title: Cerebral venous thrombosis in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma during induction chemotherapy with l-asparaginase: The GRAALL experience.
abstract: Central nervous system (CNS) thrombotic events are a well-known complication of acute lymphoblastic leukemia (ALL) induction therapy, especially with treatments including l-asparaginase (l-ASP). Data on risk factors and clinical evolution is still lacking in adult patients. We report on the clinical evolution of 22 CNS venous thrombosis cases occurring in 708 adults treated for ALL or lymphoblastic lymphoma (LL) with the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-induction protocol, which included eight L-ASP (6,000 IU/m(2) ) infusions. The prevalence of CNS thrombosis was 3.1%. CNS thrombosis occurred after a median of 18 days (range: 11-31) when patients had received a median of three l-ASP injections (range: 2-7). Patients with CNS thrombosis exhibited a median antithrombin (AT) nadir of 47.5% (range: 36-67%) at Day 17 (range: D3-D28), and 95% of them exhibited AT levels lower than 60%. There were no evident increase in hereditary thrombotic risk factors prevalence, and thrombosis occurred despite heparin prophylaxis which was performed in 90% of patients. Acquired AT deficiency was frequently detected in patients with l-ASP-based therapy, and patients with CNS thrombosis received AT prophylaxis (45%) less frequently than patients without CNS thrombosis (83%), P = 0.0002). CNS thrombosis was lethal in 5% of patients, while 20% had persistent sequelae. One patient received all planned l-ASP infusions without recurrence of CNS thrombotic whereas l-ASP injections were discontinued in 20 patients during the management of thrombosis without a significant impact on overall survival (P = 0.4).
authors.affiliation:  Hématologie Hôpital Morvan, CHU, Brest, France.
authors.forename: Marie-Anne
authors.initials: MA
authors.lastname: Couturier
authors.affiliation: Hématologie Hôpital Purpan, CHU, Toulouse, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Huguet
authors.affiliation: Hématologie, CHU, Nantes, France.
authors.forename: Patrice
authors.initials: P
authors.lastname: Chevallier
authors.affiliation: Hématologie Hôpital Necker AP-HP, France.
authors.forename: Felipe
authors.initials: F
authors.lastname: Suarez
authors.affiliation: Hématologie, HCL, Centre hospitalier Lyon Sud, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.affiliation: Hématologie, CHU, Rennes, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Escoffre-Barbe
authors.affiliation: Hématologie, CHU, Clermont-Ferrand, France.
authors.forename: Victoria
authors.initials: V
authors.lastname: Cacheux
authors.affiliation: Hématologie, CH Dunkerque, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pignon
authors.affiliation: Hématologie, CHU, Nancy, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Bonmati
authors.affiliation: Hématologie, CH Perpignan, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Sanhes
authors.affiliation: Hématologie, Strasbourg, CHU, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bories
authors.affiliation: Hématologie, CHU, Besançon, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Daguindau
authors.affiliation: Hématologie, CHR, Metz, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dorvaux
authors.affiliation: Hématologie, CHU, Caen, France.
authors.forename: Oumedaly
authors.initials: O
authors.lastname: Reman
authors.affiliation: Hématologie, Meaux, CHU, France.
authors.forename: Jamile
authors.initials: J
authors.lastname: Frayfer
authors.affiliation: Maladies Du Sang, CHU, Angers, France.
authors.forename: Corentin
authors.initials: C
authors.lastname: Orvain
authors.affiliation: Coordination du groupe GRAALL, Centre Hospitalier Lyon Sud, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Lhéritier
authors.affiliation: Maladies Du Sang, CHU, Angers, France.
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.affiliation: Hématologie Hôpital Saint-Louis AP-HP, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.affiliation: Maladies Du Sang/INSERM U892 PRES LUNAM, Angers, CHU, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Hunault-Berger
authors.affiliation: Maladies Du Sang/INSERM U892 PRES LUNAM, Angers, CHU, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Tanguy-Schmidt
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000991:Antithrombins / Q000097:blood; D001215:Asparaginase / Q000627:therapeutic use*; D002550:Cerebral Veins / Q000187:drug effects / Q000473:pathology; D004334:Drug Administration Schedule; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006493:Heparin / Q000627:therapeutic use; D006801:Humans; D060828:Induction Chemotherapy; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012189:Retrospective Studies; D012307:Risk Factors; D016019:Survival Analysis; D013997:Time Factors; D020246:Venous Thrombosis / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D000991:Antithrombins; D005343:Fibrinolytic Agents; D006493:Heparin; D001215:Asparaginase