Antithrombin Supplementation in Adults with Acute Lymphoblastic Leukemia (ALL) Following Asparaginase Therapy: A Meta-Analysis

Abstract

Background: Aspagarinase is a fundamental component for the treatment of patients with acute lymphoblastic leukemia (ALL). Venous thromboembolism (VTE) is a known complication of asparaginase therapy during treatment for ALL. This is attributed to the depletion of anticoagulants, particularly acquired antithrombin deficiency following asparaginase administration. The incidence of thrombosis following asparaginase is more prevalent in adults versus children and is estimated to be around 5-35 % and 2.4-8% respectively. Multiple studies have investigated the efficacy and safety of antithrombin supplementation. The recent THROMBOTECT study showed that prophylactic use of antithrombin (AT) or low molecular weight heparin (LMWH) is associated with significant risk reduction of thromboembolism in children and adolescents during induction chemotherapy of ALL. Our study sought to review the cohort studies comparing VTE in adults with and without AT supplementation in ALL receiving asparaginase and specifically evaluate the efficacy of this strategy. Methods: We performed a systematic search using PubMed, Google Scholar, EMBASE, SCOPUS and ClinicalTrials.gov without language restriction up until July 20th 2020. A random effects model was utilized to calculate risk ratio (RR) and mean difference (MD) with 95% confidence interval (CI). Results: Eight studies fulfilled our inclusion criteria (table 1) and were retrospective cohort studies. In adult patients, with ALL treated with asparaginase, the incidence of VTE was significantly lower in those who received AT [RR=0.46 (95 % CI= 0.31-0.70; p= 0.0002) (figure 1.1). The threshold for AT supplementation was 60-70% in most of the studies, with the exception of two studies where the threshold was 50%. Conclusion: In our meta-analysis of the current available data,Antithrombin supplementation in adults with ALL receiving asparaginase was associated with a significant decrease in the risk of venous thromboembolism compared to those who didn't receive thromboprophylaxis. Our data suggest the benefit of antithrombin supplementation in adults with ALL treated with asparaginase. We suggest that this strategy be implemented in a large prospective clinical trial to further confirm the benefit of this intervention. Disclosures No relevant conflicts of interest to declare.

Antithrombin Therapy: Current State and Future Outlook

“…120 More recently, a 2020 meta-analysis of 8 retrospective studies on AT in patients with ALL found that the risk of VTE was significantly lower in adults with AT therapy versus those without. 13 Guidelines from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis recommend AT therapy for adults with ALL receiving l -asparaginase treatment at a threshold AT level of 50% to 60%, targeting AT concentration in the normal range (80%-120%). 121…”

“…157 Meta-analyses of pooled trials exist, but they have low quality of evidence due to high probability of bias and heterogeneity in the patient populations of the pooled trials, which are variable in participants, severity of condition, treatment regimens, and clinical setting. 13,15,47,48,80,157 Patients and providers would benefit from a large-scale randomized controlled trial with low bias risk that would provide a high level of evidence concerning the effectiveness of AT use and supplementation.…”

“…8,9 Given the potential for hemostatic and anti-inflammatory benefits associated with ATc, there are a plethora of studies describing investigation of additional uses for ATc. [10][11][12][13][14][15] For example, AT therapy may benefit the treatment of individuals with sinusoidal obstruction syndrome, previously known as veno-occlusive disease (SOS/VOD), 11 heparin resistance, 10,13 and sepsis-induced disseminated intravascular coagulation (DIC). 15 Other works describe benefits to AT therapy during asparaginase therapy for acute lymphoblastic leukemia (ALL), 13 extracorporeal membrane oxygenation (ECMO), 12 and continuous renal replacement therapy (CRRT).…”

“…[10][11][12][13][14][15] For example, AT therapy may benefit the treatment of individuals with sinusoidal obstruction syndrome, previously known as veno-occlusive disease (SOS/VOD), 11 heparin resistance, 10,13 and sepsis-induced disseminated intravascular coagulation (DIC). 15 Other works describe benefits to AT therapy during asparaginase therapy for acute lymphoblastic leukemia (ALL), 13 extracorporeal membrane oxygenation (ECMO), 12 and continuous renal replacement therapy (CRRT). 14 Recent evidence also suggests that AT plays a role in coronavirus disease 2019 (COVID-19), 16 hemorrhagic shock, 17 and in modulation of tumor cell activity.…”