PhD Scientific Days 2025

Poster Session I. - D: Pathological and Oncological Sciences

Deep Molecular Profiling Reveals Prognostic Markers For Refined Patient Stratification And Targetable Alterations In Pediatric Acute Lymphoblastic Leukemia

Name of the presenter

Péterffy Borbála

Institute/workplace of the presenter

Department of Pathology and Experimental Cancer Research

Authors

Borbála Péterffy¹, Szilvia Krizsán², Bálint Egyed², Gábor Bedics¹, Anne Benard-Slagter³, Sander Palit³, Dániel János Erdélyi², Judit Müller², Tibor Nagy⁴, Lajos László Hegyi¹, Anna Bekő¹, Lili Anna Kenéz¹, Zsuzsanna Jakab⁵, György Péter⁶, Krisztina Csanádi⁶, Ágnes Vojcek⁷, Gábor Ottóffy⁷, Katalin Csernus⁷, Lilla Györgyi Tiszlavicz⁸, Krisztina Mita Gábor⁸, Ágnes Kelemen⁹, Péter Hauser¹⁰, Krisztián Kállay¹⁰, Gabriella Kertész¹⁰, Zsuzsanna Gaál¹¹, István Szegedi¹¹, Gábor Barna¹², Ágnes Márk¹², Irén Haltrich², Zsuzsanna Hevessy¹³, Anikó Ujfalusi¹³, Béla Kajtár¹⁴, Botond Timár¹², Csongor Kiss¹¹, Gergely Kriván¹⁰, András Matolcsy¹², Suvi Savola³, Gábor Kovács², Csaba Bödör¹, Donát Alpár¹

1: HCEMM-SE Molecular Oncohematology Research Group; MTA-SE „Lendület” Molecular Oncohematology Research Group, Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
2: Pediatric Center, Semmelweis University, Budapest, Hungary
3: MRC Holland, Department of Oncogenetics, Amsterdam, The Netherlands
4: Department of Biochemistry and Molecular Biology, University of Debrecen, Hungary
5: Hungarian Childhood Cancer Registry, Hungarian Pediatric Oncology Network, Budapest, Hungary
6: Hemato-Oncology Unit, Heim Pál Children's Hospital, Budapest, Hungary
7: Department of Pediatrics, Oncohaematology Division, University of Pécs Medical School, Pécs, Hungary
8: Department of Pediatrics and Pediatric Health Care Center, Faculty of Medicine, University of Szeged, Szeged, Hungary
9: Velkey László Child's Health Center, Borsod-Abaúj-Zemplén County Central Hospital and University Teaching Hospital, Miskolc, Hungary
10: Pediatric Hematology and Stem Cell Transplantation Department, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary
11: Division of Pediatric Hematology-Oncology, Institute of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen
12: Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
13: Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Hungary
14: Department of Pathology, University of Pécs Medical School, Pécs, Hungary

Text of the abstract

Despite the remarkable progress made in the clinical management of pediatric acute lymphoblastic leukemia (ALL), survival rates remain below the average across some genetically defined subtypes of ALL. Early identification of molecular aberrations contributing to disease progression can aid relapse prediction, inform therapy adjustment, and even guide targeted treatment against relapse-prone leukemic cell populations.
In a real-world cohort of consecutively diagnosed Hungarian children with ALL, we aimed to identify patients eligible for targeted therapy and uncover alterations associated with relapse.
Diagnostic bone marrow samples from 180 children diagnosed with B-ALL (n=150) or T-ALL (n=30), and paired samples drawn at the time of diagnosis and relapse were from 19 patients were analysed. Somatic mutations were identified with a custom QIASeq Targeted DNA Panel covering 102 disease-relevant genes, while gene fusions were detected using the TruSight RNA Pan-Cancer Panel targeting 1,385 genes.
Survival analysis demonstrated shorter 3-year event-free survival (EFS) in B-ALL patients with TP53 (p=0.008) or CREBBP mutations (p=0.010). Strikingly, 3-year EFS of MRD negative patients on day 33 of therapy was also inferior in TP53 mutant cases (p=0.0004). Over half of high-risk patients (55.9%) and 31.6% of standard/intermediate-risk patients harbored potentially targetable fusions or mutations with a VAF≥10%. Furthermore, deep sequencing revealed putatively actionable alterations with a VAF<10% in eleven additional patients, expanding the number of potential candidates for targeted therapy. TP53 and PIK3R1 mutations were enriched, whereas NT5C2 and CDKN2A mutations were exclusively identified at relapse, with CREBBP and TP53 mutations being the most prevalent alterations in relapse samples.
Our mutational screening strategy clearly established its worth by identifying disease-relevant mutations with prognostic relevance across all risk categories, including a considerable proportion of subclonal mutations, underscoring the importance of deep sequencing across all subgroups. Druggable alterations were also revealed in a substantial number of patients, paving the way for targeted therapy.
Funding: FK20_134253,K21_137948,H2020-739593,BO/00125/22,EFOP-3.6.3-VEKOP-16-2017-00009,TKP2021-EGA-24,TKP2021-NVA-15,PD145889,LP2024-3, Richter Gedeon Talenum Fundation