53. Clinical utility of molecular profiling in the management of Richter syndrome

Richter syndrome (RS) is a deadly complication of chronic lymphocytic leukemia (CLL) which results in transformation to aggressive lymphoma, typically diffuse large B-cell lymphoma (DLBCL). RS affects 5-16% of CLL patients with median time to transformation of under two years. Up to 47% of patients transform prior to receiving any therapy for CLL. Considering that many new therapeutic agents developed for CLL are not efficient in RS, early identification of patients with high risk CLL and CLL at risk of transformation is of the utmost importance. Next-generation sequencing (NGS) and chromosomal microarray analysis (CMA) allow for the detection of important molecular characteristics associated with high transformation risk. Molecular lesions of regulators of proliferation (e.g. CDKN2A, NOTCH1, MYC) and apoptosis (TP53) associate with 90% of DLBCL-type RS. In particular, NOTCH1 and TP53 mutations are linked to the highest risk of transformation. Whole genome CMA not only reveals the presence of independent high risk copy number factors for developing RS, but can also determine the clonal relationship between the CLL and the aggressive lymphoma clones, which is an important prognostic factor in RS since clonally unrelated RS have a significantly better prognosis. We present molecular profiling of two representative RS cases, one with a related RS clone and the other unrelated to the original CLL clone and discuss potential for incorporation of NGS and CMA testing into routine clinical assessment of CLL patients to identify those patients at highest risk for transformation who may be eligible for early intervention.