Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia

Elaine Coustan-Smith, Charles G. Mullighan, Mihaela Onciu, Frederick G. Behm, Susana C. Raimondi, Deqing Pei, Cheng Cheng, Xiaoping Su, Jeffrey E. Rubnitz, Giuseppe Basso, Andrea Biondi, Ching Hon Pui, James R. Downing, Dario Campana

Research output: Contribution to journalArticlepeer-review

754 Scopus citations

Abstract

Background: About a fifth of children with acute T-lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome. Methods: Leukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL. Findings: 30 patients (12·6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a-, CD8-, CD5weak with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% [95% CI 40-100] at 10 years vs 10% [4-16] at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% [25-89] at 2 years vs 14% [6-22] at 2 years for patients treated in the AIEOP trial). Interpretation: ETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management strategy. Funding: US National Cancer Institute, Cariplo Foundation, Citta della Speranza Foundation, Italian Association for Cancer Research (AIRC), Italian Ministry for University and Research, and American Lebanese Syrian Associated Charities (ALSAC).

Original languageEnglish (US)
Pages (from-to)147-156
Number of pages10
JournalThe lancet oncology
Volume10
Issue number2
DOIs
StatePublished - Feb 2009
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

Fingerprint

Dive into the research topics of 'Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia'. Together they form a unique fingerprint.

Cite this