Cancer-Associated Thrombosis: Risk Assessment, Prevention, and Treatment.

The risk of developing venous thromboembolism (VTE) is four to seven times higher in patients with cancer than in those without. At JADPRO Live 2022, presenters discussed risk factors and assessing patients for VTE, as well as how to protect patients against VTE in both the inpatient and outpatient clinic settings. They reviewed selecting an appropriate anticoagulation treatment, including the choice of agent and duration of treatment for the patient with cancer, and finally the steps needed to assess and treat patients experiencing therapeutic anticoagulation failure.

PI3K Inhibition Restores and Amplifies Response to Ruxolitinib in Patients with Myelofibrosis.

PURPOSE: Treatment options are limited beyond JAK inhibitors for patients with primary myelofibrosis (MF) or secondary MF. Preclinical studies have revealed that PI3Kδ inhibition cooperates with ruxolitinib, a JAK1/2 inhibitor, to reduce proliferation and induce apoptosis of JAK2V617F-mutant cell lines. PATIENTS AND METHODS: In a phase I dose-escalation and -expansion study, we evaluated the safety and efficacy of a selective PI3Kδ inhibitor, umbralisib, in combination with ruxolitinib in patients with MF who had a suboptimal response or lost response to ruxolitinib. Enrolled subjects were required to be on a stable dose of ruxolitinib for ≥8 weeks and continue that MTD at study enrollment. The recommended dose of umbralisib in combination with ruxolitinib was determined using a modified 3+3 dose-escalation design. Safety, pharmacokinetics, and efficacy outcomes were evaluated, and spleen size was measured with a novel automated digital atlas. RESULTS: Thirty-seven patients with MF (median age, 67 years) with prior exposure to ruxolitinib were enrolled. A total of 2 patients treated with 800 mg umbralisib experienced reversible grade 3 asymptomatic pancreatic enzyme elevation, but no dose-limiting toxicities were seen at lower umbralisib doses. Two patients (5%) achieved a durable complete response, and 12 patients (32%) met the International Working Group-Myeloproliferative Neoplasms Research and Treatment response criteria of clinical improvement. With a median follow-up of 50.3 months for censored patients, overall survival was greater than 70% after 3 years of follow-up. CONCLUSIONS: Adding umbralisib to ruxolitinib in patients was well tolerated and may resensitize patients with MF to ruxolitinib without unacceptable rates of adverse events seen with earlier generation PI3Kδ inhibitors. Randomized trials testing umbralisib in the treatment of MF should be pursued.

A 35-Year-Old Man with Fever.

A 35-Year-Old Man with FeverA 35-year-old man presented for evaluation of fever for 2 weeks with left-sided abdominal pain. How do you approach the evaluation, and what is the diagnosis?

Myeloproliferative Neoplasms, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

The classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) consist of myelofibrosis, polycythemia vera, and essential thrombocythemia and are a heterogeneous group of clonal blood disorders characterized by an overproduction of blood cells. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for MPN were developed as a result of meetings convened by a multidisciplinary panel with expertise in MPN, with the goal of providing recommendations for the management of MPN in adults. The Guidelines include recommendations for the diagnostic workup, risk stratification, treatment, and supportive care strategies for the management of myelofibrosis, polycythemia vera, and essential thrombocythemia. Assessment of symptoms at baseline and monitoring of symptom status during the course of treatment is recommended for all patients. This article focuses on the recommendations as outlined in the NCCN Guidelines for the diagnosis of MPN and the risk stratification, management, and supportive care relevant to MF.

Cancer-Associated Venous Thromboembolic Disease, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease focus on the prevention, diagnosis, and treatment of patients with cancer who have developed or who are at risk for developing venous thromboembolism (VTE). VTE is a significant concern among cancer patients, who are at heightened risks for developing as well as dying from the disease. The management of patients with cancer with VTE often requires multidisciplinary efforts at treating institutions. The NCCN panel comprises specialists from various fields: cardiology, hematology/hematologic oncology, internal medicine, interventional radiology, medical oncology, pharmacology/pharmacy, and surgery/surgical oncology. This article focuses on VTE prophylaxis for medical and surgical oncology inpatients and outpatients, and discusses risk factors for VTE development, risk assessment tools, as well as management methods, including pharmacological and mechanical prophylactics. Contraindications to therapeutic interventions and special dosing, when required, are also discussed.

Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology.

Eosinophilic disorders and related syndromes represent a heterogeneous group of neoplastic and nonneoplastic conditions, characterized by more eosinophils in the peripheral blood, and may involve eosinophil-induced organ damage. In the WHO classification of myeloid and lymphoid neoplasms, eosinophilic disorders characterized by dysregulated tyrosine kinase (TK) fusion genes are recognized as a new category termed, myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1 or with PCM1-JAK2. In addition to these aforementioned TK fusion genes, rearrangements involving FLT3 and ABL1 genes have also been described. These new NCCN Guidelines include recommendations for the diagnosis, staging, and treatment of any one of the myeloid/lymphoid neoplasms with eosinophilia (MLN-Eo) and a TK fusion gene included in the 2017 WHO Classification, as well as MLN-Eo and a FLT3 or ABL1 rearrangement.

Safety and Outcomes of Permanent and Retrievable Inferior Vena Cava Filters in the Oncology Population.

BACKGROUND: The role for inferior vena cava (IVC) filters in the oncology population is poorly defined. OBJECTIVES: Our primary endpoint was to determine the rate of filter placement in cancer patients without an absolute contraindication to anticoagulation and the rate of recurrent VTE after filter placement in both retrievable and permanent filter groups. Patients/. METHODS: A single-institution, retrospective study of patients with active malignancies and acute VTE who received a retrievable or permanent IVC filter between 2009-2013. Demographics and outcomes were confirmed on independent chart review. Cost data were obtained using Current Procedural Terminology (CPT) codes. RESULTS: 179 patients with retrievable filters and 207 patients with permanent filters were included. Contraindication to anticoagulation was the most cited reason for filter placement; however, only 76% of patients with retrievable filters and 69% of patients with permanent filters had an absolute contraindication to anticoagulation. 20% of patients with retrievable filters and 24% of patients with permanent filters had recurrent VTE. The median time from filter placement to death was 8.9 and 3.2 months in the retrievable and permanent filter groups, respectively. The total cost of retrievable filters and permanent filters was $2,883,389 and $3,722,688, respectively. CONCLUSIONS: The role for IVC filters in cancer patients remains unclear as recurrent VTE is common and time from filter placement to death is short. Filter placement is costly and has a clinically significant complication rate, especially for retrievable filters. More data from prospective, randomized trials are needed to determine the utility of IVC filters in cancer patients.

TNF-α-driven inflammation and mitochondrial dysfunction define the platelet hyperreactivity of aging.

Aging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. We hypothesized that aging-associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi. We identified tumor necrosis factor α (TNF-α) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-α receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status, and thrombocytosis. Single-cell RNA-sequencing analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic, and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF-α was endogenously increased) and from young mice exposed to exogenous TNF-α exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-α blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-α levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously unrecognized evidence that TNF-α critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.

Systemic Mastocytosis, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Mastocytosis is a group of heterogeneous disorders resulting from the clonal proliferation of abnormal mast cells and their accumulation in the skin and/or in various extracutaneous organs. Systemic mastocytosis is the most common form of mastocytosis diagnosed in adults, characterized by mast cell infiltration of one or more extracutaneous organs (with or without skin involvement). The identification of KIT D816V mutation and the emergence of novel targeted therapies have significantly improved the diagnosis and treatment of systemic mastocytosis. However, certain aspects of clinical care, particularly the diagnosis, assessment, and management of mediator-related symptoms continue to present challenges. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with systemic mastocytosis.

NCCN Guidelines Insights: Cancer-Associated Venous Thromboembolic Disease, Version 2.2018.

Venous thromboembolism (VTE) is common in patients with cancer and increases morbidity and mortality. VTE prevention and treatment are more complex in patients with cancer. The NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease outline strategies for treatment and prevention of VTE in adult patients diagnosed with cancer or in whom cancer is clinically suspected. These NCCN Guidelines Insights explain recent changes in anticoagulants recommended for the treatment of cancer-associated VTE.

NCCN Guidelines Insights: Myeloproliferative Neoplasms, Version 2.2018.

Myeloproliferative neoplasms (MPNs) are a group of heterogeneous disorders of the hematopoietic system that include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). PV and ET are characterized by significant thrombohemorrhagic complications and a high risk of transformation to MF and acute myeloid leukemia. The diagnosis and management of PV and ET has evolved since the identification of mutations implicated in their pathogenesis. These NCCN Guideline Insights discuss the recommendations outlined in the NCCN Guidelines for the risk stratification, treatment, and special considerations for the management of PV and ET.

Disease characteristics and prognosis of myelodysplastic syndrome presenting with isolated thrombocytopenia.

Patients with myelodysplastic syndrome (MDS) who present with isolated thrombocytopenia (TCP) constitute a poorly described subgroup. The aim of the present study was to retrospectively evaluate disease characteristics and prognosis in patients with MDS and isolated TCP at a tertiary care center. Fifty patients (12 %) had isolated thrombocytopenia as the first presentation of MDS. Patients had varying MDS sub-classifications and cytogenetic profiles. The most common IPSS-R risk score was low (n = 24), although half of the patients had either IPSS-R intermediate (n = 18), high or very high risk disease (n = 7). Leukemic transformation occurred in 10 patients and there were 14 deaths (28 %) amongst all IPSS-R risk scores. Therapeutic agents used in this patient subgroup included hypomethylating agents and thrombopoietin receptor agonists. Overall, MDS with isolated TCP did not appear to have an inherently indolent course, as has been suggested previously. Future studies are needed to improve risk stratification, identify relevant contributors to disease pathogenesis, and better define treatment modalities.

Update on Anticoagulation: What the Interventional Radiologist Needs to Know.

The novel oral anticoagulants (NOACs) represent a major advance in the treatment of patients with nonvalvular atrial fibrillation and venous thromboembolism (VTE). They have several advantages over vitamin-K antagonists such as warfarin, including more predictable pharmacokinetics and improved safety, particularly with fatal bleeding and intracranial hemorrhage. However, several issues remain surrounding the use of NOACs in certain subpopulations and with the approach to reversal. The periprocedural management of anticoagulation with these relatively new agents can also present several challenges. This article reviews the basic pharmacology, efficacy, and safety of these drugs. Several populations at higher risk for complications with use of NOACs are discussed, including those undergoing procedures. Finally, several target-specific reversal agents have either received FDA approval or likely will be approved in the near future; these agents and their roles in the approach to anticoagulation reversal will also be discussed.

Survey of Provider Transfusion Practices for Oncology Patients in an Academic Medical Center.

OBJECTIVES: Hospitalized oncology patients receive care from a variety of professionals, each of whom plays a role in decisions related to blood transfusions. We sought to examine differences in transfusion practices based on professional role, years of experience, and patient clinical scenario. METHODS: We surveyed general medicine residents, hospitalists, and oncologists caring for inpatients at a large academic medical center between August 2013 and June 2014. Respondents reported transfusion practices in three different patient scenarios: a generally healthy patient, a patient with solid tumor malignancy, and a patient with hematologic malignancy. We also assessed rationale for transfusion practices. Bivariate comparisons of respondent characteristics and transfusion threshold were conducted using the Fisher exact test. Multivariate logistic regression was performed to assess the relative relations among professional role, years in practice, clinical scenario, and transfusion threshold <7 g/dL. RESULTS: Of 158 physicians surveyed, 97 responded (61.4%). In bivariate analyses, fewer oncologists than residents or hospitalists used a threshold of <7 g/dL, but the result was significant for only one of three scenarios. The multivariate odds of transfusing at a threshold <7 g/dL were significantly higher among nononcologists (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.03-4.28). Residents and practitioners in practice for <4 years also were more likely to use a threshold <7 g/dL (OR 1.82, 95% CI 0.99-3.33). Providers were less likely to use a restrictive threshold when an underlying malignancy was present (solid tumor OR 0.31, 95% CI 0.15-0.64; hematologic malignancy OR 0.34, 95% CI 0.16-0.70). CONCLUSIONS: Transfusion thresholds differed based on professional role, years in practice, and patient scenario. Further research is needed to determine the optimal transfusion threshold for oncology patients.

Evolving Therapeutic Strategies for the Classic Philadelphia-Negative Myeloproliferative Neoplasms.

Despite the emergence of JAK inhibitors, there is a need for disease-modifying treatments for Philadelphia-negative myeloproliferative neoplasms (MPNs). JAK inhibitors ameliorate symptoms and address splenomegaly, but because of the heterogeneous contributors to the disease process, JAK inhibitor monotherapy incompletely addresses the burden of disease. The ever-growing understanding of MPN pathogenesis has provided the rationale for testing novel and targeted therapeutic agents, as monotherapies or in combination, in preclinical and clinical settings. A number of intriguing options have emerged, and it is hoped that further progress will lead to significant changes in the natural history of MPNs.

Clinical Use of Anti-Xa Monitoring in Malignancy-Associated Thrombosis.

Introduction. Low molecular weight heparin (LMWH) is preferred for malignancy-associated venous thromboembolism (VTE). Many providers monitor LMWH with anti-Xa levels, despite little validation on correspondence with patient outcome. Methods. This is a retrospective, single institution study of anti-Xa measurement in malignancy-associated thrombosis. Cases were identified using the Electronic Data Warehouse, and inclusion was confirmed by two independent reviewers. Malignancy type, thrombotic history, measurement rationale and accuracy, clinical context, and management changes were evaluated. Results. 167 cases met inclusion criteria. There was no clear rationale for anti-Xa testing in 56%. Impaired renal function (10%), documented or suspected recurrent thrombosis despite anticoagulation (9%), and bleeding (6%) were the most common reasons for testing. Incorrect measurement occurred in 44%. Renal impairment was not a significant impetus for testing, as 70% had a GFR > 60. BMI > 30 was present in 40%, and 28% had a BMI < 25. Clinical impact was low, as only 11% of patients had management changes. Conclusions. Provider education in accuracy and rationale for anti-Xa testing is needed. Our study illustrates uncertainty of interpretation and clinical impact of routine anti-Xa testing, as management was affected in few patients. It is not yet clear in which clinical context providers should send anti-Xa levels.