Venous Thromboembolism In Pts Research Articles

Monogenic and Polygenic Contributions to Venous Thromboembolism (VTE) and Splanchnic Thrombosis in Patients (pts) with Pancreatic Cancer (PC)

BACKGROUND Cancer-associated VTE is a significant cause of morbidity and mortality. The Khorana score (KS), which includes cancer type, body mass index, and prechemotherapy laboratory studies, is commonly used to stratify the risk of cancer-associated VTE (1). KS has low discriminative ability in some clinical situations (2) and does not include genomic information. We investigated a cohort of 753 pts with PC for germline and somatic predictors of VTE and splanchnic thrombosis and developed a PC-specific polygenic risk score (PC-PRS) to predict VTE. METHODS We manually abstracted clinical risk factors for VTE in pts of European ancestry with PC, sequenced at Dana-Farber Cancer Institute (DFCI). VTE was defined as 1) thrombosis in deep veins of the lower extremities/upper extremities or 2) pulmonary embolism. Splanchnic thrombosis was separately analyzed and defined as thrombosis of the portal, hepatic, splenic, or superior/inferior mesenteric veins. Incident VTE/splanchnic thrombosis was defined as the first occurrence of thrombosis or thrombosis-related death. KS was calculated using pretreatment laboratory values obtained prior to cancer treatment. A genome-wide association study (GWAS) was conducted for time to VTE across 5.35 million common imputed germline variants. A germline PRS was computed by cross-validation: 1) the cohort was split into 5 subsets; 2) GWAS was conducted within 4/5 subsets and PRS weights calculated using pruning and thresholding; 3) each score was predicted into the held out 1/5 subset; 4) this was repeated five times; 5) significance of the association between held-out PRS and VTE was evaluated by permutation. Associations between both PC-PRS and KS and time to VTE were determined. To assess PRS and GWAS specificity, we conducted an association analysis of 5760 solid tumors sequenced at DFCI and treated with anti-neoplastic therapy for which VTE information was available. Pathogenic somatic variants in tumor suppressor genes included truncating variants, splice-site variants affecting consensus nucleotides, or homozygous deletions. For proto-oncogenes, pathogenic calls included gene amplifications and missense variants with functional impact determined using SIFT(3) and Polyphen-2(4). False discovery rate was applied using Benjamini Hochberg (FDR<10%) RESULTS Of 753 pts with PC, 305 (40.5%) underwent PC surgery and 661 (87.8%) received chemotherapy within 6 months (mo) of diagnosis. During a median follow-up of 4.4 years, 223 (29.6%) incident VTEs and 94 (12.5%) splanchnic thromboses were identified. For 529 pts with available KS, 131 (24.8%) were intermediate-risk while the remaining were high-risk. GWAS across 753 samples identified 1 locus that was genome-wide significant for VTE (p<5x10-8). The lead SNP was rs13327332, with the minor allele associated with a significantly lower risk of VTE (HR=0.13, p=2.8x10-8, fig 1) in the PC cohort. The variant was not associated with VTE in other solid tumors. To investigate genome-wide polygenic effects, a risk score was estimated using all GWAS SNPs and evaluated by cross-validation (PC-PRS). Individuals in the top 20% of PC-PRS were at 5-fold higher risk for developing a VTE in the first 6 mo relative to the lowest 20% of PC-PRS, after accounting for the competing risk of death. Cumulative incidence of VTE in the first 6 mo was similar between pts with intermediate and high KS (fold-change=1). After adjusting for sex, age, chemotherapy within 6 months, history of prior VTE, surgery for pancreatic cancer, metastatic disease at time of VTE, and tumor purity, PC-PRS was significantly associated with time to incident VTE (HR=1.9, p=0.02) while KS was not (HR=1, p=0.96, fig 2). The PC-PRS was specific to PC and was not associated with other solid tumors. Analyzing 445 genes for associations between pathogenic somatic alterations and time-to-VTE, CNV amplifications in CIC were associated with significantly higher risk of VTE (HR=2.5, p=0.0001, FDR<10%). MAP3K1 gene alterations (n=12) were associated with 9.3x higher risk of splanchnic thrombosis (p=0.0001, FDR<10%). CONCLUSION We suggest a role for PC-PRS in VTE risk stratification and identify multiple somatic alterations with high effects on VTE incidence. Implementation of PC-PRS and integration with somatic data may provide a more refined risk estimation of VTE risk in PC than current clinical tools permit. Further validation in independent cohorts is warranted. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Peri-Transplant Venous Thromboembolism in Patients with Multiple Myeloma

Introduction Risk of venous thromboembolism (VTE) is increased in patients (pts) with multiple myeloma (MM) as a result of the biology of the disease and the use of immunomodulatory drugs (IMiDs). These patients frequently undergo autologous hematopoietic cell transplantation (AHCT) transplantation in order to improve disease-free and potentially overall survival. We conducted this study to better understand the incidence and risk factors associated with peri-transplant VTE in this population. Methods 160 MM pts who received IMiD therapy and underwent AHCT between 6/2004 and 11/2016 at our institution were the subjects of this analysis. The peri-transplant period was defined as time from central venous catheter (CVC) insertion up to 60 days post-transplant. None of the pts received VTE prophylaxis during this period. Results All patients received at least one IMiD-based regimen before transplant including thalidomide (31%), lenalidomide (74%), pomalidomide (6%). Imids were stopped at a median of 38 days prior to collection (range 0 days-4 years). CVCs (double lumen n=103, triple lumen n=50, unknown n=7) were inserted a median of 2.5 days prior to mobilized blood collection (range 0-48 days) and were removed a median of 52.5 days after insertion (range 2-303 days). Twenty of 160 patients (12.5%) developed VTE in the peri-transplant period; there was 11 (55%) CVC-related VTE, 6 (30%) lower extremity VTE and 3 (15%) pulmonary embolism. There was no VTE-related death. Median platelet count at the time of VTE was 90 (range, 30-130) x109/L. Eleven VTEs occurred between time of initiation of progenitor cell mobilization and infusion (T-0), and 9 occurred between T-0 and 60 days post-transplant. The rate of catheter-related VTE that occurred before or after T-0 was similar (55%). Thirty-nine percent of pts had a catheter size of less than 14 french; 49% had a catheter size of 14 french or more; the size could not be collected in 12% of the pts. Rate of catheter-related VTE in pts with ≥ 14 and Conclusion In this retrospective single institution analysis, we found a 12.5% incidence of peri-transplant VTEs, which is higher than what was reported in patients receiving transplant for other malignancies [1]. The size of the catheter did not affect the risk of VTE. About half of the VTEs were catheter-related, half of which occurred before T-0. If confirmed on a larger scale, it may be beneficial to give VTE prophylaxis during mobilization to minimize this risk.

Large retroperitoneal lymphadenopathy (RPLN) and increased risk of venous thromboembolism (VTE) in patients (pts) with metastatic germ cell tumours (mGCT): A Global Germ Cell Cancer Group (G3) Study.

e16058Background: Data suggest that large RPLN significantly increase the risk of VTE in pts with mGCT receiving first line platinum based chemotherapy (chemo). This multinational G3 study aims to ...

The Incidence, Risk Factors, and Prognosis of Recurrent Venous Thromboembolism (VTE) in Patients with Advanced Solid Cancers Receiving Anticoagulation Therapy After the Diagnosis of Index Vte; A Korean Venous Thromboembolism Registry Study.

AbstractAbstract 2247 IntroductionPatients (pts) with cancer have been associated with increased risk of recurrent venous thromboembolism (VTE). However, few data are available regarding the recurrent VTE in Asian pts with advanced solid cancers. Thus, the aim of the study is to investigate the incidence and risk factors for recurrent VTE in pts with advanced solid cancers receiving anticoagulation therapy after index VTE. And, we also evaluate the prognostic impact of recurrent VTE on overall survival (OS) in this population. MethodsThis study was conducted using data from the web-based registry of the Korean Thrombosis Working Party (http://kdvt.chamc.co.kr), which is an ongoing, multicenter database for recruiting consecutive pts presenting with VTE. Pts were included in the study cohort if they had been diagnosed with recurrent/metastatic solid cancers between May 2004 and Dec 2011 and initiated anticoagulation therapy. Pts were excluded if they had received a diagnosis of hematologic malignancies, if solid cancers were not recurrent or metastatic disease, if index VTE was intra-abdominal venous thrombosis or vascular access-induced thrombosis, or if anticoagulation therapy was not instituted. Pts were also excluded if they were lost to follow-up within 1 week after initiating anticoagulation therapy. Maximal duration of anticoagulation therapy was 12 months and pts in whom anticoagulation therapy was stopped within 12 months were censored at the time of discontinuation. ResultsA total of 456 pts were included in this analysis. The median age was 65 (range, 27–91) years and 249 pts (55%) were male. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0 or 1 in 185 pts (41%). The primary sites of tumor were breast in 22 (5%), genito-urinary tracts in 38 (8%), esophago-gastric in 76 (17%), colo-rectum in 81 (18%), hepato-biliary tracts in 37 (8%), pancreas in 66 (15%), and lung in 136 (30%). Palliative chemotherapy was administered in 328 pts (72%). The location of index VTE was isolated pulmonary embolism (PE) in 196 (43%), isolated lower-extremity deep venous thrombosis (DVT) in 169 (37%), and concomitant PE and DVT in 91 (20%). For initial anticoagulation therapy, low molecular weight heparin was administered in 362 pts (79%), and for long-term therapy, 306 pts (75%) received warfarin. The median duration of anticoagulation therapy after index VTE was 2.4 (range, 0.1–58.3) months.The 6-months and 12-month cumulative incidences of recurrent VTE were 22.4% (95% CI, 19.4–25.4) and 28.7% (95% CI, 24.0–33.4), respectively. In the multivariate analysis for identifying the risk factors associated with the development of recurrent VTE, pancreas (HR, 6.12; 95% CI, 2.00–18.73) and lung (HR, 2.98; 95% CI, 1.03–8.58) as the primary tumor site, poor ECOG PS (HR, 1.74; 95% CI, 1.14–2.67) and VTE initially presented with PE (HR, 2.29; 95% CI, 1.17–4.47) were independent risk factors for increased risk of recurrent VTE.With a median follow-up of 29.1 (range, 1.0–91.2) months, median OS was 11.9 (95% CI, 10.2–13.6) months. Pts with recurrent VTE had a significantly shorter OS than those without recurrent VTE (median, 8.4 vs. 13.0 months, P<0.001). In the multivariate model, occurrence of recurrent VTE was independently associated with the increased risk of death (HR, 1.39; 95% CI, 1.03–1.88). ConclusionAlthough Asian populations are thought to have lower risk for developing recurrent VTE, our study demonstrates that the incidence of recurrent VTE in pts with advanced solid cancers is comparable to that of Western populations. Lung or pancreas as a primary tumor site, poor PS, and initial presentation with PE are independent risk factors for recurrent VTE. Additionally, survival is adversely affected by recurrent VTE. Further studies are needed to validate the results of our study and to optimize the treatment strategies for improving treatment outcomes in advanced cancer pts. Disclosures:No relevant conflicts of interest to declare.

Prevalence of venous thromboembolism (VTE) among patients (pts) with acute leukemia (AL) prior to treatment.

6595 Background: Cancer and cancer treatment increases the risk of VTE. However, the association of AL and VTE is unknown. Methods: We performed a retrospective chart review to determine the prevalence of VTE prior to treatment and recurrence of VTE. Medical records of 1295 pts [299 acute lymphoblastic leukemia (ALL) pts and 996 acute myelogenous leukemia (AML) pts] at MD Anderson Cancer Center between November 1999 and May 2005 were reviewed and analyzed. All computations were conducted using Stata version 11. Results: Of the 1295 pts with AL, the overall prevalence of VTE was 1.6% (22 VTE cases, median age: 63.5 yrs). The prevalence was 2.3 % (7/299) and 1.5% (15/996) among ALL and AML patients, respectively. Two of 14 AML pts were M3-AML. In the ALL group, 1 pt had VTE approximately 1 month prior to ALL diagnosis (dx), and 6 pts developed VTE at the time of ALL dx. In the AML group, 3 pts had VTE prior and 12 pts developed VTE at AML dx. Pulmonary embolism occurred in 4 pts [3 had associated lower extremity (LE) deep venous thrombosis (DVT)]. Nine pts (7 AML, 2 ALL) had upper extremity DVTs, and 9 pts (6 AML, 3 ALL) had LE DVTs. Recurrent VTE occurred in 5/22 (23%) pts. In a univariate model, pts with baseline platelet (plt) count ≤ 50 x 109/L or 50-99 x 109/L had a protective effect on VTE development, with 69% and 85% less likely to develop VTE than pts who had plt count 100-349x 109/L, respectively. Pts with prior history of VTE were 17.8 times (95%CI: 6.3-49.27) more likely to develop a VTE than pts without a prior VTE history. Pts with phlebitis were 4.8 times (95%CI: 1.07-21.9) more likely to develop VTE than pts without phlebitis. In a multivariate model, significant predictors of VTE were baseline plt count and prior history of VTE. Overall survival did not differ between pts who developed VTE prior to treatment versus others. Conclusions: Acute leukemia pts have a high prevalence of VTE. Occurrence of VTE prior to initiation of chemotherapy was not associated with poor prognosis. Further studies should be conducted to establish guidelines for the prevention and management of VTE in pts with leukemia.

Tinzaparin Is Effective and Safe for the Treatment and Extended Secondary Prophylaxis In Cancer Patients with Venous Thromboembolism.

AbstractAbstract 1104 Background:Venous thromboembolism (VTE) is a major complication in cancer patients. The traditional treatment algorithm for VTE of UF or LMW heparin followed warfarin is associated with a higher risk of recurrent VTE and bleeding in cancer patients. A recent randomized trial has demonstrated that initial treatment and secondary prophylaxis with LMWH is associated with a lower VTE recurrence when compared to secondary prophylaxis with warfarin. We initiated a single arm Phase 2 IRB approved study to evaluate the efficacy and safety of once daily tinzaparin for the initial treatment and extended prophylaxis (6 months) of VTE in cancer patients. Included in this study was a prospective analysis of plasma biomarkers to assess whether any biomarkers could predict treatment failure or be predictive of patient survival. Methods:Patients (pts)with objectively confirmed symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE) or unexpected PE detected on staging CT scans by the criteria of OConnell et al. (JCO 24:4928, 2006) were eligible for this study, if they had an ECOG score <2 and an estimated 6 month survival. After informed consent, treatment was initiated with tinzaparin 175 U/Kg for 6 months. Planned enrollment was 100 pts. Pts who completed the 6 month study could continue on treatment for an additional 6 months if clinically appropriate. All pts who received at least one injection of tinzaparin were evaluable for efficacy and safety. Study endpoints were objectively confirmed DVT, PE or major bleeding events. Serial blood samples were obtained prior to treatment, at 1 wk, 1 month, 3 months and 6 months. Biomarkers to be studied included D-dimer (D-D), Thrombin-antithrombin complex (TAT), interleukin 6 and 8 (Il-6, Il-8) and plasma tissue factor. Only pts in whom the pretreatment, I week and 1 month blood samples were collected were included in the biomarker analysis. Results:At time of this submission 91 pts were treated on study. Of 91 pts enrolled 39 (42.9%) have completed the 6 months and 5 (5.5%) remain on active treatment. Eight (8.8%) pts withdrew from study for hospice care and one pt was withdrawn due to poor compliance. Forty-two (46%) pts died before 6 months. Ten (11%) pts continued on treatment after 6 months and one pt transitioned to warfarin treatment. Treatment endpoints included 8 (8.8%) pts with recurrent VTE (5 DVT, 3 PE); 2 occurred within the first 4 wks on treatment and the 6 events before month 3. No recurrent VTE occurred after 12wks. Three pts (3%) had major bleeding events. There were no fatal thrombotic or bleeding events. All deaths were considered due to progressive cancer, although the possible fatal VTE in pts who died at home or in hospice could not be excluded. There were 76 (83.5%) pts were evaluable for the biomarker study. Biomarker data failed to show a correlation between the level of D-D, TAT or Il-6 and patient survival from the time of their thrombotic event. However, in pts who developed recurrent VTE after 1 month, the D-D level at month 1 was higher than the pretreatment in 4/6 (66.7%) patients compared to 8/70 (11.4%) pts with no recurrence in whom month 1 samples were obtained. Conclusion:In this prospective study of tinzaparin for initial treatment and secondary prophylaxis of cancer-associated VTE, treatment appeared both safe and efficacious. Our recurrent VTE event rate of 8.8% compares favorably with the 8% recurrent VTE reported in the pts treated with dalteparin. The 3% of patients who had major bleeding events also compares favorably with the CLOT trial. Survival was difficult to predict at the time of enrollment since 46% failed to survive the 6 months. Biomarker data failed to predict survival, but patients who recurred after the first month were more likely to have month 1 D-D levels greater than pretreatment. The reason for the failure of tinzaparin treatment to effectively suppress thrombin generation in these patients remains unexplained. Disclosures:Tagawa:Leo Pharmaceutical: Research Funding; Celgene: Research Funding. Liebman:Leo Pharmaceutical: Research Funding; Celgene: Research Funding.

Venous Thromboembolism (VTE) in Patients (pts.) with Monoclonal Gammopathy of Undetermined Significance (MGUS)

Introduction: MGUS is considered to be a pre-malignant condition, and previous studies have reported VTE as a marker for a subsequent malignancy. We conducted a retrospective study to evaluate the incidence of VTE among MGUS patients (pts) and to correlate this incidence with different risk groups for developing malignancy in MGUS pts.Methods: The complete medical records of all MGUS pts at Cleveland Clinic Cancer Center at Fairview hospital from Jun/2005–Jun/2008 were retrospectively reviewed. Of 237 pts diagnosed with MGUS, 112 pts (65 males, 47 females) were eligible for our study. These pts were divided into 2 risk groups: low risk (LR)/low-intermediate risk (LIR) group (78 pts.) and high intermediate risk (HIR)/high risk (HR) group (34 pts) based on the Risk Stratification Model using three adverse risk factors; serum M-protein level ≥ 3 gm/dL, non-IgG MGUS, and an abnormal kappa/lambda free light chain ratio. Only pts with ≥ 12 months follow up were included. Exclusion criteria included a personal history of inherited thrombophilia, previous episode of VTE or anticoagulant treatment, thrombocytosis, malignancy, and renal impairment. Risk factors (RF) for VTE were identified in each pt and categorized into four groups: no RF, 0; one RF, 1; two RF, 2; and > 2 RF, >2. RF included > 48 hours of immobilization, surgery in the past 3 months, current hospitalization at the time of VTE occurrence, oral contraceptive use, and congestive heart failure.Objectives:To compare the proportion of pts with MGUS who developed VTE to the proportion of pts in the general population who developed VTE.To compare VTE incidence between the two risk groups.Results: During the study period, 9 pts with MGUS experienced VTE. In the general population, the incidence of VTE is 117/100,000 persons/year (from literature). Therefore, the proportion of pts in the general population over 3 years was 117/100000 × 3 =0.0035. The proportion of VTE in MGUS pts, adjusted for 3 years, of 0.080 is significantly higher than that for the general population (p<0.001). Comparison of VTE incidence between the two risk groups, while adjusting for the number of risk factors, showed no difference (Cox Proportional Model, p=0.38). There is no significant difference in the risk of VTE among different levels of risk factors (p=0.96). The Kaplan-Meier estimates of the proportions of pts free of VTE at 24 months are 0.96 and 0.93 for the LR/LIR and HIR/HR groups, respectively.Conclusions: MGUS is associated with a significantly higher rate of VTE compared to the general population. Despite many studies indicating VTE as a marker for subsequent malignancy, we did not find a difference in the incidence of VTE among the various risk factor groups. Any suggestive signs of VTE in pts with MGUS should be promptly evaluated and treatment initiated as soon as possible. Since the number of pts is small and the period of follow-up relatively short, a prospective cohort study is needed to verify our results.Table?: Comparison of event rate:VTEPop-valueTotal number of ptsRisk stratification model (pts)Groups (pts)VTE Proportion112LR (38)LR/LIR (78)(5)LIR (40)0.0800.0035<0.001HIR (26)HIR/HR (34)(4)HR (8)Note: Po is the VTE proportion for the general population over a 3-year time period.