title: Trend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study.
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.
authors.affiliation: Population Health Sciences, Hospital For Sick Children, 555 University Avenue, Toronto, Ontario, Canada. M5G 1X8. lesley.mitchell@sickkids.ca
authors.forename: Lesley
authors.initials: L
authors.lastname: Mitchell
authors.forename: Maureen
authors.initials: M
authors.lastname: Andrew
authors.forename: Kim
authors.initials: K
authors.lastname: Hanna
authors.forename: Thomas
authors.initials: T
authors.lastname: Abshire
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Halton
authors.forename: John
authors.initials: J
authors.lastname: Wu
authors.forename: Ron
authors.initials: R
authors.lastname: Anderson
authors.forename: Irene
authors.initials: I
authors.lastname: Cherrick
authors.forename: Sunil
authors.initials: S
authors.lastname: Desai
authors.forename: Donald
authors.initials: D
authors.lastname: Mahoney
authors.forename: Patricia
authors.initials: P
authors.lastname: McCusker
authors.forename: Peter
authors.initials: P
authors.lastname: Chait
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdolell
authors.forename: Gabrielle
authors.initials: G
authors.lastname: de Veber
authors.forename: David
authors.initials: D
authors.lastname: Mikulis
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000991:Antithrombins / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001215:Asparaginase / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003328:Coronary Thrombosis / Q000453:epidemiology; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D007223:Infant; D020767:Intracranial Thrombosis / Q000453:epidemiology; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D016037:Single-Blind Method; D013927:Thrombosis / Q000453:epidemiology / Q000517:prevention & control*; D016896:Treatment Outcome; D020246:Venous Thrombosis / Q000453:epidemiology
chemical_list: D000970:Antineoplastic Agents; D000991:Antithrombins; D001215:Asparaginase