Richter Transformation in Chronic Lymphocytic Leukemia: Update in the Era of Novel Agents

Abstract

Richter transformation (RT) is a poorly understood complication of chronic lymphocytic leukemia (CLL) with a dismal prognosis. It is associated with a switch in histopathology and biology, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or less frequently to Hodgkin’s variant of Richter transformation (HVRT). It occurs in 2–10% of CLL patients, with an incidence rate of 0.5–1% per year, and may develop in treatment-naïve patients, although it is more common following therapy. In recent years, there has been a deeper understanding of the molecular pathogenesis of RT that involves the inactivation of the TP53 tumor suppressor gene in 50–60% of cases and the activation of aberrations of NOTCH1 and MYC pathways in about 30% of cases. Compared to the preceding CLL, 80% of cases with DLBCL-RT and 30% of HVRT harbor the same IGHV-D-J rearrangements, indicating a clonal evolution of the disease, while the remaining cases represent de novo lymphomas that are clonally unrelated. Despite advances in understanding the molecular variations and the pathogenesis of the disease, there is still no significant improvement in patient outcomes. However, if no clinical trials were designed for patients with RT in the past, now there many studies for these patients that incorporate new drugs and novel combinations that are being explored. In this review, we summarize the new information accumulated on RT with special emphasis on results involving the novel therapy tested for this entity, which represents an unmet clinical need.

The immunomodulatory molecule TIGIT is expressed by chronic lymphocytic leukemia cells and contributes to anergy

“…TIGIT and CD226 are expressed on Richter's Syndrome samples Stemming from these observations, we evaluated expression of TIGIT and CD226 in cases of Richter's Syndrome (RS), a rare but often fatal complication of CLL characterized by transformation of the leukemia into an aggressive lymphoma [27][28][29] . To this aim, we exploited RNAseq analysis performed on primary FFPE RS lymph nodes and compared it to that of CLL samples and matched healthy subjects, from previously published datasets [EGA accession numbers EGAD00001004046 and EGAD00001000258 30,31 ].…”

KRAS and RAS-MAPK Pathway Deregulation in Mature B Cell Lymphoproliferative Disorders

“…CLL is characterized by remarkable clinical heterogeneity, ranging from an indolent disease with no requirement for treatment in some patients to rapid disease progression and subsequent treatment refractoriness in others [91]. CLL may undergo histologic transformation into an aggressive B cell lymphoma, commonly DLBCL or HL, a process termed Richter's transformation (RT), associated with a very dismal clinical outcome [92]. A plethora of prognostic factors, both clinical and biological parameters, has been identified to allow a better prediction of the individual prognosis of a given patient, including disease stage, the presence of chromosomal abnormalities (see below), IGHV mutational status, gene mutations (such as TP53, NOTCH1, SF3B1, BIRC3), and surface antigen expression (CD49d, CD38, ZAP-70) [93][94][95].…”

Case Report: Sequential Development of Three Mature Lymphoid Neoplasms in a Single Patient: Clonal Relationship and Molecular Insights

“…Richter syndrome (RS) is defined as the occurrence of an aggressive lymphoma in patients with a previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL) ( 1 ). Approximately 2%–8% of patients with CLL may progress to RS, most frequently with a diffuse large B-cell lymphoma (DLBCL) variant, while the classical Hodgkin lymphoma (HL) variant is definitely less common (<10%) ( 2 – 4 ). Concomitant DLBCL and HL transformation has been reported in few cases ( 5 , 6 ).…”