SIGNIFICANCE OF ADDITIONAL STRUCTURAL ABERRATIONS IN BONE MARROW CELLS OF 115 CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA AND HIGH HYPERDIPLOIDY

ABSSUB-4410

Background: High hyperdiploidy (HeH), defined as the presence of 51 to 67 chromosomes in karyotype, is the most common cytogenetic finding in bone marrow cells of childhood B-cell precursor acute lymphoblastic leukemia (B-ALL), occurring in 25-30% of cases. HeH is characterized by nonrandom gain of specific chromosomes and clinically by favorable prognosis. Nevertheless, around a quarter of these children will suffer an adverse event within 5 years after diagnosis, which could be caused by increased genomic instability of leukemic cells leading to creation of additional cryptic structural aberration.

Aims: The aim of this study was to determine the frequency and the recurrence of structural chromosomal aberrations in hyperdiploid cells and to evaluate the impact of these aberrations for prognosis of children with ALL and HeH.

Methods: Karyotypes of all patients were analyzed at the time of diagnosis by conventional cytogenetic analysis and interphase fluorescence in situ hybridization (I-FISH) with a panel of Vysis DNA probes (Abbott Molecular) in order to detect heteroploid cells.  In patients with structural or suspected cryptic aberrations multicolor FISH and multicolor banding (24XCyte/XCyte Probe Kit; MetaSystems) and array CGH (Cytochip Cancer 4x180K; BlueGnome) were performed. For overall and event free survival Kaplan-Maier analysis and Mantel-Cox test were done.

Results: During the years 1997-2013 we examined 115 children with B-ALL and high hyperdiploidy. This group included 64 boys and 51 girls with median of age 4 years (range 1 - 17) and median of the follow up to 82 months (range 1 - 210). Cryptic structural chromosomal rearrangements were found in 27 (23,5%) of them. Patients with ALL-specific chromosomal aberrations were excluded from the cohort. The majority of structural aberrations were unbalanced and chromosomes the most frequently affected were found to be Nos.: 1, 13, 6, 7 and 21. The most common recurrent abnormality was the duplication of the long arm of chromosome 1 (9x). The minimal duplicated region in all patients was 1q31 to 1q32.3 (22.5 Mb). In addition, the deletion of the long arm of chromosome 13 (5x), rearrangements of the long arm of chromosome 21 (3x) and the deletion of the long arm of chromosome 6 (2x) were proved. Event (relapse and/or exitus) occurred in six patients with high hyperdiploidy and five patients with high hyperdiploidy and structural aberrations, respectively. There was no difference in overall survival between these two cohorts. However, patients with cryptic structural changes showed a tendency to shorter event free survival (p=0,082).

Summary/Conclusion: Non-random structural abnormalities were found in approximately a quarter of children with B-ALL and high hyperdiploidy. Although high hyperdiploidy is well known as a powerful favorable prognostic marker in childhood ALL, our study demonstrates that prognosis may be influenced by the presence of these structural aberrations. Therefore, a detailed cytogenetic analysis of every patient with high hyperdiploid cell clones by all available methods is necessary to identify those at an increased risk of relapse.

Supported by grants RVO-VFN64165/2012 and GACR-P302/12/G157/1.

Keywords: B cell acute lymphoblastic leukemia, Children, Chromosomal abnormality

http://www.ehaweb.org/