Identification of Genomic Structural Variants (SVs) with Adverse Prognostic Significance in Normal-Karyotype (nk) Acute Myeloid Leukemia (AML) Patients

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.65-65
• Main Authors: Bartalucci, Niccolò, Mannelli, Francesco, Tarantino, Danilo, Scappini, Barbara, Enderti, Alessio, Gianfaldoni, Giacomo, Piccini, Matteo, Romagnoli, Simone, Colazzo, Daniele, Signori, Leonardo, Irushani, Fiorenza, Salmoiraghi, Silvia, Ottone, Tiziana, Piciocchi, Alfonso, Vannucchi, Margherita, Siciliano, Maria Chiara, Boccacci, Roberto, Orsi, Silvia, Civini, Alessia, Fazi, Paola, Santi, Raffaella, Vignetti, Marco, Bortoluzzi, Stefania, Bosi, Alberto, Venditti, Adriano, Rambaldi, Alessandro, Voso, Maria Teresa, Guglielmelli, Paola, Vannucchi, Alessandro M.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-198342

Background: nkAML accounts for 40% of all AML. Although nkAML pts are included into favorable (fav) and intermediate (int) European Leukemia Net (ELN2022) risk category, the outcome is highly heterogeneous, and poses therapeutic challenges particularly as regards indication to stem cell transplant (SCT). Aim: To improve ELN-based prognostication, we characterized genomic SVs in nkAML pts through Long-Read Whole Genome Sequencing (WG-LRS). Methods: A total of 311 intensively treated nkAML pts were included; a discovery cohort (DC) was made up of 162 pts from the prospective NILG 02/06 and GIMEMA 1310 trial, a validation cohort (VC) included 149 cases from Florence center. WG-LRS was performed on blast-enriched samples by GridION platform to median depth of 5x. SVs identified in the DC were correlated to overall (OS) and event-free (EFS) survival by machine learning and Cox regression. Results: In the DC, 120 SVs were retained after extensive filtering based on technical parameters and database information; 80.3% insertions, 15.6% deletions, 2.5% duplications, 1.6% inversions, average span 269 bp (range, 52-3.1x10³). Feature selection identified 38 SVs negatively associated with OS that were introduced into a multivariable model including NPM1, FLT3-ITD, CEBPA, ASXL1, TP53 and RUNX1 mutation status. Cox-based model identified 5 SVs with statistical significance for OS: chr2p13.1_del (HR 2.8; 95%CI:2.2-6.6; P=0.016), chr3p34.3_ins (HR 7.1; 2.2-23.2; P=0.001), chr5p12_ins (HR 6.2; 1.9-20.4; P=0.002), chr9q34.3_del (HR 7.6; 2.7-21.6 P≤0.001), chr18q23_ins (HR 3.3; 1.2-9.2; P=0.002). All other input covariates lost significance. Overall, 21 (13%) DC pts had >1 high-risk SVs (HRSV+); their median OS (9.7mo, 95%CI:0-19.4) was significantly shorter compared to HRSV- (not reached, NR; P