Increased risk of arterial thromboembolic events with combination lenalidomide/dexamethasone therapy for multiple myeloma

2017 ◽  
Vol 17 (7) ◽  
pp. 585-591 ◽  
Author(s):  
Satish Maharaj ◽  
Simone Chang ◽  
Karan Seegobin ◽  
Ivan Serrano-Santiago ◽  
Lara Zuberi
Keyword(s):  
Multiple Myeloma ◽  
Thromboembolic Events ◽  
Increased Risk ◽  
Dexamethasone Therapy ◽  
Arterial Thromboembolic Events

Risk Factors of Thromboembolic Events in Multiple Myeloma Treated with IMiDs-Based Therapy While on LMWH Prophylaxis,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3340-3340
Author(s):  
Xavier Leleu ◽  
Simona Iacobelli ◽  
Alain Barrois ◽  
Benjamin Pelle ◽  
Liz Clark ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Research Funding ◽  
Autologous Transplantation ◽  
Working Party ◽  
Routine Practice ◽  
Thromboembolic Events ◽  
Minor Response ◽  
Oral Agents ◽  
Increased Risk

Abstract Abstract 3340 Background. Immunomodulator drugs (IMiDs) are promising oral agents in Multiple Myeloma (MM); and MM that cannot benefit from novel agents, including IMiDs, only have 9 months survival. On the other hand IMiDs are associated with an increased risk of thromboembolic events (TE) in MM, and must be stopped when TE occurs with a potential shortened life expectancy. Although DVT (Deep Venous Thrombosis), including PE (Pulmonary Embolism), was primarily observed, arterial events were also described. Guidelines have proposed LWMH for VTE prophylaxis for patients that displayed greater than 2 risk factors of VTE. Studies have showed a decrease incidence of TE since a prophylaxis was mandatory; however TE remained despite use of LMWH. We sought to characterize and study the incidence of TE in MM treated with an IMiDs-based regimen and having LMWH as TE prophylaxis, and to determine risk factors for patients to develop TE. Method. MMVAR/IFM 2005–04 is a large multicenter, prospective, randomized, open-label, phase 3, EBMT and IFM combined study that compared VTD to TD for MM patients in first progression after autologous transplantation. Treatment comprised 8 cycles of bortezomib 1.3 mg/m2 IV bolus on days 1, 4, 8 and 11 of a 21-days cycle and then on days 1, 8, 15 and 22 of a 42-days cycle for 4 more cycles. In both arms, oral thalidomide was administered at 200 mg/day for 1 year with dexamethasone at 40 mg/day for 4 days every 3 weeks for 1 year. A TE prophylaxis was mandatory in both arms using enoxaparin 40 mg/day during one year. TTP was the primary end point. Response was assessed by EBMT criteria. Adverse events were graded by the NCI-CTCAE, Version 3.0. Results. The MMVAR trial was stopped because of superiority of VTD over TD at first interim analysis, as 157 relapsed were recorded out of 267 patients randomized in arm VTD (n=135) and arm TD (n=132), respectively. With a median follow-up of 27 months, the probability of achieving CR and CR+PR during the first year, the median TTP and PFS were greater in the VTD arm, although it did not translate into a better OS, yet. In the VTD and TD arms, the mean number of treatment cycles for the 12 cycles was 7.56 vs 9.93, respectively. Treatment was discontinued due to toxicity in 48 patients, including 8 (17%) related to occurrence of TE, and 33 patients died during the treatment period. There were 24 (8.9%) TE recorded, 12 in either arm; we have then decided to pool the 2 groups for the subsequent analysis. The characteristics of the MM with TE were not different from the overall population, 14 male/10 female, median age (range) was 63 (42–76) with 25% patients older than 65. The median (min-max) time from start of MMVAR to occurrence of TE was 3.4 months (0.3–11.9), not different in either arm. TE occurred in 16 (66%) vs. 8 (33%) patients in the first 4 months and after 4 months, respectively. 15 (62.5%) pts had at least some tumor burden reduction (minor response and better) at time of occurrence of TE, while 12.5% had progression of MM, 12.5% stable disease, and 12.5% were non evaluable. All TE occurred while pts were on LMWH prophylaxis since the initiation of the study treatment but one. The occurrence of TE impacted the treatment of MM as 16 (67%) pts did stop their IMiDs-based treatment, either transiently for 8 (33%) pts or definitely for 8 (33%) pts. The doses of the IMiDs were reduced for 5 pts when IMiDs were reintroduced. Overall only 5 pts had no change applied to their MM treatment while TE occurred. The occurrence of TE might have impacted response rate, CR rate, and the survival end points, TTP, PFS and OS. An update of this sub analysis will be presented at ASH with multivariate analysis to determine risk factors for occurrence of TE while on LMWH prophylaxis. Conclusion. Although LMWH is recommended to patients with high risk of TE, the optimal dose and duration of LMWH remains to be determined. More studies are needed to determine risk factors of TE in MM patients treated with IMiDs-based regimen, and to guide physician in their routine practice with the optimal TE prophylaxis. On behalf of the Myeloma Subcommittee of the Chronic Leukemia Working Party of the EBMT (European Group for Blood and Marrow Transplantation) and the IFM (Intergroupe Francophone du Myélome). Disclosures: Leleu: Amgen: Honoraria; Roche: Research Funding; Janssen Cilag: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; LeoPharma: Honoraria, Research Funding; Novartis: Research Funding. Masszi:Centocor Ortho Biotech Research & Development: Research Funding. Hajek:Merck:; Janssen: Honoraria; Celgene: Honoraria.

Risk of arterial thromboembolic events (ATEs) with tyrosine kinase inhibitors (TKIs) used in renal cell carcinoma: A systematic review and meta-analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e13119-e13119
Author(s):  
Muhammad Zain Farooq ◽  
Jessey Mathew ◽  
Saad Malik ◽  
V V Pavan Kedar Mukthinuthalapati ◽  
Noureen Asghar ◽  
...  
Keyword(s):  
Systematic Review ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Thromboembolic Events ◽  
Phase 2 ◽  
Open Label ◽  
Increased Risk ◽  
Arterial Thromboembolic Events

e13119 Background: Tyrosine kinase inhibitors (TKIs) are routinely used in the treatment of metastatic RCC and Sunitinib is approved for the use in adjuvant setting. Arterial thromboembolic events (ATEs) have been described with these agents, although the overall risk remains unclear. We did a systematic review and meta-analysis to determine the incidence associated with the use of FDA approved TKIs used in treatment of RCC. Methods: PubMed, EMBASE, Cochrane Central and Scopus databases were searched to identify phase 2 and 3 RCTs of TKI therapy in RCC. Trials were included if they reported ATEs defined as arterial thrombosis, cerebral ischemia or infarction, myocardial ischemia and myocardial infarction. The DerSimonian-Laird random effects meta-analysis was performed using CMAv3 software to derive pooled estimates of incidence rates of ATEs with its 95% confidence interval (CI). I2 statistic was computed to express the percentage of the total observed variability due to study heterogeneity. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: 1755 studies retrieved in the initial search, and 13 phase 2 and 3 clinical trials (n = 4983) were included in the quantitative analysis. The trials had open label design which can potentially result in bias. Risk of bias was low in all other domains. TKIs used for the treatment of RCC included sunitinib (n = 2632), sorafenib (n = 981), cabozantinib (n = 78), pazopanib (n = 844), axitinib (n = 189) and tivozanib (n = 259). The incidence of ATEs with the use of TKIs was 2.9% (95% CI: 2-3%). Cabozantinib was associated with the highest rate of ATEs (11.5%, 95% CI: 6-21%), followed by sunitinib (2.6%, 95% CI:2-3%) pazopanib (2.6%, 95% CI:2-4%) and axitinib (2.1%, 95% CI: 1-6%). The TKI with lowest event rate of ATE was tivozanib (0.8%, 95% CI:0.2-3%). Conclusions: The use of TKIs is associated with increased risk of developing ATEs. Clinicians should be aware of the possibility of increased ATEs and counsel the patients about this increased risk to enhance the process of informed decision making.

scholarly journals Sex‐, Race‐ and Ethnicity‐Based Differences in Thromboembolic Events Among Adults Hospitalized With COVID‐19

2021 ◽  
Author(s):  
Sadia Ilyas ◽  
Stanislav Henkin ◽  
Pablo Martinez‐Camblor ◽  
Bjoern D. Suckow ◽  
Jocelyn M. Beach ◽  
...  
Keyword(s):  
Native American ◽  
Race And Ethnicity ◽  
Heart Association ◽  
Thromboembolic Events ◽  
Black Patients ◽  
Increased Risk ◽  
Venous Thromboembolic Events ◽  
Venous Thromboembolic ◽  
Arterial Thromboembolic Events ◽  
Hispanic White

Background Patients hospitalized with COVID‐19 have an increased risk of thromboembolic events. Whether sex, race or ethnicity impacts these events is unknown. We studied the association between sex, race, and ethnicity and venous and arterial thromboembolic events among adults hospitalized with COVID‐19. Methods and Results We used the American Heart Association Cardiovascular Disease COVID‐19 registry. Primary exposures were sex and race and ethnicity, as defined by the registry. Primary outcomes were venous thromboembolic events and arterial thromboembolic events. We used logistic regression for risk adjustment. We studied 21 528 adults hospitalized with COVID‐19 across 107 centers (54.1% men; 38.1% non‐Hispanic White, 25.4% Hispanic, 25.7% non‐Hispanic Black, 0.5% Native American, 4.0% Asian, 0.4% Pacific Islander, and 5.9% other race and ethnicity). The rate of venous thromboembolic events was 3.7% and was more common in men (4.2%) than women (3.2%; P <0.001), and in non‐Hispanic Black patients (4.9%) than other races and ethnicities (range, 1.3%–3.8%; P <0.001). The rate of arterial thromboembolic events was 3.9% and was more common in men (4.3%) than women (3.5%; P =0.002), and in non‐Hispanic Black patients (5.0%) than other races and ethnicities (range, 2.3%–4.7%; P <0.001). Compared with men, women were less likely to experience venous thromboembolic events (adjusted odds ratio [OR], 0.71; 95% CI, 0.61–0.83) and arterial thromboembolic events (adjusted OR, 0.76; 95% CI, 0.66–0.89). Compared with non‐Hispanic White patients, non‐Hispanic Black patients had the highest likelihood of venous thromboembolic events (adjusted OR, 1.27; 95% CI, 1.04–1.54) and arterial thromboembolic events (adjusted OR, 1.35; 95% CI, 1.11–1.65). Conclusions Men and non‐Hispanic Black adults hospitalized with COVID‐19 are more likely to have venous and arterial thromboembolic events. These subgroups may represent at‐risk patients more susceptible to thromboembolic COVID‐19 complications.

Hereditary Deficiencies of Protein C or Protein S Confer Increased Risk of Arterial Thromboembolic Events at Young Age. Results from a Large Family Cohort Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 422-422
Author(s):  
Bakhtawar Khan Mahmoodi ◽  
Jan-Leendert P. Brouwer ◽  
Nic J.G.M. Veeger ◽  
Jan van der Meer
Keyword(s):  
Risk Factors ◽  
Protein C ◽  
Protein S ◽  
Thromboembolic Events ◽  
Antithrombin Deficiency ◽  
Increased Risk ◽  
Atherosclerosis Risk ◽  
History Of ◽  
Arterial Thromboembolic Events ◽  
Atherosclerosis Risk Factors

Abstract Introduction: Hereditary deficiencies of protein S, protein C or antithrombin are strong risk factors for venous thromboembolism (VTE). Whether these deficiencies are associated with arterial thromboembolism (ATE) and whether history of VTE in these subjects predisposes to subsequent ATE has yet to be determined. Methods: Based on pedigree analysis we enrolled a total 552 subjects (52% women; mean age, 46±17 years), belonging to 84 different kindreds, in this retrospective family-cohort study. Detailed information on previous episodes of VTE, ATE, anticoagulants use and atherosclerosis risk factors (i.e. diabetes, hypertension, hyperlipidemia, and smoking) were collected. In addition to the index deficiencies participants were also tested for other thrombophilic defects; including factor V Leiden, prothrombin G20210A, increased FVIII and lupus anticoagulants. Primary study outcome was objectively verified symptomatic ATE. As the assumption for proportional hazards for the final model was not met over the entire observation period, we opted for a piecewise Cox model with a cut off point set at 55 years of age. Results: Of 552 subjects (mean age±SD, 46±17 years; 52% women), 308 had either protein S (35%), protein C (39%) or antithrombin deficiency (26%). Age, atherosclerosis risk factors and other thrombophilic defects were similar (P&gt;0.23) between deficient and non-deficient subjects. A total of 44 arterial thromboembolic events had occurred, corresponding to an overall annual incidences of 0.34% (95% CI, 0.23–0.49) in deficient and 0.17% (0.09–0.28) in non-deficient subjects, hazard ratio 2.3 (1.2–4.5; P=0.01). However, the risk hazards varied over lifetime; while risk of ATE conferred by these deficiencies was 5.4 (1.6–18.4; P=0.006) before age 55 years, it was 1.3 (0.6–2.9; P=0.51) thereafter. After adjusting for atherosclerosis risk factors and clustering of ATE within families, deficient subjects had 4.7-fold (1.5–14.2; P=0.007) higher risk of ATE before age 55 years, versus 1.1 (0.5–2.6; P=0.84) thereafter, compared to non-deficient family members. For separate deficiencies these were 4.6 (1.1 – 18.3), 6.9 (2.1 – 22.2) and 1.1 (0.1 – 10.9) in protein S-, protein C- and antithrombin-deficient subjects, respectively, before age 55 years. History of VTE was not related to subsequent ATE, hazard ratio 1.1 (0.5 – 2.2). Conclusions: Compared to non-deficient family members, subjects with protein S or protein C deficiencies but not antithrombin deficiency have an increased risk for ATE before age 55 years, independent of prior VTE. After age 55 years conventional atherosclerosis risk factors accounted for ATE. In thrombophilic families, deficiencies of protein S and protein C should be considered in atherothrombotic risk assessment before age 55 years.

scholarly journals Hereditary Deficiency of Protein C or Protein S Confers Increased Risk of Arterial Thromboembolic Events at a Young Age

Circulation ◽  
2008 ◽  
Vol 118 (16) ◽  
pp. 1659-1667 ◽  
Author(s):  
Bakhtawar K. Mahmoodi ◽  
Jan-Leendert P. Brouwer ◽  
Nic J.G.M. Veeger ◽  
Jan van der Meer
Keyword(s):  
Protein C ◽  
Protein S ◽  
Young Age ◽  
Thromboembolic Events ◽  
Increased Risk ◽  
Arterial Thromboembolic Events

scholarly journals Arterial thromboembolic events preceding the diagnosis of cancer in older persons

Blood ◽  
2019 ◽  
Vol 133 (8) ◽  
pp. 781-789 ◽  
Author(s):  
Babak B. Navi ◽  
Anne S. Reiner ◽  
Hooman Kamel ◽  
Costantino Iadecola ◽  
Peter M. Okin ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Cancer Diagnosis ◽  
Older Persons ◽  
Population Based ◽  
Primary Diagnosis ◽  
Thromboembolic Events ◽  
Arterial Thromboembolism ◽  
Non Hodgkin Lymphoma ◽  
Increased Risk ◽  
Arterial Thromboembolic Events

Abstract Cancer patients face an increased risk of arterial thromboembolism; however, it is uncertain when this excess risk begins. This study evaluated the risk of arterial thromboembolism before cancer diagnosis. Using the population-based Surveillance Epidemiology and End Results-Medicare linked dataset, we identified 374 331 patients ≥67 years of age with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, uterine, pancreatic, gastric cancer, or non-Hodgkin lymphoma from 2005 through 2013. Cancer patients were individually matched by demographics and comorbidities to Medicare beneficiaries without cancer, who served as controls. Validated diagnosis codes were used to identify arterial thromboembolic events, defined as a composite of myocardial infarction or ischemic stroke. The Mantel-Haenszel estimator was used to compare risks of arterial thromboembolic events between cancer and noncancer groups during 30-day periods in the 360 days before date of cancer diagnosis. From 360 to 151 days before cancer diagnosis, the 30-day interval risks of arterial thromboembolic events were similar between cancer patients and matched controls. From 150 to 1 day before cancer diagnosis, the interval 30-day risks of arterial thromboembolic events were higher in cancer patients vs matched controls, progressively increasing as the cancer diagnosis date approached and peaking during the 30 days immediately before cancer diagnosis, when 2313 (0.62%) cancer patients were diagnosed with an arterial thromboembolic event vs 413 (0.11%) controls (odds ratio, 5.63; 95% confidence interval, 5.07-6.25). In conclusion, the risk of arterial thromboembolic events begins to increase 150 days before the date of cancer diagnosis in older persons and peaks in the 30 days before.

Coagulation profiles and thromboembolic events of bortezomib plus thalidomide and dexamethasone therapy in newly diagnosed multiple myeloma

2011 ◽  
Vol 35 (2) ◽  
pp. 147-151 ◽  
Author(s):  
Yunfeng Shen ◽  
Xin Zhou ◽  
Zhi Wang ◽  
Guohua Yang ◽  
Yuanqiang Jiang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Thromboembolic Events ◽  
Newly Diagnosed ◽  
Dexamethasone Therapy

Targeting Angiogenesis in Cancer: Bevacizumab-Induced Platelet Activation as a Possible Cause for Unexpected Arterial Thromboembolic Events in Clinical Trials.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1091-1091 ◽  
Author(s):  
Todd Meyer ◽  
Theresa Robson ◽  
Ali Amirkhosravi ◽  
Florian Langer ◽  
Hina Desai ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Binding Sites ◽  
Critical Role ◽  
Thromboembolic Events ◽  
Heparin Binding ◽  
Platelet Surface ◽  
Increased Risk ◽  
Arterial Thromboembolic Events ◽  
Static Conditions

Abstract The humanized monoclonal VEGF antibody, bevacizumab (Avastin, Genentech), is approved in combination with standard chemotherapy for first-line treatment of patients with metastatic colorectal cancer (CRC) and also shows promising efficacy as anti-angiogenic immunotherapy in patients with non-small-cell lung cancer (NSCLC). A pooled analysis of five randomized, controlled trials (n=1745) showed that, compared to placebo, bevacizumab was associated with an increased risk of arterial thromboembolic events, especially in patients 65 years of age and older (8.5% vs. 2.9%, P&lt;0.01). Because platelets play a crucial role in arterial thrombosis, we hypothesized that bevacizumab has direct platelet-stimulating activity. In a washed platelet system, bevacizumab alone had no effect on platelet aggregation. However, when combined with heparin (0.3 U/ml) and recombinant human VEGF (rhVEGF165 — a homodimeric protein with heparin binding sites) in a 1:2 molar ratio of antibody to antigen to allow optimal formation of immune complexes (ICs) in solution, bevacizumab potently induced platelet aggregation (up to 80–100%; n=5). Bevacizumab-induced platelet aggregation (BIPA) was functionally dependent on Fc domain binding to the platelet low-affinity IgG receptor, FcγRIIA, as demonstrated by an inhibitory monoclonal CD32 antibody (IV.3). BIPA was potentiated in platelets pre-sensitized with low concentrations of ADP or epinephrine. In contrast, BIPA was virtually absent at excess concentrations of heparin (100 U/ml), suggesting that translocation of ICs to the platelet surface via available heparin binding sites (on platelets) was crucial for this platelet response. Unfractionated heparin and the low-molecular-weight heparin, enoxaparin, were equally effective in promoting BIPA. In a manner similar to heparin-PF4 antibodies from patients with heparin-induced thrombocytopenia (HIT), bevacizumab-rhVEGF165-heparin ICs induced significant FcγRIIA-dependent dense granule release (&gt;80%) in a 14C-serotonin release assay (SRA). While strong platelet responses were observed in both SRA and aggregometry, in which platelets were subjected to constant movement and low shear forces, respectively, bevacizumab-rhVEGF165-heparin ICs had only negligible effects on platelet CD62P expression under static conditions, indicating a critical role for platelet-platelet contacts in bevacizumab-mediated FcγRIIA signaling. In summary, our results suggest bevacizumab can induce strong FcγRIIA-dependent platelet activation in vitro when complexed with rhVEGF165 and heparin in an optimal stoichiometry. Due to their analogy to the pathomechanism of HIT, an acquired IgG-mediated disorder potentially associated with deleterious thrombosis, these findings may have direct clinical implications for older cancer patients with cardiovascular comorbidity, especially considering that many patients receive low doses of heparin for thromboprophylaxis and that elevated serum VEGF levels have been demonstrated in various types of malignancy, including CRC and NSCLC.

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