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

• Published in: Haematologica (Roma) Vol. 101; no. 6; pp. 732 - 740
• Main Authors: Bond, Jonathan, Marchand, Tony, Touzart, Aurore, Cieslak, Agata, Trinquand, Amélie, Sutton, Laurent, Radford-Weiss, Isabelle, Lhermitte, Ludovic, Spicuglia, Salvatore, Dombret, Hervé, Macintyre, Elizabeth, Ifrah, Norbert, Hamel, Jean-François, Asnafi, Vahid
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.06.2016
• Subjects: Adult; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Cluster Analysis; Female; Gene Expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Humans; Immunophenotyping; Life Sciences; Male; Middle Aged; Phenotype; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - diagnosis; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - mortality; Prognosis; Recurrence; Thymus Gland - metabolism; Thymus Gland - pathology; Treatment Outcome; Young Adult; HOXA; ETP-ALL; Cytogenetics and Molecular Genetics; Adult Acute Lymphoblastic Leukemia
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2015.141218

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.