Citations

Abstract Introduction: High-dose cytarabine consolidation chemotherapy for acute myeloid leukemia (AML) induces profound transient myelosuppression. Thrombocytopenia is a limiting factor in chemotherapy administration for maintaining dose intensity and schedule as thrombocytopenic-related hemorrhage may contribute to significant morbidity and mortality. Therapeutic and prophylactic platelet (plt) transfusions remain the treatment of choice but the benefits typically last only 3-7 days, are expensive, time consuming, and may induce alloimmunization and transmit infection. PrE0901 was a phase I multi-center study to evaluate the safety and toxicity of eltrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, for plt recovery in AML patients (pts) receiving consolidation therapy. Methods: The primary objectives were to determine the safety, tolerability, and optimal dosing of eltrombopag while describing the kinetics of plt recovery in AML pts receiving intensive consolidation. Plt recovery was defined as a sustained plt count of ≥ 20 x 109/L following the nadir with no plt transfusions in prior 7 days or a continued upward trend in plt count for at least 2 successive measurements despite no plt transfusions in 48 hours. We used a standard 3+3 design utilizing a novel dose escalation/de-escalation strategy for pts in either first or second complete remission, ≥18 and ≤70 years of age, who had an ECOG performance status of 0-2. Cytarabine was administered at 3 g/m2 (1.5 g/m2 for pts >60 years) IV over 3 hours twice daily on days 1,3,5. Eltrombopag at assigned dose was administered with a first cycle of cytarabine only. Planned eltrombopag dose levels -2, -1, 1, 2, 3, 4, and 5 were 50, 100, 150, 150, 150, 200, and 300 mg, respectively (Table 1). Eltrombopag was to start on days X, X, 3, -1, -5, -5, and -5 relative to day of cytarabine start and levels -2, -1, 1, 2, 3, 4, and 5, respectively, with day X being variable depending on timing of observed dose limiting toxicities (DLTs). The eltrombopag was continued until plt recovery or for up to 35 consecutive days, whichever occurred first. An exploratory objective was to determine if eltrombopag had an effect on TPO and EPO blood concentrations in this setting. Results: Accrual began on July 31, 2012 and the trial closed on January 8, 2016 upon recommendation after an independent Data and Monitoring Committee reviewed a separate trial of eltrombopag therapy in MDS which demonstrated futility. 104 pts were screened. 54 declined participation and 35 were deemed medically ineligible. A total of 15 eligible pts were enrolled; 14 were treated on study with one pt being withdrawn prior to starting treatment due to infection. Three pts were treated at each of dose levels 1-4 and two were treated on dose level 5. No DLTs were observed. Median time to plt recovery of all pts treated on study was 22.5 (range 16-43) days. Pts in cohort 1 dosed with eltrombopag 150 mg daily starting on day 3 of consolidation demonstrated the fastest plt recovery (median =19 days; range 19, 19, 19) compared to cohort 2 who received 150 mg daily starting on day -1 of consolidation and recovered the slowest (median 23 days; range 16, 23, 43). Dose escalation in terms of starting eltrombopag further in advance of chemotherapy exposure as within cohort 3 (150 mg starting day -5) was associated with a median plt recovery of 27 (range 22, 27, 27) days. Eltrombopag dose intensification with cohort 4 at 200 mg daily and cohort 5 at 300 mg daily was associated with median plt recoveries of 24 (range 18, 24, 26) and 23 (range 19, 27) days, respectively. Kinetics of plt recovery for all cohorts are represented in Figure 1 and duration of eltrombopag exposure for each individual patient is represented in Table 2. Conclusions: Endogenous cytokine (TPO and EPO) levels varied inversely with plt and hematocrit values and did not appear to be affected by eltrombopag dose / schedule (details to be provided at ASH Annual Mtg). Unusually high screen fail numbers warrant examination to guide future trial design in the post-remission setting. The addition of eltrombopag to high-dose cytarabine consolidation therapy was well-tolerated and no DLTs were observed. The results for cohort 1 [eltrombopag 150 mg daily starting on day 3 of consolidation] demonstrated the fastest plt recovery. Further investigation is needed to define the optimal role, dose, and schedule of eltrombopag in the treatment of chemotherapy associated myelosuppression. Disclosures Strickland: Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding.

Abstract Although molecularly and clinically heterogeneous, AML is characterised by aberrant transcription and abnormal epigenetic regulation. The transcriptional co-activators CBP and p300 have well characterised roles in hematopoiesis and hematopoietic stem cell (HSC) function. These are mutated in AML and also bind a number of AML-associated oncogenes. However, despite this, their roles in the induction and maintenance of AML are poorly understood. To address this question, we have combined genetic and pharmacological inhibition of CBP and p300 in AML and normal hematopoiesis. Using a murine model where Cbp was conditionally deleted from murine hematopoietic stem and progenitor cells (HSPC), either prior to, or following expression of a number of AML-associated oncogenes, we assessed the role of Cbp in the induction and maintenance of AML. We demonstrated that although not an absolute requirement, Cbp confers a selective advantage for robust immortalisation in vitro, and that Cbp is also an important requirement for the generation and maintenance of AML in vivo. Furthermore, redundancy between Cbp and p300 in myeloid transformation was demonstrated, as p300 knockdown further decreased proliferation in Cbp-/- AML cells. We next validated CBP/p300 as potential therapeutic targets, using a pharmacological strategy. Using a selective small molecule inhibitor (C646) of the lysine acteyltranferase (KAT) activity of CBP/p300, we demonstrated a significant decrease in growth and clonogenic potential across multiple AML subtypes in vitro. This was mediated through induction of apoptosis and cell cycle arrest. Importantly, no alteration in the growth of normal murine and human hematopoietic progenitors was detected at similar doses. We further demonstrated that inhibition of CBP/p300 KAT activity in human leukemia cells alters a transcriptional programme associated with genomic integrity, linking transcriptional changes to the cellular phenotype. Finally, we demonstrated the efficacy of the HAT inhibitors to decrease clonogenic growth across a panel of primary AML patient samples, representing multiple genetic subtypes. Taken together, these data suggest that CBP/p300 are involved in leukemogenesis across multiple subtypes in AML and that targeting these proteins may be possible with an acceptable side-effect profile. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction : Follicular lymphoma (FL) remains an incurable malignancy as patients eventually experience progressive disease. A subset of patients is at risk of early lymphoma-related mortality due to histological transformation (TFL) to aggressive lymphoma (2-3% of patients per year) or early progression after immuno-chemotherapy, each of which leads to shortened survival. Mutations associated with transformation and/or early progression have been reported in the literature (e.g. CDKN2A, TP53, B2M) and the m7-FLIPI clinico-genetic risk model defines a high-risk patient group with poor failure-free survival after first-line treatment. However, the current knowledge of genetic alterations underlying transformation and/or early progression is inadequate to explain the majority of transformed cases and accurately predict early progressive disease. Materials and Methods: We performed targeted capture-based sequencing of 94 genes in a large cohort of fresh-frozen and formalin-fixed and paraffin-embedded patient specimens (402 samples in total). This cohort comprised 277 samples from 159 patients that experienced transformation (including 128 samples at T1 (the time of FL) and 149 samples at T2 (the time of transformation) with 118 paired biopsies) and 125 samples from 125 patients (pre-treatment samples only) presenting with either early progression within 2.5 years after starting immunochemotherapy (n=41) or late or never progression for at least 5 years after starting immunochemotherapy or observation (n=84). Mutations were called using MutationSeq and putative single nucleotide polymorphisms were filtered out using either matching germline samples (n=84) or dbSNP (v147). Bayesian proportion tests were used to compare the prevalence of gene mutations between groups. Results : We first compared T1 (n=128) and T2 (n=149) samples from 159 patients experiencing transformation. Eleven genes were more commonly altered in transformed lymphoma. These included genes that had previously been associated with transformation, such as TP53, B2M, MYC and EBF1, as well as genes that have not yet been implicated as contributing to this process, for example EZH2, CCND3, PIM1 and ITPKB. Moreover, mutations in GNA13, S1PR2 and P2RY8, that have been implicated in dissemination of germinal centre B cells, were enriched in T2 samples. In addition, cell-of-origin classification was available for 108 of the TFL cases with DLBCL histology, 18 and 90 of which were of the ABC and GCB subtype, respectively. Although the number of ABC-TFL cases was small, we observed higher percentages of BCL10 (16% versus 1%, Fisher P=0.004), CD79B (22% versus 4%, Fisher P=0.005) and MYD88 mutations (28% versus 9%, P=0.006) in ABC-TFL than in GCB-TFL, suggesting that B-cell receptor signaling and NF-κB signaling are important contributors to the ABC phenotype in TFL. Next, we assessed the association of gene mutations with patient outcomes contrasting early progressers (n=41) and late or non-progressers (n=84). Eleven genes were mutated more commonly in early progressers than in late progressers, including KMT2C, TP53, BTG1, MKI67, XBP1 and SOCS1. Overall, 32 out of 41 early progressers (78%) had mutations in at least one of the 11 early progression-associated genes, but none of the individual early progression-associated genes were mutated at a frequency > 22%. Thus, early progression appears to be related to relatively infrequent genetic alterations. None of the early progression-associated gene mutations form part of the m7-FLIPI outcome predictor. Furthermore, in our cohort that was enriched for clinical extremes, the m7-FLIPI was similarly associated with early progression when compared to the FLIPI but it was not superior, having higher specificity (89% versus 76%), but lower sensitivity (36% versus 63%). Conclusions: We found novel associations of gene mutations with transformation and showed that TFL is molecularly heterogeneous, with the ABC subtype being characterized by differential gene mutation when compared to the GCB subtype. With regards to progressive disease after immuno-chemotherapy, our approach identified early progression as a distinct clinico-genetic disease category that is imperfectly captured by traditional prognostic tools. Disclosures Connors: Seattle Genetics: Research Funding; Bristol Myers Squib: Research Funding; F Hoffmann-La Roche: Research Funding; NanoString Technologies: Research Funding; Millennium Takeda: Research Funding. Scott:NanoString Technologies: Patents & Royalties: named inventor on a patent for molecular subtyping of DLBCL that has been licensed to NanoString Technologies.

Abstract We and others previously reported that leukemic CLL cells spontaneously secrete VEGF and that VEGF can enhance the leukemic B cell apoptosis resistance via unknown mechanisms. Here, we report elevated VEGF secretion is associated with CLL B cell over-expression of hypoxia inducible factor-1 alpha (HIF-1α), a transcription factor that is a key regulator of VEGF synthesis. Immunostaining analysis confirmed CLL B cells in blood and bone marrow over-expressed both HIF-1α and VEGF. The high HIF-1α levels were not linked to proline residue (402/564) mutations in oxygen dependent degradation domains; absence of proline hydroxylation dependent enzymes (PHD1, 2, 3, and FIH); or to pVHL mutation (exon 1, 2 and 3); or aberrant transcription of HIF-1α. However, pVHL, a regulator of HIF-1α degradation, was found to be lower in CLL B cells and unable to physically interact with HIF-1α in CLL B cells. Nuclear extraction assay revealed that HIF-1α interacted with its co-factor, p300/CRP in B cells, indicating that HIF-1α was transcriptionally active. We hypothesized that reduction of pVHL expression in CLL B cells could be related to repression by micro RNA function which is known to be aberrantly expressed in CLL. We focused on miR-92-1 known to be over-expressed in CLL B cells and it has pVHL as a putative target. In a luciferase assay of transfected human megakaryocytic cell line, MEG-01, we found a direct effect for miR-92-1 on pVHL, with significant repression of luciferase activity of VHL expression by miR-92-1 compared to both control vectors and a mutated target mRNA sequences. This result indicated that wild-type miR-92-1 was able to interact directly with the 3′ UTR sequence of pVHL and subsequently repress pVHL expression. To further confirm this finding, we did transient transfections of either the CLL cell line Mec-1, primary CLL B cells or normal B cells with a sense oligo miR-92-1 (both Mec-1 and CLL B cells) or wild-type miR-92-1 plasmid (normal B cells). We found the level of flow detectable pVHL lower when compared to non-transfected cells. Because we were interested in the relationship of HIF-1α to CLL B cell survival we studied if chemotherapeutic drugs can downregulate HIF-1α in CLL B cells. To do this we studied flavopiridol a drug that has very promising activity in CLL. Our results indicated that flavopiridol does down-regulate HIF-1α levels in CLL B cells. This latter change was associated with induction of apoptosis in CLL B cells. Overall, our data show that elevated VEGF secretion is related to constitutively elevated HIF-1α levels and is an explanation for the VEGF-based autocrine pathway found in CLL B cells. We also show that elevated HIF-1α levels could be partially related to depressed pVHL with a unique mechanism for its repression: the over-expressed microRNA, miR-92-1 in CLL-B cells.

Abstract Abstract 1618 Introduction: Primary breast lymphoma is a rare type of non-Hodgkin lymphoma (NHL), representing about 1% of breast tumors and 2% of extranodal NHL. Diffuse large B-cell lymphoma (DLBCL) is the most common primary subtype presenting in the breast. Due to the low incidence of primary breast DLBCL, outcome data is limited. The aim of this study was to retrospectively assess the natural history of primary breast DLBCL in the pre and post rituximab eras, with specific emphasis on the incidence of local, systemic and central nervous system (CNS) relapses. Methods: Data was retrospectively collected on patients with primary breast DLBCL from seven USA academic medical centers. Institutional review board approval was obtained at each participating site. Patients were identified through institutional databases and tumor registries at each site. Charts were reviewed to obtain demographic and clinical variables including treatment history and dates of relapse and death when applicable. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. All histologies apart from primary DLBCL were excluded. Overall survival (OS) was calculated from the diagnosis date to the date of death or last follow-up. Time to Progression (TTP) was calculated from diagnosis data until the date of pathological evidence of recurrence or death. Data were summarized using descriptive statistics, and survival was analyzed using the Kaplan-Meier method. Results: Between 1984 and 2012, 75 patients were identified who met the eligibility criteria. The median age was 62 years (range 17–87); 81% presented with a palpable mass; 12% had their disease detected incidentally by mammography; 4% presented with B-symptoms; 59% had right breast involvement; 67% had stage I and 33% had stage II disease. The stage-adjusted international prognostic index (IPI) score was 0 in 28% of patients, 1 in 41%, 2, in 25%, 3 in 4% and 4 in 1%. 91% of patients were treated with chemotherapy; 31% of these were treated in the pre-rituximab era and 69% received rituximab. Radiation therapy (RT) was utilized in 68% of patients and was the only treatment modality in 8% of those receiving RT. 8% of patients received CNS prophylaxis with intrathecal chemotherapy. After a median follow-up of 4.5 years (range 0.6 – 20.6 years), the Kaplan-Meier estimated median TTP was 10.4 years (95% CI 6.2 – 14.6 years) and the median OS was 14.6 years (95% CI 6.5 – 22.6 years). The 5-year TTP and 5-year OS were 65% (95% CI 53–77%) and 75% (95% CI 64–86%) respectively. Among the patients who relapsed, 67% occurred within the first 2 years. A total of 7 relapses in the breast were observed, none in patients treated with combination of chemotherapy and RT. In univariate analysis, rituximab exposure was not associated with any difference in TTP or OS. The stage-adjusted IPI was associated with OS; the 5-year OS was 88% (95% CI 79–98%) in patients with a score of 0–1 versus 48% (95% CI 25–71%) in those with a score of 2–4 (log rank p < 0.001). The very limited-disease group with a stage-adjusted IPI of 0 had a 5-year OS of 94% (95% CI 83–100%) compared to all others who had a 5-year OS of 67% (95% CI 52–81%; log rank p = 0.001). There was no difference in TTP and OS in patients with solitary versus multiple breast masses or between patients with tumors less than versus more than 7cm. Patients receiving RT in addition to chemotherapy had a longer TTP than those who did not (log rank p = 0.03), but RT was not associated with an improved OS. Patients who relapsed and underwent stem cell transplant (SCT) had similar OS to those who never relapsed. Ten patients (13%) had CNS relapse (3 with leptomeningeal disease, 5 with brain parenchymal disease and 2 with both). All CNS relapses occurred within the first 2.8 years from the time of diagnosis. There was no difference in the rate of CNS relapse in the patients who received IT prophylaxis versus those who did not. Conclusions: In this multicenter study, the largest published to date, primary breast DLBCL appears to have a worse prognosis than early-stage DLBCL in nodal or other extranodal sites. RT was associated with improved TTP. Patients who relapsed were successfully salvaged with SCT, and had similar survival times to those who never relapsed. A high CNS relapse rate (∼1 in 8 patients, including parenchymal disease in 70%) was observed. The small numbers preclude definitive conclusions on the value of intrathecal prophylaxis or the utility of rituximab. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Secondary CNS involvement (SCNS) is a detrimental complication seen in ~5% of patients with diffuse large B-cell lymphoma (DLBCL) treated with modern immunochemotherapy. Data from older series report short survival following SCNS, typically <6 months. However, data in patients that develop SCNS following primary therapy that contains a rituximab-based-regimen as well as the impact of more intensified treatment for SCNS are limited. Aims: The aims of this study were to i) describe the natural history of SCNS in a large cohort of patients treated with immunochemotherapy, and ii) determine prognostic factors after SCNS. Patients and methods: We performed a retrospective study of patients diagnosed with SCNS during or after frontline immunochemotherapy (R-CHOP or equivalently effective regimens). SCNS was defined as new involvement of the CNS (parenchymal, leptomeningeal, and/or eye) in patients without known CNS involvement at the time of first pathologic diagnosis of DLBCL. Patients were identified from local databases and/or regional/national registries in Denmark, Canada (British Columbia), Australia, Israel, US (University of Iowa/Mayo Clinic SPORE), and England (Guy's and St. Thomas' Hospital, London). Clinico-pathologic and treatment characteristics at the time of SCNS were collected from medical records. Results: In total, 281 patients with SCNS diagnosed between 2001 and 2016 were included. Median age at SCNS was 64 (range 20-93) years and male:female ratio was 1.3. SCNS occurred as part of first relapse in 244 (87%) patients and 112 (40%) had documented concurrent systemic disease at the time of SCNS. The median time from initial DLBCL diagnosis to SCNS was 9 months, which was similar for patients treated with (N=76, 27%) or without upfront CNS prophylaxis (N=205, 73%) (10 vs 9 Mo; P=0.3). The median post-SCNS OS was 4 months (interquartile range 2-13) and the 2yr survival rate was 20% (95% CI 15-25) for the entire cohort. Associations between clinicopathologic features, management strategy, and post-SCNS survival are shown in Table 1, which excludes patients who did not receive any treatment against SCNS, patients treated with steroids alone, and a patient with unavailable treatment information (n=43, 15%). In multivariable analysis, performance status >1, concurrent leptomeningeal and parenchymal involvement, SCNS developing before completion of 1st line treatment, and combined systemic and CNS involvement by DLBCL were associated with inferior outcomes. Upfront CNS prophylaxis did not influence post-SCNS OS. High-dose methotrexate (HDMTX) and/or platinum based treatment regimens (i.e. ICE, DHAP, or GDP [+/- IT treatment and/or radiotherapy], N=163) for SCNS were associated with reduced risk of death (HR 0.45 [0.32-0.62, P<0.01]). The 2yr post-SCNS survival for patients treated with HDMTX and/or platinum-based regimens (N=163) was 29% (95% CI 22-37). For patients with isolated parenchymal SCNS, single modality treatment with radiotherapy resulted in 2-yr OS of 19% (95% CI 8-35). For the subgroup of 49 patients treated with HDMTX- and/or platinum-based regimens for isolated SCNS after 1st line DLBCL treatment and with performance status 0 or 1, the 2yr post-SCNS survival was 46% (95% CI 31-59). Overall, 9% of the patients received HDT with ASCT as part of salvage therapy at the time of SCNS. Amongst 36 SCNS patients without systemic involvement and in CR following intensive treatment (HDMTX and/or platinum-based treatments), 11 patients consolidated with HDT had similar outcomes to 25 patients treated without consolidating HDT (P=0.9, Fig 1) Conclusions: Outcomes for patients with SCNS remain poor in this large international cohort of patients from the immunochemotherapy era. Combined parenchymal and leptomeningeal disease, presence of systemic disease concurrent with SCNS, performance status >1, and SCNS developing during first line treatment were independently associated with inferior OS. However, a significant fraction of patients with isolated SCNS after first line DLBCL treatment and with good performance status may achieve long-term remissions after intensive regimens for SCNS. Disclosures El-Galaly: Roche: Consultancy, Other: travel funding. Cheah:Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Other: Speaker's Bureau. Kansara:Celgene: Honoraria. Connors:Bristol Myers Squib: Research Funding; NanoString Technologies: Research Funding; F Hoffmann-La Roche: Research Funding; Millennium Takeda: Research Funding; Seattle Genetics: Research Funding. 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. Opat:Roche: Consultancy, Honoraria, Other: Provision of subsidised drugs, Research Funding. Seymour:Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Villa:Celgene: Honoraria; Lundbeck: Honoraria; Roche: Honoraria, Research Funding.

Abstract Abstract 47 Background In adults with newly diagnosed, poor-risk AML we previously demonstrated that induction therapy with Flavopiridol in combination with Ara-C and Mitoxantrone (FLAM,) in a timed-sequential manner, yields complete remission (CR) rates of 67% and median disease-free survival (DFS) of 13.6 months. These data suggest that FLAM might improve outcomes relative to standard “7+3” in newly diagnosed AML with poor-risk features. Thus, we are conducting a phase II randomized trial comparing the CR rates with FLAM vs. 7+3 induction for all newly diagnosed adult patients with AML with intermediate and poor-risk features. We also previously identified a population of CD34+CD38− cells with intermediate aldehyde dehydrogenase (ALDH) activity that appears to represent a leukemic stem cell (LSC) population. We are examining the effects of FLAM vs. 7+3 in eradicating this LSC population and determining if persistence of LSC's predicts for relapse. Objectives The primary objective is to compare the rate of CR after 1 cycle of FLAM vs. 1 cycle of 7+3. The secondary objectives are to compare toxicities, survival rates, and presence or absence of minimal residual disease (MRD) after both induction regimens. Methods All newly diagnosed adult patients aged 18–70 without favorable risk features were randomized in a 2:1 fashion between FLAM and 7+3 at 90 mg/m2 of Daunorubicin. To achieve balanced randomization, patients were stratified by age, secondary AML and leukocyte count. CD34+ cell subsets were analyzed by flow cytometry for CD38 expression and ALDH activity by Aldefluor. The trial is ongoing. Results To date, 62 patients are evaluable for the primary end point. Demographics and results are depicted in table 1. Patient characteristics were similar in both arms, although there were more patients with poor risk features in the FLAM arm than 7+3. Overall grade > 3 toxicity was similar between both arms. However, there were 3 cases of grade > 3 tumor lysis syndrome (TLS) with FLAM, with 1 death, vs. 0 with 7+3. There were also 3 deaths with FLAM before day 60 vs. 0 with 7+3. CR rate with FLAM was 68% (28/41), with 1 cycle of 7+3 was 48% (10/21) (p = 0.17), and with 2 cycles (7+3 + 5+2) was 52% (11/21). CR rates based on specific risk factors are depicted in table 2. There was a trend toward improved CR rates in patients with adverse genetics with FLAM (p = 0.17). Putative AML LSC's were distinguished from normal hematopoietic stem cells based on ALDH activity. The persistence of putative LSC's in patients after therapy was highly predictive of subsequent clinical relapse. Conclusions Based on the current CR rate of 68%, FLAM holds promise as a therapeutic option for patients with newly diagnosed AML with intermediate and poor risk features. In this preliminary analysis, there is a suggestion that FLAM leads to higher CR rates in patients with adverse genetics than 7+3. Additionally, the detection of MRD consisting of a residual putative LSC population strongly portended subsequent relapse, even in patients without evidence of leukemia. Disclosures: Off Label Use: Flavopiridol (Alvocidib) is an anti-leukemia agent.

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib safety in patients (pts) with UC was evaluated in an 8-week induction Phase (P) 2 study (NCT00787202), 1 2 8-week induction P3 studies (OCTAVE Induction 1 & 2; NCT01465763 & NCT01458951), 2 a 52-week maintenance P3 study (NCT01458574), and an ongoing, open-label, long-term extension (OLE) study (OCTAVE Open, NCT01470612). 3 We present updated infections data (Sep 2018) from the tofacitinib UC clinical program. 4,5 METHODS: Pts receiving placebo, tofacitinib 5 or 10 mg twice daily (BID) were analyzed as Induction (P2 & P3, n = 1220), Maintenance (P3, N = 592), and Overall (pts in P2, P3 & OLE receiving tofacitinib 5 or 10 mg BID, N = 1157 [Sep 2018]) Cohorts. Proportions and incidence rates (IRs; pts with events per 100 pt-years [PY] of exposure) were evaluated for infections of special interest (incl. serious infections [SIs], opportunistic infections [OIs; independently adjudicated], and herpes zoster [HZ]). RESULTS: A total of 1157 pts received ≥1 dose of tofacitinib 5 or 10 mg BID (83% predominantly 10 mg BID [avg. daily dose ≥15 mg]), with 2403.6 PY of exposure (median 623 days, up to 6.1 years of treatment). The Table 1 shows infection IRs by Cohort. In the Overall Cohort, nasopharyngitis was the most frequent infection. For SIs, the Overall Cohort “Tofacitinib All” IR (1.75 [95% CI 1.27, 2.36]) was similar to the Maintenance Cohort IRs for tofacitinib 5 and 10 mg BID. No SIs resulted in death. OIs were infrequent (28 pts) and most were HZ (24 pts; IR 0.99 [95% CI 0.63, 1.47]), mostly cutaneous. Not all HZ events were OIs; 83 pts overall had HZ events (IR 3.57 [95% CI 2.84, 4.43]; 6 serious). CONCLUSION: In induction, SIs and OIs occurred with tofacitinib but not with placebo. Overall, SIs were generally infrequent and Overall Cohort IRs did not suggest increased risk with longer tofacitinib treatment vs the Maintenance Cohort. Non-HZ OIs were rare. SI incidence was similar in the UC and rheumatoid arthritis programs (incl. increased HZ risk) 6 and to other UC therapies incl. biologics. 7

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib safety and efficacy were demonstrated in patients (pts) with moderate to severe UC in 3 Phase 3 studies, 1 and are being evaluated in an ongoing, open-label, long-term extension (OLE) study. 2 METHODS: We present updated safety and efficacy data from the OCTAVE Open OLE study (NCT01470612; Sep 2018; database not locked) 2 in completers/treatment failures in OCTAVE Sustain (NCT01458574) or non-responders in OCTAVE Induction 1/2 (NCT01465763/NCT01458951). Week (Wk) 8 data (OCTAVE Induction 1/2) and Wk 52 (completers) or early-termination data (OCTAVE Sustain) determined eligibility. Pts in remission (total Mayo score ≤2, no individual subscore >1, rectal bleeding subscore 0) at Wk 52 of OCTAVE Sustain (central read) received tofacitinib 5 mg twice daily (BID) in the OLE study; all others received 10 mg BID. At Month 2, all pts had endoscopy, and induction non-responders with no clinical response were withdrawn. Incidence rates (IRs; unique pts with events per 100 pt-years [PY]) for adverse events (AEs) of special interest were calculated. Efficacy endpoints were derived from Mayo score (local read). RESULTS: Of 944 pts receiving ≥1 tofacitinib dose (for up to 5.5 years), 175 (18.5%) and 769 (81.5%) received 5 and 10 mg BID, respectively (454 and 1550 PY, respectively). 337 (35.7%) pts discontinued due to insufficient clinical response and 78 (8.3%) due to AEs excl. worsening UC. The most frequent AE class was infections and infestations (52.1%). The most frequent AEs were nasopharyngitis (20.3%) and worsening UC (19.5%). IRs (95% CI) for “Tofacitinib All” were: serious infections 1.61 (1.10, 2.27); herpes zoster (all) 3.35 (2.58, 4.27); major adverse cardiovascular events 0.15 (0.03, 0.44); malignancies excl. non-melanoma skin cancer (NMSC) 0.85 (0.50, 1.36); and NMSC 0.81 (0.46, 1.32), with no clustering of malignancy type. Table 1 shows AEs and IRs by dose. No new safety risks were identified. Table 2 shows efficacy data at Month 36. CONCLUSION: In pts with UC in the OLE study, no new safety risks emerged at 5.5 years vs earlier OLE analyses 2 or with tofacitinib in rheumatoid arthritis. Efficacy data continue to support long-term efficacy of tofacitinib 5 or 10 mg BID up to 36 months beyond OCTAVE Sustain.