Elsevier

The Lancet Oncology

Volume 10, Issue 2, February 2009, Pages 147-156
The Lancet Oncology

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

https://doi.org/10.1016/S1470-2045(08)70314-0Get rights and content

Summary

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).

Introduction

T-cell acute lymphoblastic leukaemia (T-ALL) is a malignant clonal expansion of immature T cells that accounts for 10–15% of childhood and 25% of adult ALL cases. With wider use of intensive chemotherapy, the prognosis for childhood T-ALL has improved remarkably: nearly 80% of patients can currently be cured.1, 2 Further gains in treatment outcome will require methods to identify patients who continue to fail on contemporary protocols, so that alternative therapy can be introduced as early as possible. Demographic and clinical presenting features, such as older age and a high leucocyte count at diagnosis, are now regarded as unreliable predictors of outcome in patients with T-ALL treated with intensive chemotherapy;2, 3 cell-marker profiling has led to conflicting conclusions about its prognostic significance.3, 4, 5, 6 More recent studies have provided insights into the genetic abnormalities underlying T-ALL development, some of which seem to correlate with prognosis.7, 8, 9, 10 However, the prognostic associations of molecular abnormalities in T-ALL are not sufficiently compelling to justify their use in treatment planning.

Early T-cell precursors (ETPs) are a subset of thymocytes representing recent immigrants from the bone marrow to the thymus; they retain multilineage differentiation potential, suggesting their direct derivation from haemopoietic stem cells.11, 12, 13 We postulated that a proportion of T-ALL cases originate from oncogenically transformed ETPs and might therefore respond poorly to lymphoid-cell-directed chemotherapy. To test these predictions, we used a set of genes that are differentially expressed in ETPs11, 14, 15, 16 to identify cases of ETP leukaemia and then did a comprehensive study to establish the biological and clinical features of these leukaemias.

Section snippets

Patients and treatment

139 consecutive patients with T-ALL (median age 8·8 years [range 0·5–18·9]) were enrolled in Total Therapy Studies XIII,17 XIV,18 and XV2 at St Jude Children's Research Hospital in Memphis, TN, USA, between Jan 10, 1992, and Dec 14, 2006. The diagnosis of T-ALL was made by at least two expert pathologists. In all 139 patients, leukaemic lymphoblasts had ALL L1 or L2 morphology, with less than 3% of lymphoblasts expressing cytochemical myeloperoxidase; none of the cases of T-ALL showed Auer

Results

By use of a set of genes shown to be differentially expressed in ETPs compared with more mature thymic subpopulations (webappendix),11, 14, 15, 16 we searched for leukaemias with an ETP-related gene profile in 55 newly diagnosed cases of T-ALL (figure 1). By unsupervised clustering analysis, we identified a cluster of 13 cases with gene-expression profiles that strongly resembled those described for ETPs (figure 2). Overexpressed genes in this group included CD44, CD34, KIT, GATA2, CEPBA, SPI1,

Discussion

We have identified a unique biological subtype of childhood leukaemia, ETP-ALL, which is associated with a high risk of remission induction failure or relapse in patients treated with contemporary protocols of intensive chemotherapy for ALL. We used the gene-expression profile of normal ETP to identify their leukaemic counterparts and define their immunophenotype. ETP-ALL cases have characteristic gene-expression profiles, an increased number and size of genomic lesions, denoting genomic

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