EARLY T-CELL PRECURSOR LEUKEMIA: A SUBTYPE OF VERY HIGH-RISK ACUTE LYMPHOBLASTIC LEUKEMIA IDENTIFIED IN TWO INDEPENDENT COHORTS

Background—Approximately one-fifth of children with acute T-lymphoblastic leukemia (TALL) succumb to the disease, suggesting unrecognized biologic heterogeneity that may contribute to drug resistance. We hypothesized 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 leukemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome. Methods—Leukemic cells from 239 patients with T-ALL enrolled at St. Jude and in the Italian national study AIEOP ALL-2000 were examined 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. Correspondence: D. Campana, M.D., Ph.D., Department of Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis TN 38105; Telephone 901-595 2528; FAX 901-595 5947; E-mail: dario.campana@stjude.org. CONTRIBUTORS ECS initiated the study, collected data on immunophenotype and MRD in the St. Jude cohort and analyzed all data. CGM, XS and JRD collected and analyzed gene expression and SNP array data in the St. Jude cohort. MO and FGB were responsible for the initial laboratory diagnosis, and SCR for the cytogenetic analyses in the St. Jude cohort. DP and CC undertook the statistical analysis; JER took care of St. Jude patients and contributed to data collection; GB and AB were responsible for the data of the AIEOP cohort; CHP took care of St. Jude patients and led the St Jude clinical trials; DC designed the study, analyzed data and wrote the paper with the input of all other authors. CONFLICT OF INTEREST STATEMENT There are no potential conflicts of interest relevant to this article to report. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript Lancet Oncol. Author manuscript; available in PMC 2010 March 17. Published in final edited form as: Lancet Oncol. 2009 February ; 10(2): 147–156. doi:10.1016/S1470-2045(08)70314-0. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript Findings—Thirty patients (12.6%) had leukemic lymphoblasts with an ETP-related gene expression signature or its associated distinctive immunophenotype (CD1a−, CD8−, CD5weak with stem-cell/myeloid markers). Cases of ETP-ALL showed increased genomic instability. Patients with this form of leukemia had a very high proportion of remission failure or hematologic relapse: 72% (95% confidence interval, 40% to 100%) at 10 years versus 10% (4% to 16%) for typical TALL patients treated at St. Jude; and 57% (25% to 89%) at 2 years versus 14% (6% to 22%) for patients treated in the AIEOP trial. Interpretation—ETP-ALL is a distinct, previously unrecognized, pathobiologic entity that confers a dire prognosis with use of standard intensive chemotherapy. Its early recognition, using the criteria outlined here, is essential for the development of an effective clinical management strategy.