title: An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study.
abstract: Gene expression studies have consistently identified a HOXA-overexpressing cluster of T-cell acute lymphoblastic leukemias, but it is unclear whether these constitute a homogeneous clinical entity, and the biological consequences of HOXA overexpression have not been systematically examined. We characterized the biology and outcome of 55 HOXA-positive cases among 209 patients with adult T-cell acute lymphoblastic leukemia uniformly treated during the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003 and -2005 studies. HOXA-positive patients had markedly higher rates of an early thymic precursor-like immunophenotype (40.8% versus 14.5%, P=0.0004), chemoresistance (59.3% versus 40.8%, P=0.026) and positivity for minimal residual disease (48.5% versus 23.5%, P=0.01) than the HOXA-negative group. These differences were due to particularly high frequencies of chemoresistant early thymic precursor-like acute lymphoblastic leukemia in HOXA-positive cases harboring fusion oncoproteins that transactivate HOXA Strikingly, the presence of an early thymic precursor-like immunophenotype was associated with marked outcome differences within the HOXA-positive group (5-year overall survival 31.2% in HOXA-positive early thymic precursor versus 66.7% in HOXA-positive non-early thymic precursor, P=0.03), but not in HOXA-negative cases (5-year overall survival 74.2% in HOXA-negative early thymic precursor versus 57.2% in HOXA-negative non-early thymic precursor, P=0.44). Multivariate analysis further revealed that HOXA positivity independently affected event-free survival (P=0.053) and relapse risk (P=0.039) of chemoresistant T-cell acute lymphoblastic leukemia. These results show that the underlying mechanism of HOXA deregulation dictates the clinico-biological phenotype, and that the negative prognosis of early thymic precursor acute lymphoblastic leukemia is exclusive to HOXA-positive patients, suggesting that early treatment intensification is currently suboptimal for therapeutic rescue of HOXA-positive chemoresistant adult early thymic precursor acute lymphoblastic leukemia.
  
  
  
  The GRAALL-2003 and -2005 studies were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM),
  Institut National de Recherche Médicale (INSERM) U1151, and Laboratory of OncoHematology,
  Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker EnfantsMalades,
  Paris
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bond
authors.affiliation: Department of Hematology, University Hospital and INSERM UMR 917,
  Rennes 1 University, Rennes
authors.forename: Tony
authors.initials: T
authors.lastname: Marchand
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM),
  Institut National de Recherche Médicale (INSERM) U1151, and Laboratory of OncoHematology,
  Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker EnfantsMalades,
  Paris
authors.forename: Aurore
authors.initials: A
authors.lastname: Touzart
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM),
  Institut National de Recherche Médicale (INSERM) U1151, and Laboratory of OncoHematology,
  Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker EnfantsMalades,
  Paris
authors.forename: Agata
authors.initials: A
authors.lastname: Cieslak
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM),
  Institut National de Recherche Médicale (INSERM) U1151, and Laboratory of OncoHematology,
  Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker EnfantsMalades,
  Paris
authors.forename: Amélie
authors.initials: A
authors.lastname: Trinquand
authors.affiliation: Department of Hematology, Centre Hospitalier Argenteuil
authors.forename: Laurent
authors.initials: L
authors.lastname: Sutton
authors.affiliation: Université Paris 5 Descartes, Department of Cytogenetics, Assistance PubliqueHôpitaux
  de Paris, Hôpital Necker-Enfants Malades, Paris
authors.forename: Isabelle
authors.initials: I
authors.lastname: Radford-Weiss
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM),
  Institut National de Recherche Médicale (INSERM) U1151, and Laboratory of OncoHematology,
  Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker EnfantsMalades,
  Paris
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lhermitte
authors.affiliation: Technological Advances for Genomics and Clinics (TAGC), INSERM U1090, Aix-Marseille University UMR-S 1090, Marseille
authors.forename: Salvatore
authors.initials: S
authors.lastname: Spicuglia
authors.affiliation: Université Paris Diderot, Institut Universitaire d’Hématologie, EA-3518, Assistance Publique-Hôpitaux de Paris, University Hospital Saint-Louis, Paris
authors.forename: Hervé
authors.initials: H
authors.lastname: Dombret
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM),
  Institut National de Recherche Médicale (INSERM) U1151, and Laboratory of OncoHematology,
  Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker EnfantsMalades,
  Paris
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Macintyre
authors.affiliation: PRES LUNAM, CHU Angers Service des Maladies du Sang et INSERM U 892, Angers, France
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.affiliation: PRES LUNAM, CHU Angers Service des Maladies du Sang et INSERM U 892, Angers, France
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Hamel
authors.affiliation: Université Paris Descartes Sorbonne Cité, Institut Necker-Enfants Malades (INEM),
  Institut National de Recherche Médicale (INSERM) U1151, and Laboratory of OncoHematology,
  Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker EnfantsMalades,
  Paris
authors.forename: Vahid
authors.initials: V
authors.lastname: Asnafi
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016000:Cluster Analysis; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D012008:Recurrence; D013950:Thymus Gland / Q000378:metabolism* / Q000473:pathology*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D018398:Homeodomain Proteins; C088144:HoxA protein