Prevention of Venous Thrombotic Events in Adult Patients with Acute Lymphoblastic Leukemia Treated in a Pediatric-Inspired Protocol - a Graall Study
Authors: Orvain Corentin , Balsat Marie , Lhéritier Véronique , Tavernier Emmanuelle , Marolleau Jean-Pierre , Pabst Thomas , Chevallier Patrice , De Gunzburg Noémie , Cacheux Victoria , Huguet Francoise , Chantepie Sylvain , Caillot Denis , Chalandon Yves , Frayfer Jamilé , Bonmati Caroline , Boissel Nicolas , Dombret Hervé , Ifrah Norbert , Hunault-Berger Mathilde 
Published: October 2019

Abstract
Background: Patients undergoing treatment for acute lymphoblastic leukemia (ALL) are at risk for thrombosis, in part due to the use of L-asparaginase (L-ASP) and subsequent antithrombine (AT) deficiency. Previous reports showed that patients with venous thrombotic events (VTE) have a lower event-free survival that may be due to early discontinuation of L-ASP. It has been suggested that AT replacement could decrease the rate of thrombosis and prevent L-ASP discontinuation. We report herein the results of the prophylactic replacement strategy in the pediatric-inspired prospective GRAALL-2005 study.
Methods: All patients received a 5-drug induction therapy with 8 native E. Coli-ASP intravenous injections (6,000 UI/m2/injection). Patients in complete remission (CR) received two consolidation courses each containing two L-ASP intravenous injections (10000 UI/m2/injection). All patients in persistent CR for whom allogeneic stem cell transplantation was not indicated in first CR received a late intensification with the same drugs as in the induction course, followed by the repetition of one consolidation course. Platelet transfusion support was recommended for platelets below 20 x 109/L, fresh frozen plasma (FFP) or fibrinogen concentrates were recommended if fibrinogen levels fell below 0.5 g/L, and AT concentrate substitution therapy was recommended in order to maintain AT levels above 60%. Prophylactic heparin was recommended during induction and late intensification. All cases of VTE were identified prospectively by clinical signs and confirmed by radiological imaging based on institutional guidelines.
Results: Between 2006 and 2014, 787 adult patients with newly diagnosed Philadelphia-negative ALL were included. The incidence rate of VTE was 14.4% (113 VTEs in 110 patients). VTEs included 72 (64%) deep vein thromboses (DVT), with one third in the lower limb and two thirds in the upper limb, 32 (28%) cerebral venous thrombosis (CVT), and 13 (12%) pulmonary embolism (PE). No disease characteristic was associated with a higher risk of thrombosis. Patients with DVT and/or PE were older (median age of 40 versus 38 for those with CVT versus 35 for those without VTE, p=0.04), had a higher BMI (median BMI of 26 versus 23 for those with CVT and 24 for those without VTE, p=0.01), and had a higher platelet count at diagnosis (median platelet count of 100 G/l versus 84 G/l for those with CVT versus 68 G/l for those without VTE, p=0.06) whereas patients with CVT had higher hemoglobin levels (median hemoglobin level of 11.7 g/dl versus 10.1 g/dl for those with DVT/PE versus 10.2 g/dl for those without VTE, p=0.03). Sixty-seven percent of VTEs occurred during induction therapy. Other VTEs occurred as follows: 17 (15%) during consolidation phase 1 (688 patients), 4 (4%) during consolidation phase 2 (537 patients), 9 (8%) during late intensification (356 patients), and 7 (6%) in 335 during consolidation phase 3 (335 patients). The type of thrombosis was different according to treatment phase as most CVT occurred during induction therapy (29 versus 3 CVTs during subsequent phases of treatment, p=0.003). During induction therapy, patients with VTE were more likely to have received heparin prophylaxis (82% versus 60% for those without VTE, odds ratio (OR) 1.8, p=0.06) and fibrinogen prophylaxis (14% versus 8% for those without VTE, OR 2, p=0.05) whereas they received less AT prophylaxis (82% versus 88% for those without VTE, OR 0.5, p=0.05). Patients with VTE received less L-ASP infusions during induction therapy (median number of 7 versus 8 injections for those without VTE, p<0.001) and they were less likely to receive L-ASP during late intensification (64% versus 69% for those without TVE during induction and who went on to receive late intensification, p<0.001). Among 25 patients who experienced VTE during induction and in whom L-ASP, either native E. Coli-ASP or Erwiniase-ASP, was reintroduced during late intensification, none presented with recurrence of VTE.
Conclusion: In ALL patients receiving L-ASP therapy, appropriate AT prophylaxis was associated with less VTE and should be used extensively. Maintaining higher AT levels in patients at increased risk for VTE should be evaluated. L-ASP can be reintroduced in patients who experienced VTE during induction as none had thrombotic recurrence. Fibrinogen concentrates may increase the risk of thrombosis and should be restricted to patients with hemorrhage.

Disclosures
Dombret: Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau.