Prophylaxis Does Not Fully Prevent VTE Risk in Patients With ALL Treated With Asparaginase

Antithrombin (AT) replacement and heparin prophylaxis was not entirely effective for the prevention of venous thromboembolism (VTE) in adult patients with acute lymphocytic leukemia (ALL) who received L-asparaginase (L-ASP), according to a study published in Blood.

Mathilde Hunault-Berger, MD, PhD, of Angers University Hospital Center in France, and colleagues say the results suggest additional VTE prophylactic strategies are needed for this patient population.

The investigators examined the occurrence of any thrombosis in patients who participated in the Group for Research on Adult Acute Lymphoblastic Leukemia 2005 (GRAALL-2005) trial performed between 2006 and 2014 at multiple centers across France, Belgium, and Switzerland. The randomized GRAALL-2005 trial examined the effect of high-dose cyclophosphamide and rituximab during induction therapy in 784 adults with newly diagnosed Philadelphia-negative ALL.

The mean age of enrolled patients was 36 years (range = 25-48); 7% (n=55) of patients had central nervous system involvement by leukemia. During intensive chemotherapy, which included induction, 3 consolidation phases (9 blocks), and late intensification, with L ASP administered throughout, the VTE incidence rate was 16%. The 1-year cumulative incidence of first VTE in this cohort was 17%. Deep vein thrombosis/pulmonary embolism was reported in 85 patients, and cerebral vein thrombosis was reported in 32 patients.

The majority of VTE (69%) occurred during the induction phase. Approximately 15% of VTE occurred during consolidation phase I, 3% occurred during consolidation phase II, 7% occurred during late intensification, and 6% occurred during consolidation phase III.

Most (87%) patients received AT supplementation. In an analysis that excluded 18 patients who did not receive L-ASP or who developed thrombosis prior to receiving L-ASP, supplementation with AT was not associated with a significant impact on the rate of VTE (8% vs. 14%, odds ratio [OR] = 0.6; p=0.1).

In contrast, patients treated with fibrinogen concentrates for hypofibrinogenemia more often had VTE (17% vs. 9%; OR=2.2; 95% CI 1.1-4.3; p=0.02). The investigators found no impact of prophylactic fresh-frozen plasma on VTE. Moreover, and perhaps surprisingly, a higher proportion of patients who received heparin prophylaxis subsequently experienced VTE compared with those who did not receive heparin (13% vs. 7%, respectively; OR=1.9; 95% CI 1-3.6; p=0.04).

A total of 39 grade 3 to 4 bleeding complications (in 5% of enrolled patients) were reported, with 88% of these events occurring during induction. The most frequent were gastrointestinal bleeding (36%), followed by intracranial bleeding (31%). There was no association between the incidence of grade 3 to 4 bleeding and either VTE or receipt of AT concentrates or heparin.

The authors concluded that in patients with ALL receiving L-ASP therapy, the use of routine prophylaxis with fibrinogen concentrates may increase the risk of thrombosis and should be restricted to rare patients with hypofibrinogenemia-induced hemorrhage. Patients developed VTE despite extensive AT supplementation and heparin, which advocates for additional prophylactic measures.


Orvain C, Balsat M, Tavernier E, et al. Thromboembolism prophylaxis in adult patients with acute lymphoblastic leukemia treated in the GRAALL-2005 study. 2020 Apr 22. Blood. [Epub ahead of print]