Abstract IA25: Human genetic studies: CLL and transformation

Across cancers, histologic transformation remains a major challenge due to its association with rapid tumor progression and resistance. This is well-exemplified by Richter syndrome (RS) – the occurrence of an aggressive lymphoma of dismal prognosis in patients with chronic lymphocytic leukemia (CLL). RS is now a major obstacle to long-term CLL cure since the targeted agents developed for CLL have failed to either prevent or treat RS. In short, RS is becoming a frequent mode of progression and escape through therapeutic resistance. Thus far, definitive evolutionary studies and understanding of the genomic basis of transformation have yet to be completed. Major challenges towards this goal include the very fact that patient biopsy specimens contain an admixture of both CLL and RS tumor cells within the same tumor microenvironment, thereby limiting reliable investigations of RS cells. For CLL, large-scale sequencing studies have successfully demonstrated the diverse spectrum of recurrent gene mutations associated with CLL and the high level of genetic heterogeneity amongst patient samples, consistent with the high degree of clinical variability that is characteristic of this malignancy. We will review new studies to integrate multiple data layers in a cohort of >1000 patients, providing us with a ‘CLL map.’ Recently, we have been developing highly novel analytics that allow us to discern, within a sample that is admixed with both CLL and RS cells, the contributions of CLL vs that of RS. In doing so, we are able to identify new drivers and molecular subtypes of RS, and profile the trajectory from CLL to RS. Such studies are paradigm shifting for the clinic in relationship to both detection, diagnosis and prognosis of RS, and advances our efforts to attain a molecular definition of RS. Moreover, the methodologies, conclusions and detailed studies presented in our work are highly relevant to other hematologic malignancies and solid tumors.

Citation Format: Catherine J Wu. Human genetic studies: CLL and transformation [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr IA25.