Article
Reference
Thromboembolism prophylaxis in adult patients with acute lymphoblastic leukemia treated in the GRAALL-2005 study
ORVAIN, Corentin, et al.
Abstract
Patients undergoing treatment of acute lymphoblastic leukemia (ALL) are at risk for thrombosis, caused in part by the use of l-asparaginase (L-ASP). Antithrombin (AT) replacement has been suggested to prevent venous thromboembolism (VTE) and thus may increase exposure to ASP. We report herein the results of the prophylactic replacement strategy in the pediatrics-inspired prospective GRAALL-2005 study. Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia- ALL were included. The incidence rate of VTE was 16%, with 69% of cases occurring during induction therapy. Most patients received AT supplementation (87%). After excluding patients who did not receive L-ASP or who developed thrombosis before L-ASP, AT supplementation did not have a significant impact on VTE. Administration of fibrinogen concentrates was associated with an increased risk of VTE, whereas transfusion of fresh frozen plasma had no effect. Heparin prophylaxis was associated with an increased risk of VTE. Prophylactic measures were not associated with an increased risk of grade 3 to 4 bleeding complications. The rate of VTE recurrence [...]
ORVAIN, Corentin,
et al. Thromboembolism prophylaxis in adult patients with acute
lymphoblastic leukemia treated in the GRAALL-2005 study.
Blood, 2020, vol. 136, no. 3, p.
328-338
DOI : 10.1182/blood.2020004919 PMID : 32321172
Available at:
http://archive-ouverte.unige.ch/unige:154831
Disclaimer: layout of this document may differ from the published version.
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GRAALL2005 : centres participants (Cliniciens, biologistes, ARCs)
France Aix en Provence : Drs Caillères, Chaib, blanc, Brunel, Mme Cuvelier ; Amiens : Drs Marolleau, Damaj, Vaida, Royer, Gruson, Merlusca, Copin, Capiod, Mme Dubus, M.Mpari ; Angers : Drs Hunault, Ifrah, Schmidt, Dib, Francois, Moles, Foussard, Guardiola, Zandecki, Blanchet, Baranger, Chassevent, Genevieve, Mme Marie ; Annecy : Drs Parry, Orsini-Piocelle, Corront, Daguindau, Cony-Makhoul, Reynes, Mme Cadoux, Mme Vittet ; Argenteuil : Drs Sutton, Al Jijakli, Genet, Chaoui, Mesbah, Morel, Touahri, Mossafa, Fourcade, Mme Guerekobaya ; Avignon : Drs Zerazhi, Azzedine, Boulat, Lepeu, Touchais, Derre, Mme Beyrne ; Bayonne : Drs Araujo, Bauduer, Banos, Renoux, Menard, Mme Labarrère ; Besançon : Drs Legrand, Berceanu, Daguindau, Deconinck, Larosa, Ferrand, Brion, Collonge-Rame, Garnache Ottou, Mme Peria ; Blois : Drs Rodon, Elyamadi, Mme Kadiri ; Bobigny : Drs Gardin, Ades, Fenaux, Braun, Cayuela, Eclache, Letestu, Mme Nloga ; Bordeaux : Drs Leguay, Milpied, Lascaux, Dilhuydy, Dimicoli, ,Pigneux, Tabrizi, Dumas, Lacombe, Lippert, M. Sauvezie ; Boulogne sur mer : Drs Choufi, Kadiata, Barry, Voronina, Brument, M. Nouvel ; Brest : Drs Guillerm, Berthou, Dalbies, Tempescul, Ianotto, Couturier, Eveillard, Ugo, De Braekeleer, Le Calvez Mme Gillet ; Caen : Drs Reman, Leporrier, Chantepie, Johnson Ansah, Gac, Macro, Benabed, Cheze, Naguib, Plessis, Salaun Mme Marin ; Clamart : Drs Malfuson, Konopacki, Souleau, De Revel, Fagot, Foissaud, Mme Harrouche ; Clermont-Ferrand : Drs Cacheux, Bay, Tournilhac, Hermet, Guieze, Bailly, Chaleteix, De Renzis, Chabrot, Calvet, Sapin, Tchirkov, Périssel, Veronese, Chassagne Berger, Mme Roy ; Colmar : Drs Auduy, Raby, Kohser, Humbrecht, Barats, Husseini, Moskovtchenko, Mazurier, Mme Camara ; Corbeil Essonnes : Dr Salanoubat, Haiat, Petitdidier, Cereja, Joly, Devidas, Quillet Mme Boutant ; Créteil : Drs Maury, Cordonnier, Pautas, Toma, Hichri, Kuentz, Bories, Jouault, Wagner-Ballon, Perot, Plonquet, M. Cabanne ; Dijon : Drs Caillot, Lafon, Casasnovas, Ferrant, Bastié, Teyssier, Mugneret, Mme Grandjean ; Dunkerque : Drs Pignon, Bemba, Wetterwald, Roumier, Mme Paquez ; Grenoble : Drs Cahn, Thiebaut, Gressin, Bulabois, Simon, Pégourie, Courby, Molina, Callanan, Lefebvre, Jacob, M.Pittet ; La Réunion : Drs Agapé, Belkaid, Henni, Berg, Pequin ; Lens : Drs Stalnikiewicz, Dupriez, Morel, M.Declercq ; Lille : Drs Berthon, Quesnel, Preudhomme, Grardel, Roche Lestienne, Lai, Lepelley, M. Djeda ; Limoges : Drs Turlure, Bordessoule, Touati, Remenieras, Abraham, Gourin, Girault, Moreau, Jaccard, Chaury, Penot, Trimoreau, Gachard, Feuillard, Mmes Tisseuil, Philippon, Bosselut, Nlend ; Lyon CHLS : Drs Salles, Coiffier, Espinouse, Michallet, Karlin, Bouafia-Sauvy, Broussais-Guillaumot, Traullé, Callet-Bochu, Tigaud, Hayette, Mme Maire ; Lyon HEH : Drs Thomas, Chelghoum ; Nicolini, Ducastelle, Labussière, Detrait, Plesa, Mme Boucher ; Marseille : Drs Etienne, Prebet, Charbonnier, Brunelle, D'Incan, Vey, Rey, Mozziconacci, Sainty, Laibes, Arnoulet, Mmes Dridi, Redortier ; Meaux : Drs Frayfer, Allard, Mme Matis ; Metz : Drs Dorvaux, Guibaud, Zamfir, Christian, Staal, Benet , Mme Hagopian ; Montpellier : Drs Vincent, Quittet, Navarro, Ceballos, Fegueux, Cartron, Legouffe, Rossi, Tondeur, Cacheux, Bret, Taviaux, Portales, Lavabre, Taib, Eliaou, Mme Leroux, M.Theis ; Mulhouse : Drs Ojeda-Uribe, Drenou, Eisenmann, Arkam, Rimelen, Jeandidier, Debliquis, Mmes Iglarz, Haby ; Nancy : Drs Bonmati, Witz, Feugier, Randa, Namour, Grégoire, Monhoven, Léotard, Jonveaux, Béné, M. Schwartz ; Nantes : Drs Chevallier, Mohty, Harousseau, Le Gouill, Gastinne, Peterlin, Guillaume, Delaunay, Vigouroux, Mahé, Lode, Garand, Robillard, Talmant, Avet-loiseau, Mme Le Houerou ; Nice : Drs Sirvent, Mannone, Gratecos, Legros, Raynaud, Philip, Ticchioni, Mme Bouskila ; Nîmes : Drs Jourdan, Richard, Gaillard, Arnaud, Chiesa, Brun, Mme Nicolas ; Orléans : Drs Alexis, Boulet, Carp, Benbrahim, Schoenwald, Legac, M. Michel ; Paris Cochin : Drs Dreyfus, Bouscary, Al Nawakil, Picard, Vigue, M. Mekdour ; Paris Necker : Drs Buzyn, Suarez, Delarue,
Sibon, Cheminant, Marcais, Frenzel, Brignier, Asnafi, Radford-Weiss, MacIntyre, Mme Berdous Saheb;
Paris Saint Antoine : Drs Isnard, Legrand, Lapusan, Marzac, Perot, Feger, Mme Ikhlef ; Paris Saint Louis : Drs Dombret, Raffoux, Lengline, Boissel, Cluzeau, Micléa, Zini, Cayuela, Maarek, De Labarthe, Beldjord, Mmes Treilhou, Klein ; Paris Pitié Salpétrière : Drs Vernant, Leblond, Dhedin, NGuyen, Merle Beral, Davi ; Perpignan : Drs Sanhes, Karangwa, Burcheri, Roland, Vallantin, Andary, Gueudet, Mmes Barbier, Touhami ; Poitiers : Drs Randriamalala, Guilhot, Chomel, Brizard, lecron, turhan, M.
Larchée ; Pontoise : Drs Fouillard, Gonzales, Mallet, Guignedoux, Mme Amirault ; Reims : Drs Himberlin, Le, Kolb, Delmer, Quinquenel, Carcelle, Cornillet-Lefebvre, Daliphard, Luquet, Lafon, Mme Haby, M. Meur ; Rennes : Drs Escoffre-Barbe, Doncker, Houot, Lamy de la Chapelle, De Guibert, Bernard, Nimubona, Dauriac, Fest, Boulland, Henry, Roussel Mme Picouleau ; Roubaix : Drs Plantier, Detourmignies, Fawaz, Dervite, Mme Thiriez ; Rouen : Drs Leprêtre, Lanic, Lenain, Tilly, Contentin, Stamatoullas, Lemasle, Jardin, Brehar, Bastard, Etancelin, Boutet, Penther, Lenormand, Mme Simon ; Saint Cloud : Drs Janvier, Fabre, Samieh, Elias, Al Jassem, Bourguignat, Glaisner, Soussain, Malak, Vargaftig, Bennani, M Vavasseur ; Saint Priest en Jarez : Drs Tavernier, Guyotat, Jaubert, Cornillon, Mounier, Flandrin-Gresta, Nadal, Vasselon, Solly, Campos, Mme Marchand ; Strasbourg : Drs Bilger, Lioure, Herbrecht, Bories, Fornecker, Fohrer, Moulin, Gaub, Gervais, Mauvieux, Oudet, Eischen, Mmes Aubry, Magnier, Kravanja ; Toulouse : Drs Huguet, Huynh, Roussel, Tavitian, Ysebaert, Recher, Borel, Hebraud, Oberic, Laurent, Nouvel, Delabesse, Kuhlein, Dastugue, Demas, Luquet, Vergez, M.
Daniel, Mme Leclerc ; Tours : Drs Lissandre, Dartigeas, Gyan, Renaud, Monjanel, Ertault de la Bretonniere, Benboubker, Estienne, Barin, Watier Mme Nollet ; Valenciennes : Drs Fernandes, Pollet, Tricot, Simon, Bremeault, Daudignon, Bisiau, M. Crametz ; Versailles : Drs Rousselot, Castaigne, Salmeron, Lambert, Taksin, Rigaudeau, Farhat, Merabet, Ghez, Spentchian, Terre, Garcia, Mme Henri ; Villejuif : Drs De Botton, Bourhis, Arnaud, Micol, Garnier, Willekens, Bennaceur, Auger, Saada.
Suisse Aarau : Drs Bargetzi, Heinzmann, Sigle, Mme Gurtner ; Bâle: Drs Gratwohl, Passweg, Medinger, Halter, Heim, Gerull, Mmes Villa, Martin; Bellinzona : Drs Stüssi, Servida, Marongui, Christinat, Steffanoni, Taborelli, Cresto, Mme Busi; Berne : Drs Pabst, Mme Rettich, Genève : Drs Chalandon, Tirefort, , Matthes, Samii, Tsopra, Masouridi-Levrat, Salamanczuk, Mme Trembleau, Lausanne : Drs Lambert, Spertini, Jotterand, Schoumans Pouw, Abbal, Mme Jeckelmann, Voegtin ; Kunkel, Quarroz, Mulhematter, Porter; Lucerne : Drs Gregor, Wuillemin, Nagler ; Mme Fahrni; Saint Gallen : Drs Driessen, Hess, Hitz, Weder, Mme Raess, Demmer, Frey, Wolf-Linder, Fesrer ; Zurich : Drs Jacky, Reiner, Schanz, Sasselli, Schafer ; SAKK coordination : Mmes Genton, Largiader, Kuenzle, Keunecke.
Supplementary Table 1. Characteristics of patients who received heparin prophylaxis or not.
All (n=784) No Heparin Prophylaxis
(n=177)
Heparin Prophylaxis
(n=485)
p
Age 36 (25 - 48) 35 (23 - 48) 36 (25 - 48) .37
Female 312 (40%) 64 (36%) 192 (40%) .42
BMI 24 (21 - 27) 23 (21 - 27) 24 (21 - 27) .12 Smoking
No 396 (50%) 89 (50%) 246 (51%) .4
Yes 226 (29%) 57 (32%) 135 (28%)
Missing Data 162 (21%) 31 (18%) 104 (21%)
Contraception
No 124 (16%) 20 (11%) 82 (17%) .21
Yes 78 (10%) 22 (12%) 44 (9%)
Missing Data 110 (14%) 22 (12%) 66 (14%)
Not applicable 472 (60%) 113 (64%) 293 (60%)
Phenotype
B-cell 523 (67%) 120 (68%) 322 (66%) .73
T-cell 261 (33%) 57 (32%) 163 (34%)
CNS involvement 55 (7%) 7 (4%) 37 (7%) .09
White Blood Cell Count at Diagnosis (G/l) 12 (4 - 42) 12 (4 - 55) 11 (4 - 41) .81 Hemoglobin Level at Diagnosis (g/dl) 10 (8 - 12) 10 (8 - 12) 10 (8 - 13) .13 Platelet Count at Diagnosis (G/l) 72 (32 - 154) 59 (27 - 148) 79 (74 - 92) .05 Prothrombin Ratio at Diagnosis (%) 82 (72 -92) 80 (70 - 93) 83 (74 - 92) .12 Fibrinogen Level at Diagnosis (g/l) 4 (3 - 5) 4 (3 - 5) 4 (3 - 5) .64 Poor Early PB Blast Clearance (%) 184 (24%) 45 (25%) 103 (21%) .25 BM: Bone Marrow; BMI: Body Mass Index; CNS: Central Nervous System; CR: Complete Remission;
CVT: Cerebral Vein Thrombosis; DVT: Deep-Vein Thrombosis; PB: Peripheral Blood; PE: Pulmonary Embolism.
Supplementary Table 2. Incidence of thrombosis according to prophylactic measures received (antithrombin and/or heparin prophylaxis).
AT Prophylaxis
No Yes
Heparin
Prophylaxis No 2/23 (9%) 9/148 (6%)
Yes 9/38 (24%) 47/432 (11%)
AT: antithrombin.
Supplementary Table 3. Prophylactic Measures in Patients Without, With DVP/PE, and With TC During Induction
All (n=784) No thrombosis during induction
(n=706)
DVT/PE during
induction (n=49) CVT during induction
(n=29)
p
No. L-ASP infusions (IQR) 8 (5-8) 8 (5 - 8) 7 (5 - 8) 3 (3 - 4) <.001 AT nadir (%) (IQR) 51 (45-58) 51 (45 - 58) 46 (40 - 55) 60 (53 - 72) <.001
AT prophylaxis (%) 684 (87%) 620 (88%) 44 (90%) 20 (69%) .003
FFP prophylaxis (%) 76 (10%) 68 (10%) 6 (12%) 2 (7%) .7
Fibrinogen Prophylaxis (%) 70 (9%) 58 (8%) 8 (16%) 4 (14%) .06
Heparin Prophylaxis (%) .04
No 177 (23%) 164 (23%) 11 (22%) 2 (7%)
Yes 485 (62%) 421 (60%) 38 (78%) 26 (90%)
Missing data 122 (15%) 121 (17%) 0 1 (3%)
AT: Antithrombin; FFP: Fresh Frozen Plasma; L-ASP: L-asparaginase.
Supplementary Table 4. Prophylactic Measures in Patients Without and With Thrombosis during Late Intensification.
All (n=354) No thrombosis during late intensification
(n=345)
Thrombosis during late intensification
(n=9)
p
AT nadir (IQR) 55 (47 - 67) 55 (47 - 66) 59 (53 - 81) .19
AT prophylaxis (%) 206 (58%) 202 (58%) 5 (56%) .72
FFP prophylaxis (%) 7 (2%) 6 (2%) 1 (11%) .19
Fibrinogen Prophylaxis (%) 19 (5%) 19 (5%) 0 1
Heparin Prophylaxis (%) .47
No 158 (45%) 155 (45%) 3 (33%)
Yes 128 (36%) 123 (36%) 5 (56%)
Missing data 68 (19%) 67 (19%) 1 (11%)
AT: Antithrombin; FFP: Fresh Frozen Plasma; L-ASP: L-asparaginase.
Supplementary Figure 1. The GRAALL-2005 protocol.
Supplementary Figure 2. Cumulative incidence of VTE.
Supplementary Figure 3. Impact of age (A), BMI (B), and platelet count at diagnosis (C) on the risk of DVT/PE and of hemoglobin level at diagnosis (D) on the risk of CVT.
A.
B.
0%
5%
10%
15%
20%
18 - 25 (n=200) 25 - 30 (n=98) 30 - 40 (n=156) 40 - 50 (n=161) 50 - 60 (n=169)
Percentage of Patients (%)
Age (years)
0%
5%
10%
15%
20%
< 18 (n=37) 18 - 25 (n=433) 25 -30 (n=214) > 30 (n=99)
Percentage of Patients (%)
Body Mass Index (kg/m2)
C.
D.
0%
5%
10%
15%
20%
< 30 (n=181) 30 - 50 (n=116) 50 - 100
(n=188) 100 - 200
(n=176) > 200 (n=123)
Percentage of Paients (%)
Platelet Counts at Diagnosis (G/l)
0%
5%
10%
15%
20%
< 8 (n=187) 8 - 10 (n=186) 10 - 12 (n=193) > 12 (n=216)
Percentage of Patients (%)
Hemoglobin Levels at Diagnosis (g/dl)
