PB1651 INFERIOR PROGNOSIS OF TLX3 GENE REARRANGEMENTS IN PEDIATRIC T‐ALL
Authors: Lizcova L. , Prihodova E. , Pavlistova L. , Sladkova L. , Svobodova K. , Mejstrikova E. , Hrusak O. , Luknarova P. , Janotova I. , Sramkova L. , Stary J. , Michalova K. , Zemanova Z. 
Published: June 2019

Background:

T‐cell acute lymphoblastic leukemia (T‐ALL) is a clinically and genetically heterogeneous disease that comprises 10‐15% of newly diagnosed pediatric ALL. Despite improved survival rates of children with T‐ALL, relapse occurs in almost 20% of patients and is associated with a dismal subsequent outcome. Therefore, it is of vital importance to identify children already early on during treatment who are at increased risk of such an event. Although several clinical and genetic factors were identified, prognostic implication of majority of them remains unclear. Therefore, the patients risk stratification is currently based only on minimal residual disease (MRD) monitoring.

Aims:

We performed retrospective and/or prospective comprehensive molecular cytogenomic analysis of bone marrow cells of children with T‐ALL with the aim to determine recurrent chromosomal aberrations and to identify those with significant impact on event free (EFS) and overall survival (OS).

Methods:

Samples of all patients were analyzed at the time of diagnosis with combination of conventional and molecular cytogenomic methods. For detection of the most frequent known chromosomal changes, i.e. rearrangements of TCR loci and TLX3 gene, deletion of CDKN2A and amplification of ABL1, interphase FISH with locus‐specific probes (Dako, Abbott Molecular) was used. MLPA analysis using SALSA MLPA ALL‐IKZF1 probemix (MRC‐Holland) was performed to detect deletions/amplifications of additional genes. Complex chromosomal rearrangements were proved with multicolor FISH and multicolor banding (24XCyte/XCyte Probe Kit; MetaSystems) or array CGH/SNP (SurePrint G3 Cancer CGH + SNP 4x180K, Agilent). For OS and EFS Kaplan‐Meier analysis with Mantel Cox test was done.

Results:

During the years 1996‐2017 we examined archived material of 68 children with T‐ALL (21 girls and 47 boys, median age 8.25 years), treated according to ALL Interfant and/or BFM based protocols. Median follow up was 9.5 years. In total, chromosomal aberrations were detected in 91% of patients. The most frequent were deletion of CDKN2A gene in 47/68 patients (27x homozygous, 20x heterozygous), rearrangements of TCR loci in 18/68 children (11x TRA/TRD, 7x TRB) and TLX3 gene rearrangement in 15/68 cases. Complex chromosomal aberrations were proved in 14/68 children. All chromosomal changes occurred in various combinations, however TLX3 aberrations never appeared along with TCR loci rearrangements. 48 patients are living in the first (45x)/second (3x) complete remission, 16 patients relapsed, 19 children died. Best outcome (EFS and OS) was associated with TRA/TRD locus translocations (p < 0.05). Conversely, patients with TLX3 rearrangement had significantly worse OS (p < 0.05).

Summary/Conclusion:

Considering the poor survival after relapse, it is of utmost importance to identify children at an increased risk of this event. MRD monitoring at different time points is a strong prognostic indicator and is used for risk stratification. In addition, rearrangements of TLX3 gene correlated with poor outcome in contrast to TRA/TRD translocations, which correlated with a more favorable course of the disease.

Supported by grant RVO‐VFN64165, GACR P302/12/G157.