Venous thromboembolism in adrenocortical carcinoma: a retrospective analysis.

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of death in patients with cancer. Limited data exist about VTE in patients with adrenocortical carcinoma (ACC). The primary objective of this study was to identify the prevalence of VTE in a cohort of patients with ACC. Secondary objectives were to determine the impact of VTE events on overall survival (OS) and to describe the characteristics of VTE in patients with ACC. PATIENTS AND METHODS: We retrospectively reviewed data from 289 patients with ACC cared for at a major referral center from February 2010 to June 2022. RESULTS: VTE prevalence was 18.7% (54 events). Thirty patients (55.6%) had pulmonary embolism (PE); 12 patients (22.2%) had deep vein thrombosis (DVT); and 12 patients (22.2%) had both PE and DVT. VTE occurred after ACC diagnosis in 50 patients (92.6%) including 44 patients (88%) with stage 3 or 4 ACC. VTEs were CTCAE grade ≤2 in 32 cases (59.3%), grade 3 in 17 (31.5%), and grade 4 in 2 (3.7%). Thirteen patients (24%) died within 6 months after VTE diagnosis, although there was no statistically significant association between VTE and overall survival. CONCLUSION: Despite the potential to underestimate the prevalence of VTEs, we found a high frequency of VTE events in patients with ACC. A majority of VTEs occurred in the context of advanced ACC and we observed high short-term mortality. Further studies are needed to validate our findings and investigate mechanisms associated with VTE in ACC.

Thrombosis risk prediction in lymphoma patients: A multi-institutional, retrospective model development and validation study.

Venous thromboembolism (VTE) poses a significant risk to cancer patients receiving systemic therapy. The generalizability of pan-cancer models to lymphomas is limited. Currently, there are no reliable risk prediction models for thrombosis in patients with lymphoma. Our objective was to create a risk assessment model (RAM) specifically for lymphomas. We performed a retrospective cohort study to develop Fine and Gray sub-distribution hazard model for VTE and pulmonary embolism (PE)/ lower extremity deep vein thrombosis (LE-DVT) respectively in adult lymphoma patients from the Veterans Affairs national healthcare system (VA). External validations were performed at the Harris Health System (HHS) and the MD Anderson Cancer Center (MDACC). Time-dependent c-statistic and calibration curves were used to assess discrimination and fit. There were 10,313 (VA), 854 (HHS), and 1858 (MDACC) patients in the derivation and validation cohorts with diverse baseline. At 6 months, the VTE incidence was 5.8% (VA), 8.2% (HHS), and 8.8% (MDACC), respectively. The corresponding estimates for PE/LE-DVT were 3.9% (VA), 4.5% (HHS), and 3.7% (MDACC), respectively. The variables in the final RAM included lymphoma histology, body mass index, therapy type, recent hospitalization, history of VTE, history of paralysis/immobilization, and time to treatment initiation. The RAM had c-statistics of 0.68 in the derivation and 0.69 and 0.72 in the two external validation cohorts. The two models achieved a clear differentiation in risk stratification in each cohort. Our findings suggest that easy-to-implement, clinical-based model could be used to predict personalized VTE risk for lymphoma patients.

Management of DOAC-related bleeding in cancer patients: a single center-case series.

Venous thromboembolism (VTE) and stroke carry significant mortality and morbidity in cancer patients. Direct oral anticoagulants (DOACs) have been demonstrated to be effective for the treatment of VTE and prevention of stroke in atrial fibrillation (AF). Bleeding rates are variable and are based on the cancer type and the patient's specific risk factors. There are approved specific antidotes for DOAC-associated bleeding. Other strategies are available for bleeding reversal, including the use of prothrombin complex concentrate (PCC). No randomized studies have compared head-to-head the efficacy and safety of reversal agents. We aim to examine the safety and effectiveness of hemostatic agents in cancer patients with DOAC-related major bleeding. A retrospective chart review study of patients at MD Anderson Cancer Center with DOAC-related major bleeding between 2014 and 2019. Bleeding severity and clinical hemostasis were described based on ISTH guidelines and the Sarode criteria, respectively. The rates of thrombotic complications and mortality at 30-day from the index bleeding event were described. We identified 23 patients with DOAC-related major bleeding; 14 patients received PCC and 9 patients received andexanet alfa. The most common sites of bleeding were the gastrointestinal tract and intracranial. Effective hemostasis and 30-day mortality were similar to reported results from other reports of outcomes of reversal agents for DOAC related-bleeding in non-cancer patients. One patient in each treatment group experienced a thrombotic event. Further larger scale studies are needed to confirm our findings in cancer patients.

Phase 1b study of combined selinexor and eribulin for the treatment of advanced solid tumors and triple-negative breast cancer.

BACKGROUND: Selinexor (KPT-330) is a potent inhibitor of exportin 1 (XPO1), in turn inhibiting tumor growth. Selinexor enhances the antitumor efficacy of eribulin in triple-negative breast cancer (TNBC) in vitro and in vivo. Given the unmet medical need in TNBC and sarcoma, the authors explored the safety and efficacy of this combination. METHODS: The authors conducted a phase 1b trial of combined selinexor and eribulin using a 3 + 3 dose-escalation design in patients who had advanced solid tumors and in those who had TNBC in a dose-expansion cohort. RESULTS: Patients with TNBC (N = 19), sarcoma (N = 9), and other cancers (N = 3) were enrolled in the dose-escalation cohort (N = 10) and in the dose-expansion cohort (N = 21). The median number lines of prior therapy received was four (range, from one to seven prior lines). The most common treatment-related adverse events for selinexor were nausea (77%), leukopenia (77%), anemia (68%), neutropenia (68%), and fatigue (48%). One dose-limiting toxicity occurred at the first dose level with prolonged grade 3 neutropenia. The recommended phase 2 dose was 80 mg of selinexor orally once per week and 1 mg/m2 eribulin on days 1 and 8 intravenously every 3 weeks. The objective response rate (ORR) was 10% in three patients. In the dose-escalation cohort, the ORR was 10%, whereas six patients with had stable disease. In the TNBC dose-expansion cohort (n = 18), ORR was 11%, and there were two confirmed partial responses with durations of 10.8 and 19.1 months (ongoing). CONCLUSIONS: Selinexor and eribulin had an acceptable toxicity profile and modest overall efficacy with durable responses in select patients. PLAIN LANGUAGE SUMMARY: Effective therapies for advanced, triple-negative breast cancer and sarcoma represent an unmet need. Exportin 1 is associated with the transport of cancer-related proteins. Preclinical studies have demonstrated tumor growth inhibition and enhanced tumor sensitivity in patients who receive selinexor combined with eribulin. In this phase 1b study, the authors evaluated the safety profile and clinical activity of the combination of selinexor, a potent oral inhibitor of exportin 1, and eribulin in patients with advanced cancers enriched for triple-negative breast cancer or sarcoma. The combination was well tolerated; most adverse events were mild or moderate, reversible, and managed with dose modifications or growth factor support. The combination of selinexor and eribulin produced an antitumor response, particularly in some patients with triple-negative breast cancer. This work lays the foundation for prospective investigations of the role of selinexor and eribulin in the treatment of triple-negative breast cancer.

Safety and Effectiveness of Direct Oral Anticoagulants for the Treatment of Gastrointestinal Cancer-Associated Venous Thromboembolism.

BACKGROUND: Patients with gastrointestinal cancer (GICA) are at high risk for venous thromboembolism (VTE). Data from randomized clinical trials in cancer-associated VTE suggest that direct oral anticoagulants (DOACs) conferred similar or superior efficacy but a heterogeneous safety profile in patients with GICA. We compared the safety and effectiveness of DOACs in patients with GICA and VTE at MD Anderson Cancer Center. MATERIALS AND METHODS: This was a retrospective chart review of patients with GICA and VTE receiving treatment with DOACs for a minimum of 6 months. Primary outcomes were the proportion of patients experiencing major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and recurrent VTE. Secondary outcomes were time to bleeding and recurrent VTE. RESULTS: A cohort of 433 patients with GICA who were prescribed apixaban (n = 300), or rivaroxaban (n = 133) were included. MB occurred in 3.7% (95% confidence interval [CI] 2.1-5.9), CRNMB in 5.3% (95% CI 3.4-7.9), and recurrent VTE in 7.4% (95% CI 5.1-10.3). The cumulative incidence rates of CRNMB and recurrent VTE were not significantly different when comparing apixaban to rivaroxaban. CONCLUSION: Apixaban and rivaroxaban had a similar risk of recurrent VTE and bleeding and could be considered as anticoagulant options in selected patients with GICA and VTE.

Measurement of adherence and health-related quality of life during anticoagulation therapy in cancer-associated venous thromboembolism (VTE): a multicenter quantitative study.

PURPOSE: Therapy for cancer-associated venous thromboembolism (VTE) includes long-term anticoagulation, which may have substantial impact on the health-related quality of life (HRQL) of patients. We assessed patient-reported outcomes to characterize the HRQL associated with VTE treatment and to begin to examine those HRQL elements impacting anticoagulation adherence (AA). METHODS: Participants were adult cancer patients with confirmed symptomatic acute lower extremity deep venous thrombosis. Patients were excluded if there was an indication for anticoagulation other than VTE, ECOG performance status >3, or life expectancy < 3 months. Participants were assessed with a self-reported adherence tool. HRQL was measured with a 6-domain questionnaire using a seven-point Likert scale. Evaluations were performed at 30 days and 3 months after enrollment. For the primary objective, an overall adherence rate was calculated at each time point of evaluation. For the HRQL domains, non-parametric testing was used to compare results between subgroups. RESULTS: Seventy-four patients were enrolled. AA and HRQL at 30 days and 3 months were assessed in 50 and 36 participants, respectively. At 30 days the AA rate was 90%, and at 3 months it was 83%. In regard to HRQL, patients suffered frequent and moderate-severe distress in the domains of emotional and physical symptoms, sleep disturbance, and limitations to physical activity. An association between emotional or physical distress and AA was observed. CONCLUSION: Patients with VTE suffer a substantial impairment of their HRQL. Increased emotional distress correlated with better long-term AA. These results can be used to inform additional research aimed at developing novel strategies to improve AA.

Complexity and clinical significance of drug-drug interactions (DDIs) in oncology: challenging issues in the care of patients regarding cancer-associated thrombosis (CAT).

Cancer patients have an increased risk of developing venous thromboembolic events. Anticoagulation management includes prophylactic or therapeutic doses of low molecular weight heparins (LMWHs) or direct oral anticoagulants (DOACs). However, the management of thrombosis in patients with cancer is complex due to various individual and disease-related factors, including drug-drug interactions (DDIs). Furthermore, DDIs may impact both, cancer and venous thrombosis, treatment effectiveness and safety; their relevance is highlighted by the advances in cancer therapeutics. Given that these new oncology drugs are extensively used, more attention should be given to monitoring potential DDIs to minimize risks. Recognition of DDIs is of utmost importance in an era of rapid developments in cancer treatments and introduction of novel treatments and protocols. When managing cancer-associated thrombosis (CAT), the concomitant use of a DOAC and a moderate or strong modulator (inhibitor or inducer) of CYP3A4 or a P-glycoprotein (P-gp) is most likely to be associated with significant DDIs. Therefore, LMWHs remain the first-line option for the long-term management of CAT under these circumstances and physicians must consider utilizing LMWHs as first line. This review describes the risk of DDIs and their potential impact and outcomes in patients with cancer associated thrombosis (CAT) receiving anticoagulation.

Thrombosis and bleeding outcomes in the treatment of cerebral venous thrombosis in cancer.

BACKGROUND: There is a need for clinical outcome data of cerebral venous thrombosis (CVT) in cancer patients. We examined the recanalization, thrombosis recurrence and major bleeding during CVT treatment in a cancer exclusive adult population. METHODS: We performed a retrospective review of cancer associated CVT identified through an institutional data warehouse. The primary endpoint was radiological and comprised the evaluation of thrombus recanalization at 12 months. Secondary endpoints were clinical and included rates of bleeding complications and recurrence of CVT. Variables were compared across subgroups of study outcomes. The backward stepdown procedure was used to identify variables for the final logistic model regarding thrombosis and bleeding outcomes. RESULTS: The population included forty-five patients, slightly predominant of male adults (55.6%) with a median age of 54.5 years. Solid malignancies comprised 64.4% of cases. A total of 31 cases were treated with anticoagulation. CVT recanalization was documented in almost 60% of cases. The cerebral venous thrombosis recurrence or propagation rate at 12 months was 15.6%. Major bleeding complications were observed in 15 patients. CONCLUSIONS: Our findings are suggestive of a narrow therapeutic index of anticoagulation in cancer-CVT. Careful monitoring of anticoagulation effect and bleeding complications are of utmost clinical relevance in cancer patients. Further larger and controlled studies are needed to confirm our observations.

Development of a clinical prediction tool for cancer-associated venous thromboembolism (CAT): the MD Anderson Cancer Center CAT model.

INTRODUCTION: Cancer-associated venous thromboembolism (CAT) is a major complication of malignancy. Our goal was to develop a prediction model for VTE that better represented to the population seen at large referral cancer centers. MATERIALS AND METHODS: This study was nested in a prospective cohort study at the University of Texas MD Anderson Cancer Center that evaluated adult patients during outpatient cancer-staging computed tomography to estimate the prevalence of incidental VTE. Data from patients in whom incidental VTE was not found on initial CT were collected until 24 months ± 7 days from the study inclusion date to determine the occurrence of new VTE events. Demographics, clinical data, current cancer treatment information, and the use of erythropoietin stimulating agents (ESAs) along with hematologic variables were collected in all patients and analyzed to determine differences between those who developed VTE versus those who did not. All candidate variables with significance p value (≤ 0.1) under univariate analysis were considered to enter the final multivariate model. RESULTS: Data of 548 patients were analyzed. The presence of metastatic disease and the use of platinum-based chemotherapy were strongly associated with CAT occurrence. The use of ESAs and specific malignancies showed trends of association with CAT, while associations were not statistically significant.Those characteristics were utilized to develop a clinical prediction model for CAT readily available and effective (c-index = 0.74). CONCLUSION: Our model is effective and easy to incorporate in busy clinical settings and it does not depend on esoteric or difficult-to-obtain laboratory testing. Future external validation studies may provide further evidence for the applicability of our results.

Concurrent presentation of a hemorrhagic pericardial effusion and venous thromboembolism in malignancy: a systematic review of case studies.

The concurrent presentation of symptomatic malignant pericardial hemorrhage and venous thromboembolism is a rare event that poses a clinical dilemma. Existing VTE guidelines do not indicate when, or if, anticoagulation therapy should be started after the treatment of the pericardial bleed. We performed a systematic review to compile the published clinical evidence on the occurrence of coexisting pericardial hemorrhage and VTE in cancer patients and to describe the clinical presentations and bleeding and thrombosis outcomes before and after anticoagulation therapy. We studied published case reports on patients with cancer who presented to the hospital with pericardial hemorrhage and VTE through April 11, 2019. We found seven published case reports. All patients had suffered from a pulmonary embolism and had pericardiocentesis during hospitalization. Five patients (71%) had lung cancer. Four patients (57%) were started on anticoagulation after pericardial drainage and survived the index event. Two patients (29%) were not started on anticoagulation after pericardiocentesis; only one of these patients survived the hospitalization. Pericardial bleeding risk in cancer may be inherent to malignancy, and it is unclear if anticoagulation use increases the risk of recurrent pericardial bleeding. The management of pericardial bleeding typically requires pericardiocentesis, and clinical registries, prospective collaboration projects, and case adjudication are needed to establish the safety of initiation of antithrombotic therapy in such patients.

The role of direct oral anticoagulants in cancer-related venous thromboembolism: a perspective beyond the guidelines.

Cancer-related venous thromboembolism (Wickham et al., Intern Med J 42(6):698-708, 2012) is an important source of morbidity and mortality in that population. The standard of care for the treatment of cancer-related venous thromboembolism (VTE) is a low molecular weight heparin (LMWH) for long periods of time. The favorable clinical trial results for efficacy and safety and availability of direct oral anticoagulants (DOAC) have remodeled the care and options for treatment of venous thromboembolism in the adult population. The data of cancer population-subgroup analysis of those studies have shown that DOAC are as effective and safe as conventional long-term oral anticoagulation with vitamin K antagonists (VKA). Additionally, non-controlled retrospective and prospective cohort data have been published describing efficacy and safety outcomes for the use of DOAC in cancer-related VTE. Altogether, the results from clinical studies have shown that direct oral anticoagulants may represent a treatment option for cancer-related VTE and an alternative to anticoagulation with VKA. Little is known about the patient-centered and system-based variables that determine the use of DOAC outside consensus guidelines, neither is known the impact of different anticoagulant modalities in adherence and quality of life in cancer patients. The objectives of this manuscript are to summarize the clinical trial-based and cohort data of cancer patients treated with DOAC for VTE and to highlight the aspects that may influence adherent to therapy, effectiveness, and safety outcomes in the treatment of cancer-related VTE.

Comparative outcomes of thrombocytopenic acute leukemic patients with venous thromboembolism at a Comprehensive Cancer Center.

Patients with hematological malignancies often have severe thrombocytopenia, which poses problems when making thrombosis management decisions. A retrospective study was conducted to analyze the clinical outcomes associated with different management options in acute leukemic patients with thrombocytopenia (≤ 50 × 109/L) following an acute venous thromboembolic event. A total of 74 patients were divided into three treatment groups: observation only (n = 30); anticoagulation (n = 23); or inferior vena cava placement (n = 21). Multivariate analysis showed that anticoagulant administration was significantly associated with improved overall survival without an increased rate of clinical relevant bleeding events when compared to other thrombosis management modalities. This study notes that dose adjusted-anticoagulant therapy may offer a safe and clinical advantageous strategy for the treatment and secondary prevention of recurrent venous thrombosis in thrombocytopenic patients with hematologic malignancies.

Risk of intracranial hemorrhage associated with therapeutic anticoagulation for venous thromboembolism in cancer patients: a systematic review and meta-analysis.

Intracranial hemorrhage (ICH) in cancer patients can result from tumor bleeding and from antitumor and anticoagulation therapy. The effect of anticoagulation on the incidence of ICH in cancer patients has not been quantified. Our objective was to determine the risk of intracranial hemorrhage associated with anticoagulation therapy for cancer-associated venous thromboembolism (VTE). Systematic review and meta-analysis of studies assessing the safety of anticoagulation therapy in patients with cancer-associated VTE. The primary endpoint of interest was the incidence of ICH and secondary outcomes included all major bleeding, and the time to ICH and major bleeding. After identifying 595 studies, five studies and 2089 patients were included in the analyses. We found that the relative risk (RR) for ICH was 0.494, 95 % CI (0.105-2.331) when low molecular weight heparin (LMWH) with vitamin K antagonist (VKA) anticoagulants were compared. No statistically significant differences in risk were measured. The risk of major bleeding using any type of anticoagulation therapy in patients with cancer-associated VTE was RR 0.853, 95 % CI (0.549, 1.327). After meta-analytic review of data published through August 2015, we conclude that therapeutic anticoagulation with LMWH given ≤6 months does not increase the risk of ICH in cancer patients compared to VKA. The risk of ICH in cancer patients is also similar to that of non-cancer patients. Available data were insufficient to determine if the ICH risk increase changes when the duration of anticoagulation is >6 months.

Performance of 4T score and heparin-platelet factor 4 antibody in the diagnosis of heparin-induced thrombocytopenia (HIT) in cancer.

Cancer patients have characteristics which significantly influence the 4T score and heparin-platelet factor 4 antibody (H-PF4 ab). Our aim was to determine among cancer patients the correlation of the 4T score and H-PF4 ab with the serotonin release assay (SRA). We performed a retrospective analysis of records of cancer patients in whom H-PF4 polyclonal (IgG, IgM and IgA) enzyme-linked immunosorbent assay (ELISA) and SRA were evaluated. Cases were defined as heparin induced thrombocytopenia (HIT) when SRA confirmed the diagnosis. Logistic regression model and the receiver operating characteristic curves were conducted to identify the optimal cutting point for the optical density (OD) and 4T score to discriminate the SRA status. Among 246 patients, the optimal cutoff of 4T score for HIT diagnosis was 5 (sensitivity 90.0%, specificity 73.6%), and the optimal cutoff of H-PF4 polyclonal ELISA OD was 1.004 (sensitivity 81.8%, specificity 97.0%). Our findings suggest that cancer patients may need higher cutoff values for the 4T score. Conventional H-PF4 ab testing seem to perform similarly for the diagnosis of HIT when compared to published data from non-cancer cohorts. Additional studies are necessary to confirm our findings.

Mechanical Venous Thrombectomy for Deep Venous Thrombosis in Cancer Patients: A Single-Center Retrospective Study.

PURPOSE: Venous thromboembolism (VTE) is a major contributor to the mortality of cancer patients. Mechanical thrombectomy (MT) is an endovascular technique that physically removes a thrombus without thrombolytics. The purpose of this study was to evaluate safety, efficacy, and clinical outcomes following MT for lower extremity DVT in cancer patients. METHODS: This single-center, retrospective study evaluated outcomes following MT of lower extremity DVT in cancer patients from November 2019 to May 2023. The primary outcome measure was clinical success, defined as a decrease in Villalta score by at least 2 points following the intervention. Secondary outcomes included repeat intervention-free survival and overall survival. Technical success was defined as restoring venous flow with mild (< 10%) or no residual filling defect. RESULTS: In total, 90 patients and 113 procedures were included. Technical and clinical success was achieved in 81% and 87% of procedures performed. Repeat intervention-free survival at 1 month, 3 months, and 6 months post-procedure was 92%, 82%, and 77%, respectively. The complication rate was 2.7%. Pathologic analysis of the extracted thrombus revealed tumor thrombus in 18.4% (18/98) samples. Overall survival for the study cohort was 87% at 1 month, 74% at 3 months, and 62% at 6 months. Patients who were found to have tumor thrombi were noted to have a decreased overall survival compared to patients with non-tumor thrombi (P = 0.012). CONCLUSION: MT is safe and efficacious in reducing cancer patients' VTE-related symptoms. The high rate of tumor thrombus in thrombectomy specimens suggests this phenomenon is more common than suspected.

The novel oral anticoagulants.

After the introduction of warfarin, long-term oral anticoagulation treatment remained unchanged for more than 50 years. Most recently, with the development and approval of new oral anticoagulants, the treatment of medical conditions that require thrombosis prophylaxis and long-term anticoagulation has become more complex. In the case of venous thromboembolism (VTE) prevention after orthopedic surgery, the new oral agents will be less costly than the parenteral alternative. In other settings (such as atrial fibrillation or treatment of acute VTE), the new agents will offer additional convenience at higher cost, but the degree to which they will reduce clinically important events such as thrombosis or bleeding will be limited, especially for patients on optimally controlled warfarin. As the use of the new oral anticoagulants becomes more widespread, it will be important for all clinicians to have a basic understanding of their pharmacology, advantages, and limitations. Although the need to measure or reverse the effect of these drugs will arise infrequently, clinicians--especially hematologists--will desire evidence-based recommendations about how to manage such scenarios, which will require research studies.

Secondary erythrocytosis.

INTRODUCTION: Erythrocytosis is associated with an elevation of the hemoglobin level above 16.5 g/dL in men and above 16 g/dL in women and an elevation of the hematocrit level above 49% in men and > 48% in women. In primary erythrocytosis, the defect is a clonal disorder in the myeloid compartment of the bone marrow, leading to an increased red cell production. Secondary erythrocytosis is the result of external stimuli to the bone marrow, leading to the production of red cells in excess. Secondary erythrocytosis is more common than primary erythrocytosis and has a broad differential diagnosis. AREAS COVERED: This review will discuss secondary erythrocytosis, its causes, clinical presentation, and both diagnostic and therapeutic approaches. EXPERT OPINION: Although secondary erythrocytosis is more common than PV, there are still challenges and difficulties associated with the distinction between these two conditions. Moreover, there is a paucity of data and guidance when it comes to the management of certain congenital and acquired conditions. A pragmatic approach is recommended in order to identify the cause for this condition. Treatment should be directed at the management of the underlying cause.