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This article discusses the clonal dynamics of Richter transformation in chronic lymphocytic leukemia (CLL). Richter's syndrome (RS) is an aggressive lymphoma that occurs in a small percentage of CLL patients. The study used whole exome sequencing to analyze samples from CLL and RS patients, revealing genomic heterogeneity and clonal evolution during RS transformation. The findings suggest that RS is characterized by the expansion of rare or undetectable clones from the CLL phase, while CLL specimens show relatively stable clonal dynamics. The study highlights the need for timely diagnosis of RS based on symptoms, imaging, and pathology. [Extracted from the article]

Despite the advances of targeted therapeutics in chronic lymphocytic leukemia (CLL), 3%-20% of CLL patients transform into aggressive lymphoma (commonly diffuse large B cell lymphoma, DLBCL) known as Richter's syndrome (RS).1 Patients who develop RS typically do not respond to standard chemotherapy and have poor overall survival (less than 1 year).1 Thus, translational studies to understand RS pathogenesis particularly regards to drug resistance, could provide insights for therapeutic development. Similar to the results from ibrutinib-treated CLL,9 we observed downregulation of I MS4A1 i in ibrutinib-treated RS, which may be associated with a lack of efficacy in adding rituximab to ibrutinib in CLL.10 The serial analysis for RS9 samples showed upregulation of several chemokine genes in the ibrutinib-resistant RS phase, suggesting their possible contribution in RS transformation. In this study we investigated transcriptomic profiles of six ibrutinib-resistant and five ibrutinib-naïve RS-involved lymphoid tissue using samples collected from a cohort of refractory RS patients. Ibrutinib has been shown to inhibit BCR and NF B signaling in CLL cells from both peripheral blood and tissue compartments.6 However, in our study we observed upregulation of several NF I i B-related genes in ibrutinib-resistant RS. [Extracted from the article]

Richter syndrome (RS) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma. RS is known to be associated with a number of genetic alterations such as TP53 and NOTCH1 mutations. However, it is unclear what immune microenvironment changes are associated with RS. In this study, we analyzed expression of immune checkpoint molecules and infiltration of immune cells in nodal samples, and peripheral blood T-cell diversity in 33 CLL and 37 RS patients. Compared to CLL, RS nodal tissue had higher PD-L1 expression in histiocytes and dendritic cells (median 16.6% vs. 2.8%, P < 0.01) and PD1 expression in neoplastic B cells (median 26.0% vs. 6.2%, P < 0.01), and higher infiltration of FOXP3-positive T cells (median 1.7% vs. 0.4%, P < 0.01) and CD163-positive macrophages (median 23.4% vs. 9.1%, P < 0.01). In addition, peripheral blood T-cell receptor clonality was significantly lower in RS vs. CLL patients (median [25th–75th], 0.107 [0.070–0.209] vs. 0.233 [0.111–0.406], P = 0.046), suggesting that T cells in RS patients were significantly more diverse than in CLL patients. Collectively these data suggest that CLL and RS have distinct immune signatures. Better understanding of the immune microenvironment is essential to improve immunotherapy efficacy in CLL and RS. [ABSTRACT FROM AUTHOR]