Chronic lymphocytic leukemia with IGH::BCL3-translocation is characterized by a homogenous and distinct genetic and epigenetic landscape

DNA methylation analysis assigned 77% (51/66) of patients with IGH::BCL3-translocation with at least 60% tumor cell content to the naive B-cell-like group but unraveled a distinct and during follow-up stable signature resembling in part plasma cell-like epigenetic features. A binary DNA methylation classifier using 20 CpGs could distinguish IGH::BCL3-translocated CLL samples from other CLL subtypes. In an efficacy cohort of 3832 previously untreated patients from GCLLSG trials, IGH::BCL3 was associated with shorter progression-free survival (PFS) and overall survival (OS) in 28 patients when treated with chemoimmunotherapy, but not in those receiving venetoclax.

Our findings highlight the genetic and epigenetic homogeneity of IGH::BCL3-translocated CLL samples and their differences from other types of CLL suggesting IGH::BCL3 leukemic B-cell neoplasms to be a biological distinct subtype of CLL.