Incidence and Risk Factors for Thrombosis in Patients with Acute Promyelocytic Leukemia. Experience of the PETHEMA LPA96 and LPA99 Protocols.

Background: Thrombo-ischemic events can be a severe complication in patients with active acute promyelocytic leukemia (APL). In a recently published study, the incidence of thrombosis among 90 patients with APL was 9%, and it was related to CD2 surface antigen expression, FLT3 mutations and leukocytes >10×10⁹/L. The introduction of coagulopathy prophylaxis with tranexamic acid has not shown a benefit on hemorrhagic mortality, but its impact on the incidence of thrombotic events is unclear.

Objectives:

1. Analyze the incidence and risk factors for the development of thrombosis in patients with APL undergoing induction chemotherapy.

2. Analyze the impact of prophylaxis with tranexamic acid on development of thrombosis.

Material and methods: Between 1996 and 2005 759 patients with newly diagnosed APL were registered in the multicenter PETHEMA LPA96 and LPA99 trials. Twenty-six patients (3.5%) died due to complications before start of chemotherapy (CT). Induction consisted of ATRA plus idarubicin. In the LPA99 trial prophylactic tranexamic acid 100 mg/kg/day was introduced in case of platelets <50×10⁹/L. At the end of the LPA99 trial its use was not recommended, and overall, initiation of tranexamic acid was reported in 257 patients (35%) We performed a univariate analysis to assess clinico-biological factors associated with thrombosis. Significant variables (p<0.05) were included in a multivariate analysis.

Results: 39/759 patients (5.1%) developed thrombosis. Among 26 patients who died before initiation of CT, 6 (23%) presented with thrombotic complications: 3 cerebral stroke (CNS), 2 pulmonary embolism (PE) and 1 acute myocardial infarction (AMI). Thirty-three (4.5%) of the 733 patients in whom CT was initiated experienced thrombosis: 3 at diagnosis (1 AMI, 1 CNS and 1 deep venous thrombosis (DVT)) and 30 after the start of CT (16 DVT, 6 CNS, 3 PE, 2 AMI and 2 others). Four thrombotic events were related with initiation of tranexamic acid: 2 DVT, 1 skin necrosis and 1 renal necrosis. The following factors were related to a higher incidence of thrombosis: leukocytes >10×10⁹/L (9% vs 4%, p<0.01), M3-variant subtype (11% vs 4%, p=0.02), fibrinogen <170 mg/dl (7% vs 3%, p=0.02) and hemoglobin >10 g/dl (8% vs 4%, p=0.03). No significant relation was observed with CD2 or other surface antigens, as well as FLT3 mutations. Use of tranexamic acid showed a trend towards a higher incidence of thrombosis (6% vs 3%, p=0.08). In multivariate analysis hypofibrinogenemia and M3-v subtype remained as independent prognostic factors. Thrombosis was related with a higher induction mortality (including deaths before start of CT), 28% vs 11%, p<0.01.

Conclusion: Thrombo-ischemic events are relatively frequent in active APL patients implying an elevated early mortality. Hypofibrinogenemia and M3-v are associated with a higher incidence of thrombosis. Treatment with tranexamic acid has not decreased hemorrhagic mortality and it could be related to increased thrombotic events. Therefore its prophylactic use should not be recommended.