Risk Factors for Richter Syndrome in Chronic Lymphocytic Leukemia

Richter syndrome (RS) is defined as the transformation of chronic lymphocytic leukemia (CLL) to a more aggressive B-cell lymphoma, most commonly diffuse large B-cell lymphoma. Approximately 5 - 10 % of CLL patients develop this complication during long-term follow-up. Traditional risk factors for future RS include clinical (advanced Rai stage), biological (ZAP-70, CD38, CD49d) and genetic (del17p, del11q) characteristics at the time of CLL diagnosis. The impact of CLL therapy (purine-nucleoside analogue and/or alkylator-based chemoimmunotherapy and kinase inhibitor therapy) on the risk of RS remains controversial. Both heritable (germline) and acquired (somatic) genetic mutations contribute to risk of RS. Germline polymorphisms in genes related to CD38, LRF4, and BCL-2 have been implicated in the development of RS. Somatic mutations contributing to the development of RS include TP53 disruption, c-myc activation, CDKN2A loss and NOTCH1 mutations. This review summarizes recent advances in our understanding of the biological and genetic factors contributing to RS in CLL patients.