ALBERT

Description: Background Multiple myeloma (MM) remains incurable despite treatment advances. While passive immunotherapy such as anti-CD38 antibodies is highly effective, active immunotherapy may provide long-lasting remissions by virtue of triggering memory. A phase 1 nivolumab study, an antibody targeting programmed death-1 (PD1), was unable to yield any responses in multiply relapsed MM patients. Conversely, preliminary trial data of lenalidomide combined with pembrolizumab, a different anti-PD1 antibody, found significantly higher response rates. These two differing outcomes reflect our limited understanding of checkpoint inhibition and immunotherapy in MM. There is a paucity of preclinical models to guide therapeutic studies. Cell lines and xenografted murine models are incapable of exploring active immunotherapy due to a lack of microenvironment and endogenous immune cell signals. Furthermore, malignant cells responsive to drugs in 2-dimensional (2D) cultures are known to display a more resistance in 3D. We have previously demonstrated that B-cell malignancies can be accurately studied using a 3D culture system of patient bone marrow mononuclear cells (BMCs) and can better inform translational trials. Herein we describe an ex vivo, 3D tissue culture model of patient-derived MM samples to more accurately test therapeutics including checkpoint inhibition using ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte antigen 4 (CTLA) which is crucial in co-stimulatory signaling of effector T-cells. Methods A 3D extracellular matrix was created using matrigel in 12-well plates. BMCs were isolated from marrow aspirates of 5 MM patients at time of diagnosis and individually cultured. Each patient sample was tested for sensitivity against increasing concentrations of ipilimumab (1X, 3X, and 10X clinical doses) added into supportive medium. Plates were monitored visually by microscopy followed by harvest on day 21 using enzymatic degradation. Unique clonotypic heavy chain immunoglobulin rearrangement (IgH VDJ) from each sample was sequenced, validated and used for semi-quantitative PCR. Semi-QT PCR with clone-specific primers estimated malignant cell survival after harvest. Flow cytometry was used to define cell populations present in culture and to correlate with clonotypic PCR data. T-cell mediated activity was examined by reverse transcription of trizol-extracted, T-cell RNA after harvest. Results All samples were successfully cultured, followed for 21 days and harvested. Flow cytometry confirmed presence of T-cell subsets, B-cells, NK cells and dendritic cells before and after culture in 3D. Minimal depletion of clonotypic cells was observed at 3x clinical levels of drug. At 10x simulated clinical therapeutic levels, 3 MM samples demonstrated 〉90% death of clonotypic MM cells while the other 2 demonstrated 62% and 72% death, respectively, compared to untreated control cultures. The extent to which the drug diffuses into the matrigel is as yet unknown. Flow cytometry of harvested cells suggest that T-cells demonstrate a modest shift toward CD4 and CD8 effector cells. Preliminary mechanistic data from one MM sample using trizol-extracted RNA and reverse transcriptase PCR harvested at 21 days from 3D culture suggests that anti-malignant, cytotoxic T-cell effect may be driven by granzyme B expression. Expanded data from the remaining samples will be presented. Conclusions We demonstrate that an ex vivo 3D tissue culture model of MM is both feasible and informative in studying immunotherapy. By culturing unselected BMCs which include stromal cells, immune cells and malignant populations, the 3D culture more closely mimics the tumor microenvironment with both the patient's immune system present as well as stromal supportive signals. In this study, we show that in the presence of active immune effector cells, ipilimumab has activity against patient-derived MM cells. The data suggests the importance of targeted cytotoxic T-cell activation as a primary mechanism of action. We have previously studied standard MM therapeutics such as cytotoxic chemotherapy, immunomodulatory drugs, and proteasome inhibitors in the same way. Consequently, this model is well positioned to study other immunotherapies such as other checkpoint inhibitors, cellular therapy, and combinations. Further testing with therapeutics targeting PD1/PDL1, and adenosine receptors are underway. Disclosures Venner: Takeda: Honoraria; Celgene: Honoraria, Research Funding; J+J: Research Funding; Janssen: Honoraria; Amgen: Honoraria. Belch:Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria.

Description: BACKGROUND Outcomes in multiple myeloma have improved dramatically over the last decade however, optimal sequencing of therapy remains unknown. Specifically, in an era where post-transplant lenalidomide (L) maintenance is now as established standard of care, questions remain around the utility of full dose L-based regimens in second line therapy. In this series, we sought to evaluate the impact of different regimens used at first relapse in patients who received autologous stem cell transplant (ASCT) in the frontline setting treated with and without lenalidomide maintenance (LM). We focused on the impact of L-based therapies in patients relapsing on LM. METHODS Using our prospectively maintained institutional MM database we retrospectively analyzed patients treated at the Cross Cancer Institute from January, 2005 to January, 2016 to ensure 2 years of follow-up for surviving patients. 4 categories were identified based on 2 variables: receipt of LM following 1st line therapy (yes or no) and receipt of L-based 2nd line therapy (yes or no). The primary endpoint was 2nd PFS defined as time of initiation of second line therapy to relapse, death or last follow-up. OS was defined as time of initiation of first line induction therapy to death or last follow-up. Second OS was defined as time of initiation of second line therapy to death or last follow-up. Survival statistics were determined using the Kaplan-Meier method with SPSS software. A p - value of

Description: Introduction: Multiple myeloma (MM) evolves from precursor disorders such as monoclonal gammopathy of undetermined significance (MGUS) and SMM (Landgren O, et al. Blood 2009. 113[22]:5412-5417). Currently, there are no approved therapies for SMM, and guidelines recommend close monitoring of SMM patients (pts) and initiating treatment only upon progression to MM. However, therapeutic intervention at the SMM stage, especially in pts at higher risk of progression to MM, may yield clinical benefit and prevent the development of MM-associated complications. DARA is a CD38-targeting IgG1κ monoclonal antibody with on-tumor and immunomodulatory mechanisms of action. Based on the demonstrated efficacy and favorable safety profile of DARA monotherapy in pts with relapsed/refractory MM (RRMM; Usmani SZ, et al. Blood 2016. 128[1]:37-44), we hypothesized that DARA could delay progression from SMM to MM. A prespecified primary analysis (15.8-month median follow-up) of the phase 2 CENTAURUS study (NCT02316106) revealed that DARA monotherapy was active and well tolerated in pts with intermediate- or high-risk SMM (Hofmeister CC, et al. ASH 2017. Abstract 510). Here, we present updated data from CENTAURUS based on 10 months of additional follow-up. Methods: Eligible pts had had a confirmed diagnosis of high-risk or intermediate-risk SMM for

Description: Background Ixazomib is the first orally administered PI studied in the clinic. The feasibility of combining ixazomib weekly and lenalidomide-dexamethasone (Rd) in the first all-oral PI- and immunomodulatory drug-containing triplet regimen was evaluated in a phase 1/2 trial of 65 pts with newly diagnosed MM. Results indicated a 90% ORR (62% ≥VGPR) using ixazomib 4 mg (recommended phase 2/3 dose), with a manageable safety profile, including 14% gr ≥3 skin/subcutaneous tissue disorders and limited (4% gr 3) peripheral neuropathy (PN) (Kumar et al, Lancet Oncol 2014). These data provided the rationale for phase 3 investigation of IRd vs placebo-Rd in pts with RRMM in this randomized, double-blind, placebo-controlled, international, multicenter study. Methods Adults with RRMM after 1-3 prior lines of therapy who were not refractory to prior lenalidomide or PI-based therapy were randomized 1:1 to receive ixazomib 4 mg or matching placebo weekly on d 1, 8, and 15, plus lenalidomide 25 mg PO on d 1-21 (dose reduced for renal impairment per local label/practice) and dexamethasone 40 mg PO on d 1, 8, 15, and 22, in 28-d cycles. Randomization was stratified by number of prior therapies (1 vs 2/3), PI exposure (naïve vs exposed), and ISS disease stage (I/II vs III). Cycles were repeated until disease progression or unacceptable toxicity. Primary endpoint was PFS as assessed by an independent review committee blinded to treatment, per IMWG criteria. Key secondary endpoints were OS and OS in high-risk pts with del(17). Sample size was determined to provide 80% power for the OS endpoint and adequate power to test PFS. Three interim analyses (IAs) and a final analysis were planned to test PFS and OS; here, we report data from the first IA, the final analysis for PFS. Results 722 pts were randomized (360 IRd; 362 Rd). Baseline characteristics were balanced between groups; overall median age was 66 yrs (30-91), 70% were PI-exposed, 88% were ISS stage I/II, 59% had received 1 prior therapy, and 77%/11%/11% were relapsed/refractory/relapsed and refractory, with 6% primary refractory. Based primarily (97%) on central laboratory evaluation, 19% had high-risk cytogenetics by FISH (del(17), t(4;14), or t(14;16)), including 10% del(17). Prior therapies included 69% bortezomib, 45% thalidomide, and 12% lenalidomide. The study met the primary endpoint at the first IA (median follow-up 14.8 vs 14.6 mos with IRd vs Rd), demonstrating a 35% improvement in PFS with IRd vs Rd (HR 0.742; p=0.012; Table). In pts with high-risk cytogenetics, the PFS HR was 0.543 with IRd vs Rd (HR 0.596 in pts with del(17)), with a median PFS similar to the overall IRd group, indicating ixazomib may overcome the negative impact of cytogenetic alterations. OS data were not yet mature. Key response data are shown in the Table. Pts received a median of 13 (1-26) vs 12 (1-25) cycles of IRd vs Rd; 55% and 52% of pts remained on treatment. With IRd vs Rd, 68% vs 61% of pts had gr ≥3 AEs (driven by thrombocytopenia), 40% vs 44% had serious AEs, 13% vs 11% discontinued all study drugs due to AEs, and 3% vs 5% died on treatment. AEs observed with IRd were consistent with reported safety profiles for the individual agents. Common gr ≥3 AEs were neutropenia (19% vs 16%), anemia (9% vs 13%), thrombocytopenia (13% vs 5%), and pneumonia (6% vs 8%). Gastrointestinal events included 42% vs 36% diarrhea (6% vs 2% gr 3), 26% vs 21% nausea (2% vs 0% gr 3), and 22% vs 11% vomiting (1% vs

Description: Introduction: Cyclophosphamide, bortezomib and Dexamethasone (CyBorD) has become the standard frontline approach for the treatment of multiple myeloma (MM) in many centers across Canada. In the non-transplant eligible setting, recently a randomized controlled trial reported on the impact of Lenalidomide and Dexamethasone (LD), showing that this doublet-therapy is a feasible and efficacious combination. Based on the above-mentioned success of the LD combination, we aimed to compare the effect of CyBorD and LD for the treatment of non-transplant eligible MM (NTE) patients in the Alberta Myeloma and Dysproteinemia Program (AMDP). Patients and Methods: The primary objective was to assess ORR and PFS for NTE MM patients treated with CyBorD and LD. The recommended CyBorD regimen was as follows: bortezomib 1.3-1.5 mg/m2 SC or IV days 1, 8, 15 of a 28 day cycle (as of August, 2013 we adopted the a strategy whereby bortezomib can also be given on day 22), cyclophosphamide 300 mg/m2 PO days 1, 8, 15 and 22 and dexamethasone 20-40 mg PO days 1, 8, 15 and 22 with an aim to deliver a minimum of 9 cycles of treatment. LD was given at 25 mg days 1-21 of a 28-day cycle with Dexamethasone 20-40 mg PO days 1, 8, 15 and 22. Dose adjustments were at the discretion of the treating physician. Two-sided Fisher exact test was used to test for differences between categorical variables. A p value of

Description: Background: Overall survival (OS) in older patients (pts) with AML and poor-risk cytogenetics is only ~2-3 months (mos) (Burnett, Cancer, 2007). Often these pts receive only palliative treatment (Tx) with best supportive care (BSC). Low-dose Ara-C (LDAC) provides no OS benefit in pts with poor cytogenetics (Döhner, Blood, 2010). Typically, intensive chemotherapy (IC) is either not suitable for older AML pts with poor cytogenetics or, when it is used, provides no OS benefit (Kantarjian, Blood, 2010). The phase 3, multicenter, randomized, open-label AZA-AML-001 trial showed azacitidine (AZA) Tx in older pts with newly diagnosed AML (〉30% bone marrow [BM] blasts) prolonged median OS by ~4 mos vs conventional care regimens (CCR) (10.4 vs 6.5 mos; p=0.1009) and improved 1-year survival (46.5% vs 34.2%) (Dombret, EHA, 2014). Cytogenetic risk is a prognostic indicator in elderly AML and a frequent determinant of Tx approach and outcomes. Objective: To determine the effect of Tx with AZA vs CCR on OS and 1-year survival in AZA-AML-001 pt subgroups based on cytogenetic risk classification. Methods: Pts aged ≥65 years with newly diagnosed de novo or secondary AML who were ineligible for transplant, with intermediate- or poor-risk cytogenetics (pts with favorable cytogenetics were excluded from study), ECOG performance status 0-2, and WBC count ≤15x109/L, were eligible. Before randomization, each pt was preselected to receive 1 of 3 commonly used CCR for older pts with AML, per investigator choice: IC (standard 7+3 regimen), LDAC (20 mg SC BID x 10 days/28-day cycle), or BSC only. Pts were then randomized to AZA (75 mg/m2/day SC x 7 days/28-day cycle) or to CCR, in which case they received their preselected Tx. The primary endpoint was OS. Cytogenetic risk groups were assessed per NCCN criteria by central review: intermediate (INT; all cases), intermediate with normal karyotype (cytogenetic normal [CN]), and poor. Survival at 1 year was compared between Tx. Median OS for AZA vs CCR was calculated using Kaplan-Meier methods, hazard ratios (HR) and 95% confidence intervals (CI) were determined by unstratified Cox proportional hazards model, and p values by log-rank test. Results: In all, 488 pts were randomized, 241 to AZA and 247 to CCR. Cytogenetic risk was balanced between Tx groups: 315 pts had INT-risk cytogenetics (AZA n=155 [64%], CCR n=160 [65%]), including 218 who were CN (AZA n=113 [73%], CCR n=105 [66%]), and 170 pts had poor-risk cytogenetics (AZA n=85 [35%], CCR n=85 [34%]). Within each of the 3 cytogenetic risk subgroups, the distribution of pts receiving individual CCR was very consistent: ~18% of each cytogenetic risk subgroup received BSC, ~64% received LDAC, and ~18% received IC. Baseline characteristics were generally balanced among the AZA and CCR Tx arms and the 3 cytogenetic risk groups (Table). At baseline, proportionately more pts with poor-risk cytogenetics in the AZA group were aged ≥75 years (57.6% vs 47.1% with CCR) and more pts in the CCR group had AML with myelodysplastic changes (45.9% vs 37.6% with AZA). Median OS (95%CI) in poor-risk pts was significantly prolonged with AZA vs CCR: 6.4 mos (4.2, 8.1) vs 3.2 mos (2.2, 4.7), respectively; HR=0.68 (0.50, 0.94), p=0.019 (Figure). Median OS in INT-risk pts was 13.0 mos (11.2, 16.3) vs 10.1 mos (7.1, 13.3) with AZA vs CCR; HR=0.90 (0.70, 1.16), p=0.41. Median OS in the CN subgroup was 14.1 mos (12.6, 19.5) vs 10.0 mos (6.4, 13.3); HR=0.81 (0.59, 1.10), p=0.18. Estimated 1-year survival was higher with AZA vs CCR in all cytogenetic risk subgroups. Twice the proportion of AZA-treated pts in the poor-risk subgroup were alive at 1 year vs. CCR pts (30.9% vs 14.0%, respectively), a clinically meaningful difference of 16.9% (95%CI 4.4, 29.5). Similarly, in the CN subgroup, 60.7% vs 44.1% of pts were alive at 1 year in the AZA and CCR groups, a difference of 16.5% (3.2, 29.8). AZA effect on 1-year survival in the INT-risk subgroup was also favorable (55.2% vs 45.5% with CCR) (difference 9.7% [-1.4, 20.8]). Grade 3-4 hematologic adverse event rates with AZA were consistent with previous reports (Santini, Eur J Haematol, 2010), with no meaningful differences among all cytogenetic risk groups. Conclusions: Median OS in older pts with AML and poor-risk cytogenetics was meaningfully improved with AZA compared with the CCR currently used for AML, with those pts receiving AZA twice as likely to be alive at 1 year as those treated with CCR. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Döhner: Celgene: Consultancy. Off Label Use: Use of azacitidine in AML with blast count 〉30%. Seymour:Celgene: Consultancy, Honoraria, Speakers Bureau. Wierzbowska:Celgene: Honoraria, Speakers Bureau. Selleslag:Celgene: Consultancy, Research Funding, Speakers Bureau. Cavenagh:Celgene: Honoraria. Kumar:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schuh:Celgene: Membership on an entity's Board of Directors or advisory committees. Candoni:Celgene: Consultancy, Speakers Bureau. Récher:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sandhu:Celgene: Honoraria. Bernal del Castillo:Celgene: Consultancy. Al-Ali:Celgene: Honoraria, Research Funding. Martinelli:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy. Falantes:Celgene: Consultancy. Stone:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Minden:Celgene: Honoraria. McIntyre:Celgene: Employment. Songer:Celgene: Employment, Equity Ownership. Lucy:Celgene: Employment, Equity Ownership. Beach:Celgene: Employment, Equity Ownership. Dombret:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: BACKGROUND: Anthracycline based treatment for acute myeloid leukemia (AML) can be associated with significant morbidity and mortality amongst older patients or those with significant co-morbidities. Furthermore, for patients with previous anthracycline exposure or preexisting cardiac disease anthracyclines pose an increased risk of cardiotoxicity. For such patients intensive treatment options are limited. The FLAG (fludarabine, cytarabine and filgrastim) regimen is a non-anthracycline based chemotherapy useful for relapsed/refractory AML and as initial therapy for “fit” eligible patients. We present our experience using FLAG as first line therapy in a cohort of newly diagnosed AML patients with advanced age, significant co-morbidities or preexisting cardiac disease. METHODS: A single institution retrospective chart review was undertaken of patients treated with FLAG as frontline therapy from 2004 – 2013 with follow-up until June 2014. All patients were considered ineligible for standard ‘3+7’ treatment by the attending physician. RESULTS: Over the study period 56 patients received FLAG. Due to patient refusal or induction complications bone marrow assessments to ascertain remission status were not performed in 10 patients – to minimize bias these patients were evaluated for toxicity and overall survival (OS) but excluded from complete remission (CR) and relapse free survival (RFS) analysis. Of the 56 patients, 68% were males. The median age was 69 (21 – 80) with 79% aged ≥ 60 and 43% aged ≥ 70. Fifty-five percent (31) of the patients had primary AML and cytogenetics were favorable in 5% (3), intermediate in 66% (37), poor-risk in 21% (12) and failed in 7% (4). Forty-six percent (26) were treated with FLAG due to preexisting cardiac disease and others due to advanced age (20%), poor performance status (16%), co-morbidities (16%) or previous anthracycline exposure (2%). The ages of patients treated with FLAG due to cardiac disease or other reasons was similar (63.5 years vs. 66.9 years, p=0.27). Amongst patients with cardiac disease a pre-chemotherapy cardiac evaluation revealed wall motion abnormalities in 39% and an ejection fraction (EF) ranging from 33% - 81% with a borderline (≤ 50-51%) EF in 46%. Febrile neutropenia was observed in 82% (46) of patients, 27% (15) required intensive care support and the induction mortality was 16% (9). Amongst patients evaluated for a CR (46/56), 48% (22/46) obtained a CR. Although a CR was seen in 100% (3/3), 46% (15/33) and 37% (3/8) of patients with favorable, intermediate and poor-risk cytogenetics respectively there was no statistically significant difference (p=0.22) between groups. A CR was obtained in two additional patients following a second course of FLAG for an overall CR rate of 52% (24/46). Of these 24 patients, 8 (33.3%) received no additional treatment while 16 (66.7%) received consolidative chemotherapy. Of 10 eligible patients, 4 proceeded to an allogeneic stem cell transplant (allo-SCT) including two with preexisting cardiac disease. Of patients not transplanted 50% (10/20) eventually relapsed. There was no difference in relapse rates for those receiving FLAG for age/co-morbidities vs. cardiac disease (60% vs. 40%, p= 0.66) or for patients age

Description: Background:Although outcomes for patients with multiple myeloma (MM) have improved, it remains an incurable malignancy for which new therapies are needed. Aurora kinases are overexpressed in MM. Inhibition of Aurora A kinase, a key component of the centrosome, in MM cell lines induces apoptotic cell death. Inhibition of Aurora B, a chromosome passenger protein, has therapeutic effects against myeloma lines, primary bone marrow plasma cells and murine xenografts. Histone H3 is a direct downstream substrate of Aurora B. The Aurora A and B kinase inhibitor AT9283 has shown anti-myeloma activity in pre-clinical studies. Based on an NCIC CTG phase I trial in patients with advanced malignancy the recommended phase 2 dose (RP2D) was 40 mg/m2 on days 1 and 8 of a 21 day cycle. This single arm phase II trial was designed to explore the efficacy of AT9283 in patients with relapsed and refractory multiple myeloma. Methods: Eligibility criteria included age ≥ 18, neutrophils ≥ 1 and platelets ≥ 70 x109/L. There was no upper limit on the number of prior regimens. The primary endpoint was response rate; secondary endpoints included toxicity and evaluation of potential biomarkers. According to the 2-stage design at least 1 response was required in the first 15 patients to proceed to a full sample size of 30, assuming an HA of ≥ 0.20. Initially AT9283 was administered by 24 hour continuous infusion at the RP2D. Hematological toxicity in the first 2 patients met protocol specified criteria for reduction of the starting dose to 30 mg/m2 for subsequent patients. Adverse events were graded according to CTCAE V4.0. Phosphorylated Histone H3 (Ser10), a marker of Aurora B activity, and total Histone H3 protein expression was measured by western blot analysis in baseline and day 21 bone marrow samples. Results:Over 18 months, eight eligible patients (3 male, 5 female) with MM (4 IgG, 2 IgA, 2 light chain) were accrued. All were evaluable for toxicity and 7 evaluable for response. Median age was 60 (range 48 – 75). The median number of prior regimens was 3 (range 1 - 5). Patients received between 1 – 4 cycles of AT9283 (median 1) with 25% of patients receiving ≥ 90% of the planned dose intensity. No responses were observed. The trial was closed due to slow accrual and toxicity, in particular myelosuppression. Transient neutropenia occurred in all patients (63% grade 3, 37% grade 4). Recovery from nadir to normal range was rapid in the majority (range 1 – 8 days, median 5) but prolonged in 2 patients who were neutropenic at baseline (11 and 13 weeks). Grade 3/4 thrombocytopenia occurred in 50% of patients. There were 3 infections ≥ grade 3 including 1 death. Grade 3 skin ulceration thought possibly related to AT9283 by the investigator occurred in 1 patient. The most common non-hematologic adverse events reported as possibly, probably or definitely related to AT9283 were grade 1-3 nausea (50%), grade 1 and 3 vomiting (38%), grade 4 febrile neutropenia (25%), grade 1/2 anorexia (25%), grade 1/2 diarrhea (25%) and grade 1/2 fatigue (25%). Paired baseline and day 21 bone marrow samples were provided from 4 patients; sufficient protein was extracted from both samples for western blot analysis from 3 patients. Of these, 2 showed a reduction in Histone 3 phosphorylation (H3-P) after the first cycle of treatment consistent with inhibition of Aurora B. Both of these patients had a best response of stable disease (SD). Abstract 5734. Table Patient Dose (mg/m2) Number of cycles Best response Non-hematological toxicity ≥ Grade 3* Reason off study H3-P/H3Baseline Day 21 1 40 1 PD Gr 3 skin ulceration Toxicity 0.3 0.5 2 40 1 SD Gr 3 lung infection Intercurrent illness 1.6 0.5 3 30 3 SD None PD 0.6 0.5 4 30 1 PD Gr 4 febrile neutropenia & gr 4 left ventricular systolic dysfunction Toxicity NE NE 5 30 1 NE Gr 4 febrile neutropenia & gr 5 sepsis** Death NE NE 6 30 4 PD Gr 3 nausea & vomiting PD NE NE 7 30 3 SD None PD NE NE 8 30 1 PD None Death NE NE * Reported as possibly, probably or definitely related to AT9283 by investigator ** Neutrophil count recovered to normal range prior to death PD progressive disease, NE not evaluable, Gr grade Conclusions: This study failed to reach full accrual. No objective responses were observed. Administration of AT9283 to patients with previously treated myeloma at this dose and schedule is associated with toxicity, particularly myelosuppression. Disclosures Sandhu: Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Reece:Otsuka: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Millenium: Honoraria, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria. Lyons:Astex: Employment. Seymour:Astex: Research Funding.

Description: Background: Heparin-induced thrombocytopenia (HIT) is associated with anti-platelet factor-4 (PF4)/heparin antibodies that activate platelets, resulting in thrombocytopenia and a pro-thrombotic state. At our institution antibody-mediated platelet activation is demonstrated by lumi-aggregometry, which is a method previously validated against the gold standard serotonin-release assay (SRA). Lumi-aggregometry does not involve radioactive isotopes, which is its major advantage over the SRA. The clinical course of HIT diagnosed via SRA and ELISA has been previously described, and clinical prediction tools such as the 4-T score were validated using these diagnostic tests. However, the clinical picture of HIT diagnosed by lumi-aggregometry has not been previously described. Aims: The objective of this study is to describe the clinical and laboratory presentation of patients diagnosed with HIT by lumi-aggregometry. Methods: Patients with clinically suspected HIT and quantitative anti-PF4 IgG-specific ELISA OD ≥0.400 (Gen-Probe, San Diego) received confirmatory HIT testing by lumi-aggregometry. Briefly, HIT antibody-induced activation of washed healthy donor platelets was tested at therapeutic (0.1U/mL and 0.5U/mL) and high (100U/mL) porcine heparin concentration. The degree of platelet activation was quantitated luminographically based on the light flash reaction of ATP (released from platelet dense-granules) with luciferin luciferase reagent. A ratio of therapeutic to high heparin luminescence amplitude of 〉5.0 and platelet aggregation at therapeutic, but not high, concentrations was considered a positive result. The results of assays performed by our regional HIT testing referral laboratory from June 2009 to July 2012 were reviewed to identify patients with positive HIT testing by lumi-aggregometry. Patient records were retrospectively reviewed to obtain predefined data on baseline patient characteristics, heparin exposure, platelet counts, and thrombotic events occurring in the 5 days preceding or the 30 days following the date of positive HIT testing. Results: We identified 43 patients diagnosed with HIT by lumi-aggregometry (median age 68.0, 49% male) while under the care of local academic (46%) or urban community hospitals (37.2% medical; 53.5% surgical; 9.3% intensive care). Median baseline platelet count was 187 (14-349). Median date of platelet drop post-heparin exposure was 6 days (range 3-14) in patients without prior heparin exposure or platelet transfusions (Figure 1). Platelet drop 〉50% and platelet nadir ≥20x109/L were present in the majority of patients (Table 1). Thrombocytopenia occurred prior to (70.5%) or the same day (23.5%) as thrombosis in 16/17 patients with serial platelet counts who developed HIT-associated thromboembolism. Conclusion: Patients diagnosed with HIT by lumi-aggregometry present with similar findings to those described in SRA-confirmed HIT. These findings lend support to the use of lumi-aggregometry as an accurate diagnostic assay for the clinico-pathologic syndrome of HIT. Figure 1 Figure 1. Table 1. Percentage platelet drop from baseline and platelet nadir Percent platelet drop Platelet nadir 〉50% 30-50%