Early Diagnosis and Targeted Treatment of Very High-Risk Childhood Acute Lymphoblastic Leukemia – The I-BFM Approach

We recently demonstrated that acute lymphoblastic leukemia (ALL) patients with a persistently high post-consolidation minimal residual disease (MRD) load during high-risk (HR) treatment were neither curable by chemotherapy alone nor by stem cell transplantation. Therefore, we aim at early identification of VHRL patients and their subsequent rational treatment based on the exploration of treatment targets.

We present data on gene expression profiling of VHRL patients performed in parallel to the ongoing extensive MRD analysis. In addition, non-VHRL patients were profiled. Comparing VHRL patients to the entire group of Non-VHRL patients, 135 genes (57 down-, 78 upregulated in VHRL) were identified. Focusing on genes involved in apoptosis in each single VHRL patient, at least one potentially targetable anti-apoptotic gene with an expression of at least 2-fold the median was identified. Connectivity Map searches identified several substances with highly significant connections to VHRL signatures.

VHRL patients seem to be characterized by specific genomic profiles independent of their heterogeneous molecular background. The present data are currently evaluated in a prospective study and will be complemented by those obtained through additional other genome-wide screening approaches (e.g., epigenetic profiling). The resulting information will then be utilized to build up an integrated VHRL classifier and to discover new treatment options with the ultimate goal of individualized early experimental treatment of VHRL patients based on their specific molecular characteristics.