Clinical and molecular characterization of early T-cell precursor leukemia: a high-risk subgroup in adult T-ALL with a high frequency of FLT3 mutations

Abstract

A subgroup of pediatric acute T-lymphoblastic leukemia (T-ALL) was characterized by a gene expression profile comparable to that of early T-cell precursors (ETPs) with a highly unfavorable outcome. We have investigated clinical and molecular characteristics of the ETP-ALL subgroup in adult T-ALL. As ETP-ALL represents a subgroup of early T-ALL we particularly focused on this cohort and identified 178 adult patients enrolled in the German Acute Lymphoblastic Leukemia Multicenter studies (05/93-07/03). Of these, 32% (57/178) were classified as ETP-ALL based on their characteristic immunophenotype. The outcome of adults with ETP-ALL was poor with an overall survival of only 35% at 10 years, comparable to the inferior outcome of early T-ALL with 38%. The molecular characterization of adult ETP-ALL revealed distinct alterations with overexpression of stem cell-related genes (BAALC, IGFBP7, MN1, WT1). Interestingly, we found a low rate of NOTCH1 mutations and no FBXW7 mutations in adult ETP-ALL. In contrast, FLT3 mutations, rare in the overall cohort of T-ALL, were very frequent and nearly exclusively found in ETP-ALL characterized by a specific immunophenotype. These molecular characteristics provide biologic insights and implications with respect to innovative treatment strategies (for example, tyrosine kinase inhibitors) for this high-risk subgroup of adult ETP-ALL.

Figure 1

Kaplan–Meier analyses for OS (a) and remission duration (b) for patients with ETP-ALL and early T-ALL with a non-ETP immunophenotype. Patients were enrolled in the GMALL study trials GMALL 05/93, GMALL 06/99 and GMALL 07/03.

Figure 2

Expression of genes known to be correlated with outcome in T-ALL and AML. Analysis of samples with sufficient RNA was carried out by RT-PCR. For each entity the median expression is shown by a horizontal bar with the s.e. of the mean. (a) Comparison between ETP-ALL and the remaining non-ETP T-ALL. (b) Expression in the different immunophenotype-defined subgroups of T-ALL. Early T-ALL refers to non-ETP early T-ALL.

Figure 3

Distribution of mutations (FBXW7, NOTCH1, FLT3, WT1) in percent in ETP-ALL (n=16 on the left) and non-ETP T-ALL (n=212 on the right). Not all T-ALL samples tested for WT1 were also tested for NOTCH1 and FLT3 mutations in the cohort of non-ETP T-ALL.