The occurrence of venous thromboembolism (VTE) in acute lymphocytic leukemia patients receiving L-asparaginase therapy may cause significant morbidity, neurological sequela and possibly worse outcomes. The prophylactic use of antithrombin infusion (to keep antithrombin activity >60%) or low molecular weight heparin (LMWH) may reduce the risk of VTE. The decision to continue L-asparaginase therapy after the development of VTE should be based on anticipated benefits, severity of VTE and the ability to continue therapeutic anticoagulation. In patients receiving asparaginase rechallenge, the use of therapeutic LMWH, monitoring of anti-Xa level and antithrombin level are important. Novel oral anticoagulants are not dependent on antithrombin level, hence offer theoretical advantages over LMWH for the prevention and therapy of asparaginase-related VTE.
KEYWORDS• acute lymphocyticThe use of L-asparaginase, along with multiagent systemic chemotherapy including anthracycline, vincristine and steroid, has made acute lymphocytic leukemia (ALL) a curable malignancy, particularly in children [1,2]. L-asparaginase catalyzes the conversion of asparagine (useful for protein synthesis) to aspartic acid and ammonia, thereby depleting the supply of asparagine to the leukemic cells that rely on an exogenous source due to their inability to synthesize it [3]. This leads to cell cycle arrest in the G1 phase and DNA strand breaks, thereby promoting apoptosis of leukemic cells [4]. L-asparaginase also deaminates glutamine to glutamic acid, which decreases the glutamine levels in the circulation [5]. Glutamine is believed to be a nitrogen donor for synthesis of RNA and DNA by the tumor cells, hence its depletion halts tumor growth and enhances cell apoptosis [6]. L-asparaginase is available in three forms, which include Escherichia coli asparaginase, Erwinia asparaginase and pegylated form of the native E. coli asparaginase (pegaspargase) [7]. Although a useful agent, the use of L-asparaginase has several potential toxicities including the risk of thrombosis [8][9][10]. In this review, we summarize the key studies on L-asparaginase-related venous thromboembolism (VTE) in patients with ALL with a focus on identification of high-risk patients, approaches to prevent VTE and management of patients who develop VTE.
EpidemiologyThe incidence of VTE in ALL patients has been reported to vary from 1 to 36% depending upon the age group of the patients, study designs, treatment protocols, symptomatic thromboembolism versus detection with screening radiography [10][11][12]. Caruso et al. reported a meta-analysis of 17 prospective studies on thrombotic complications in childhood ALL and demonstrated a thrombosis rate of 5.2%; more than half of the patients had CNS thrombotic events [12].