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2832 Recurrent Molecular Variants, Clonal Evolution and Clinical Relevance in T-Cell Lymphoblastic Neoplasia Comparing Lymphoma and Leukemia Samples Derived from Children and Adults

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Biomarkers, Molecular Markers, and Minimal Residual Disease in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Sarah Sandmann1*, Marcel Te Vrugt2*, Gerrit Randau2*, Thomas Beder3,4,5*, Martin Neumann, MD3*, Amelie Alfert2*, Cornelia Eckert, MD, PhD6*, Anja Moericke7*, Johanna Horns8*, Monika Brüggemann8* and Birgit Burkhardt, MD, PhD9

1Institute of Medical Informatics, University of Muenster, Muenster, DEU
2University Hospital Muenster, Department of Paediatric Hematology, Oncology and BMT and NHL-BFM study center, Muenster, Germany
3Medical Department II, Hematology and Oncology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
4Clinical Research Unit CATCH ALL (KFO 5010/1) funded by the Deutsche Forschungsgemeinschaft, Kiel, Germany
5University Medical Center Schleswig-Holstein, University Cancer Center Schleswig-Holstein, Kiel, Germany
6Department of Pediatric Oncology and Hematology, Charité University Medical Center, Berlin, Germany
7Christian Albrechts University Kiel and University Hospital Schleswig-Holstein, Department of Pediatrics I, Pediatric Hematology/Oncology, ALL-BFM Study Group, Kiel, Germany
8Medical Department II, Hematology and Oncology, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
9University Hospital Muenster, Department of Paediatric Hematology, Oncology and BMT and NHL-BFM study center, Münster, Germany

Background:

T-cell lymphoblastic lymphoma (T-LBL) and acute lymphoblastic leukemia (T-ALL) originate from the malignant transformation of similar subsets of immature T-cell precursors in the thymus. Unique genetic and epigenetic aberrations lead to distinct clinical presentations. Both are distinguished by bone marrow infiltration. Patient’s age at diagnosis is associated with the distribution of molecular subgroups in T-ALL (Neumann, et al. Leukemia, 2024). Despite sharing many clinical features and molecular alterations, there is ongoing debate about whether T-LBL and T-ALL represent a spectrum of a disease or are distinct entities. Recent papers identified TRB::NOTCH1 fusions exclusively in T-LBL and associated with high relapse risk (te Vrugt, et al. Blood, 2024). Both diseases are characterized by poor survival in resistant or relapsed cases, highlighting a clear unmet medical need. Understanding varying therapy resistance and molecular pathogenesis across ages is crucial. Clonal evolution analysis can help reconstruct tumor development, explore treatment responses, and identify reasons for therapy failure (Sandmann, et al. Int J Environ Res Public Health, 2023). This study compares DNA samples from pediatric and adult T-LBL and T-ALL patients to uncover genetic differences and tackle therapy resistance.

Methods:

DNA samples include material from initial diagnosis, corresponding germline, and, if applicable, relapse. Subcohorts include 87 pediatric T-LBL cases (27 relapsed, 60 non-relapsed), 36 pediatric T-ALL (12 relapsed, 24 non-relapsed), 47 adult T-LBL (of which 3 corresponding relapse samples were available), and 41 adult T-ALL, (of which 4 corresponding relapse samples were available). Besides targeted sequencing, CNV analysis is performed by Illumina Infinium Global Screening Array v3.0.

Results and Discussion:

For T-LBL and T-ALL, there were no significant differences in the average number of single nucleotide variants (SNV) per sample, either within or between the groups. For CNVs, a clear increase with age was observed for both T-LBL and T-ALL, except deletions and LOH affecting chromosome 9, which were more frequent in pediatric cases and decreased with age.

Detailed analysis revealed subgroup-specific characteristics in initial samples. In adult T-LBL vs pediatric T-LBL samples, variants in PHF6 (34% vs 13%), JAK1 (9% vs 0%), TP53 (6% vs 0%), NOTCH3 (11% vs 5%), JAK3 (11% vs 5%), STAT5B (11% vs 5%), TET2 (6% vs 1%), and NRAS (9% vs 3%) were more prevalent. NOTCH1 (60% vs 49%), PIK3CA (10% vs 2%), PTEN (15% vs 9%), PIK3R1 (8% vs 3%), CCND3 (6% vs 0%), and KMT2C (6% vs 0%) were more frequent in pediatric T-LBL than adult T-LBL patients.

In the T-ALL cohort, some variants, such as DNM2 (17%) and RUNX1 (10%) were almost exclusively found in adult cases. The increased prevalence of TP53 mutations in pediatric relapse samples underscored the critical role of TP53 in treatment resistance and disease progression (T-ALL: 8% primary vs 29% relapse; T-LBL: 0% primary vs 13% relapse).

Clonal evolution analysis showed that CNVs appeared early, especially deletions or LOH affecting chromosome 9. Subsequently, additional subclones with point mutations evolved. Pediatric cases revealed differential timing and frequency of mutations in T-LBL vs in T-ALL: MYB (nested level 4.6 vs 1.0), SMARCA4 (4.7 vs 1.5), or TET2 (4.0 vs 1.0). In pediatric T-LBL, deletions and LOH on chromosome 9 occurred equally in primary samples of patients who suffered/did not suffer relapse. In relapse samples, the clonal population with CNV increased, indicating a growth advantage. Frequent CNVs in chromosome 9, encompassing genes like CDKN2A/B and MTAP, underscored the importance of this region in both T-LBL and T-ALL. These CNVs, involving tumor suppressor genes such as p16INK4a and p14ARF, were early events in clonal evolution.

Conclusion:

Our integrated genomic analysis highlights differences and similarities between pediatric and adult T-LBL and T-ALL cases. The analysis of CNVs revealed their role in clonal evolution, particularly with frequent deletions and LOH affecting chromosome 9 in pediatric cases. This emphasize the importance of genomic profiling for each subgroup. By understanding distinct genetic landscapes and mutation patterns, we aim to discover potential novel targets to improve risk group stratification of patients with T-LBL and T-ALL.

Disclosures: Brüggemann: Jazz: Honoraria; Janssen: Honoraria, Speakers Bureau; AstraZeneca: Honoraria; Becton Dickinson: Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Speakers Bureau. Burkhardt: Miltenyi, Roche, Novartis, Janssen, AbbVie: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Miltenyi: Consultancy.

*signifies non-member of ASH