Abstract: The c-kit (CD117) receptor is expressed on 〉 10% blasts in 64% of de novo AMLs and mediates proliferation and anti-apoptotic effects. High c-kit levels [defined as mean fluorescent intensity (MFI) 〉 20] correlate with a shorter time to relapse and decreased overall survival (OS). Imatinib mesylate (IM), a c-kit inhibitor, has activity against relapsed/ refractory AML. The primary objective of this study was to determine whether adding maintenance IM for 1 yr after completion of standard induction (IT) and post-remission therapy (PRT) in pts with newly diagnosed c-kit + AML improves progression-free survival (PFS) compared to historical controls. We previously presented our toxicity and correlative data at ASH 2012 (Abstract 3597). Here, we present our long term follow-up results. Methods: Pts were treated at Cleveland Clinic, Duke, Roswell Park, and University Hospitals of Cleveland from 2008 to 2012. IM was supplied by Novartis. Eligibility criteria: pts age ≥ 18 yrs, AML in first complete remission (CR1), ≥ 20% c-kit+ blasts at diagnosis (dx), ECOG performance status 0-2. Cytogenetics (CG) were classified per CALGB 8461. Pts must have received IT (7+3 [continuous infusion cytarabine and an anthracycline] or ADE [cytarabine, daunorubicin, etoposide] ) and PRT (≥ 1 course for pts ≥ 60 yrs; ≥ 2 courses for pts 〈 60 yrs). CR was confirmed by bone marrow analysis prior to study enrollment. MDR expression was analyzed by IHC on diagnostic samples (n=19); AF1q gene expression was analyzed by RT-PCR on RNA from available diagnostic pt samples (n=9). C-kit MFI was calculated as the mean channel number (MCN) of the blasts/ MCN auto fluorescence using a CD45/orthogonal light scatter gate to isolate blasts and lymphocytes. All pts received IM 600 mg/day for 12 months (mos) unless they experienced toxicity or disease progression. Dose modifications were made for Grade 2-4 non-hematologic toxicity and Grades 3-4 neutropenia and thrombocytopenia. PFS was measured from the CR date to the time of relapse or death. Primary endpoints: Based on historical data from the Cleveland Clinic and SWOG, the median PFS for all AML pts undergoing IT 〈 60 yrs of age is 13 mos and for pts ≥ 60 yrs of age is 8 mos. The goal of this study was to see a 30% improvement in PFS at these time points in the respective age groups (i.e. 65% PFS at 13 mos for pts 〈 60 yrs; 65% PFS at 8 mos for pts ≥ 60 yrs). Results: Of 32 pts enrolled, the median age was 54 yrs (range 19-81), median WBC at dx 22.13 K/ uL (1.55-98.44), median peripheral blood blasts at dx 23.6% (range 0-85), and 44% were male. CG risk included: 16% (5) good, 66% (21) intermediate, 16% (5) poor, 3% (1) miscellaneous. Of the pts with normal CG, 10 were NPM1+, FLT3 ITD negative; and 1 pt was FLT3 ITD+. The median c-kit+ blast % was 79.9, and median c-kit MFI 39.8 (range 6.5-120.1). Median AF1q expression was 9.59 (range 1.83-161.85) ( 〉 9 is considered high and is associated with a poor prognosis; high AF1q is also associated with high c-kit expression). Eight-four percent of pts had moderate or high levels of drug resistance factors (GST1, MDR1, LRP1, and/or MRP1); almost half (47%) had high expression. There was no correlation between MDR and c-kit MFI. Pts received IM for a median of 4.0 mos (range 0.1-12.2) and the median daily dose was 600 mg. Twelve pts (38%) were dose reduced to 400 mg. Forty-five percent of pts experienced Grade 3 reactions possibly related to treatment, with the majority (31%) being myelosuppression. With a median follow-up time of 56.3 mos, the estimated median OS was 51.3 mos and estimated median relapse-free survival (RFS) 18.9 mos. The estimated PFS at 13 mos for pts 〈 60 yrs of age was 71 ± 10% (p=0.017, compared to the null hypothesis); and the estimated PFS at 8 mos for pts ≥ 60 yrs of age was 64 ± 15% (p=0.166, compared to the null hypothesis). Predictors of worse RFS included: age, WBC at dx, % peripheral blasts at dx, CG risk, and MDR expression. C-kit MFI and Af1q were not associated with RFS or OS. Conclusions: Use of IM maintenance therapy appeared to be associated with improved PFS compared to historical controls in pts 〈 60 yrs of age. In addition to a high c-kit MFI, these pts had other adverse characteristics (moderate to high levels of MDR. high AF1q). Though previous studies have demonstrated that c-kit MFI 〉 20.3 was an independent adverse prognostic factor for RFS and OS (median RFS 10.7 months) in AML, use of IM maintenance therapy in this study appeared to mitigate this, supporting further investigation. Disclosures Off Label Use: imatinib in the treatment of AML. Rao:Boehringer-Ingelheim: Other: Advisory Board; amgen: Other: ad board; novartis: Other: ad board. Rizzieri:Teva: Other: ad board, Speakers Bureau; Celgene: Other: ad board, Speakers Bureau. Wang:Immunogen: Research Funding. Griffiths:Alexion Pharmaceuticals: Honoraria; Astex: Research Funding; Celgene: Honoraria. Sekeres:TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.

Abstract: MEC (mitoxantrone, etoposide, cytarabine) is a standard regimen for relapsed/ refractory (R/R) acute myeloid leukemia (AML), but outcomes remain poor. The overexpression of proteasomes and constitutive activation of NF-KB in AML cells suggest that proteasome inhibitors (PI) such as bortezomib (Bz) may be effective anti-leukemia therapy. PI or a decoy NF-KB oligonucleotide increase chemosensitivity to both anthracyclines and cytarabine. To test the hypothesis that PI may improve the efficacy of MEC, we conducted a phase 1 trial of Bz in combination with MEC. Here, we present final results of this trial: response rate, toxicity, and correlation of outcomes with mutation analysis. As CD74 expression may identify a subset NF-KB-dependent AML with predicted increased sensitivity to PI (Clin Can Res 2008; 14: 1446-54), we also explored this correlation. Methods: All pts were treated at the Cleveland Clinic from Aug 2010-Mar 2014. This protocol was approved by the institution’s review board. Eligibility included: age 18-70 yrs, R/R AML, cardiac ejection fraction ≥ 45%. CD74 was assessed by flow cytometry using CD45 PE (BD Biosciences San Jose, CA) and CD74-Alexa 488 (AbD Serotec Raleigh, NC). A myeloid panel mutational analysis was performed on extracted DNA in pts with banked samples (n=26). All pts received 1 cycle of MEC: mitoxantrone (6 mg/m2/d), etoposide (80 mg/ m2), and cytarabine (1000 mg/ m2) Days 1-6. Bz was administered IV on Days 1, 4, 8, and 11. Dose was escalated using a standard 3 x 3 design. Dose levels (DL) were: -1 (0.40 mg/ m2), 1 (0.70 mg/ m2), 2 (1.0 mg/ m2), and 3 (1.3 mg/m2). Response was defined by IWG criteria (Cheson, 2006). The maximum tolerated dose (MTD) of Bz with MEC was 1.0 mg/m2 (Advani et al, ASH 2012, Abstract 3595). Results: Of 35 pts enrolled, the median age was 55 yrs (range 33-69), 13 (38%) were male, and median baseline WBC was 4.0 K/ µL (range 0.82-84.7). The median time from initial diagnosis of AML to enrollment was 8.4 months (range 1.1-88.2) and 6 pts (17%) had an antecedent hematologic disorder. Salvage status (S) at enrollment: S1 (24 pts, 69%), S2 (7 pts, 20%), S4 (4 pts, 11%). Nine pts (26%) were refractory to all prior therapies, and 3 pts (9%) had received prior allogeneic hematopoietic cell transplant (AHCT). Adverse cytogenetics per CALGB/ Alliance 8461 criteria occurred in 19% of pts at study entry and 15 of 26 pts (58%) had poor-risk molecular mutations (RUNX1, ASXL1, TET2, p53, IDH1, MECOM, FLT3 ITD). Ten pts were enrolled on DL1, 13 pts on DL2, 11 pts on DL3, and 1 pt died prior to treatment. Overall, 3 pts (9%) died during induction. In addition to febrile neutropenia and Gr 4 hematologic toxicity, the most commonly reported adverse events (AEs) were metabolic, constitutional, gastrointestinal (GI), and dermatologic, with the majority of these being Gr 1 or 2. GI toxicity was the only reported AE attributable to Bz: 12 pts had constipation or ileus (10: Gr 1 or 2; 2: Gr 3 or 4). Seventeen of the 33 evaluable pts (52%) have achieved a complete remission (CR) or complete remission with incomplete count recovery (CRi); with 1 pt inevaluable due to donor lymphocyte infusion. The estimated median overall survival was 7.2 months; median duration of response was 10.3 months. DL did not correlate with response. Eleven pts (32%) went on to receive AHCT. Among pts with poor-risk molecular mutations, 64% achieved CR/ CRi. Inhibition of NF-KB signaling in leukemia cells with mutated RUNX1 efficiently blocks growth and development of leukemia (Blood 2011; 118: 6626-37). Of the 5 pts with RUNX1 mutations, 3 (60%) achieved CR/ CRi, suggesting that Bz may have promising clinical benefit in this difficult subset of pts. Among the 17 pts with CD74 expression testing who were evaluable for response, the mean CD74 expression trended higher in non-responding pts (32.6%) than in responders (11.1%) (p=0.14). Conclusions: The combination of MEC/Bz was well-tolerated and resulted in high response rates, even within a molecularly-defined poor risk population of pts with R/R AML. Our data do not confirm the expectation that higher CD74 expression would correlate with response in this R/ R AML cohort, but larger pt numbers are needed. These results, especially in pts with poor-risk mutations, support development of a randomized study to address the benefit of adding Bz to MEC in the treatment of R/R AML. Disclosures Advani: Takeda: Research Funding. Carew:Takeda: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees.

Abstract: We have studied an acute promyelocytic leukemia (APL) patient with a variant t(5;17)(q32;q12). This translocation fuses the gene for the nucleolar phosphoprotein nucleophosmin (NPM) to the retinoic acid receptor alpha (RARA). Two alternatively spliced transcripts are expressed, which differ in 129 bases immediately upstream of the RARA sequence. The NPM sequences contained in the shorter NPM-RAR cDNA are identical to the NPM sequences contained in the NPM-ALK fusion gene expressed in t(2;5) lymphomas. The RARA sequences are the same as the RARA sequences found in the PML-RAR and PLZF-RAR fusion seen in t(15;17) and t(11;17) APL, respectively. Both NPM-RAR transcripts fuse NPM and RARA sequence in the same reading frame, to generate translation products of 57 kD and 62 kD. Both NPM-RAR proteins are expressed in the patient's leukemic cells, along with wild-type RARA derived from the uninvolved allele. In transcriptional assays using a retinoic acid response element reporter construct, both NPM-RAR fusion proteins act as retinoic acid-dependent transcriptional activators. This case defines a third class of APL rearrangements, all of which generate fusion proteins of RARA.

Abstract: Background: Most pulmonary embolism (PE) research has focused on outcomes such as mortality and PE recurrence. Patient-centered outcomes such as persistent dyspnea, impaired quality of life (QOL) and reduced walking capacity after PE have been largely unstudied. To address this knowledge gap, we performed the ELOPE (Evaluation of Longterm Outcomes after PE) study, a prospective, observational, multicenter cohort study of long-term outcomes after acute PE (www.clinicaltrials.gov NCT01174628). Objectives: To describe and quantify dyspnea, quality of life and walking capacity during the 1 year following PE diagnosis. Methods: Patients ³ 18 years old with a 1st episode of acute PE diagnosed within the previous 10 days screened at 5 Canadian recruiting centers were potentially eligible to participate. Exclusion criteria were subsegmental-only PE, preexisting severe cardiopulmonary comorbidity, previous proximal DVT, contraindication to CT pulmonary angiography, life expectancy & lt;1 year, unable to read questionnaire in English and French or to attend follow-up visits, and unable or unwilling to consent. At baseline, 1, 3, 6 and 12 months after PE, we measured dyspnea (UCSD Shortness of Breath Questionnaire [SOBQ]), generic QOL (SF-36), PE-specific QOL (PEmbQoL), and walking capacity (6-minute walk test (6MWT)). Cardiopulmonary exercise testing (CPET) was performed at 1 year; the primary outcome of the study was maximal aerobic capacity defined by peak oxygen uptake (VO2) as a percent of predicted maximal VO2 (VO2max) on 1-year CPET, with & lt;80% predicted VO2max considered abnormal, as per American Thoracic Society guidelines. For this analysis, we summarized demographic and clinical characteristics of study subjects, and calculated mean (SD) dyspnea scores, QOL scores and 6MWT distance at each study visit during 1 year follow-up in the total population and according to 1-year CPET result. Results: 984 patients were screened for participation; of these, 150 were eligible and 100 (67%) consented to participate. Mean (SD) age was 50 (15) years, 57% were male, 80% were outpatients and 33% had concomitant DVT. PE was provoked in 21% and unprovoked in 79%; none were cancer-related. During 1 year follow-up, SOBQ scores improved by an average of 16.9 points compared with baseline, SF-36 PCS (physical component score) by 9.0 points, SF-36 MCS (mental component score) by 5.6 points, PEmbQoL (e.g. intensity of complaints dimension) by 33.4 points, and 6MWT by 43 meters. Improvement tended to be more marked during the first 3 months after PE and tapered off thereafter. For all measures, degree of improvement was significantly reduced and 1 year scores were significantly worse among the 46.5% (40/86) of patients with & lt;80% predicted VO2max on 1-year CPET (e.g., SF-36 PCS: see Figure). Conclusions: On average, dyspnea, QOL and walking capacity improve during the year after PE, most notably during the first 3 months after PE diagnosis. However, those patients with abnormal VO2max at 1 year had less improvement over time and worse 1 year scores for all measures, compared to those with normal VO2max at 1 year. Further analyses will focus on identifying clinical, biomarker and imaging-based determinants of dyspnea, poor QOL and reduced walking capacity at 1 year after PE. Funding: Canadian Institutes of Health Research (MOP-93627) Figure 1. Figure 1. Disclosures Wells: BMS/Pfizer: Research Funding; Bayer: Honoraria.

Abstract: Abstract 118 Background: Myelodysplastic syndromes (MDS) are characterized by excess elaboration of myelosuppressive cytokines contributing to increased apoptotic loss of hematopoietic precursors, the hallmark of lower-risk MDS. p38a MAP kinase (MAPK) is a key downstream convergence point and effector of hematopoietic inhibitory cytokines and death receptors in hematopoietic precursors and stromal elements. The actions of Tie2 complement this regulatory axis by promoting cytokine production and altering cellular quiescence. ARRY-614 is a small-molecule inhibitor of both p38 MAPK and Tie2 that may improve hematopoiesis in lower-risk MDS patients (pts). Methods: This Phase 1 study was designed to determine the maximum tolerated dose (MTD) of ARRY-614 and evaluate safety, pharmacokinetics (PK), preliminary efficacy (International Working Group [IWG] 2006) and pharmacodynamic (PD) effects. Eligible pts had International Prognostic Scoring System (IPSS) risk group Low or Int-1 MDS, and had either received prior therapy or were not eligible or refused treatment. ARRY-614 was administered in 28-day cycles. A standard 3+3 dose escalation design was used and an expansion cohort at the MTD in red blood cell (RBC) transfusion-dependent (TD) pts was evaluated. Results: Forty-five pts with Low (n = 11) or Int-1 (n = 34) risk MDS were enrolled with a median age of 72 years (range 47–84). All but one pt had disease refractory to and/or relapsed from prior therapy with a median of 3 prior regimens (range 0–10); 82% received hypomethylating agents (HMAs), 49% received erythropoietin (EPO)-stimulating agents and 40% received lenalidomide. As of July 2011, 7 pts remain on study. ARRY-614 was administered in a fasting state at doses of 400–1200 mg once daily (QD) and 200–300 mg twice daily (BID), and under fed conditions at 400 mg QD. Dose-limiting toxicities (DLTs) reported at QD doses included single events of Grade (Gr) 3 diarrhea (400 mg QD fasting), Gr 3 macular skin rash (1200 mg QD) and Gr 3 QTc prolongation (400 mg QD fed). Due to the high number of capsules required per dose, the maximum administered QD dose was 1200 mg; the MTD was not reached. The 300 mg BID dose was dose limiting due to 5/7 pts with DLTs of Gr 3 rash (n = 2), Gr 3 asthenia and jitteriness (n = 1), Gr 3 allergic reaction to study medicine (n = 1), and Gr 3 muscle weakness with Gr 3 elevated AST/ALT (n = 1); therefore BID dosing was discontinued. The most common (≥ 10% of pts) treatment-related adverse events (AEs) across all dose cohorts included rash (29%), diarrhea (22%), dry skin (13%) and QTc prolongation (11%). The median duration of treatment was 16 wks (range 1–76). ARRY-614 exposure was dose proportional, but high inter-pt variability was observed. The median Tmax was 3 hours and the t1/2was ∼ 8 hours; both parameters were consistent across all doses evaluated. Plasma EPO was elevated at baseline in pts with erythroid response (471 ± 285 U/L, n = 4) and decreased by 92 ± 4% overall. In non-responding pts, baseline EPO was 984 ± 315 U/L (n = 41) and 68 ± 22% maximal decrease was observed. In 68% (13/19) of pts that were above 500 U/L at baseline, EPO was suppressed below 500 U/L during time on study supporting a drug effect in these pts as well. Eight of 43 evaluable pts experienced hematological improvement (HI) per IWG 2006 criteria. HI responses (duration 8 to 80 wks) occurred in all lineages (4 HI-erythroid, 5 HI-neutrophil and 4 HI-platelet) including 5 bi-lineage responses and some pts had a reduction in platelet transfusions. All IWG 2006 responders failed prior treatment with ≥ 1 HMA. At doses ≥ 900 mg QD, 6 of 18 evaluable pts achieved HI in one or more lineage. Conclusions: ARRY-614 has shown encouraging preliminary multi-lineage hematologic activity as a single agent in a heavily pretreated pt population. At the QD doses studied to date, it has demonstrated an acceptable safety profile. Correlative studies of preliminary drug activity with PD analyses from bone marrow samples are ongoing (final results to be presented). Given the variable but dose-proportional drug exposure, a new oral formulation with improved PK profile will be evaluated in MDS pts starting 4Q2011. Because ARRY-614 has promising preliminary activity, additional investigation in this lower-risk MDS population who have received prior treatment with HMAs is warranted. In addition, the treatment-related reductions in plasma EPO suggest that combination treatment with recombinant EPO may optimize erythroid response. Disclosures: List: Array BioPharma: Consultancy. Winski:Array BioPharma: Employment. Bell:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Maloney:Array BioPharma: Employment. Ptaszynski:Array BioPharma Inc.: Consultancy. Kantarjian:Array BioPharma: Research Funding.

Abstract: Introduction Introduction of next-generation sequencing has defined the somatic mutational landscape in MDS. Comprehensive high-throughput structural variant profiling (SVP) is as important as mutation profiling in characterizing MDS clonal architecture since these large genomic aberrations have already shown to be critical for diagnosis and risk-stratification of MDS. A subset (MECOM, KMT2A rearrangements) are therapeutic targets in clinical trials. At this time, technical advances in SVP for copy number alterations (CNAs) and fusions have not been congruent with mutation profiling due to the inability of short-read (150bp) NGS to detect SVs. Currently available long-read (10-20Kbp) and whole genome sequencing cannot detect all SVs due to the presence of repeat sequences. Hence, conventional karyotyping (CK) remains the gold standard. Optical genome mapping (OGM) is a novel single-platform technique that measures ultra-long-range sequence patterns ( & gt;300Kbp), thereby unaffected by repeat sequences, enabling unbiased evaluation of all types of SVs at a high resolution. Here, we performed comprehensive SVP and mutation profiling in a large well-characterized cohort of MDS. Methods We selected samples with available fresh/frozen BM cells from consecutive treatment-naïve MDS pts who also underwent standard-of-care tests (CK, FISH, targeted 81-gene NGS for mutations). For OGM, ultra-high-molecular-weight-DNA was extracted, followed by labeling, linearization and imaging of DNA (Saphyr, Bionano) [median coverage: & gt;300X]. The results were analyzed using de novo ( & gt;500 bp), rare variant ( & gt;5000 bp) and copy number ( & gt;500,000 bp) pipelines. The data was compared against 200 healthy controls to exclude common germline SVs. Clinical significance of the SVs was determined based on the location/overlap with the coding region of myeloid malignancy associated genes. The detection sensitivity was 10%. Results There were 76 treatment naïve MDS patients. Baseline characteristics, comprehensive cytogenetic scoring system (CCSS) and R-IPPS risk categories and somatic mutations are in Fig 1. OGM identified all clonal abnormalities detected by CK [CNAs, inversions, inter/intra-chromosomal translocations, dicentric, complex derivative chromosomes]. Precise mapping of SVs by OGM at gene-level allowed determining the status of clinically informative biomarkers such as TET2, MECOM, TP53 and KMT2A, without the need for confirmatory assays. Detailed gene-level characterization of different SVs included KMT2A-ELL [t(11;19)] in MDS with WT1 mut, t(9;11) with SYTL2 fusion (and not KMT2A), der(1;7) leading to del(7q) in MDS with GATA2 mut/IDH2 mutand t(1;3)(p36;q21) rearrangements with potential PRDM16 disruption in SF3B1 mut/RUNX1 mutMDS, among others. Using OGM, we mapped the sequence patterns in both samples with IM with high level of confidence. Additionally, OGM identified 23 cryptic, clinically significant SVs in 14 (18%) of 76 pts. These included deletions of TET2, KMT2A, and del(5q), KMT2A amplification in MDS with FLT3-ITD/DNMT3A mut/RAS mut, NUP98-PRRX2, MECOM rearrangement in TET mut mutated NK-MDS. In addition, there were SVs of uncertain significance: duplications of chr1 (PDE41P), deletions of chr21 (involving RUNX1), chr2 (DNMT3A, ASXL2), chr12 (ETV6) and chr22 (EP300) and der(16)t(12;16)(q21.1;q12.1). These cryptic SVs were noted across all R-IPSS risk categories (highest yield in very-low and low R-IPSS) and across all cytogenetic risk-groups (very-good to very-poor). In complex karyotype setting, OGM could resolve the markers and additional genetic material, and in most cases, showed a much higher the degree of complexity within the genome than was apparent by CK. Four pts showed SV patterns typical of chromothripsis/chromoplexy. The median number of mutations per pt was 1 (0-6). When compared to mutation subsets, cryptic SVs were only identified in pts with ≤3 mutations. Majority represented either MDS with TP53 mut (6, 29%) or SF3B1 mut/TET mut (deletions of TET2, KMT2A, NOTCH1 and EP300 genes). Conclusions Unbiased, high-throughput whole genome SVP revealed cryptic, clinically significant SVs in ~18% of MDS pts. OGM is a single-platform cytogenomic tool that can facilitate SVP at a gene-level resolution. This study provides strong support for further validation in expanded cohorts to guide clinical implementation and integration of SVP for routine work-up. Figure 1 Figure 1. Disclosures Wei: Daiichi Sanko: Research Funding. Kantarjian: Ipsen Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria; Astra Zeneca: Honoraria; AbbVie: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; Ascentage: Research Funding; Aptitude Health: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; BMS: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria.

Abstract: Abstract 3597 The c-kit (CD117) receptor is expressed on 〉 10% blasts in 64% of de novo AMLs and mediates proliferation and anti-apoptotic effects. High c-kit levels correlate with a shorter time to relapse and decreased overall survival (OS). Imatinib mesylate (IM), a c-kit inhibitor, has activity against relapsed/refractory AML. The primary objective of this study was to determine whether adding maintenance IM for 1 yr after completion of standard induction (IT) and post-remission therapy (PRT) in patients (pts) with newly diagnosed c-kit+ AML improves relapse-free survival (RFS) compared to historical controls. Secondary objectives included: (1) assessing the feasibility of this approach; (2) evaluating outcomes based on c-kit expression (c-kit mean fluorescent intensity [MFI]); (3) determining whether c-kit expression correlates with AF1q gene and/or multi-drug resistance (MDR) gene expression. Methods: Pts were treated at Cleveland Clinic, Duke, Roswell Park, and University Hospitals of Cleveland from 2008 to 2012. IM was supplied by Novartis. Eligibility criteria included: pts age ≥ 18 yrs, AML in first complete remission (CR1), ≥ 20% c-kit+ blasts at diagnosis (dx), ECOG performance status 0–2. Cytogenetics (CG) were classified by CALGB 8461. Pts must have received IT (7+3 [continuous infusion cytarabine (C) and an anthracycline] or ADE [C, daunorubicin, etoposide] ) and PRT (≥ 1 course for pts 〉 60 yrs; ≥ 2 courses for pts 〈 60 yrs). CR status was confirmed by bone marrow analysis prior to study enrollment. MDR expression was analyzed by immunohistochemistry on diagnostic samples (n=19); AF1q gene expression was analyzed by RT-PCR on RNA from available diagnostic pt samples (n=9) as previously described (Tse et al. Blood 2004; 104: 3058–63). C-kit MFI was calculated as the mean channel number (MCN) of the blasts/MCN autofluorescence using a CD45/orthogonal light scatter gate to isolate blasts. All pts received IM 600 mg/day for 12 months (mos) unless they experienced toxicity or disease progression. Dose modifications were made for Grades 2–4 non-hematologic toxicity and Grades 3–4 neutropenia and thrombocytopenia. Pts remaining off IM for 〉 4 wks were removed from treatment. Cumulative dose intensity was defined as the proportion of the total optimum dose administered over time. Results: Thirty-three pts were enrolled, with 32 pts having complete data. The median age was 54 yrs (range 19–81), median WBC at dx 22.13 K/μL (1.55–98.44), median peripheral blood blasts at dx 23.6% (range 0–85), and 44% were male. CG risk included: 47% (15) good, 31% (10) intermediate, and 22% (7) poor. The median c-kit % was 79.9, and median c-kit MFI 39.8 (range 6.5–120.1). Median AF1q expression was 9.59 (range 1.83–161.8.5). Eighty-four percent of pts had moderate or high levels of MDR expression (GSTP1, MDR1, LRP1, and/or MRP1); almost half (47%) had high expression. The majority of pts (74%, n=20) received PRT with high dose C (3 g/m2/dose × 6 doses/cycle). Pts received IM for a median of 4.0 mos (range 0.1–12.2), and the median daily dose was 600 mg. Twelve pts (38%) were dose reduced to 400 mg. Forty-five percent (13/29) of pts experienced grade 3 reactions possibly related to treatment, with the majority (31%) being myelosuppression. The most commonly reported adverse events were Grade 1/2 nausea and vomiting (72%), edema (59%), and fatigue (41%). Twelve pts (38%) discontinued treatment for adverse events. The median RFS survival is 18.8 mos, with a median follow-up of 19.1 mos (range 6.4–37.2). Estimated 2-yr OS is 62% ± 10%. Predictors of RFS included: age, WBC at dx, % peripheral blasts at dx, and CG risk. Dose intensity of IM did not correlate with outcome. AF1q and MDR expression did not correlate with c-kit MFI; although the number of pts with AF1q data was small. Of note, neither c-kit MFI nor AF1q expression were prognostic in this subset of pts treated with IM. With the exception of LRP1 expression (p=0.03), there was no correlation of MDR expression with RFS. Conclusions: Previous studies have demonstrated that c-kit MFI 〉 20.3 is an independent adverse prognostic factor for RFS and OS (median RFS 10.7 months). Considering the high c-kit MFI of pts in this study, the outcomes using IM maintenance are encouraging, and suggest that further study of this approach is warranted. Given the toxicities observed, reducing the dose of IM to 400 mg in the maintenance setting may be better tolerated. Disclosures: Advani: Novartis: Research Funding. Rizzieri:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kalaycio:Novartis: Research Funding, Speakers Bureau. Maciejewski:Novartis: Research Funding.

Abstract: Proteasome inhibitors (PIs) capitalize on the constitutive activation of NF-KB in AML cells and increase chemosensitivity to anthracyclines and cytarabine. We combined the second generation PI, ixazomib, with the standard AML salvage regimen of MEC (mitoxantrone, etoposide, cytarabine). The primary objectives of this study were to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and phase 2 dose of ixazomib in combination with MEC in relapsed/ refractory (R/R) AML. Secondary objectives included evaluating the efficacy of this combination and correlating response to the gene expression profile and CD74 expression, which may identify a subset of leukemias in which NF-KB is operative with increased sensitivity to PI (Attar et al. CCR 2008; 14: 1446-54). Methods: Patients (pts) were treated at Cleveland Clinic and University Hospitals of Cleveland from Oct 2014 to present. An IND was approved by the FDA, and the protocol was approved by each institutional review board. Eligibility: age 18-70 yrs, R/R AML, and cardiac ejection fraction ≥ 45%. The fraction of blasts positive for CD74 was assessed by flow cytometry. Samples were stored for gene expression profiling pre- and post-treatment (at the time of response assessment). Pts received MEC: mitoxantrone (8 mg/ m2), etoposide (80 mg/m2), and cytarabine (1000 mg/m2) intravenous (IV) Days 1-6. Ixazomib, provided by Takeda, was given orally on Days 1, 4, 8, and 11 and was dose escalated using a standard 3x3 design. Dose levels (DLs): 1 (1.0 mg), 2 (2.0 mg), 3 (3.0 mg), 4 (3.7 mg). An additional 18 pts were to be treated at the MTD. One cycle of treatment was administered. Response was assessed by bone marrow aspirate/ biopsy by Day 45 and complete remission (CR) was defined by IWG criteria (Cheson 2006). Toxicities were graded according to NCI CTCAE v 4.03. Toxicities secondary to neutropenia or sepsis were not considered DLTs. DLTs included: (1) ≥ Grade 4 non-hematologic toxicity (NHT) with the exception of nausea, vomiting/ alopecia and drug-related fevers; (2) any ≥ Grade 3 neurologic toxicity; (3) grade 4 platelet or neutrophil count 50 days beyond the start of chemotherapy and not related to leukemia; (4) any Grade 4 NHT 〉 grade 2 by 45 days beyond the start of chemotherapy. Grade 2, 3, and 4 hyperbilirubinemia were redefined as 1.5- 〈 10x upper limits of normal (ULN), 10-20 x ULN, and 〉 20 x ULN. Results: Of 23 pts enrolled, 22 are evaluable. The median age was 58 yrs (range 31-70), 12 (52%) were male and the median baseline WBC was 2.56 K/ uL (range 0.1-62.9). The median time from initial diagnosis to registration was 7.1 months (range 1.4-36.8) and 7 pts (30%) had a history of an antecedent hematologic disorder. Thirteen pts were in 1st relapse and 10 pts were refractory to their last therapy. One pt had received a prior allogeneic hematopoietic cell transplant (AHCT), 7 pts had FLT3 ITD mutations and 7/ 21 pts (33%) had adverse cytogenetics per CALGB 8461 criteria at the time of relapse. At DL1, 1 DLT occurred (grade 4 thrombocytopenia), so this DL was expanded to 6 pts. At DL2, 2 pts developed Grade 4 thrombocytopenia; therefore, the MTD of ixazomib was 1.0 mg. The most common grade 3-5 NHTs in the dose escalation phase were febrile neutropenia (100%), hypoalbuminemia (25%), hypokalemia (42%), hypotension (33%), and respiratory failure (33%). No adverse events in the dose escalation phase were attributed to ixazomib alone. The overall response rate was 55% [CR/ CR with incomplete count recovery (CRi)], and 9 pts proceeded to AHCT. Five of these 9 pts remain alive with a median follow-up of 12.8 months. Five pts had CD74 expression performed. Two pts had high levels of CD74 expression ( 〉 80%); and both achieved CRi. Myeloid mutation panel data was available in 14 pts. Previous data has demonstrated the number of mutations in DNTMT3A, TP53, ASXL1, and NRAS (0, 1, 〉 1) is associated with a worse response to salvage therapy (Advani et al, abstract 3825, ASH 2015). Seven pts had at least one of these mutations and 6 of the 7 achieved CR/ CRi. Conclusions: The combination of MEC and ixazomib was well-tolerated and produced an overall response rate of 55% in patients with relapsed/ refractory AML irrespective of molecular mutation status. The combination is safe with a similar toxicity profile to MEC alone. CD74 expression may represent a biomarker for response to this therapy. Results from gene expression profiling will be complete by the time of the meeting and will be presented. Disclosures Mukherjee: Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Caimi:Genentech: Speakers Bureau; Gilead: Consultancy; Roche: Research Funding; Novartis: Consultancy. Maciejewski:Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

Abstract: Background: FIL (ARRY-520), a specific kinesin spindle protein (KSP) inhibitor, represents a novel class of agent under investigation for the treatment of patients (pts) with MM. Prognosis of pts refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) is poor. These pts have a median survival of 9 months underscoring the importance of novel therapeutic strategies incorporating new mechanisms of action. FIL has shown interesting preliminary activity as a single agent as well as in Phase 1 studies in combination with bortezomib (BTZ) and with CFZ, all with a manageable safety profile. Methods: This trial is an ongoing, randomized, multicenter, open-label Phase 2 study for pts with relapsed and refractory MM who received at least 2 prior regimens, including BTZ and an IMiD, and with disease refractory to the last regimen as per IMWG criteria. No prior treatment with CFZ is allowed. Approximately 75 pts will be randomized 2:1 to receive CFZ (20/27 mg/m2 intravenous [IV] on Days 1, 2, 8, 9, 15 and 16) plus FIL (1.25 mg/m2 IV on Days 1, 2, 15 and 16) or single-agent CFZ, at the same dose as in the combination, in a 28-day cycle. Prophylactic filgrastim is administered in the CFZ + FIL arm. The primary endpoint is progression-free survival (PFS). Patients with progressive disease (PD) on CFZ are allowed cross-over to the CFZ + FIL arm if they continue to meet eligibility criteria. Results: As of 15 June 2015, 72 pts have been randomized (23 CFZ, 49 CFZ + FIL) with a median age of 65 years. Pts who could have potentially received ≥ 2 cycles of treatment (20 CFZ, 30 CFZ + FIL) were evaluable for efficacy. These pts were heavily pretreated with a median of 4 and 5 prior regimens in the CFZ and CFZ + FIL arm, respectively. A total of 25% and 30 % of pts, respectively, received prior pomalidomide. The objective response rate (ORR) was 10% in the CFZ arm and 30% in the CFZ + FIL arm. In the CFZ arm, 2 pts achieved a partial response (PR) and 2 pts (10%) achieved an MR. In the CFZ + FIL arm, 3 pts achieved a very good partial response and 6 pts achieved a PR, with 2 additional pts (7%) achieving an MR. In the population of pts who were refractory to both prior BTZ and prior IMiDs, the ORR was 14% and 35%, respectively. Grade 3-4 hematological laboratory abnormalities (≥ 5% of pts) were leukopenia (9% CFZ vs. 21% CFZ + FIL), neutropenia (14% vs. 24%), thrombocytopenia (14% vs. 24%), and anemia (9% vs. 26%). Neutropenia and thrombocytopenia were reversible. No adverse events (AEs) of febrile neutropenia were reported. The only Grade 3-4 non-hematological AE occurring in ≥ 5% of pts was dyspnea (5% vs.11%). The most common reason for treatment discontinuation was confirmed PD (39% vs. 28%) or Investigator discretion in case of unconfirmed PD or clinical PD (17% vs. 12%). Conclusions: The combination of FIL and CFZ was well-tolerated and noticeably increased the ORR compared to CFZ alone in heavily pretreated pts with advanced MM. The preliminary efficacy in pts who are double refractory to IMiDs and BTZ who were randomized to CFZ + FIL appears higher than in pts treated with CFZ alone (in the CFZ arm of this trial and in previously published reports involving such pts). Updated safety and efficacy data, including PFS, will be presented at the meeting. Table. Efficacy evaluable pts (potential to have received ≥ 2 cycles of treatment) CFZ (N = 20) CFZ + FIL (N = 30) Prior regimens, median (range) 4 (2,11) 5 (2,11) N cycles on study, median (range) 4 (1 - 16) 4 (1 - 15+) % ORR (≥ PR) 10 30 % CBR (≥ MR) 20 37 N (%) IMiD & BTZ Refractory 14 (70) 20 (67) % ORR (≥ PR) 14 35 % CBR (≥ MR) 21 40 CBR = clinical benefit rate Disclosures Zonder: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support. Off Label Use: carfilzomib; treatment of myeloma, but not in combination with filanesib. Usmani:Celgene Corporation: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Berdeja:Onyx: Research Funding; Array: Research Funding; Takeda: Research Funding; Acetylon: Research Funding; Janssen: Research Funding; BMS: Research Funding; MEI: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Curis: Research Funding. Anderson:Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Hari:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Singhal:Celgene: Speakers Bureau. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Faber:Celgene: Consultancy. Schiller:Sunesis: Honoraria, Research Funding. Schreiber:Array BioPharma: Employment. Oliver:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Tunquist:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Raje:Eli Lilly: Research Funding; Millenium: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; BMS: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy; Amgen: Consultancy; Celgene Corporation: Consultancy; Acetylon: Research Funding.

Abstract: Background: Most pulmonary embolism (PE) research has focused on acute and short-term outcomes such as mortality and PE recurrence. Whether long-term morbidity such as exercise limitation, impaired quality of life (QOL) and persistent dyspnea occurs after PE is largely unstudied. To address this knowledge gap, we performed the ELOPE study, a prospective, observational, multicenter cohort study of long-term outcomes after acute PE (www.clinicaltrials.gov NCT01174628). Objectives: The objectives of the ELOPE (Evaluation of Long-term Outcomes after PE) Study were: (1) to describe and quantify degree of exercise limitation, QOL impairment and persistent dyspnea at 1 year after PE; and (2) to identify predictors of poor functional status at 1 year. Methods: Patients ≥18 years old with a 1st episode of acute PE diagnosed within the previous 10 days screened at 5 Canadian recruiting centers were potentially eligible to participate. Exclusion criteria were subsegmental-only PE, preexisting severe cardiopulmonary comorbidity, previous proximal DVT, contraindication to CT pulmonary angiography (CTPA), life expectancy 〈 1 year, unable to read questionnaire in English and French or to attend follow-up visits, and unable or unwilling to consent. After the Baseline (B) visit, patients attended follow-up (FU) visits at 1, 3, 6 and 12 months to measure QOL (SF-36, PEmbQoL), dyspnea (UCSD SOBQ), and 6-minute walk test (6MWT) [all FU visits]; undergo CTPA [B, 12] , echocardiogram [B, 12], Q scan [6, 12] , cardiopulmonary exercise testing (CPET) [1, 12] and pulmonary function tests [1, 12] ; and measure biomarkers (BNP, ddimer, troponin) [B, 6]. The primary study outcome was maximal aerobic capacity defined by peak oxygen uptake (VO2) as a percent of predicted maximal VO2 (VO2max) on 1-year CPET, with 〈 80% predicted VO2max considered abnormal, as per American Thoracic Society guidelines. For the present analysis, we summarized demographic and clinical characteristics of study subjects, the proportion of patients with VO2max 〈 80% predicted on 1 year CPET (primary outcome), and compared mean QOL and dyspnea scores in patients with vs. without the primary outcome. Multivariate logistic regression analyses were done to identify demographic, clinical and functional predictors of abnormal VO2max at 1 year, with adjustment for relevant confounding variables. Results: 984 patients were screened for participation; of these, 150 were eligible and 100 (67%) consented to participate. Mean (SD) age was 50 (15) years, 57% were male, 80% were outpatients and 33% had concomitant DVT. PE was provoked in 21% and unprovoked in 79%; none were cancer-related. At 1 year, 40/86 (46.5%) of patients had 〈 80% predicted VO2max on CPET; these patients had worse 1-year SF-36 MCS (mental) (p=0.002) and PCS (physical) (p=0.009) scores, PEmbQoL scores (p=0.002) and SOBQ scores (p=0.003), compared to patients with 〉 80% predicted VO2max at 1 year. Independent baseline predictors of abnormal VO2max at 1 year included: male sex (relative risk (RR)= 3.2 [95% CI 1.3-8.1]; p=0.015), age (RR 0.98 [95% CI 0.96-0.99] per 1 year age increase; p=0.002), BMI (RR 1.1 [95% CI 1.01-1.2] per 1 kg/m2 BMI increase; p=0.023), and smoker (RR 1.8 [95% CI 1.1-2.9]; p=0.023). In addition, VO2max 〈 80% predicted at 1 month and 6MWT distance at 1 month were significantly associated with risk of abnormal VO2max at 1 year (RR 3.8 [95% CI 1.9-7.2; p 〈 0.0005] and RR 0.82 [95% CI 0.7-0.9; p=0.001] per 30m increased walking distance, respectively). Inpatient status at enrolment, previous lung disease, unprovoked vs. provoked PE, concurrent DVT, and number of days with symptoms before PE diagnosis did not influence VO2max at 1 year. Conclusions: PE is a common and serious cardiovascular illness, yet clinically relevant information on characteristics and determinants of long-term outcome after PE have been lacking. Results of the ELOPE Study indicate that almost half of PE patients can be considered to have a "post-PE syndrome" characterized by exercise limitation at 1 year, which influences their QOL and degree of dyspnea. Predictors of this post-PE syndrome include male sex, younger age, higher BMI and smoking. CPET testing or 6MWT testing at 1 month may help to identify patients with a higher risk of post-PE syndrome at 1 year. Funding: Canadian Institutes of Health Research (MOP-93627) Disclosures Wells: Bayer: Honoraria; BMS/Pfizer: Research Funding.