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Introduction: Over the past several years, inhibitors of cyclin-dependent kinases 4 and 6 (CDK 4/6) have revolutionized the treatment of hormone receptor (HR)-positive breast cancer. However, evidence suggests an increased risk of venous thromboembolism (VTE) with use of these agents. Recent studies additionally suggest higher VTE rates in real-world populations receiving palbociclib as compared with the highly selected population of published clinical trials. Such study in real-world patients has not been performed for abemaciclib, a newer CDK 4/6 inhibitor with unique pharmacokinetic and pharmacodynamic properties. This study evaluated rates and predictors of thrombosis in patients receiving abemaciclib for metastatic breast cancer. Methods: We conducted a multicenter observational cohort study of patients with metastatic breast cancer receiving abemaciclib at 5 affiliated hospitals. A research patient data repository was queried to identify all patients receiving abemaciclib and manual chart review was used to extract all data. Patient demographics, concurrent medications, labs, Khorana risk score, tumor characteristics, and relevant venous and arterial thrombotic risk factors (including age, BMI, prior thrombosis, recent surgery, hereditary thrombophilia, systemic inflammatory diseases, presence of brain metastases, hypertension, hyperlipidemia, diabetes mellitus, atrial fibrillation, heart failure, and atherosclerosis) were collected for all patients. The primary endpoint was thrombosis during abemaciclib treatment or within 30 days of discontinuation. Multivariable logistic models assessed predictors of VTE and a multivariable Cox proportional hazards model was used to compare mortality in patients developing VTE with those who did not. Data are presented as median (IQR) or number (%). Results: Patient Cohort and Thrombosis Risk Factors. 364 patients were included in the analysis. 360 (98.9%) patients were female, with median (interquartile range) age of 61 (53-71) years. 320 (88.7%) were post-menopausal and 291 (79.9%) were concurrently on endocrine therapy (of which 19 (5.2%) were on tamoxifen). At the time of abemaciclib initiation, 51 (14.0%) were receiving long-term anticoagulation and 47 (12.9%) were receiving aspirin. Khorana scores were between 0-3 with 339 (93.1%) patients having a score of 0 or 1. 267 (73.4%) and 46 (12.6%) were diagnosed with invasive ductal and lobular carcinoma, respectfully. Brain metastases were present in 71 (19.5%) patients. Venous and arterial thrombosis risk factors for this cohort are highlighted in TABLE 1. The median duration of abemaciclib therapy was 5.5 (2.8-13.0) months and median duration of follow-up was 12.7 (6.2-22.1) months. Thrombotic Events. 27 patients (7.4%) developed one or more thrombotic event (17 VTE, 9 arterial thrombosis, 1 both). Events are described in TABLE 2. Risk Factors for VTE. In a multivariable logistic model including age, race, BMI, receipt of long-term anticoagulation, receipt of aspirin, brain metastases, Khorana risk score, receipt of tamoxifen, prior VTE, systemic autoimmune disease, and known thrombophilia, HER2 positivity was predictive of VTE during or after abemaciclib treatment (odds ratio 5.20, 95% CI 1.29-20.93, P=0.020). Association of VTE with Mortality. In a multivariable Cox model controlling for age, race, HER2 status, receipt of long-term anticoagulation, receipt of aspirin, brain metastases, Khorana risk score, receipt of tamoxifen, prior VTE, systemic autoimmune disease, and known thrombophilia, patients developing VTE during abemaciclib therapy had a significantly higher risk of death (hazard ratio, 2.04, 95% CI, 1.03-4.01, P=0.040), FIGURE 1. Median survival in patients developing a VTE vs. those who did not was 9.6 months vs. 25.8 months, respectively. Conclusions: In this study, we provide the first real-world data describing risk of venous and arterial thrombosis in a large cohort of patients with metastatic breast cancer treated with the CDK 4/6 inhibitor abemaciclib. As the role of abemaciclib continues to expand both within and beyond the metastatic disease setting, understanding the VTE risk of this agent has become critical. Thrombosis occurred in 7.4%, and in multivariable models controlling for relevant covariates, HER2 positivity predicted for development of VTE, and patients developing VTE had an approximate 2-fold risk of mortality. Figure 1 Figure 1. Disclosures Al-Samkari: Moderna: Consultancy; Amgen: Research Funding; Novartis: Consultancy; Rigel: Consultancy; Argenx: Consultancy; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding.

Mutations in genes encoding the isocitrate dehydrogenase 1/2 (IDH 1/2) enzymes increase production of the oncometabolite 2-hydroxyglutarate (2HG), resulting in elevated 2HG in patients with IDH-mutant AML. This may allow for non-invasive diagnostic and predictive markers of disease; however, the optimal threshold of 2HG levels to predict IDH mutation status, or whether 2-HG measurements in different compartments are equally predictive, is unknown. We measured 2-HG levels in serum, urine, bone marrow aspirate, and bone marrow cell pellet to determine the optimal predictive value of 2HG levels for IDH mutations at AML diagnosis. Patients with newly diagnosed AML had prospective measurements of 2HG levels at diagnosis by liquid chromatography-tandem mass spectrometry in serum, urine, marrow aspirate, and marrow pellet samples. Patients analyzed had IDH1 R132 and IDH2 R140 and R172 testing. Hotspot mutational profiling was performed for AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, KIT, KRAS, MAP2K1, NOTCH1, NRAS, PIK3CA, P53, and PTEN; patients were also tested for FLT3, NPM1, and CEBPA mutations. IDH1/2 mutant patients were compared to wildtype (WT) patients using a Wilcoxon rank sum, Fisher's exact, or Kruskal Wallis test, as appropriate. Performance characteristics of 2HG to predict the presence of IDH1/2 mutations were done using a recursive partitioning algorithm in R version 3.2.1, with the rpart package. 228 patients with newly diagnosed AML had 2HG levels in serum, urine, marrow aspirate, and marrow pellet samples. All patients had testing for IDH1 R132 and IDH2 R140 and R172 mutations. The patients were 56% male; 13 patients had APL, none with IDH mutations. IDH mutations were identified in 23% (n=52) of the cohort: IDH1 R132C (n=12), IDH2 R172 (n=9), and IDH2 R140Q (n=29), and 2 additional patients had mutations in both IDH1 R132 and IDH2 R140 (Table 1). The optimal test cut-off of 2HG to predict IDH status was 534.5 ng/mL in the serum (n=221), 16650 ng/mL in the urine (n=213), 2210 ng/mL in the marrow aspirate (n=190), and 1146 ng/2*10^6 cells in the pellet (n=159). Serum and pellet values had the greatest specificity for the presence of an IDH1/2 mutation (0.9882 and 1.000, respectively; Table 2). The positive predictive value of an elevated serum or pellet 2HG level at these cut-offs was 95.4% and 100%, given a 23% IDH mutation prevalence in this study population. The marrow aspirate had the greatest sensitivity (0.8837) and negative predictive value (96.6%). Urine 2HG levels were less sensitive than serum 2HG levels, although above the urine cut-off the specificity for IDH mutations was similar (Figure 1). 2HG levels in the serum, urine, and marrow can be used to identify IDH mutations in AML. Serum 2HG testing is an effective non-invasive mechanism to predict IDH1/2 mutation status. A serum cut-off of 534.5 ng/mL has a specificity of 0.9882 and, with an IDH mutation prevalence of 23%, was associated with a PPV of 0.9535.Table 1.Patient CharacteristicsNo IDH mutationIDH mutationTotalp-valueMale sex101 (57%)26 (50%)127 (56%)0.43Cytogenetics0.0002Favorable26 (15%)026 (12%)Intermediate95 (54%)41 (82%)136 (61%)Adverse52 (30%)9 (18%)61 (27%)Age (median, range)66 (20, 87)66.5 (41, 86)66 (20, 87)0.27WBC (median, range)5.35 (0.60, 315.4)3.65 (0.20, 333.2)5.25 (0.20, 333.2)0.33No IDH mutationIDH mutationNumber assessedp-valueNRAS27 (17%)9 (19%)2100.83KRAS16 (10%)0 (0%)2100.03TP5315 (9%)1 (2%)2100.13KIT2 (1%)1 (2%)2100.54FLT3ITD34 (20%)4 (8%)2180.06FLT3TKD10 (6%)2(4%)2180.74NPM129 (17%)15 (30%)2190.07CEBPA13 (13%)3 (10%)1021.002HG MeasurementsNo IDH mutationIDH mutationTotalSerum (ng/mL)79.5 [52,123] n=1701420 [675,2735] n=51101 [58,101] n=221Urine (ng/mL)3590 [2230,6220] n=16318300 [7260,59500] n=504330 [2450,8580] n=213Marrow aspirate (ng/mL)BQL [BQL,BQL] n=14718400 [4270,43100] n=43BQL [BQL,1430] n=190Pellet (1000 ng/2*10^6 cells)64 [BQL,169] n=1271420 [675,2735] N=32107 [BQL,500] n=159 Table 2. Test characteristics based on optimal 2HG cut-off, by compartment. Compartment 2HG cut-off Sensitivity Specificity 23% prevalence PPV NPV Serum 534.5 ng/mL 0.8039 0.9882 0.9535 0.9438 Urine 16650 ng/mL 0.5600 0.9877 0.9333 0.8798 Marrow Aspirate 2210 ng/mL 0.8837 0.9660 0.8837 0.9660 Marrow Pellet 1146 ng/2*10^6 cells 0.7813 1.000 1.000 0.9478 Figure 1. Relative frequencies of 2-HG levels according to cut-off values in serum (top) urine (bottom). Figure 1. Relative frequencies of 2-HG levels according to cut-off values in serum (top) urine (bottom). Figure 2. Figure 2. Disclosures Chen: Bayer: Consultancy, Research Funding. Stone:Agios: Consultancy; Celator: Consultancy; Pfizer: Consultancy; Merck: Consultancy; AROG: Consultancy; Abbvie: Consultancy; Celgene: Consultancy; Roche/Genetech: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Juno: Consultancy; Novartis: Research Funding. Fathi:Exelexis: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Takeda Pharmaceuticals International Co.: Research Funding.

Mutations in genes encoding isocitrate dehydrogenase 1/2 (IDH 1/2) enzymes result in increased 2-hydroxyguterate (2-HG) levels, which may provide a non-invasive marker of disease in IDH-mutant AML. The purpose of this study was to characterize patients with IDH-mutant AML by assessing presenting features, concurrent mutations, and 2-HG levels. From 7-2011 through 6-2014, we identified 170 consecutive patients with newly diagnosed AML and measured 2-HG by liquid chromatography-tandem mass spectrometry in serum, urine, marrow aspirate, and marrow pellet samples. All patients had IDH1 R132, IDH2 R140 and R172 testing; 169/170 had hotspot mutational profiling for AKT1, APC, BRAF, CTNNB1, EGFR, ERBB2, KIT, KRAS, MAP2K1,NOTCH1, NRAS, PIK3CA, P53, and PTEN. We assessed FLT3 (168/170), NPM1 (168/170), CEBPA (100/170) mutational status as routine clinical care; 2 patients had BCR/ABL alterations, and 6 were JAK2 positive (of 36 tested). IDH1/2-mutant were compared to wildtype (WT) patients using a Wilcoxon rank sum test, Fisher's exact test, or Kruskal Wallis test, as appropriate. The group was 54% male; 83% white, 2.4% black, 2.4% Asian, and 6.5% Hispanic. 12 patients had APL. IDH mutations included IDH1 R132C (n=10), IDH2 R172 (n=7), and IDH2 140Q (n=22). Other mutations included NPM1 (20.8%), FLT3-ITD (17.3%), FLT3-TKD (6.6%), NRAS (18.4%), TP53 (3%), KRAS (6.5%), and KIT (1.2%). CEBPA mutations occurred in 13 of 100 patients. IDH mutations (n=39) more frequently co-occurred with normal cytogenetics and NPM1 mutations, vs IDH-WT, consistent with prior reports (Table 1). No patients with favorable cytogenetics harbored an IDH1/2 mutation. Significantly higher 2-HG levels were detected among those with IDH1/2 mutations compared to IDH WT, in the serum (p 1000 ng/mL in serum and > 1000ng/2x10^6 cells in marrow pellet) in 30/38 and 24/29 IDH-mutant patients, respectively, compared to 1/129 and 5/117 IDH WT patients. All but 2 IDH-mutant patients displayed either or both an elevated marrow pellet or serum 2-HG. Patients with IDH2 R172 mutations had lower marrow 2HG levels compared to those with R140Q mutations (Figure 1, p=0.0434). The WBC and blast count was lower among IDH2 R172-mutant compared to R140Q- or IDH1 R132C-mutant patients (p= 0.0134 and p=0.0039, respectively); there was no significant difference in serum 2HG levels. All three canonical IDH1/2 mutations have higher 2HG levels compared to IDH WT. IDH2 R172 mutated AML may present with lower WBC counts and peripheral blast percentage compared to IDH1 R132C and IDH2 R140Q mutant AML. Urine and serum 2HG levels effectively identify patients with mutant IDH1/2, of particular relevance given targeted therapies for these mutations. Table 1. Characteristics of IDH1/2-mutant and WT AML patients. IDH1/2 Mutated IDH1/2 WT p-value Age, y (median, range) 67 (41-86) 65 (20-87) 0.4718 AML History (n, %) De Novo 28 (72%) 82 (63%) 0.6336 Therapy-related 4 (10%) 15 (11%) MDS 2 (5%) 17 (13%) Cytogenetic Risk (n, %) Favorable 0 23 (18%) 0.0006 Intermediate 30 (81%) 71 (55%) Normal 25 (68%) 44 (34%) Poor 7 (19%) 34 (27%) Concurrent Mutations (n, %) NPM1 15 (38%) 20 (16%) 0.0033 FLT3-ITD 3 (8%) 26 (20%) 0.0907 FLT3-TKD 2 (5%) 9 (7%) 1.000 CEBPA Heterozygous Homozygous 3 (14%) 0 8 (10%) 2 (3%) 0.8118 NRAS 9 (23%) 22 (17%) 0.4788 KRAS 0 11 (8%) 0.0700 KIT 1 (3%) 1 (1%) 0.4093 P53 1 (3%) 4 (3%) 1.000 Table 2. WBC and 2-HG levels by IDH mutation (median, range). BQL, below quantitative limit. IDH1 R132C N= 10 IDH2 R172 N=7 IDH2 R140Q N=22 IDH WT N=131 WBC count 10.1 [1.8-333.2] 1.6 [0.7-3.2] 5.9 [0.9-122.8] 6.3 [0.4-315.4] Peripheral blast % 33.0 [0-98] 1.0 [0-9.8] 18.2 [2-91] 15 [0-94] Marrow aspirate 2-HG (ng/mL) 20,900 [1330-93500] (n=7) 4300 [2230-26000] (n=6) 30800 [BQL-311000] (n=19) BQL [BQL-22000] (n=116) Serum 2-HG (ng/mL) 1807 [101-66207] (n=9) 1102 [287-2908] (n=7) 1464 [365.1-11696] (n=22) 86.9 [BQL-1224] (n=128) Urine 2-HG (ng/mL) 33850 [7260-282000] (n=10) 7430 [2460-63700] (n=7) 11300 [2070-177000] (n=20) 3140 [BQL-53200] (n=125) Marrow pellet 2-HG (ng/2*10^6 cells) 13680 [193-172,800] (n=7) 7480 [1056-79600] (n=5) 5560 [564-96400] (n=17) 65 [BQL-4040] (n=116) Figure 1 Figure 1. Disclosures Brunner: NIH T32 CA 71345-18: Research Funding. Attar:Agios: Employment. Yen:Agios: Employment. Yang:Agios Pharmaceuticals: Employment, Stockholder Other. Straley:Agios: Employment. Agresta:Agios Pharmaceuticals: Employment, Stockholder Other. Stone:Agios: Consultancy. Fathi:Millennium: Research Funding; Seattle Genetics: Advisory Board, Advisory Board Other; Agios: Advisory Board, Advisory Board Other.

The aurora kinases play an essential role in regulating mitosis and cell division. Over-expression of aurora kinases A and B has been associated with poor-risk features in acute myeloid leukemia (AML). Preclinical studies suggest that small molecule aurora kinase inhibitors have activity in AML cell lines. Alisertib (MLN8237), a novel Aurora-A kinase inhibitor, has been generally well tolerated in early clinical trials of hematological malignancies, including AML. This study sought to evaluate tolerability of alisertib combined with standard “7+3” induction chemotherapy for AML. In this phase I, 3+3 cohort dose-escalation study, alisertib was administered with standard 7+3 induction for newly diagnosed AML. Those with acute promyelocytic leukemia or with AML and core-binding factor alterations were excluded. All patients received 7+3 induction (continuous infusion cytarabine 200mg/m2 x 7 days and intravenous idarubicin 12mg/m2 x 3 days), after which on day 8, alisertib was administered twice daily (BID) for 7 days. Dose escalation occurred via three cohorts (10mg BID, 20mg BID, 30mg BID). All underwent a mid-induction bone marrow biopsy, following the course of alisertib, to assess for residual disease, which if present, was to be treated with 5+2 re-induction (cytarabine 200mg/m2 x 5 days, idarubicin 12mg/m2 x 2 days) without alisertib. Following induction, up to four cycles of consolidation were allowed, using cytarabine (3g/m2 BID days 1,3,5 for those aged Currently, 14 patients are enrolled on study (n=3, 10mg BID; n=7, 20mg BID; n=4, 30mg BID). The median age was 62 (range 43-75); 9 (64%) were male, and all but 3 were Caucasian. One patient (7%) had therapy-related AML and six (43%) had underlying myelodysplasia. FLT3 mutations were detected in 3 (21%), NPM1 mutations in 2 (14%), CEBPA mutations in 2 (14%), and IDH1/IDH2 mutations in 4 patients (28.4%). One patient in cohort 2 died of sepsis, deemed unrelated to study drug, prior to completion of the toxicity assessment period and was replaced. Five patients have gone on to SCT. All patients received induction, 7 patients have undergone first consolidation, 3 a second consolidation, 2 a third consolidation, 1 a fourth consolidation, and 1 patient has started maintenance therapy. Alisertib has been well tolerated. All patients have experienced expected grade 4 toxicities of anemia, thrombocytopenia, and febrile neutropenia seen during the induction phase of treatment. At initial dose of 10mg BID, no dose-limited toxicities (DLTs) were encountered. In the 20mg BID cohort, one DLT was encountered, of delayed thrombocytopenia (G4 at day 40). The final cohort, at 30mg BID, is currently accruing (4 of 6 enrolled). No other DLTs have been detected, and other toxicities on study will be presented. The maximum tolerated dose (MTD) will be established upon completion of this cohort. To date, 11 of 12 (92%) evaluable patients have achieved remission following induction (8 cases of CR and 3 of CRp). During the course of the study, one patient has experienced relapse, and none have died. Thirteen of 14 evaluable patients had an ablated mid-induction marrow biopsy, with the remaining patient showing 6% blasts in a 20% cellular marrow at mid-induction. None of the patients have undergone re-induction with 5+2 at mid-induction. We anticipate that the study will be fully enrolled and closed to further accrual by the time of presentation. Alisertib, a novel aurora A kinase inhibitor, appears to be well tolerated in conjunction with standard induction chemotherapy in newly diagnosed AML. Currently, 13 of 14 treated patients have demonstrated marrow ablation at the mid-induction point of therapy, and none have required re-induction with 5+2. Eleven of 12 evaluable patients have achieved remission following induction. These results suggest that alisertib is well-tolerated and may hold promise as a therapeutic agent in AML, when combined with induction chemotherapy. Ongoing efforts seek to define the MTD and establish appropriate dosing for phase II studies. Disclosures Fathi: Millennium: Research Funding; Seattle Genetics: Advisory Board, Advisory Board Other; Agios: Advisory Board, Advisory Board Other. Attar:Agios: Employment.