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Ferrata Storti Foundation
Acute Myeloid Leukemia
Dexamethasone in hyperleukocytic acute myeloid leukemia
Sarah Bertoli,1,2,3* Muriel Picard,4* Emilie Bérard,5,6* Emmanuel Griessinger,7 Clément Larrue,3 Pierre Luc Mouchel,1,3 François Vergez,2,3,8 Suzanne Tavitian,1 Edwige Yon,5 Jean Ruiz,4 Eric Delabesse,2,3,8 Isabelle Luquet,8 Laetitia Karine Linares,9,10,11 Estelle Saland,3 Martin Carroll,12 Gwenn Danet-Desnoyers,12 Audrey Sarry,1 Françoise Huguet,1 Jean Emmanuel Sarry3 and
Haematologica 2018 Volume 103(6):988-998
1
Service d'Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire
Christian Récher1,2,3
du Cancer de Toulouse Oncopole, France; 2Université Toulouse III Paul Sabatier, France; 3Cancer Research Center of Toulouse, UMR1037-INSERM, ERL5294 CNRS, France; 4Service de Réanimation Polyvalente, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, France; 5Service d'Epidémiologie, Centre Hospitalier Universitaire de Toulouse, France; 6UMR 1027, INSERM-Université de Toulouse III, France; 7Université Côte d'Azur, INSERM U1065, Centre Méditerranéen de Médecine Moléculaire, Nice, France; 8Laboratoire d’Hématologie, Centre Hospitalier Universitaire de Toulouse, Institut Universitaire du Cancer de Toulouse Oncopole, France; 9IRCM, Institut de Recherche en Cancérologie de Montpellier-INSERM, U1194, France; 10Université Montpellier, F-34298, France; 11Institut Régional du Cancer Montpellier, France and 12Stem Cell and Xenograft Core, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA
ABSTRACT
Patients with acute myeloid leukemia and a high white blood cell count are at increased risk of early death and relapse. Because medi- ators of inflammation contribute to leukostasis and chemoresis- tance, dexamethasone added to chemotherapy could improve outcomes. This retrospective study evaluated the impact of adding or not adding dexamethasone to chemotherapy in a cohort of 160 patients with at least 50×109 white blood cells. In silico studies, primary samples, leukemic cell lines, and xenograft mouse models were used to explore the antileukemic activity of dexamethasone. There was no difference with respect to induction death rate, response, and infections between the 60 patients in the dexamethasone group and the 100 patients in the no dexamethasone group. Multivariate analysis showed that dexamethasone was signifi- cantly associated with improved relapse incidence (adjusted sub-HR: 0.30; 95% CI: 0.14-0.62; P=0.001), disease-free survival (adjusted HR: 0.50; 95% CI: 0.29-0.84; P=0.010), event-free survival (adjusted HR: 0.35; 95% CI: 0.21-0.58; P<0.001), and overall survival (adjusted HR: 0.41; 95% CI: 0.22-0.79; P=0.007). In a co-culture system, dexamethasone reduced the frequency of leukemic long-term culture initiating cells by 38% and enhanced the cytotoxicity of doxorubicin and cytarabine. In a patient-derived xenograft model treated with cytarabine, chemoresistant cells were enriched in genes of the inflammatory response modulated by dexamethasone. Dexamethasone also demonstrated antileukemic activi- ty in NPM1-mutated samples. Dexamethasone may improve the out- come of acute myeloid leukemia patients receiving intensive chemother- apy. This effect could be due to the modulation of inflammatory chemoresistance pathways and to a specific activity in acute myeloid leukemia with NPM1 mutation.
*SB, MP and EB contributed equally to this work.
Correspondence:
recher.christian@iuct-oncopole.fr
Received: November 8, 2017. Accepted: March 2, 2018. Pre-published: March 8, 2018.
doi:10.3324/haematol.2017.184267
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/6/988
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