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Cancer-associated venous thromboembolism (CAT) is a well-described complication of cancer and a leading cause of death in cancer patients. The purpose of this study was to assess potential associations of molecular signatures with CAT, including tumor-specific mutations and the presence of clonal hematopoiesis. We analyzed deep-coverage targeted DNA-sequencing data of >14,000 solid tumor samples using the MSK-IMPACT™ platform to identify somatic alterations associated with VTE. Endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis. Cause-specific Cox proportional hazards regression was used, adjusting for pertinent clinical covariates. Of 11,695 evaluable individuals, 72% had metastatic disease at time of IMPACT. Tumor-specific mutations in KRAS (HR=1.34 [1.09-1.64]; adjusted p=0.08), STK11 (HR=2.12 [1.55-2.89]; adjusted pKEAP1 (HR=1.84 [1.21-2.79]; adjusted p=0.07), CTNNB1 (HR=1.73 [1.15-2.60]; adjusted p=0.09), CDKN2B (HR= 1.45 [1.13-1.85], adjusted p=0.07) and MET (HR=1.83 [1.15-2.92]; adjusted p=0.09) were associated with a significantly increased risk of CAT independent of tumor type. Mutations in SETD2 were associated with a decreased risk of CAT (HR=0.35 [0.16-0.79], adjusted p=0.09). The presence of clonal hematopoiesis was not associated with an increased VTE rate. This is the first large-scale analysis to elucidate tumor-specific genomic events associated with CAT. Somatic tumor mutations of STK11, KRAS, CTNNB1, KEAP1, CDKN2B and MET were associated with an increased risk of VTE in solid tumor patients. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types.Key PointsTumor mutations in STK11, KRAS, CTNNB1, KEAP1, CDKN2B, MET and SETD2 modulate the risk of cancer-associated thrombosis.The presence of clonal hematopoiesis does not affect the risk of cancer-associated thrombosis.

Background The National Institutes of Health define African Americans or Blacks, American Indians, Alaska Natives, Hispanics or Latinos, Native Hawaiians, and other Pacific Islanders as being underrepresented in medicine. A number of studies have demonstrated that improving diversity of such underrepresented demographics within the medical profession improves patient outcomes, medical education and reduces health disparities in patients from vulnerable racial or socioeconomic groups. Despite this recognition, significant underrepresentation of various racial, ethnic, and sexual identities still exists within nearly all medical specialties. Aims The purpose of this study was to a gain a greater understanding of the current state of diversity, equity, and inclusion (DEI) efforts among U.S. hematology and medical oncology fellowship training programs. We explored the perspectives of adult and pediatric fellowship program directors regarding current recruitment strategies and suggestions for improvement to help mitigate the effects of implicit and explicit bias. Here, we present an interim analysis of the data using descriptive statistics. Methods: We convened a multi-institutional collaboration of fellowship program directors, teaching faculty, and staff members of the American Society of Hematology to develop a survey examining perceptions of DEI efforts among hematology and medical oncology fellowship program directors. The survey was pilot tested in a small group of program directors representing 6 different academic programs (5 adult, 1 pediatric). The final online survey was distributed via email to 224 fellowship program directors at U.S. adult and pediatric hematology and medical oncology fellowship programs. The survey included 29 questions regarding perspectives on bias within the fellowship selection process, current DEI initiatives, and current faculty and fellow demographics. Survey respondents were asked to rate the importance of numerous factors in determining which applicants to invite utilizing a scale of 0-10, with 0 and 10 representing lowest and highest importance, respectively. To measure program director perceptions of certain applicant groups, survey respondents were asked to rate applicant demographics as being advantaged/disadvantaged based on survey options ranging from 0-5, with 0 and 5 representing very disadvantaged and very advantaged, respectively. Results: At interim analysis, 41 of 224 program directors completed the survey for an interim response rate of 21%, including 25 adult program directors and 16 pediatric program directors, with representation from university and community programs. Of the program directors surveyed, 28 (68%) reported having access to a dedicated diversity committee or DEI policies in place to improve recruitment of underrepresented applicants. In determining which applicants to invite, respondents placed highest value on the applicant's program director letter (mean score ± standard deviation: 7.44±1.93), caliber of the applicant's residency program (7.28±2.06) and letters of recommendations (7.15±2.23). Survey respondents viewed white and male applicants as representing the most advantaged demographic group, while LGBTQI, age>40, and U.S. citizen and non-citizen international medical graduates were the most disadvantaged (Table 1). Suggestions regarding improving DEI in the fellowship selection process included implementing bias training, identifying potentially disadvantaged applicants in ERAS, increasing faculty diversity, and pairing underrepresented applicants with interviewers based on applicant preference. Conclusion: While the majority of hematology and medical oncology fellowship program directors report having DEI programs or policies to improve recruitment of underrepresented applicants, perceptions of advantaged/disadvantaged groups may extend beyond demographics traditionally viewed as being underrepresented in medicine. As our survey is ongoing, we plan to reanalyze our data when the survey has been finalized with a higher response rate utilizing multivariable regression to identify themes that may further improve DEI efforts within the fellowship selection process. Figure 1 Figure 1. Disclosures LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Murphy: North American Thrombosis Foundation: Honoraria. Naik: Rigel: Research Funding. Podoltsev: Pfizer: Honoraria; Blueprint Medicines: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; PharmaEssentia: Honoraria; Bristol-Myers Squib: Honoraria; CTI BioPharma: Honoraria.

Background: Chemotherapy induced thrombocytopenia (CIT) is common, adversely impacts chemotherapy relative dose intensity, and may adversely impact cancer control. There is no approved therapy for CIT. In our recent phase II study of solid tumor patients with CIT (Soff et al, J. Clin. Onc., 2019), romiplostim lead to correction of platelet counts in 85% of participants within 3 weeks. While on romiplostim maintenance, only 6.8% of participants experienced chemotherapy dose reduction or delay as a result of recurrent CIT within a minimum of two cycles of chemotherapy or 8 weeks. However, there is a lack of long-term data on the efficacy and safety of romiplostim in CIT. Objectives: This is an extension analysis of the phase II study for patients receiving romiplostim maintenance for 12 months or longer. Patients/Methods: In the phase II study, 44 patients successfully met the primary endpoint of correction of their platelet count within 3 weeks and resumed chemotherapy with romiplostim maintenance. 21 patients (48%) remained on romiplostim for 12 months or longer. Data were collected from one month prior to initiation of romiplostim to one month after the last dose of drug. Data extracted included complete blood count, chemotherapy doses and dates, romiplostim doses and dates, body weight, cancer diagnosis, age, gender, date of death and thrombotic events. Efficacy was demonstrated by persistent maintenance of platelet counts during long-term chemotherapy and avoidance of episodes of reduced chemotherapy dose intensity. Safety was assessed by two methods: tracking the rates of venous or arterial thrombosis; as well as development of marrow fibrosis and/or secondary hematologic malignancy. The mean romiplostim doses and lab values are calculated by month of study participation. Results: All participants had metastatic disease. Breast (N=6) and colorectal (N=6) were the most common cancers. No participant discontinued romiplostim therapy due to an adverse event or futility. One patient received romiplostim at our institution, but chemotherapy at an outside hospital; details of his chemotherapy were not available for this analysis. 14 of the 20 (70%) of the analyzable participants experienced no episode of CIT; 4 subjects experienced a single chemotherapy dose delay due CIT. No patient experienced multiple delays in chemotherapy due to CIT. Two patients required a chemotherapy dose reduction. The mean monthly platelet counts remained controlled throughout the period of analysis. (Figure 1A). The mean romiplostim doses were in the range of 3-5 mcg/kg through 35 months. There were insufficient participants beyond month 36 to allow meaningful interpretation of platelet counts or mean romiplostim doses. There was no evidence of adverse impact on absolute neutrophil count or hemoglobin levels (Figure 1B). No patient developed leukoerythroblastic changes indicative of marrow fibrosis, and no cases of secondary hematologic malignancy were identified. Two participants experienced thrombosis. One individual experienced a deep vein thrombosis. A second participant with an established history of congenital thrombophilia, experienced multiple tumor associated infarctions. The thrombotic events did not lead to discontinuation of participation in the trial for either participant. Of the 44 patients in the phase 2 study who resumed chemotherapy, 21 were alive at 12 months (48%) and 12 were alive at 24 months (27%). Conclusions: In this long-term analysis, romiplostim was effective and safe in the treatment of CIT with no evidence of drug resistance, marrow fibrosis, or secondary hematologic malignancy. The rates of thrombosis were no higher than expected for this patient demographic. There are some limitations to our analysis which includes our inability to accurately capture non-parenteral chemotherapy (oral or investigational agents) which were excluded from our analysis. We are unable to assess an impact on overall survival or cancer progression. However, the fact that half the participants were alive at 12 months and a quarter at 24 months is a reassuring signal. The analysis also is limited to the patients who were eligible for the initial phase 2 trial and corrected their platelet count within 3 weeks. Within these limitations, the extension study provides reassurance for long-term efficacy and safety of romiplostim treatment for CIT. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Romiplostim is approved to increase platelet counts in ITP and pre-surgery. We are describing the results of a clinical trial.

Background: Cancer-associated thrombosis (CAT) is a leading cause of death in cancer patients after cancer itself. Risk factors for CAT include tumor type/stage, body mass index (BMI), blood cell counts and chemotherapy exposure. These factors form the basis of prediction algorithms for CAT risk, including most notably the Khorana Risk Score. However, significant limitations exist with these currently-available risk prediction models. Emerging data suggest that a tumor's molecular profile can impact venous thromboembolism (VTE) risk. Mutations of ALK, EGFR, IDH1, ROS1, and KRAS for example have been shown to modulate the risk of CAT; however, these studies were limited by the number of mutations and specific tumor types analyzed. We hypothesized that extended molecular testing in a large patient cohort would allow for improved detection of molecular signatures associated with CAT. We analyzed deep-coverage targeted sequencing data (up to 341 genes) of tumor samples from 11,776 cancer patients to identify gene mutations associated with VTE. Methods: Adult patients with any solid tumor diagnosis who had their tumors sequenced using MSK-IMPACT from 1/2014 to 12/2016 were retrospectively assessed for CAT events using redundant algorithmic methods and individual chart reviews. The endpoint was defined as the first instance of cancer-associated pulmonary embolism and/or proximal/distal lower extremity deep vein thrombosis (DVT). An episode of upper extremity DVT was considered a competing event. The observation period was limited to 365 days after IMPACT blood control sampling. Cause-specific Cox proportional hazards regression was used to test for an association between gene and CAT risk, adjusting for clinical covariates including age, cancer type, cytotoxic chemotherapy (time-dependent), anticoagulant use, stage (metastatic/non-metastatic) and prior history of VTE. Separate multivariate models evaluated the association for the 60 most frequently-mutated genes identified, along with ALK, MET, ROS1 which were included based on existing literature suggesting an effect on VTE risk. Final p-values were adjusted for false discovery using the Benjamini-Hochberg procedure, and the threshold for statistical significance was set at 0.10. Patients with multiple cancer diagnoses were excluded. Results: Out of 11,776 individuals we observed 727 CAT events (6.2% of cohort). The most commonly represented tumor types were lung (18%), breast (15%) and colorectal cancer (10%); see Figure for a breakdown of CAT incidence by tumor type. Most (72%) of patients were metastatic at time of IMPACT testing and 4% were on anticoagulation therapy. Statistically significant predictors of CAT included cytotoxic chemotherapy (HR 1.61 [1.37-1.9]; p Conclusions: This work is the first large-scale analysis to elucidate cancer-specific genomic determinants of CAT. Using a large patient cohort, we found that somatic tumor mutations in STK11, KRAS, IDH1, KEAP1, and MET modulate the risk of venous thromboembolism in solid tumor patients. Further analysis is needed to validate these findings and identify additional molecular signatures unique to individual tumor types. We hope these findings will ultimately translate into improved risk stratification for patients at risk of CAT. Disclosures Mones: Janssen: Research Funding. Iyengar:Puma Biotechnology: Consultancy; Novartis: Consultancy. Hyman:AstraZeneca: Consultancy, Research Funding; Fount: Consultancy, Equity Ownership; Pfizer: Consultancy; Chugai Pharma: Consultancy; Loxo Oncology: Research Funding; Boehringer Ingelheim: Consultancy; Bayer Pharmaceuticals: Consultancy, Research Funding; Genentech / Roche: Consultancy; PUMA Biotechnology: Research Funding; CytomX Therapeutics: Consultancy. Park:Merck: Research Funding; Parker Institute for Cancer Immunotherapy: Research Funding; Astellas: Research Funding; Ipsen: Consultancy. Khorana:Bayer: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy. Soff:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Mantha:Medical Case Management Group: Consultancy; MJH Live Events: Other: Give CME talk; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy; Daboia Consulting LLC: Equity Ownership; Janssen: Research Funding.

In clinical practice, leukocytosis is often overlooked after infectious and hematologic disease are ruled out, particularly in patients with solid tumors. This is unfortunate, as the mechanisms that mediate paraneoplastic leukocytosis may play a significant role in the underlying pathophysiology of cancer progression and prognosis. The relatively new discovery of neutrophilic and monocytic myeloid-derived suppressor cells (MDSCs) and their role in mediating tumor metastasis has particularly shed light into this process [Annu Rev Med, 66:97-110 (2015)]. Here, we present the case of a 58-year old gentleman with non-small cell lung cancer complicated by brain metastasis, status post resection who presented with sepsis and acute kidney injury (AKI) requiring ICU care for worsening AKI, hypoxic respiratory failure and leukocytosis. His peak WBC count, absolute neutrophilia and monocytosis were: 178.1, 172.7 and 4.2k/µL, respectively. His peripheral blood smear revealed mature neutrophils with left-shift and no blast forms. The underlying etiology of his leukocytosis was initially attributed to steroids administration and infection (Figure 1). His leukocytosis progressed, however, despite improvement in his sepsis and tapering of his steroids. Thus, we suspected either an evolving hematologic neoplasm or exogenous secretion of G-CSF by his tumor. Nonetheless, given his worsening clinical status, we initiated empiric hydroxyurea and leukapheresis. His FISH and PCR for BCR-ABL were negative in addition to the absence of leukemia-associated mutations and gene fusions and a normal phenotype by flow cytometry. However, we detected the highest documented level of G-CSF secreted by any tumor in the literature at 41,108.6pg/mL (normal On evaluation of this patient's clinical history, his malignancy and white count were stable until day 388 of his diagnosis when he developed new onset leukocytosis and neutrophilia associated with disease progression and metastasis. Furthermore, he died within 23 days of developing peak leukocytosis, neutrophilia and monocytosis and the discovery of his profoundly elevated G-CSF level. The association between the onset of his leukocytosis with the discovery of his disease progression and metastasis suggest that G-CSF secretion and leukocytosis may have been linked to his poor prognosis. We performed an extensive literature review and found that neutrophilic and monocytic MDSCs may provide a potential explanation for this phenomenon. We believe that leukocytosis in the setting of solid neoplasms may be driven by increased G-CSF secretion by tumors or tumor microenvironments. Additionally, G-CSF secretion fosters the expansion of neutrophilic and monocytic MDSCs, which play a significant role in tumor progression and metastasis and may contribute to poor prognosis [PNAS 106(16): 6742-7 (2009), PNAS 107(50): 21248-55 (2010)]. Consequently, we believe that the significance of leukocytosis in patients with solid tumors should not be overlooked and that there may exist a novel, untapped paradigm between paraneoplastic G-CSF secretion, leukocytosis, neutrophilic and monocytic MDSCs and prognosis. Disclosures Mauro: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy.

Introduction: Cancer associated thrombosis (CAT) is a common complication of cancer, associated with significant morbidity and mortality. While incidence varies with cancer type, stage, chemotherapy, and other factors, estimates are that up to 20% of cancer patients will experience at least one venous thromboembolic (VTE) episode. VTE consist of deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and there is a spectrum of vascular involvement. DVTs are classified as proximal (popliteal vein or above) and PE may be subsegmental, segmental, lobar, main, or saddle embolism. Our standard approach has been to treat all DVTs and all PEs in cancer patients, regardless of the size of the involved vessel. However, it is not clear if the risk of recurrent VTE in a patient with a "small" subsegmental PE, or a calf vein DVT, is comparable to that of an individual with a larger vascular involvement. In this study, we characterized the largest vessel involved in the initial VTE episode, and the relationship with recurrent VTE. Methods: All patients at MSKCC with CAT are monitored within an existing Quality Assessment initiative. From 1/1/2014 through 10/31/2016, 1072 patients with CAT were treated with rivaroxaban (Riva). (The overall outcomes of this cohort are the subject of a separate abstract.) In this study we compared the rate of recurrent VTE in patients with a distal (calf) DVT with proximal DVT, and PE. We designated the most proximal, or largest thrombosed vessel. As patients with a PE do not routinely undergo Doppler leg ultrasound, we are unable to differentiate PE with a DVT from those without. We also analyzed if the PE was unilateral or bilateral. We used competing risk endpoints for the purpose of this analysis, including recurrent VTE, major bleeding, clinically relevant non-major bleeding leading to discontinuation of Riva, and death. Results: In the Table, we present the data on the relationship of the initial VTE and the risk of recurrence. The majority of CAT events (55%) were PE. There were no significant differences in the rates of recurrent VTE between patients with a PE, a distal DVT or proximal DVT. Within patients with a PE as the index VTE event, there was no significant association between the risk of recurrent VTE and the size of the PE. A subsegmental PE as an index event was associated with a comparable rate of recurrent VTE when compared with segmental and more proximal vessel involvement. The only meaningful trend towards a higher rate of recurrent VTE was in patients whose index event was a bilateral PE, compared with unilateral, although this association did not reach statistical significance. Conclusions: The goal of this Quality Assessment initiative was to evaluate the risk of recurrent VTE in cancer patients to determine if distal DVT's or subsegmental PEs had a significantly lower rate of recurrence than other VTE episodes. Our analysis indicated that the risk of recurrent VTE is not related to the size of the index thrombosed vessel. Within PE, from large, proximal index events through to subsegmental PE, the risk of recurrent VTE is comparable. Similarly, there was only a trend towards lower risk of recurrent VTE in patients with an index distal DVT, versus proximal DVT. But this association was not statistically significant, with overlapping 95% confidence intervals. The one parameter that appeared to have the strongest prediction of recurrent VTE was patients with bilateral PE, versus unilateral. However, this too was only a trend, not statistically significant, and was not one of the parameters within our initial hypotheses. We were unable to identify any subgroup of index VTE, based on vessels involved, that had a significantly lower rate of recurrent VTE while on anticoagulation. Within cancer patients, a subsegmental PE or a distal, calf vein DVT are associated with a risk of recurrent VTE comparable to thrombosis of larger vessels. Table Table. Disclosures Soff: Janssen: Research Funding; Amgen: Research Funding. Mantha:Janssen: Research Funding; GLG: Consultancy; Heidell, Pittoni, Murphy & Bach, LLP: Consultancy.

Introduction: Venous thromboembolism (VTE) is a common complication of cancer, associated with significant morbidity and mortality. Low-molecular weight heparin (LMWH), the most widely used anticoagulant in this setting, is expensive and burdensome. Rivaroxaban (Riva) was approved for treatment of VTE in 2012, but there is limited experience in cancer-associated thrombosis (CAT). In 2014, we established a Clinical Pathway (CP) to guide use of rivaroxaban (Riva) for CAT at Memorial Sloan Kettering Cancer Center. We were concerned that a direct oral anticoagulant (DOAC) would be more likely than LMWH to cause upper gastrointestinal (GI) bleeding in the presence of abnormal mucosa. DOACs have partial renal clearance and are active in the urine, in contrast to LMWH, and we also anticipated increased genitourinary (GU) tract bleeding in the presence of GU lesions. Therefore, the key to our CP has been to recommend against use of Riva or other DOAC in the setting of active (GI) or (GU) tract lesions. As the elderly are known to be at higher risk of bleeding from anticoagulation, the CP recommended reduced dose Riva in patients≥75 year old (yo), (10 mg bid X 3 wks., followed by 15 mg daily). Otherwise, we adhere to the standard FDA approved guidelines. We published a 200-patient cohort in 2016 demonstrating rates of recurrent VTE and bleeding that were at least as low as historical controls with LMWH. This past year, two randomized clinical trials were published comparing a DOAC with dalteparin ("Hokusai VTE Cancer" of edoxaban, Raskob G.E. et al, NEJM, 2017, and "Select-D" of Riva, Young A.M. et al, JCO 2018). Both studies showed a trend towards better efficacy with the DOAC, but with increased GI/GU bleeding. However, those studies did not exclude patients with known GI/GU lesions. We now report our expanded experience with Riva treatment of CAT, confirming the safety and efficacy of Riva treatment of CAT when guided by our CP. Methods: From 1/1/2014 through 10/31/2016, 2000 patients at MSKCC received Riva. 1072 had CAT, defined as a lower extremity DVT and/or PE in a patient with active cancer or receiving cancer therapy. (The other 928 patients did not have active cancer, or received Riva for other indication). All patients treated with Riva for CAT are included in this analysis, even in the presence of active GI/GU lesions. Recurrent VTE, major bleeding (MB), clinically relevant non-major bleeding (CRNMB) leading to discontinuation of Riva, and death were competing risk endpoints for the purpose of the analysis. We also evaluated the outcomes of the subgroup of patients ≥75 yo. Results: At 6 months, the cumulative incidence for the various endpoints estimated within a competing risks framework were; recurrent VTE (4.2%), MB (2.2%), CRNMB (5.5%). Overall, the 6-month incidence of death was 22.2%. In the elderly patients, the risks of recurrent VTE and bleeding were similar to the Conclusions: In our expanded experience of Riva therapy for CAT, applying our CP, we continue to maintain low rates of recurrent VTE and bleeding. Allowing for differences in methodology between a cohort study and randomized clinical trials, the rate of recurrent VTE was as low as the DOAC arm in Hokusai VTE Cancer and Select-D studies. Further, by applying the exclusion criteria in our CP, and not treating patients with known GI/GU lesions, we achieved a low rate of bleeding compared with the DOAC treatment arms in the two recent randomized clinical trials. Those two trials demonstrated bleeding rates greater than LMWH, particularly GI/GU bleeds. We saw no increased rates of recurrent VTE or bleeding in the elderly, which is reassuring, but we cannot conclude if reduced dose is of benefit. These new expanded observations further support the validity of our CP. The key to anticoagulation choice for CAT is not which anticoagulant is "better," but rather which anticoagulant to choose for a specific patient. In the absence of GI/GU contraindications, Riva provides effective and safe anticoagulation, at substantially lower cost and burden to the patient than LMWH. In contrast, we propose that LMWH is preferable in patients with GI/GU lesions. (We are now obtaining specific data for that subgroup). Disclosures Soff: Amgen: Research Funding; Janssen: Research Funding. Mantha:Heidell, Pittoni, Murphy & Bach, LLP: Consultancy; GLG: Consultancy; Janssen: Research Funding.