Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia

Abstract

An association has been reported between thrombotic events and the use of L-asparaginase (ASP) in children with acute lymphoblastic leukaemia (ALL). The mechanism for thrombosis is likely related to an acquired antithrombin deficiency. Since a primary prophylaxis using antithrombin concentrates may prevent thrombosis, the PARKAA (Prophylactic Antithrombin replacement in kids with ALL treated with L-asparaginase) study was performed. The objectives of PARKAA were to determine if there was a trend to efficacy and safety of antithrombin treatment as assessed by 1) incidence of thrombosis 2) incidence of bleeding and 3) plasma markers of endogenous thrombin generation as surrogate outcomes for thrombosis. The study was not powered to answer the question of efficacy and safety, but rather to detect a trend. PARKAA was an open, randomised, controlled study in children with ALL being treated with ASP. Children were randomised to receive antithrombin infusions or no antithrombin treatment. All thrombotic events were confirmed using bilateral venography, ultrasound, echocardiography and MRI. The incidence of thrombosis in patients treated with antithrombin was 28% (95% CI 10-46%), compared to 37% (95% CI 24-49%) in the non treated arm. Two minor bleeds occurred in patients in the treated arm, but were not considered to be related to antithrombin. No significant differences were seen in plasma markers by the treatment group. In conclusion, treatment with antithrombin concentrate shows a trend to efficacy and safety. In contrast, there was no difference in surrogate markers for thrombosis. Carefully designed clinical trials are needed to test the efficacy and safety of antithrombin in this population.

Safety and feasibility of lower antithrombin replacement targets in adult patients with hematological malignancies receiving asparaginase therapy

“…[13] The study was underpowered to detect a true difference in efficacy and safety and could only report trends in these outcomes. [9] The incidence of thrombosis in patients treated with AT was 28% (CI 10–46%) versus 37% (24–49%) in the non-treated arm. There was no difference in hemorrhagic events.…”

“…The high overall event rate was attributed to the routine intensive asymptomatic screening process. [9]…”

“…37%). [9] Retrospective analyses have demonstrated a statistically significant reduction in thromboembolic complications when utilizing AT replacement compared to no replacement; however, these studies contain small sample sizes and lack cost considerations. [4,10] Current guidelines do not comment on AT replacement as a supportive management strategy for asparaginase toxicity.…”

Antithrombin Concentrate Use in Children: A Multicenter Cohort Study

“…Medical diagnoses associated with antithrombin administration in the pediatric literature includes respiratory distress syndrome, 14,15 disseminated intravascular coagulation from sepsis, 16,17 clot prevention associated with L-asparaginase use in leukemia, 18,19 nephrotic syndrome, 20 liver failure, 21 thermal injuries, 22 veno-occlusive disease, 23 and necrotizing enterocolitis. 24 Patients received antithrombin either to treat or prevent acquired antithrombin deficiency, but in the case of sepsis and disseminated intravascular coagulation (DIC), antithrombin also appeared to be given for its anti-inflammatory properties.…”

Thrombotic and Hemorrhagic Complications in the Treatment of Acute Lymphoblastic Leukemia with L-Asparaginase

“…В рандомизированном контролируемом исследо-вании PARKKA [37] показано более низкое, но стати-стически незначимое уменьшение частоты тромбозов в группе АТ по сравнению с контролем (28 vs 37 %; В результате было отмечено уменьшение частоты тромбозов (0/30 vs 5/15; p < 0,001). Авторы считают, что эта стратегия должна быть принята для нацио-нального клинического исследования ОЛЛ [38].…”