Abstract
Chronic lymphocytic leukemia (CLL) is an indolent low-grade B-cell neoplasm that generally responds well to treatment. Rarely, CLL cases exhibit an IGH::CCND1 rearrangement, presenting a diagnostic challenge in distinguishing between clonal evolution within CLL and an independent mantle cell lymphoma. We report a case of CLL with the emergence of an IGH::CCND1 rearrangement and mutations associated with treatment resistance, including TP53, BTK, and BCL2, during disease progression. Immunophenotypic, cytogenetic, and molecular analyses support that these alterations are secondary events within the CLL clone. This case demonstrates dynamic clonal selection and expansion in response to treatments, which, in turn, contributes to treatment resistance.