Evolution of Antithrombin (AT) and Fibrinogen (Fg) Levels during Induction Chemotherapy with L-Asparaginase (Asp) in Adult Patients with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL). Clinical Outcomes and Use of Coagulation Supportive Treatments: The CAPELAL Study.

Abstract

The incidence of AT and Fg deficiency and of thrombotic and bleeding events after Asp has been well evaluated in children with ALL, but little is known in adults. In this study, the incidence of these events and the use of coagulation supportive treatments was evaluated in 214 adult patients with ALL (n= 191) or LBL (n=23) included in the GOELAL02 trial (Blood 2004, in press). The induction therapy included steroids (40 mg/m2/d d1-21), vincristine (2 mg d1, 8, 15, 22), idarubicine (5 mg/m2 d1, 8,15, 22) and Asp (7500 UI/m2 d10, 13, 16, 19, 22, 25) delivered through a central venous access. Fresh frozen plasma (FFP), Fg (Clottagen®) and AT (Aclotine®) concentrates were recommended to maintain their levels > 1 g/l and 60%, respectively. If no transfusion, Asp infusion was delayed for 48 hours. Platelets were transfused when < 20 x 109/l. Heparin prophylaxis was left to institutional guidelines. Symptomatic thromboses and significant bleedings were systematically recorded. Active DIC was present in 10.3% of patients on d1. Fg and AT levels were measured 4098 times (20/patient, von Clauss assay) and 1718 times (8/patient, chromogenic assay) respectively, and evolved between d1 and d35 as shown below (mean ± sd). AT nadir was < 60% in 71% of patients with values < 40% in 26% of cases. Fg levels were < 1g/l in 73% of patients with values < 0.5g/l in 9%.Twenty-one thromboses occurred two to 35d after the first Asp infusion (median = 14d) in 20 patients (9.3%), with cerebral vein thrombosis (5), pulmonary embolism (3), upper (5) or lower (8) limb deep vein thrombosis. At the time of event, the median AT level was 48% (mean 60.7) with 12 of 21 thromboses (57%) occurring with AT < 60%. Fourty-two bleedings occurred one to 45d after the first Asp infusion (median = 8d) in 31 patients, with CNS hemorrhage (1), epistaxis (24), central venous access bleeding (8), GI bleeding (1), and large ecchymoses (8). At the time of event, median Fg level was 1.3 g/l. Asp infusions were reduced or delayed in 64% of all patients due to low Fg and/or AT levels. FFP, AT and Fg were infused in 31%, 41% and 52% of patients at mean doses of 5.3 ml/kg/infusion, 31UI/kg/infusion and 7.9 g respectively. AT level increased from 58%±16 (n=79) to 86%±23.2 (n=57) after the first AT infusion but was unchanged after FFP. Fg level increased from 0.9g/l ± 0.3 (n=85) to 1.4g/l ±0.5 (n=69) after Fg infusion but was unmodified after FFP. In conclusion, Fg and AT levels are frequently decreased in adults treated by Asp, with often a less than optimal chemotherapy. Bleeding events were not associated with severe Fg deficiency, but thrombotic events could be favored in some patients by acquired AT deficiency. The benefit of AT concentrates to prevent thrombosis and to reduce delay in Asp infusions could therefore be prospectively assessed in adults treated by Asp. d1 (n) d10-Asp 1 (n) d13-Asp2 (n) d19-Asp 4 (n) d25-Asp 6 (n) AT % - 121±16 (79) 83±16 (125) 65±20 (111) 65±22 (77) Fg g/l 3.2±1.7 (142) 1.9±1.0 (159) 1.4±0.7 (195) 1.1±0.4 (169) 1.4±0.6 (118)