing the sensitivity of leukemia and leukemic stem/progenitor cells to pevonedistat ex vivo. The study will follow 3+3 design with dose escalation (Arms A and B), de-escalation in case of dose limiting toxicity (DLT) (arms Z and Y) and dose expansion phase (figure 1). Patients will be entered sequentially to each dose level, starting with dose level 0. The DLT observation period for dose-escalation will be 1 cycle. The maximal tolerated dose (MTD) will be defined as the highest dose level at which none of the first 3 treated subjects, or no more than 1 of the first 6 treated subjects experiences a DLT. A minimum of 9 and a maximum of 24 patients will be needed for the dose escalation phase and 6 patients for the dose expansion phase. Response rate, duration of response and exploratory endpoints will be analyzed using descriptive statistics. Kaplan-Meier method will be used to determine survival. Disclosures Guru Murthy: Cardinal Health Inc.: Honoraria. Michaelis:Incyte: Consultancy, Research Funding; Pfizer: Equity Ownership, Research Funding; Novartis: Consultancy; Macrogeneics: Research Funding; Millenium: Research Funding; BMS: Research Funding; Celgene: Consultancy, Research Funding; JAZZ: Other: Data Safety Monitoring Board, uncompensated, Research Funding; TG Therapeutics: Consultancy, Research Funding; Janssen: Research Funding; ASTEX: Research Funding; Bioline: Research Funding. Abedin:Jazz Pharmaceuticals: Honoraria; Agios: Honoraria; Helsinn Healthcare: Research Funding; Pfizer Inc: Research Funding; Actinium Pharmaceuticals: Research Funding. Runaas:Agios: Honoraria; Blueprint Medicine: Honoraria. Atallah:Jazz: Consultancy; Novartis: Consultancy; Takeda: Consultancy, Research Funding; Pfizer: Consultancy; Jazz: Consultancy; Helsinn: Consultancy; Helsinn: Consultancy.

Description: Introduction: Patients with International Prognostic Scoring System (IPSS) intermediate 1 and 2 (Int) and high risk (HR) MDS benefit from therapy with hypomethylating agents (HMAs) decitabine (DAC) and azacitidine (AZA). Treatment requires 5 or 7 daily parenteral doses every month while the patient is benefitting. An oral HMA taken at home would provide patient convenience, and potentially enhance adherence to treatment particularly for long-term responders. Neither DAC nor AZA is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin in preclinical models. We report here the final results of a Phase 1 study including an extension arm of a PK-guided first in human dose escalation trial of ASTX727 (the combination of oral DAC and E7727). Methods: Adult patients with Int or HR MDS or Chronic Myelomonocytic Leukemia (CMML) were enrolled in this dose-escalating trial. In addition to assessing the safety of the combination, the primary PK objective was to achieve a mean AUC of DAC following oral ASTX727 comparable to that achieved by IV DAC at the approved daily dose of 20 mg/m2. In the first cycle, each patient received an IV DAC dose of 20 mg/m2 on Day 1 as an internal comparator followed by oral ASTX727 on Days 2-5 escalated by cohort. Subsequent cycles were given with oral ASTX727 on Days 1-5 at the same dose of Cycle 1. Cycles were 28 days in length. Only one component at a time was escalated in each cohort and oral doses were not adjusted for weight or body surface area. Intrapatient dose escalation was permitted. Pharmacodynamics (PD) were evaluated by LINE-1 DNA methylation in peripheral blood. Responses were assessed using the International Working Group (IWG) criteria for response (Cheson et al, 2006). Results: 43 patients were treated in 5 cohorts of 6 patients each plus a 13 patient expansion of cohort 5. The median age was 71.5 years (range 59-86), 30/43 (70%) were male, and median time from diagnosis was 273 days (range 5-3518). Prior therapies had been administered to 22/43 (51%) patients including 20 who had received prior HMA. The AUC for IV DAC 20 mg/m2 in all patients (n=43) had a mean (CV) of 171(37%) ng*hr/mL. The Cmax for IV DAC 20 mg/m2 had a mean (CV) of 179(36%) ng/mL. Doses of each component of ASTX727 were escalated as shown in Table 1. E7727 was escalated first from 40 to 100 mg in cohorts 1 to 3 then kept constant at cohorts 4 to 6. DAC doses were kept constant at 20 mg in cohorts 1 to 3 then escalated to 40 mg at cohort 4 and de-escalated to 30 mg at cohort 5. Dose dependent increases in AUC and Cmax occurred with escalating doses. DAC AUC values after oral ASTX727 approached then exceeded IV at 149% by cohort 4. DAC Cmax values after oral ASTX727 never exceeded IV in any Cohort. Mean % LINE-1 demethylation on cycle 1 Day 8±SE increased with dose escalation reaching 12.8%±3.8 by cohort 4. Lower DAC AUC and Cmax were observed after lowering the oral DAC dose from 40 to 30 mg in cohort 5 as shown in Table 1. One patient in cohort 4 had a dose limiting toxicity of thrombocytopenia and no Grade ≥ 3 drug-related non-hematologic AEs were observed in any patient. The most common ≥ Grade 3 AEs regardless of relationship to the drug were thrombocytopenia (36%), anemia (30%), neutropenia (27%), and febrile neutropenia (21%). No drug-related Grade ≥ 3 gastrointestinal AEs were reported. A median of 5 cycles (range 1-23) were administered, 11 patients remain on therapy, and 14 (32%) have experienced objective clinical responses so far, including 5 Complete Response (CR), 4 marrow CR, and 5 Hematologic Improvement. Of 23 patients initially RBC dependent, 6 (26%), became independent and of 6 who were platelet dependent, 2(33%) became independent. Conclusions: ASTX727 (the combination of E7727 and DAC administered PO concomitantly) achieved the primary PK objective of emulating IV DAC 20 mg/m2 AUC levels with a similar safety profile. Day 8 LINE-1 demethylation in Cohort 4, overall clinical response and transfusion independence rates are consistent with those historically reported following DAC 20 mg/m2 IV for 5 days, even though 47% had received prior HMA therapy. ASTX727 has now proceeded to a randomized phase 2 study comparing IV DAC 20 mg/m2 IV daily for 5 days to oral ASTX727 at the doses of 35 mg DAC and 100 mg E7727 daily for 5 days in Int or HR MDS and CMML patients. Disclosures Odenike: Geron: Research Funding; Suneisis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta: Honoraria, Membership on an entity's Board of Directors or advisory committees. Steensma:Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Ariad: Equity Ownership; Genoptix: Consultancy; Millenium/Takeda: Consultancy. Michaelis:Incyte: Honoraria; Pfizer: Equity Ownership; Celgene: Honoraria, Speakers Bureau. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals: Employment. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Zhang:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment. Savona:Ariad: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Abstract 4913 Background: The addition of rituximab to cytotoxic chemotherapy has become standard in the initial treatment of DLBCL. However, estimations of the overall effect of the addition of rituximab to chemotherapy vary widely in the published literature. To date, no meta-analyses of rituximab in DLBCL have been published. We performed a comprehensive systematic review to compare chemotherapy with rituximab-chemotherapy in studies of newly-diagnosed DLBCL. The primary endpoint was OS; additional endpoints included disease control (DC), complete response (CR), and regimen-related toxicity (RRT). Disease control was assessed in each study as the time to treatment failure, event-free survival, progression free survival or time to progression. Methods: A comprehensive search for randomized trials (RCTs) comparing the addition of rituximab to chemotherapy was conducted in MEDLINE (January 1997 through April 2010). Also, meeting proceedings from American Society of Clinical Oncology, American Society of Hematology, European Society of Clinical Oncology and European Hematology Association, and studies listed on www.clinicaltrials.gov were manually searched for any supplementary abstracts, presentations or updates that were not identified in the original database search. The analysis included only RCTs comparing rituximab-chemotherapy with chemotherapy alone in patients with newly diagnosed DLBCL. Chemotherapy regimens were limited to CHOP or CHOP-like regimens. All three authors independently assessed each study's quality and performed blinded data extraction with conflict resolution by majority consensus. Given the inclusion of studies with both young and elderly patients, as well as HIV seropositive patients, we pooled data using a random effects model, with the estimate of heterogeneity being taken from the inverse variance fixed effect model. Results: Overall, seven RCTs involving 3539 patients with newly diagnosed DLBCL met inclusion criteria and were included in the meta-analysis. All studies were published as full-text articles. None of the studies were blinded. Studies from North America, Central America, and Europe were incorporated. The funnel plot for OS and Egger's test (1.37; 95% CI -2.25 to 4.99) did not indicate a significant publication bias. The test of heterogeneity among all RCTs was statistically significant in all endpoints. The pooled odds ratio (OR) demonstrated an increased OS for patients treated with rituximab-chemotherapy compared to chemotherapy alone (OR 0.71; 95% CI: 0.57 to 0.89). Similar improvements in CR (OR 1.64; 95% CI: 1.23, 2.17) and DC (OR 0.56; 95% CI: 0.46, 0.70) were observed in the patients treated with the rituximab containing regimens. Due to variable RRT reporting across studies, a formal meta-analysis of toxicity was not completed. In addition, varied data reporting precluded formal analysis of any differences in benefit between the International Prognostic Index groups. Conclusions: Our meta-analysis of data from more than 3500 patients with newly diagnosed DLBCL demonstrates that the addition of rituximab to chemotherapy improves the odds of OS and DC by 29% and 44%, respectively, as compared to chemotherapy alone. The survival benefit was independent of age (data not shown). This comprehensive systematic analysis enumerates and confirms the benefit of rituximab-based therapy in previously untreated DLBCL. Forest Plot for OS. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction: Patients with International Prognostic Scoring System (IPSS) intermediate (Int) and high risk (HR) MDS benefit from therapy with hypomethylating agents (HMAs). Treatment with the HMAs decitabine (DAC) and azacitidine (AZA) requires 5 or 7 daily parenteral doses respectively every month with some patients remaining on treatment for extended periods. An orally administered HMA would provide significant patient convenience, potentially enhance adherence to treatment, and may allow exploring extended treatment schedules with lower doses of DAC. Neither DAC nor AZA is readily bioavailable in oral form due to rapid clearance by cytidine deaminase (CDA) present in the gut and liver. E7727, a novel CDAi, is orally bioavailable with a large safety margin in preclinical models. We report here the first Phase 1 results of a PK-guided FIH dose escalation trial of ASTX727 (the combination of oral DAC and E7727). Methods: Adult patients with Int or HR MDS or Chronic Myelomonocytic Leukemia (CMML) were enrolled in this dose-escalating trial with a 3+3 design. In addition to assessing the safety of the combination, the primary PK objective was to achieve a mean AUC of DAC following oral ASTX727 comparable to that achieved by IV DAC at the approved dose of 20 mg/m2. In the first cycle, each patient received an IV DAC dose of 20 mg/m2 on Day 1 as an internal comparator followed by oral ASTX727 on Days 2-5 escalated by cohort. Subsequent cycles were given with oral ASTX727 on Days 1-5 at the same dose of Cycle 1. Cycles were 28 days in length. Pharmacodynamics (PD) were evaluated by LINE-1 DNA methylation in peripheral blood. A data safety review committee evaluated safety, PK and PD on patients in each completed cohort and determined dosing for each component of ASTX727 at the next cohort. Only one component at a time was escalated in each cohort and oral doses were not adjusted for weight or body surface area. Responses were assessed using the International Working Group (IWG) criteria for response (Cheson et al, 2006). Results: The Phase 1 portion of the trial completed dosing of 4 cohorts with 6 subjects each (24 subjects). The median age was 71 years (range 59-85), 15/24 (63%) were male, and median time from diagnosis was 307 days (range 5-3024). Prior therapies were administered to 10 patients including five who had received prior HMA. In cohorts 1-3 ASTX727 was given as a fixed oral DAC dose of 20 mg with escalating doses of oral E7727 at 40, 60, and 100 mg respectively. In cohort 4, the oral DAC dose was escalated to 40 mg while E7727 was kept at 100 mg. The Day 1 AUC for IV DAC 20 mg/m2 over all 4 cohorts had a mean (SD) value of 193(82) ng*hr/mL. After oral ASTX727 on Days 2-5, the mean DAC AUC as % of IV DAC AUC was 17, 19, 32, and 98% on Day 2 and 31, 41, 58 and 148% on Day 5, in cohorts 1-4 respectively (Figure). DAC AUC variability after oral ASTX727 was acceptable (CV% 35-53 across 4 cohorts). DAC Cmax values after oral ASTX727 approached IV (87%) in Cohort 4 on Day 5. Mean % LINE-1 demethylation on cycle 1 Day 8±SE was 6.8%±2.7; 8.6%±2.7; 9.5%±3.3; and 15.3%±3.4 from baseline for cohorts 1-4 respectively. No Dose Limiting Toxicities (DLTs) or Grade ≥ 3 drug-related non-hematologic AEs were observed in any patient. The most common Grade ≥ 3 AEs regardless of relationship to the drug were thrombocytopenia (37.5%), anemia (33.3%), neutropenia (29.2%) and febrile neutropenia (16.7%). Twenty patients remain on therapy, and at least 5 so far have experienced objective clinical responses (including 1 Complete Response (CR), 1 marrow CR, 1 Partial Response and 2 Hematologic Improvement). Conclusions: ASTX727 (the combination of oral DAC and oral CDAi E7727 administered concomitantly) achieved the primary PK objective of reaching (at Day 2) or exceeding (at Day 5) IV DAC 20 mg/m2 AUC levels at the doses of 40 mg DAC and 100 mg E7727 with an excellent safety profile. Day 8 LINE-1 demethylation in Cohort 4 is consistent with that historically reported following DAC 20 mg/m2 IV for 5 days. Clinical responses have been observed. The trial will explore lower doses of oral DAC and will proceed to dose expansion followed by randomized phase 2 portion comparing IV DAC to oral ASTX727 in previously untreated Int or HR MDS and CMML patients. Figure 1. Mean DAC AUC after IV DAC 20 mg/m2 (D1) and oral ASTX727 (D2 and D5) for cohorts 1-4 Figure 1. Mean DAC AUC after IV DAC 20 mg/m2 (D1) and oral ASTX727 (D2 and D5) for cohorts 1-4 Disclosures Savona: Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; Astex Pharmaceuticals, Inc: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Odenike:Sunesis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Michaelis:Incyte: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Wyeth: Membership on an entity's Board of Directors or advisory committees; Pfizer: Equity Ownership. Faderl:JW Pharma: Consultancy; Karyopharm: Consultancy, Research Funding; Seattle Genetics, Inc.: Research Funding; Astellas: Research Funding; Celator: Research Funding; Ambit: Research Funding; Onyx: Speakers Bureau; BMS: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding. Lowder:Astex Pharmaceuticals, Inc.: Employment. Taverna:Astex Pharmaceuticals, Inc.: Employment. Oganesian:Astex Pharmaceuticals, Inc.: Employment. Dua:Astex Pharmaceuticals, Inc.: Employment. Nawabi:Astex Pharmaceuticals, Inc.: Employment. Azab:Astex Pharmaceuticals, Inc.: Employment.

Description: Background: APL is a distinct but rare subtype of acute myeloid leukemia. Once very lethal, the discovery of all-trans retinoic acid (ATRA) as treatment has resulted in high rates of cure. Despite this, early mortality rates remain as high as 10% in clinical trials and may be even higher in general practice, where there may not be significant experience with this uncommon malignancy. Prompt recognition of APL and access to ATRA are critical to preventing early death, which is typically due to hemorrhage-related complications stemming from disseminated intravascular coagulation. We hypothesized that patients treated at teaching hospitals would have lower rates of early mortality as compared to non-teaching hospitals. Methods: We queried the Nationwide Inpatient Sample (NIS) from year 2008-2013 to identify patients 〉18 years of age with a discharge diagnosis of APL based on ICD-9 CM code of 205.00. A survey weighted domain analysis was conducted to describe the relationship between hospital teaching status and clinical outcomes among adult patients. Teaching hospitals have an AMA-approved residency program or have membership in the Council of Teaching Hospitals. Patient characteristics and clinical outcomes (in-hospital mortality, 7-day in-hospital mortality, disseminated intravascular coagulation (DIC), bleeding, stroke, cardiac dysrhythmia, acute myocardial infarction (AMI), pulmonary embolism (PE), deep vein thrombosis (DVT), and length of stay) were compared across hospital teaching status using ANOVA for continuous variables and Chi-squared tests for categorical variables. Multiple logistic regression was used to compare binary outcomes by hospital teaching status adjusting for patient characteristics. Results: The baseline characteristics of the patients are described in Table 1. Patients at non-teaching hospitals were older (mean age 68 yrs. vs. 60.3 yrs., p