C060 | UNRAVELING THE AGGRESSIVENESS OF ACCELERATED CLL THROUGH SINGLE-CELL TRANSCRIPTOMICS AND GENOMIC PROFILING

Introduction Accelerated chronic lymphocytic leukemia (aCLL) is a yet understudied entity consisting of CLL with specific aggressive histological features that likely falls in the biological spectrum between CLL and Richter’s transformation (RT). In this study, we aimed to shed light on the clinical and biological characteristics of aCLL in relation to CLL and RT. Methods We reviewed the medical records of patients diagnosed with a histologically proven diagnosis of aCLL, CLL and RT treated at our institution. Clinical/histological information was extracted from electronic medical records and pathology reports. We performed NGS analysis with a 108-gene panel (Sophia lymphoma solution by NextSeq) and scRNA-seq (more than 10.000 nuclei/sample, 150 bases per end by NovaSeq) on FFPE lymph-node tissues from 12 and 16 patients respectively. Results We enrolled a total of 203 patients, 32 (16%) with aCLL, 16 (8%) with RT, and 155 (76%) with CLL. The median age in the whole cohort was 69 years (39-88), and 125 (62%) were male. The median time from the diagnosis of CLL to aCLL was 28.9 months. Compared with CLL, patients with aCLL more frequently presented with lymphadenopathies >5cm (41% vs 5%; p <0.001), constitutional symptoms (34% vs 10%; p=0.001), and higher median CLL-IPI (6 vs 4; p=0.01). In aCLL Median Ki-67 was higher than in CLL but lower than in RT (16% vs 6% and 70% respectively; p <0.001 for both). In those who had an available PET/CT scan, SUVmax was higher in aCLL than CLL (median 9 vs 4; p <0.001) and more similar to patients with RT (15.4; p=0.08). Also, the aCLL group was enriched in patients with U-IGHV status (85% vs 54% in CLL; p=0.004) and TP53 disruption (39% vs 20%; p=0.04) compared with CLL. NGS analysis in patients with aCLL revealed recurrent mutations in TP53 and BRAF genes, but also in ITPKB, IRF4, SF3B1, NRAS, PLCG1, and PTPRD. scRNA-seq showed that lymph-node aCLL samples contained a larger fraction of cells clustering among those expressing a proliferative transcriptional signature. The OS of patients with aCLL was significantly shorter than CLL patients (Figure, median 63 months vs NR; p=0.002) but longer than those with RT (median 7.5 months; p <0.001). Conclusion aCLL represents an aggressive form of CLL with distinct features and poorer outcomes compared to CLL. This aggressiveness may be secondary to the enrichment in high-risk biological features and abundance of subclones with a proliferative transcriptional signature.