Antithrombotic Therapy in Cancer Patients with Cardiovascular Diseases: Daily Practice Recommendations by the Hemostasis Working Party of the German Society of Hematology and Medical Oncology (DGHO) and the Society for Thrombosis and Hemostasis Research (GTH e.V.).

Active cancer by itself but also chemotherapy is associated with an increased risk of cardiovascular disease (CVD) and especially coronary artery disease (CAD) and atrial fibrillation (AF). The frequency of CVD, CAD, and AF varies depending on comorbidities (particularly in older patients), cancer type, and stage, as well as the anticancer therapeutic being taken. Many reports exist for anticancer drugs being associated with CVD, CAD, and AF, but robust data are often lacking. Because of this, each patient needs an individual structured approach concerning thromboembolic and bleeding risk, drug-drug interactions, as well as patient preferences to evaluate the need for anticoagulation therapy and targeting optimal symptom control. Interruption of specific cancer therapy should be avoided to reduce the potential risk of cancer progression. Nevertheless, additional factors like thrombocytopenia and anticoagulation in the elderly and frail patient with cancer cause additional challenges which need to be addressed in daily clinical management. Therefore, the aim of these recommendations is to summarize the available scientific data on antithrombotic therapy (both antiplatelet and anticoagulant therapy) in cancer patients with CVD and in cases of missing data providing guidance for optimal careful decision-making in daily routine.

Venous Thromboembolism in Women with Cancer with an Additional Focus on Breast and Gynecological Cancers.

Cancer-associated venous thromboembolism (VTE) is common in women with cancer. Many clinical practice guidelines provide guidance for prevention and treatment; however, there are no specific recommendations for women. This is unfortunate because the proportion of women with breast- and gynecological cancers is high among patients with cancer-associated VTE. Thromboembolism often heralds cancer progression and poor prognosis and should-besides adequate anticoagulant management-also prompt reassessment and, if necessary, changes in cancer treatment. Recently, the new class of direct-acting oral anticoagulants (DOACs) has started to replace low-molecular-weight heparin as standard thromboprophylaxis and therapy in cancer patients. They are very effective, but they also carry a relevant risk of bleeding. Therefore, despite their ease of use, not every tumor patient qualifies for a DOAC, and this is especially true for gynecological tumor patients. Each prescription must be weighed individually. This review addresses specific aspects of VTE prophylaxis and management in women with cancer. Every physician who treats breast and gynecological cancers should be familiar with prophylaxis, diagnosis, and therapy of cancer-associated VTE. At the same time, patients should be informed by their physician what symptoms to look for and whom to contact if these symptoms occur, even outside of office hours and on weekends.

Primary Thromboprophylaxis in Patients with Malignancies: Daily Practice Recommendations by the Hemostasis Working Party of the German Society of Hematology and Medical Oncology (DGHO), the Society of Thrombosis and Hemostasis Research (GTH), and the Austrian Society of Hematology and Oncology (ÖGHO).

Patients with cancer, both hematologic and solid malignancies, are at increased risk for thrombosis and thromboembolism. In addition to general risk factors such as immobility and major surgery, shared by non-cancer patients, cancer patients are exposed to specific thrombotic risk factors. These include, among other factors, cancer-induced hypercoagulation, and chemotherapy-mediated endothelial dysfunction as well as tumor-cell-derived microparticles. After an episode of thrombosis in a cancer patient, secondary thromboprophylaxis to prevent recurrent thromboembolism has long been established and is typically continued as long as the cancer is active or actively treated. On the other hand, primary prophylaxis, even though firmly established in hospitalized cancer patients, has only recently been studied in ambulatory patients. This recent change is mostly due to the emergence of direct oral anticoagulants (DOACs). DOACs have a shorter half-life than vitamin K antagonists (VKA), and they overcome the need for parenteral application, the latter of which is associated with low-molecular-weight heparins (LMWH) and can be difficult for the patient to endure in the long term. Here, first, we discuss the clinical trials of primary thromboprophylaxis in the population of cancer patients in general, including the use of VKA, LMWH, and DOACs, and the potential drug interactions with pre-existing medications that need to be taken into account. Second, we focus on special situations in cancer patients where primary prophylactic anticoagulation should be considered, including myeloma, major surgery, indwelling catheters, or immobilization, concomitant diseases such as renal insufficiency, liver disease, or thrombophilia, as well as situations with a high bleeding risk, particularly thrombocytopenia, and specific drugs that may require primary thromboprophylaxis. We provide a novel algorithm intended to aid specialists but also family practitioners and nurses who care for cancer patients in the decision process of primary thromboprophylaxis in the individual patient.

Romiplostim in adults with newly diagnosed or persistent immune thrombocytopenia.

Introduction: Three distinct phases are recognized in immune thrombocytopenia (ITP): newly diagnosed (≤3 months after diagnosis), persistent (>3-12 months after diagnosis), and chronic (>12 months). Several international guidelines/expert recommendations have been released in the past 2 years regarding the treatment of newly diagnosed/persistent ITP. Areas covered: Across the guidelines/expert recommendations, thrombopoietin receptor agonists (TPO-RAs), including romiplostim (the focus of this review), are recommended in newly diagnosed or persistent ITP for patients who fail to respond to corticosteroids or intravenous immunoglobulin (or where these are contraindicated). To identify data relating to romiplostim in adults with newly diagnosed or persistent ITP, we conducted a search of PubMed (with no time limit applied) and abstracts from 2019 EHA/ASH meetings using the term 'romiplostim.' Expert opinion: The findings from nine clinical trials, six real-world studies and ten case reports provide insight into the early use of romiplostim, which could help to reduce exposure to the adverse effects associated with prolonged corticosteroid use, as well as reduce the risk of severe bleeding. Additionally, given the durable responses observed in patients with newly diagnosed/persistent ITP, as well as the potential for treatment-free responses following discontinuation, romiplostim might help to avoid the need for subsequent treatment.

Factors Influencing the Choice between DOACs and LMWHs: A Survey of German Physicians on the Treatment of Cancer-Associated Venous Thromboembolism.

Recently direct-acting oral anticoagulants (DOACs) have become a new therapeutic option besides parenteral anticoagulants to treat cancer-associated venous thromboembolism (VTE). With this survey we wanted to identify factors influencing the choice between low-molecular-weight heparin and DOACs among physicians treating cancer patients. A questionnaire was presented at several medical educational activities on cancer care and VTE management between August 2018 and January 2019. One hundred fifteen physicians returned their surveys. The two most compelling arguments pro DOAC were when the patient had no chemotherapy and when he expressed unwillingness to apply injections. The two most important arguments against DOACs were if the patient had problems with taking oral medications or when he had a history of severe bleeding. This survey shows that future studies need to consider many more factors, particularly patient preferences and physician concerns on bleeding risk, to improve their applicability in daily practice.

Retroperitoneal Hematoma after Bone Marrow Biopsy: The First Cut Should Not Be the Deepest.

Bone marrow biopsies are standard hematology procedures. We report the case of a patient with acute myeloid leukemia who developed retroperitoneal hematoma after the procedure. The bleeding was stopped with endovascular embolization and coiling. This case raises several issues about the standards for bone marrow biopsies and discusses the approach to patients with bleeding risk factors. We also provide a literature review.

Non-vitamin K Antagonist Oral Anticoagulants (NOAC) as an Alternative Treatment Option in Tumor-Related Venous Thromboembolism.

BACKGROUND: The risk of venous thromboembolism (VTE) is 4 to 7 times higher in cancer patients than in the normal population. Moreover, cancer patients who take anticoagulants suffer more frequently from hemorrhagic complications and VTE recurrences. Patients often find low-molecular-weight heparin (LMWH) treatment unpleasant; approximately 20% stop taking LMWH during the first six months of treatment. METHODS: Based on a non-systematic literature search, an interdisciplinary group of specialists (hematology, oncology, hemostaseology, and angiology) developed a set of recommendations concerning the treatment of tumor-related thrombosis with non-vitamin K antagonist oral anticoagulants (NOAC). RESULTS: Patient-, tumor-, and tumor-treatment-related factors and clinical situations were identified that should be considered in therapeutic decision-making in the indi- vidual case. NOAC may be an alternative that lessens the rate of VTE recurrence (though at the cost of more hemorrhagic complications), without lessening mortality. Moreover, many factors need to be considered that can limit the utility of NOAC treatment or even make it impossible. CONCLUSION: It seems likely that, in future, the treatment of tumor-related VTE will often not involve a single decision to use either NOAC or LWMH, but rather a switching of treatment in either of two directions: from LWMH to NOAC in stable phases of the underlying malignant disease, conferring better quality of life to suitable patients; or from NOAC to LWMH, e.g., in patients suffering from emesis or thrombocytopenia, to whom the greater clinical experience with LWMH, parenteral application, or stepwise dose titration can confer benefits.

[Diagnosis and Therapy of Immune thrombocytopenia]. / Diagnostik und Therapie der Immunthrombozytopenie.

Immune thrombocytopenia (ITP) is a heterogeneous disease. Diagnosis of primary ITP continues to be based on the exclusion of all known causes for secondary ITP. The new ITP classification distinguishes three categories. First line treatment consists of either dexamethasone or prednisone. The most effective options in second line treatment are splenectomy or thrombopoietin receptor agonists. The medical societies for hematology and oncology of the German-speaking countries have recently updated their guidelines on ITP.

Practice Patterns for Prophylaxis and Treatment of Venous Thromboembolism in German Cancer Patients.

BACKGROUND: Venous thromboembolism (VTE) is a serious threat for cancer patients. Guidelines recommend low-molecular-weight heparin (LMWH) for prophylaxis and treatment, but it is unknown to what extent specialists adhere to these recommendations. This survey assesses the current approach to patients with cancer-associated VTE in Germany. MATERIALS AND METHODS: A questionnaire was sent out to members of the DGHO (Deutsche Gesellschaft für Hämatologie und Onkologie), the BNHO (Berufsverband Niedergelassener Hämatologen und Onkologen) and the DGP (Deutsche Gesellschaft für Phlebologie). For most questions, more than 1 answer was possible; therefore, the total sum of percentages may exceed 100%. RESULTS: 275 specialists responded. 76% of them treat acute VTE with LMWH while 22% switch to oral treatments (vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs)) during the acute phase. For the next 3-6 months, 55% of the specialists continue LMWH, while 31% switch to VKAs and 33% to NOACs. Among those who continue LMWH for 3-6 months, 37% continue at the full dose, 26% reduce to 75% of the initial dose, and 40% even to 50%. Important factors guiding treatment decisions were the need for injections and the availability of a partner/spouse (LMWH), the need for laboratory controls (VKAs), and the number of other oral medications (NOACs). CONCLUSION: This survey reveals that practice patterns often do not follow the guideline recommendations with respect to the use of LMWH for long-term treatment of VTE in cancer patients.

Salvage therapy with high-dose cytarabine and mitoxantrone in combination with all-trans retinoic acid and gemtuzumab ozogamicin in acute myeloid leukemia refractory to first induction therapy.

Outcome of patients with primary refractory acute myeloid leukemia remains unsatisfactory. We conducted a prospective phase II clinical trial with gemtuzumab ozogamicin (3 mg/m(2) intravenously on day 1), all-trans retinoic acid (45 mg/m(2) orally on days 4-6 and 15 mg/m(2) orally on days 7-28), high-dose cytarabine (3 g/m(2)/12 h intravenously on days 1-3) and mitoxantrone (12 mg/m(2) intravenously on days 2-3) in 93 patients aged 18-60 years refractory to one cycle of induction therapy. Primary end point of the study was response to therapy; secondary end points included evaluation of toxicities, in particular, rate of sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation. Complete remission or complete remission with incomplete blood count recovery was achieved in 47 (51%) and partial remission in 10 (11%) patients resulting in an overall response rate of 61.5%; 33 (35.5%) patients had refractory disease and 3 patients (3%) died. Allogeneic hematopoietic cell transplantation was performed in 71 (76%) patients; 6 of the 71 (8.5%) patients developed moderate or severe sinusoidal obstruction syndrome after transplantation. Four-year overall survival rate was 32% (95% confidence interval 24%-43%). Patients responding to salvage therapy and undergoing allogeneic hematopoietic cell transplantation (n=51) had a 4-year survival rate of 49% (95% confidence intervaI 37%-64%). Patients with fms-like tyrosine kinase internal tandem duplication positive acute myeloid leukemia had a poor outcome despite transplantation. In conclusion, the described regimen is an effective and tolerable salvage therapy for patients who are primary refractory to one cycle of conventional intensive induction therapy. (clinicaltrials.gov identifier: 00143975).

Diagnosis, prevention, and management of bleeding episodes in Philadelphia-negative myeloproliferative neoplasms: recommendations by the Hemostasis Working Party of the German Society of Hematology and Medical Oncology (DGHO) and the Society of Thrombosis and Hemostasis Research (GTH).

Philadelphia-negative myeloproliferative neoplasms (Ph-negative MPN) comprise a heterogeneous group of chronic hematologic malignancies. The quality of life, morbidity, and mortality of patients with MPN are primarily affected by disease-related symptoms, thromboembolic and hemorrhagic complications, and progression to myelofibrosis and acute leukemia. Major bleeding represents a common and important complication in MPN, and the incidence of such bleeding events will become even more relevant in the future due to the increasing disease prevalence and survival of MPN patients. This review discusses the causes, differential diagnoses, prevention, and management of bleeding episodes in patients with MPN, aiming at defining updated standards of care in these often challenging situations.

DPYD Genotyping to Predict Adverse Events Following Treatment With Fluorouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon Cancer: A Secondary Analysis of the PETACC-8 Randomized Clinical Trial.

IMPORTANCE: Previous pharmacogenetic studies have shown the prognostic impact of several rare dihydropyrimidine dehydrogenase gene (DPYD) variants on fluorouracil-related adverse events (fluorouracil AEs). However, conflicting results highlight the need for prospective validation in large, homogeneous patient populations uniformly treated with current standard combination therapies used in colon cancer (CC). OBJECTIVE: To determine the impact of DPYD variants on fluorouracil AEs in patients with stage III CC treated with a fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) regimen. DESIGN, SETTING, AND PARTICIPANTS: Pharmacogenetic substudy of 1545 patients who participated from December 2005 to November 2009 in the European Pan-European Trials in Alimentary Tract Cancer (PETACC)-8 randomized phase 3 clinical trial. INTERVENTIONS: Patients with resected stage III CC were randomized to receive standard adjuvant FOLFOX4 alone or FOLFOX4 combined with cetuximab for 6 months. MAIN OUTCOMES AND MEASURES: Patients were genotyped on 25 DPYD variants. We tested the individual associations between each DPYD variant and grade 3 or greater fluorouracil AEs. RESULTS: A total of 1545 patients (57.6% male; median [range] age, 60 [19-75] years) were included in the analysis. The incidence of grade 3 or greater fluorouracil AEs in D949V and V732I (DPYD*6) carriers was 18 in 21 (85.7%) and 121 in 199 (60.8%), respectively. After adjusting for multiple variables, statistically significant associations were identified between grade 3 or greater fluorouracil AEs and both D949V (odds ratio [OR], 6.3 [95% CI, 2.0-27.0]; P < .001) and V732I variants (OR, 1.7 [95% CI, 1.3-2.4]; P < .001). Grade 3 or greater overall hematologic adverse events were associated with V732I (OR, 1.9 [95% CI, 1.4-2.6]) and D949V (OR, 5.2 [95% CI, 2.0-16.0]), and V732I was associated with grade 3 or greater neutropenia (OR, 1.8 [95% CI, 1.3-2.4]). The association of V732I with the occurrence of grade 3 or greater fluorouracil AEs and overall hematologic adverse events was validated in an independent cohort of 339 patients with metastatic colorectal cancer receiving FOLFOX4 in the Fédération Francophone de Cancérologie Digestive 2000-05 phase 3 trial. CONCLUSIONS AND RELEVANCE: In this large phase 3 study, statistically significant associations were found between DPYD variants (D949V and V732I) and increased incidence of grade 3 or greater fluorouracil AEs in patients treated with adjuvant fluorouracil-based combination chemotherapy. Further studies are warranted to confirm and quantitate these associations. TRIAL REGISTRATION: eudract Identifier 2005-003463-23.

Cancer Screening in Patients with Idiopathic Venous Thromboembolism--a Position Paper of the German Society of Hematology and Oncology Working Group on Hemostasis.

Cancer can trigger thromboembolism. There is a 4-10% chance of finding an asymptomatic occult cancer in patients with idiopathic venous thromboembolism (VTE). Current guidelines recommend limited cancer screening with history, physical examination, and screening examinations according to age after idiopathic VTE. Recent studies found that a more extensive screening program, including endoscopy and computed tomography, may increase the cancer detection rate. The Hemostasis Working Group of the German Society of Hematology and Oncology recommends a more extensive screening program after idiopathic VTE.

Assessing patients' anticoagulation preferences for the treatment of cancer-associated thrombosis using conjoint methodology.

Low molecular weight heparins have demonstrated superiority over coumarins in the extended treatment of cancer-associated thrombosis and are recommended as first-line therapy in clinical guidelines. Non-vitamin K oral antagonists are yet to be evaluated against low molecular weight heparin for this indication. Nevertheless, a perception that patients favor oral anticoagulants over injections may lead to an increased prescribing of warfarin or non-vitamin K oral antagonists despite the evidence gap. There has been no evaluation of cancer patient preferences for anticoagulants and whether such an evidence gap is an acceptable trade-off for patients prescribed orals. We conducted a study to assess what features are most important to CAT patients regarding their choice of anticoagulant. Two modules were applied: Initial in-depth interviews with 9 patients diagnosed with cancer-associated thrombosis, and thereafter quantitative research, where a further 100 patients completed a choice-based-conjoint exercise, where 15 different scenarios were presented to identify the most important attributes of an anticoagulant. Seventy percent of the patients were treated with injected medication (low molecular weight heparin) and 30% with oral medications. Patients most valued an anticoagulant with minimal interference with their cancer treatment (39%), low thrombosis recurrence rate (24%), and low risk of major bleed (19%). Preference for oral administration over injection had moderate importance (13%). The results show that patients prefer an anticoagulant that does not interfere with their cancer treatment, suggesting the primacy of the cancer disease over venous thromboembolism in these patients. Patients also favor efficacy and safety over convenience of route of administration.