P596: DELETION OF THE SHORT ARM OF CHROMOSOME 8 AND TNFRSF10B LOSS ASSOCIATE TO POOR PROGNOSIS AND DRUG RESISTANCE IN CHRONIC LYMPHOCYTIC LEUKEMIA

• DOI: 10.1097/01.hs9.0000969288.37251.a7
• Publication Date: 2023-08-08T16:02:00Z
• Authors: Ludovic Jondreville; Lea Dehgane; Cecile Doualle; Luce Smagghe; Beatrice Grange; Frederic Davi; Leticia Koch Lerner; Delphine Garnier; Clotilde Bravetti; Olivier Tournilhac; Damien Roos-Weil; Marouane Boubaya; Elise Chapiro; Santos A Susin; Florence Nguyen-Khac
• Keywords: IGHV@; Univariate analysis

Background: Chronic lymphocytic leukemia (CLL) is a very heterogeneous disease whose prognosis varies according to cytogenetics. Aims: We performed precise characterization of rare abnormality associated with aggressive CLL, the deletion short arm chromosome 8 (del8p). Methods: correlated patients’ cytogenetic and clinical outcomes using standard statistical methods. in vitro analyses on primary CLL cells TNFRSF10B CRISPR/Cas9 edited OSU-CLL cell lines flow cytometry for drug response assays ddPCR genes expression. Results: Comparing largest series date del8p (n=57) non-del8p cohort (n=155), was significantly poor prognostic factors: complex highly karyotypes (HCK) (72% 44%, vs 22% 8% respectively, p<.001), del11q (52% 17%, del17p (36% 10%, p<.001) unmutated IGHV (73% 46%, p=.002). Del8p had shorter time first treatment (TTFT, median 0.25y 1.7y, p=.007), overall survival (OS 10y: 30% 82%; 6.8y not reached, p<.0001), higher risk Richter transformation (RT cumulative incidence 5.5%, p=.034). Additionally, large TP53 disruption negatively affected OS. Interestingly, regarding treated fludarabine-based regimens, next treatment-free (10y: 3.7% 21.5% without new treatment, p=.002) OS 45.9% vs. 81.6%, compared including mutated IGHV. One copy gene, coding pro-apoptotic receptor activated by TRAIL, lost 91% cases. This key because haploinsufficient involved modulation fludarabine-induced death, as confirmed lines. (1) The expression lower than (median ratio 1.52 3.66; 2.41-fold decrease, p<.001). (2) functional inducing death (PCD) (3) TRAIL alone being sufficient induce PCD cells, we hypothesized that exposure drugs might modulate expression, resulting improved sensitivity TRAIL: (i) increased after fludarabine (2.8-fold), but ibrutinib or venetoclax. increase observed cells; (ii) sequential approach evaluate cytotoxic effect fludarabine. In + resulted significant loss viability, an additional 13/15 (87%) samples (Fig 1D). By contrast, this regimen failed elicit synergistic 6/7 samples, revealing avoids synergy between TRAIL-induced 1E). Summary/Conclusion: factors (CK, HCK, aberrations, IGHV), TTFT OS, RT. demonstrate plays important role resistance vivo vitro. Our results argue assessment before choosing therapy.Keywords: leukemia, Chromosomal abnormality, Gene