P374: thrombotic events in children with acute lymphoblastic leukemia: experience of italian aieop centers (2009-2017)

Background: Thrombotic events (TE) in children treated for acute lymphoblastic leukemia (ALL) are reported in 1- 37%, depending on their severity. TE impact on scheduled asparaginase treatment and may consequently have a negative effect on prognosis in children with ALL. Aims: The aim of our study was to evaluate the epidemiology and clinical relevance of TE among 2098 Italian patients enrolled in AIEOP BFM ALL 2009 protocol from October 2009 to February 2017. Methods: We included all the arterial and venous TE classified as grade 2 or more, according to Ponte di Legno Toxicity Working Group (PdLTWG) definition, confirmed by imaging (ultrasound, computed tomography or magnetic resonance). Results: Twenty-three out of 38 Italian AIEOP centers reported about TE. Sixty-two TE were reported in total, with a 2-year cumulative incidence of 3%. The incidence varied from 0% to 6,7%, according to single center’s reporting. Thirty-two (52%) were cerebral vein thrombosis (CVT), 28 (45%) were systemic deep vein thrombosis (SVT) (9 in the neck, 11 in the upper limb, 8 in the lower limb vessels) and 2 (3%) were in the right atrium. No arterial thrombosis was reported. All but one systemic thromboses were related to venous catheter. SVT were significantly more frequent in boys (OR 2.22, 95%IC: 0.99-4.97, p-value=0.048), while no gender differences were observed in CVT. Both CVT and SVT were observed more frequently in children older than 10 years (p-value= 0.0005 and 0.0003, respectively) and in T-ALL (p-value=0.0013 and 0.047, respectively). Meningeal involvement at diagnosis was significantly associated with risk of CVT (OR: 2.74, 95%IC: 1.21-6.17, p-value=0.01). Obesity, mediastinal mass, blood group, initial white blood cell count and risk group were not significant risk factors. Familial thrombophilia was identified in 2 of 41 cases, no statistical association was found. TE occurred more frequently during induction phase (39 cases) (OR: 3.05, 95%IC: 1.56-7.65, p-value=0.03). Initial treatment of TE consisted in heparin (5 unfractionated and 55 low molecular weight heparin), 2 children were treated with recombinant tissue-type plasminogen activator for symptomatic subclavian vein thrombosis. Median treatment duration was 4.5 months for SVT and 5 months for CVT. Secondary prophylaxis was administered to 55% of patients (61% of CVT and 48% of SVT). Three children experienced a second TE, two had been re-exposed to L-asparaginase and one was receiving LMWH. One patient died of subsequent cerebral hemorrhage; symptoms resolved in all other patients. Long term sequelae were observed in 8 patients (12,5%): 5 with CVT (3 patients had seizures requiring anticonvulsant therapy, 1 motor weakness, 1 cognitive impairment) and 3 with SVT (post thrombotic syndrome). Chemotherapy was modified in 21 patients (33%). Summary/Conclusion: TE reported in recent Italian protocol are rare (3%) and occur more frequently in T-ALL, boys, older children and in initial meningeal involvement. SVT are mostly related to venous lines; clinical impact is significant especially in CVT. Primary prophylaxis was not suggested; it was administered only in a girl with CVT. Prophylaxis and treatment strategies should encompass new evidence from randomized studies and the use of new oral anticoagulant drugs. Keywords: Children, Thrombophilia, Thrombosis, Acute lymphoblastic leukemia