Genomic Profiling helps to Predict Treatment Response and Outcome in Relapsed Childhood ETV6/RUNX1-Positive Acute Lymphoblastic Leukemia.

The ETV6/RUNX1 fusion, resulting from the cryptic translocation t(12;21)(p13;q22), is the most common genetic rearrangement in B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) with a prevalence of approximately 20–25% at first presentation. Although generally associated with favorable risk features and advantageous long-term survival rates, similar frequencies of ETV6/RUNX1 positivity at relapse question its prognostic significance. At relapse, a second continuous complete remission can again be achieved in the majority of patients with ETV6/RUNX1-positive ALL, however, a substantial proportion (approximately 25%) exhibit a poor response to treatment and eventually experience a subsequent relapse. Currently, critical secondary genetic events are assumed to be pivotal for t(12;21) positive ALL leukemogenesis. At the chromosomal level, additional numeric aberrations may also contribute to differences both in treatment response and course of disease, and may provide additional prognostic information. Aiming at identifying the incidence and the clinical relevance of additional genetic aberrations at the time point of first ALL relapse diagnosis, we performed whole genome high resolution tiling-path bacterial artificial chromosome (BAC) array CGH of leukemic cell DNA from 53 patients with ETV6/RUNX1-positive first relapse enrolled in the relapse trials ALL-REZ BFM of the Berlin-Frankfurt-Münster study group. Additional genetic aberrations were detected in all of the ETV6/RUNX1-positive leukemic bone marrow samples with a mean number of seven aberrations per ALL. Chromosomal losses were observed approximately 2.5 times more frequently than gains. A high proportion of the identified copy number alterations occurred in recurrently affected chromosomal regions. Copy number alterations most commonly detected by high-resolution array CGH were losses of 12p13 (49%, 26/53), 6q21 (34%, 18/53), 15q15.1 (23%, 12/53), 9p21 (21%, 11/53), 3p21 (21%, 11/53), 5q (19%, 10/53), 19q13 (17%, 9/53), 10q (13%, 7/53), 3p14.2 (11%, 6/53) and gains of 21q22 (32%, 17/53) and of 12p (21%, 11/53). Loss of the whole X-chromosome, detected in 17% (9/53) of the analyzed samples, was observed exclusively in females. In contrast, gain of Xq, identified in 13% (7/53) of the samples, was detectable solely in males. Evaluation of the clinical parameters in relation to recurrent copy number alterations revealed that loss of the whole X-chromosome was associated with a molecular good response to treatment (P=0.03), as assessed by sensitive minimal residual disease (MRD) monitoring. In contrast, loss of 5q31.3, detected in 11% (6/53) of the analyzed samples, was associated with a dismal molecular response to therapy (P=0.019) and with a tendency to a worse outcome (P=0.054). Thus, this study demonstrates that relapsed ETV6/RUNX1-positive ALL is characterized by (a.) multiple additional genomic alterations, in particular by a high incidence of chromosomal losses, which occur predominantly in recurrently affected chromosomal regions, some of which (b.) are of significant prognostic relevance. These findings support the notion that several additional chromosomal changes are not only required for the process of malignant transformation in ETV6/RUNX1-positive ALL (leukemogenesis) but also influence therapeutic success. Perspectively, high resolution genomic profiling will provide valuable information enabling a more refined, individualized therapy and an improved risk stratification in relapsed childhood ALL.