Venous thromboembolic disease in pediatric malignancies:Epidemiology and prevention

Over the past decades, survival rates for pediatric cancer increased tremendously. This improvement can be attributed to more insight in the pathogenesis and optimized treatment strategies. However, a potential drawback of these treatment regimens is the burden of toxic effects. Venous thromboembolism is one of these toxic effects and a serious complication of cancer. VTE is a disease in which a blood clot forms within a vein. However, the incidence, risk factors and recurrence rate of VTE in pediatric cancer patients are largely unknown. VTE can lead to suboptimal ALL therapy, due to the need to interrupt, delay or discontinue chemotherapy, and thereby to inferior disease outcomes. This thesis focuses on the epidemiology, treatment and prevention of venous thrombosis in pediatric oncology patients. The first part the role of inherited thrombophilic disorders in the development of pediatric venous thromboembolism is described. Part II investigated the incidence, risk factors and recurrence rate of venous thromboembolism in pediatric oncology patients. A special focus was on identification of risk factors for VTE in acute lymphoblastic leukemia patients, as well as the influence of VTE on treatment and outcome of acute lymphoblastic leukemia. The last part focused on treatment and prevention of VTE. The optimal dosage of low-molecular-weight heparin (LMWH) for treatment and prevention was studied. Furthermore different preventive antithrombotic measures were evaluated. This thesis aimed to provide insight in risk factors and effective antithrombotic strategies in pediatric oncology patients

Venous thromboembolism in a large cohort of children with acute lymphoblastic leukemia: Risk factors and effect on prognosis

Background Venous thromboembolism (VTE) is relatively common in children with acute lymphoblastic leukemia (ALL). Thrombotic risk factors in ALL are asparaginase and steroids. However, within the ALL populations treated on the same regimen, it is less clear which other risk factors play a role. Furthermore, few data are available on the effect of VTE on ALL outcomes. Methods In 778 children (1‐18 years) with newly diagnosed precursor‐B‐lineage or T‐lineage ALL, treated in the Dutch Childhood Oncology Group (DCOG) ALL‐10 protocol in the Netherlands (October 2004 to April 2013), we conducted a nested case control study with 59 VTE cases and 118 controls to identify risk factors for VTE. Results Fifty‐nine of 778 ALL patients developed VTE (7.6%), with cerebral venous sinus thrombosis (CVST) in 26 of 59 patients (44.1%). VTE occurred during induction treatment in 59.3% (n = 35) and in 40.7% (n = 24) during medium risk intensification. Conditional multivariable logistic regression analysis showed that age and ALL subtype were significantly associated with VTE (age ≥7 years: OR 2.72, 95% CI 1.33‐5.57; ALL subtype T‐ALL: OR 2.95, 95% CI 1.02‐8.57). A multivariable Cox model showed no association between the occurrence of VTE and event free survival. In CVST patients, permanent disability was present in 34.6%. Conclusion Within this large pediatric ALL cohort, we demonstrated a high morbidity in CVST patients. Age ≥7 years at diagnosis and T‐ALL subtype were the main risk factors for VTE, and should be considered in preventive strategies

TropicALL study: Thromboprophylaxis in Children treated for Acute Lymphoblastic Leukemia with Low-molecular-weight heparin: a multicenter randomized controlled trial

Contains fulltext : 174077.pdf (publisher's version ) (Open Access)BACKGROUND: Venous thromboembolism (VTE) is a common and severe complication during treatment of acute lymphoblastic leukemia (ALL). An important cause is the intensive use of asparaginase. Prospective cohort studies in which prophylactic low-molecular-weight heparin (LMWH) was used to prevent VTE showed lower VTE risk than in historic control cohorts, with a negligible bleeding risk. However, the efficacy of thromboprophylaxis with LMWH during ALL treatment has never been investigated in a randomized design. Here, we present the protocol of a randomized controlled trial in which the efficacy and safety of thromboprophylaxis with high prophylactic dose LMWH versus no thromboprophylaxis will be assessed in children treated for primary ALL with asparaginase. METHODS/DESIGN: Thromboprophylaxis in Children treated for Acute Lymphoblastic Leukemia with Low-molecular-weight heparin (TropicALL) is a multicenter, randomized controlled open-label trial conducted in the Netherlands. Patients between 1 and 19 years of age with primary ALL, who are treated within the Dutch Childhood Oncology Group (DCOG) ALL-11 or 12 study will be randomized to thromboprophylaxis with LMWH once daily, (dose of 85 IU/kg (intervention arm A)), or to no thromboprophylaxis (arm B, standard of care) during asparaginase courses of ALL treatment. Primary efficacy endpoint is symptomatic objectified VTE during ALL treatment; secondary efficacy endpoints are overall survival and the composite of symptomatic and asymptomatic objectified VTE. Primary safety endpoints are major bleeding, clinically relevant non-major bleeding and minor bleeding. A total of 324 patients will be included to obtain a relative risk reduction of 75% with a power of 80%, using a two-sided test with significance level alpha = 0.05. DISCUSSION: This trial will be the first to assess efficacy and safety of thromboprophylaxis with LMWH during asparaginase treatment for ALL in children in a randomized design. TRAIL REGISTRATION: Nederlands Trial Register NTR4707 . Registered 30 July 2014