Clinically significant bleeding can occur as a consequence of surgery, trauma, obstetric complications, anticoagulation, and a wide variety of disorders of hemostasis. As the causes of bleeding are diverse and not always immediately apparent, the availability of a safe, effective, and non-specific hemostatic agent is vital in a wide range of clinical settings, with antifibrinolytic agents often utilized for this purpose. Tranexamic acid (TXA) is one of the most commonly used and widely researched antifibrinolytic agents; its role in postpartum hemorrhage, menorrhagia, trauma-associated hemorrhage, and surgical bleeding has been well defined. However, the utility of TXA goes beyond these common indications, with accumulating data suggesting its ability to reduce bleeding and improve clinical outcomes in the face of many different hemostatic challenges, without a clear increase in thrombotic risk. Herein, we review the literature and provide practical suggestions for clinical use of TXA across a broad spectrum of bleeding disorders.

Purpose Cyclin‐dependent kinase (CDK) 4/6 inhibitors are integral treatment for advanced hormone receptor positive breast cancer; however, venous thromboembolic events (VTE) occurred in 1%‐5% of clinical trial patients. Thrombosis rates in the real‐world setting remain unclear. We aimed to define the rate of thromboembolic events, risk factors for thrombosis on CDK 4/6 inhibitors and evaluate the Khorana VTE risk score as a predictive tool for VTE in patients on CDK 4/6 therapy. Methods Multicenter retrospective analysis of adult breast cancer patients prescribed palbociclib, ribociclib, or abemaciclib. The primary endpoint was thrombosis during treatment or within 30 days of CDK inhibitor discontinuation. Cox regression was used to model time‐to‐thrombosis, starting from a patient's initiation of CDK 4/6 therapy. The extended Kaplan‐Meier method and Cox modeling were used to assess the effect of time‐varying thrombosis status on overall survival. Results Two hundred and sixty‐six patients were included (89% on palbociclib, 14% on abemaciclib, 7% on ribociclib). Twenty‐nine thrombotic events occurred in 26 (9.8%) women. Of these events, 72% were venous and 34% were arterial. The 1‐year incidence of thrombosis was 10.4% overall, 10.9% on palbociclib, 8.3% on ribociclib, and 4.8% on abemaciclib. Hemoglobin less than 10 g/dL was a statistically significant predictor of thrombosis (HR 3.53, P: .014). Khorana score ranged from 0‐3, with the majority between 0 and 1 and was not predictive of VTE. Thrombosis was associated with reduced overall survival (HR 1.28, P: .128, median 7.3 months) compared to not having a CDK‐associated clot (median 35.7 months). Discussion VTE in our analysis is higher than reported in clinical trials and arterial thrombosis comprised over one‐third of events. The highest incidence was with palbociclib, followed by ribociclib. Khorana score did not predict VTE risk. Larger, real‐world studies are needed. The role for prophylactic anticoagulation is yet to be defined in this patient population.

e13030 Background: CDKi with endocrine therapy (ET) is approved treatment of metastatic HR+/HER2- breast cancer based on PFS benefit vs ET alone. Outcomes data following CDKi discontinuation (dc) is limited, with trials ongoing in this setting. The reported phenomenon of rapid progression within 4 months of CDKi dc raises concern over CDKi impact on HR+/HER2- MBC biology. This study aims to define outcomes after CDKi dc and identify predictors of progression. Methods: This is a retrospective review of women ≥18 years with HR+/HER2- MBC who received CDKi between 4/1/14 and 12/1/19. Patient and tumor characteristics, pre and post CDKi tx, and reason for CDKi dc were collected. Time to event outcomes from date of CDKi dc (primary = PFS, secondary = Overall Survival, OS) were analyzed with Kaplan Meier estimators and Cox regression. Results: Analysis included 140 patients (median age 65 years), with most MBC (84%) arising from earlier stage disease. 51% of MBCs had visceral disease, and 66% received tx prior to CDKi. The most common CDKi was palbociclib (93%); and most common ET were letrozole (52%) and fulvestrant (40%). Median CDKi tx duration was 9 months (3.5 – 17.4) with 80% dc due to progression. Post CDKi txs included chemotherapy (44%), ET (24%), targeted tx (21%), no further tx (7%) and CDKi tx (4%). Median follow up was 12 months. mPFS post CDKi dc were 6.5 months (95% CI: 5.0 – 7.9) and 11.3 months (95% CI: 4.6 – 23.7) in patients who dc CDKi due to progression or other reasons, respectively (HR 1.77, 95%CI: 1.10-2.85). Among 112 patients who progressed on CDKi, estimated 4-month incidence of post CDKi progression or death was 31% (Table ). mOS post CDKi dc was 15.4 months (95%CI: 13.3-19.0) and mOS post CDKi initiation was 26.5 months (95% CI: 23.3 – 34.3). Visceral disease (HR 1.45, 95%CI: 1.01-2.08) and progression as reason for CDKi dc (HR 1.77, 95%CI: 1.1-2.85) were predictors of PFS (p < 0.05). Receiving fulvestrant with CDKi (HR 1.42, 95%CI: 0.96-1.0), prior chemotherapy in the metastatic setting (HR = 1.39, 95% CI: 0.90 – 2.14), and shorter CDKi duration were associated with non-significant increased risk of PFS. Conclusions: Rapid progression or death at 4 months occurred in 31% of MBCs following CDKi dc due to progression. Ongoing studies to define clinical and molecular characteristics of rapidly progressing tumors are underway to develop targeted tx approaches and improve outcomes.[Table: see text]

1054 Background: Combination of CDKi with endocrine therapy is a key treatment for mHRBC due to survival benefit and favorable safety profile. However, progressive disease inevitably develops and outcomes after CDKi discontinuation (dc) are not well-described. Within our institution, we previously reported clinical characteristics and outcomes for a cohort of 140 mHRBC patients who received CDKi therapy. Median progression-free survival (PFS) and overall survival (OS) post-CDKi dc were 7.0 and 15.4 months, respectively. However, 29% experienced rapid progression or death within 4 months following CDKi dc. Molecular predictors of rapid progression after CDKi are unknown and may help define therapies to improve outcomes. In this study, we sought to identify molecular predictors for rapid disease progression after CDKi dc in mHRBC. Methods: We identified within our cohort 34 patients with mHRBC who progressed on CDKi with next-generation sequencing (NGS) performed on pre-CDKi tissue samples. PFS and OS, measured from CDKi dc, were analyzed with the Kaplan-Meier estimator and log-rank test. Rapid progression was analyzed with logistic regression and Fisher’s exact test to evaluate association between pre-CDKi tumor mutation and rapid progression post-CDKi. Results: NGS of pre-CDKi tumor biopsies found 12 genes ( FGF3, FGF4, FGFR, PIK3CA, PTEN, AKT, RB1, CDKN2A, MYC, CCND1, ESR1, TP53) that were altered in ≥3 of the 34 patients. The six patients (18%) with a PTEN mutation (mut) had a median PFS of 3 months and median OS of 4 mo. In comparison, median PFS and OS of PTEN wild-type (wt) patients were 7 mo. (log-rank p=0.008) and 21 mo. (log-rank p<0.001), respectively. Moreover, those with PTENmut tumors were more likely to experience rapid progression compared to PTENwt (odds ratio = 7.0, 95% CI: 1.1 – 60.5, p=0.048). Notably, in the 10 rapid progression patients with pre-CDKi NGS results, alterations to PI3K pathway constituents were prevalent: PTENmut (40%), FGFRmut (50%), AKTmut (20%) and PIK3CAmut (40%). Conclusions: PI3K pathway alterations are prevalent in mHRBC patients who develop rapid progression post-CDKi dc, with PTENmut being the most significant predictor. These hypothesis-generating findings provide the basis for ongoing investigations to find clinical and molecular biomarkers that can help improve outcomes for mHRBC at risk of rapid progression post-CDKi therapy.[Table: see text]

Background: Cyclin dependent kinase (CDK) 4/6 inhibitors combined with endocrine therapy are an integral therapy for advanced hormone receptor positive breast cancer. Rates of venous thromboembolic events (VTE) were between 1-5% in clinical trials leading to CDK 4/6 inhibitor approval. Abemaciclib currently carries an FDA warning for VTE risk. However, rates of thrombosis in real world practice remain poorly described. We aim to better define the thrombotic risk associated with CDK 4/6 inhibitors, expanding to evaluate venous and arterial events. Additionally, factors that predispose to thrombosis while on CDK 4/6 inhibitors are unclear. We hypothesize the Khorana thrombosis risk score may predict which patients will experience thrombosis on CDK 4/6 therapy. Methods: We conducted a retrospective analysis of breast cancer patients aged ≥18 years who were prescribed a CDK 4/6 inhibitor (palbociclib, ribociclib, abemiciclib) at the Knight Cancer Institute and affiliated clinics between February 2015 and March 2020. Venous and arterial thrombosis occurring during treatment or within 30 days of discontinuation were included. We collected data including pre-treatment lab values, age, BMI, prior thrombosis, and smoking status and calculated a Khorana risk score for each patient. Utilizing univariate and multivariate logistic regression we compared these variables in patients who developed thrombosis and those who did not. We calculated overall survival of the two groups. Results: There were 270 patients included in the analysis and 29 patients (10.7%) developed a thrombotic event. Of these, 66% were venous, 28% were arterial, and 10% experienced &gt;1 clot. Ribociclib had the highest incidence of thrombosis; 17%, followed by palbociclib; 9% and abemaciclib; 5% (Table 1). Multivariate analysis evaluating risk factors for thrombosis did not find any statistically significant predictors of thrombosis (Table 2). Khorana scores did not predict which patients experienced thrombosis. Median overall survival did not significantly differ between those who developed thrombosis and those who did not (23 months vs 17.5 months respectively, p value = 0.37). Discussion: Incidence of thrombosis in our institutional analysis is higher than reported in clinical trials. Interestingly, we found arterial thrombosis comprised over one-third of events. Patients on ribociclib experienced the highest incidence of thrombosis, suggesting the FDA thrombosis warning may need to be expanded to the drug class. Khorna scores were not predictive of thrombosis risk in our population, however only 1% of study patients had a high risk score over 2. Larger, real world studies are needed to define the risk of thrombosis with CDK 4/6 inhibitors. The role of prophylactic anticoagulation is yet to be defined in this patient population. TABLE 1: Incidence of thrombosisCumulative Incidence:Total CDK 4/6 inhibitor populationn = 270Number of thrombotic events29 (11%)Total arterial8 (28%)Total venous19 (66%)Total arterial + venous2 (6.9%)Incidence by CDK4/6 inhibitorAbemaciclib (n = 20)1 (5%)Palbociclib (n = 233)22 (9.4%)Ribociclib (n = 17)3 (17.6%)Site of eventFirst thrombotic eventn = 26CVA2 (6.9%)CVA + DVT1 (3.5%)CVA + MI1 (3.5%)DVT10 (34.5%)MI1 (3.5%)PE4 (13.8%)PE + DVT2 (7%)Line associated DVT1 (3.5%)Retinal vein thrombosis1 (3.5%)TIA3 (10.3%)Second thrombotic eventn = 3DVT1 (3.5%)PE + MI1 (3.5%)TIA1 (3.5%) TABLE 2 Predictors of thrombosisCharacteristicOR95% CIP-ValueAge1.020.98 - 1.060.28BMI1.040.98 - 1.10.24Hemoglobin0.830.69 - 1.000.06History of thrombosis1.910.72 - 5.090.20Platelet1.00.99 - 1.010.86Smoking2.610.75 - 9.110.13WBC0.970.84 - 1.110.64 Citation Format: Malinda West, Claire Smith, Tia Kohs, Ramin Amirsoltani, Jessica Ribkoff, Joshua Choung, Alison Palumbo, Joseph Shatzel. CDK 4/6 inhibitors are associated with a high incidence of thrombotic events in real world practice [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-24.

Background The direct antiglobulin test (DAT) is frequently ordered by both hematologists and non-hematology medical professionals in the workup of possible allo- or autoimmune hemolytic anemias. Frustratingly, positive DAT results in the absence of other abnormal blood hemolysis biomarkers can be challenging to interpret, as published data on the frequency of these "false-positive" DATs is limited. We sought to characterize the frequency of "false-positive" DATs and describe potential associations with co-morbid diseases, in order to better define the diagnostic accuracy of the DAT for allo- or autoimmune hemolysis. Methods After obtaining appropriate Institutional Review Board approval, we identified all positive DAT results from Oregon Health & Science University during the calendar year between January and December 2019. Electronic medical records of the patients associated with these positive DAT results were individually reviewed, with collected data including patient demographics, specific pattern of DAT positivity (IgG, C3 or both), reason for obtaining DAT (suspicion for autoimmune hemolysis or transfusion, or as part of preparatory workup for possible blood product transfusion), hemolysis biomarkers (CBC, reticulocytes, LDH, haptoglobin, total and direct bilirubin), recent blood product transfusion or IVIG administration within the preceding 6 months, and co-morbid illnesses. True positive DAT results were considered those concurrent with at least one other positive blood hemolysis biomarker, or those in patients with a pre-existing diagnosis of autoimmune hemolytic anemia or Evans syndrome. Results 182 positive DAT tests among 134 individual patients were identified within the specified time period. 65 of these were obtained in the ambulatory setting, and 117 as inpatient. The majority of DAT results were positive for IgG only (165 of 182, 90.7%), with 17 of 182 (9.3%) positive for both IgG and C3, and no instances of isolated C3 positivity. The median values for hemolysis biomarkers were as follows: LDH 307, total bilirubin 0.9, and haptoglobin 80. Of the 134 patients with positive DAT results, 48 (36%) had at least one other positive or elevated blood biomarker of hemolysis, and 31 (23%) had two or more positive biomarkers. 55 records (41%) had no other associated findings of hemolysis, and 31 patients had not had hemolysis biomarkers drawn. 53 of 134 patients (40%) had DATs checked as part of alloantibody workup prior to potential blood product transfusion. The calculated rate of DAT positivity concurrent with other positive hemolysis biomarkers was 79 of 134 (59%), and DATs without other signs of hemolysis were seen in 55 of 134 (41%). Among patients with DAT results without signs of hemolysis, common co-morbid illnesses/conditions included recent blood product transfusion, multiple myeloma, acute myeloid leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, hypothyroidism, and cirrhosis. The majority of patients had received blood product transfusion or IVIG within the preceding 6 months (94 out of 134 [70%]). Discussion In this single-center retrospective analysis, we found a substantial rate of DAT positivity for IgG, or combined IgG and C3, without other laboratory biomarkers of hemolysis. While many of these non-hemolysis-related positive DAT results could be considered false positives, a substantial proportion of patients had also received blood product transfusion or IVIG within the previous 6 months, and thus a large fraction of included patients may have had positive DATs related to previous alloimmunization and lingering "bystander" hemolysis or agglutination of autologous red blood cells. In addition, co-morbid hepatic, autoimmune or hematologic diseases were common among this cohort, corroborating findings in previously published analyses. In summary, we found a clinically meaningful rate of false-positive DAT results in both ambulatory and inpatient settings. We posit that a positive DAT result, in isolation, need not drive extensive hemolysis workup, given the frequent association with prior blood product transfusions and numerous co-morbid illnesses. Disclosures No relevant conflicts of interest to declare.

Background Cyclin-dependent kinase 4/6 inhibitors (CDKi) have changed the landscape for treatment of patients with hormone receptor positive, human epidermal growth factor receptor 2-negative (HR+/HER−) metastatic breast cancer (MBC). However, next-line treatment strategies after CDKi progression are not yet optimized. We report here the impact of clinical and genomic factors on post-CDKi outcomes in a single institution cohort of HR+/HER2− patients with MBC. Methods We retrospectively reviewed the medical records of patients with HR+/HER2− MBC that received a CDKi between April 1, 2014 and December 1, 2019 at our institution. Data were summarized using descriptive statistics, the Kaplan-Meier method, and regression models. Results We identified 140 patients with HR+/HER2− MBC that received a CDKi. Eighty percent of patients discontinued treatment due to disease progression, with a median progression-free survival (PFS) of 6.0 months (95% CI, 5.0-7.1), whereas those that discontinued CDKi for other reasons had a PFS of 11.3 months (95% CI, 4.6-19.4) (hazard ratio (HR) 2.53, 95% CI, 1.50-4.26 [P = .001]). The 6-month cumulative incidence of post-CDKi progression or death was 51% for the 112 patients who progressed on CDKi. Patients harboring PTEN mutations pre-CDKi treatment had poorer clinical outcomes compared to those with wild-type PTEN. Conclusion This study highlights post-CDKi outcomes and the need for further molecular characterization and novel therapies to improve treatments for patients with HR+/HER2− MBC.