Can Apixaban Succeed Where Others Have Failed?

A Study of the Safety and Effectiveness of Apixaban in Preventing Blood Clots in Children With Leukemia Who Have a Central Venous Catheter and Are Treated With Pegylated (PEG) L-Asparaginase

NCT02369653

Bristol-Myers Squibb

Approximately 58 study sites in North America, Australia, Canada

Randomized, open-label

500

This is a phase III, randomized, open-label study comparing apixaban with no anticoagulants for prevention of a composite of fatal and nonfatal venous thromboembolism (VTE) in children (ages 1-17 years) with a central venous catheter and a new diagnosis of acute lymphoblastic leukemia (ALL), lymphoma or mixed-phenotype acute leukemia. All participants must also receive induction chemotherapy with a corticosteroid, vincristine, and single or multiple doses of pegylated (PEG) L-asparaginase (+/– daunorubicin) and have a platelet count greater than 20×10⁹/L. The primary safety outcome will be major bleeding. Key exclusion criteria include: requirement for more than three lumbar punctures, prior VTE, recent surgery, uncontrolled hypertension, coagulopathy, and liver or renal impairment. Participants randomly assigned to the experimental arm will receive apixaban (<35 kg: 0.07 mg/kg solution; >35 kg: 2.5 mg tablets) twice daily for 25 to 28 days.

L-asparaginase reduces plasma concentrations of coagulation factors, particularly antithrombin, which contributes to a high prothrombotic state in patients with ALL.¹  Catheter-associated thrombosis is the most frequent thrombotic complication of this treatment, accounting for 95 percent of the VTE cases in a prospective study of pediatric ALL patients (total incidence of VTE: 22 [36.7%] of 60; 95% CI 24.4-48.8).²  Catheter-associated thrombosis is important not only because it leads to limb morbidity, but because it may also compromise administration of chemotherapy due to loss of venous access.

This trial faces several important hurdles. First, there is the failure of other anticoagulants, such as low-molecular-weight heparin (LMWH) and warfarin, to prevent catheter-associated thrombosis in pediatric patients with cancer.³  Second, L-asparaginase can cause profound thrombocytopenia and hypofibrinogenemia, which increases the risk of major bleeding, especially within the context of anticoagulant therapy. Lastly, experience with the direct oral anticoagulants in this patient population is limited, which raises questions about efficacy and safety.⁴ 

Despite these hurdles, there are also important advantages to evaluating apixaban. These include oral administration and reduction/elimination of the need for laboratory coagulation monitoring. Both properties would greatly improve quality-of-life for pediatric patients. Furthermore, apixaban does not depend on the presence of antithrombin to exert its anticoagulant effect, which may improve efficacy in patients receiving L-asparaginase. If successful, this trial will break new ground for cancer patients who require central venous catheters, both pediatric and adult.