Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia - PubMed (original) (raw)
doi: 10.1016/S1470-2045(08)70314-0. Epub 2009 Jan 13.
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
Affiliations
- PMID: 19147408
- PMCID: PMC2840241
- DOI: 10.1016/S1470-2045(08)70314-0
Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia
Elaine Coustan-Smith et al. Lancet Oncol. 2009 Feb.
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(-), CD5(weak) 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).
Conflict of interest statement
CONFLICT OF INTEREST STATEMENT
There are no potential conflicts of interest relevant to this article to report.
Figures
Figure 1
Schematic representation of the studies performed.
Figure 2
Gene expression and immunophenotypic features of ETP-ALL. (a) Unsupervised clustering analysis of diagnostic bone marrow samples from 55 pediatric patients with T-ALL, using a set of genes differentially expressed in ETP (Supplementary Table 1).;– One cluster (indicated by red bars) had a gene expression profile resembling that of ETP cells. (b) Flow cytometric contour dot plots illustrating the immunophenotypes of normal thymocytes (discarded material from infants undergoing open heart surgery), and representative cases of ETP and typical T-ALL. Each sample was labeled simultaneously with the indicated antibodies (cCD3 = cytoplasmic CD3) and analyzed with an LSRII flow cytometer and DIVA software using a log density and biexponential setting. Vertical and horizontal lines in each plot correspond to zero immunofluorescence. (c) The heat map shows percentages of positive leukemic cells for each of the listed markers among the 139 St Jude T-ALL cases studied at diagnosis; gray indicates missing data. Each row represents one case and each column the percentage of positive leukemic cells with the indicated marker. (d) Heat map of the top 150 differentially expressed genes (see Supplementary Table 3), ranked by P value.
Figure 3
Genetic abnormalities in ETP-ALL. (a) Expression of transcription factors previously implicated in the pathogenesis of T-ALL; in cases with an ETP origin (n = 9) or typical T-ALL (n = 46) immunophenotypes, as measured by the Affymetrix 133A GeneChip. Bars indicate median values. (b) SNP array analysis of genetic lesions in 11 ETP-ALL and 43 typical T-ALL cases. Total numbers of genomic gains and losses and the sizes of genomic lesions are shown. Further details can be found in Supplementary Fig. 3 and Supplementary Table 5. Bars indicate median values in all panels.
Figure 4
Prevalence of MRD during the early phases of therapy for patients with ETP or typical T-ALL. MRD levels were measured by flow cytometry (a) or by polymerase chain reaction amplification of antigen-receptor genes (b). Horizontal bars indicate median values, if above 0.01%.
Figure 5
Kaplan-Meier plots of (a, d) overall survival, (b, e) event-free survival, and (c, f) the cumulative incidence of remission failure or hematologic relapse in patients with typical T-ALL (gray line) versus ETP-ALL (black line) treated on either St. Jude (a–c) or AIEOP protocols (d–f). The event-free survival curves start at the end of remission induction (day 43 for St. Jude and day 33 for AIEOP patients). Outcome estimates at 10 and 2 years of follow-up are shown; P values are from the log-rank test.
Comment in
- Early T-cell precursor acute lymphoblastic leukaemia.
Taub JW. Taub JW. Lancet Oncol. 2009 Feb;10(2):105-6. doi: 10.1016/S1470-2045(09)70010-5. Lancet Oncol. 2009. PMID: 19185830 No abstract available.
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