Two main genetic pathways lead to the transformation of chronic lymphocytic leukemia to Richter syndrome

Abstract

Key Points• Richter syndrome has genomic complexity intermediate between chronic lymphocytic leukemia and diffuse large B-cell lymphoma.• Inactivation of TP53 and of CDKN2A is a main mechanism in the transformation to Richter syndrome.Richter syndrome (RS) occurs in up to 15% of patients with chronic lymphocytic leukemia (CLL). Although RS, usually represented by the histologic transformation to a diffuse large B-cell lymphoma (DLBCL), is associated with a very poor outcome, especially when clonally related to the preexisting CLL, the mechanisms leading to RS have not been clarified. To better understand the pathogenesis of RS, we analyzed a series of cases including 59 RS, 28 CLL phase of RS, 315 CLL, and 127 de novo DLBCL. RS demonstrated a genomic complexity intermediate between CLL and DLBCL. Cell-cycle deregulation via inactivation of TP53 and of CDKN2A was a main mechanism in the histologic transformation from CLL phase, being present in approximately one half of the cases, and affected the outcome of the RS patients. A second major subgroup was characterized by the presence of trisomy 12 and comprised one third of the cases. Although RS shared some of the lesions seen in de novo DLBCL, its genomic profile was clearly separate. The CLL phase preceding RS had not a generalized increase in genomic complexity compared with untransformed CLL, but it presented clear differences in the frequency of specific genetic lesions. (Blood. 2013;122(15):2673-2682

Chronic lymphocytic leukemia: Time to go past genomics?

“…Branched evolution is associated with disease evolution and dismal prognosis, probably because the generated genetic diversity allows for a more efficient selection of fitted cells. Dismal evolution of CLL into DLBCL, the Richter syndrome, occurring in 10% of the patients, seems however to be associated to linear evolution [12,133].…”

A krónikus lymphocytás leukaemia korszerű molekuláris diagnosztikája és kezelése az új célzott terápiák korszakában

“…A TP53-státusz vizsgálatára a nemzetközi ajánlások a CLL-es betegek esetén egyhangúan a 17p-és a TP53-mutációk egyidejű vizsgálatát javasolják a kezelés megkezdése előtt [1, 15-17, 25, 26]. A CLL-ben jól ismert terápia indukálta klonális evolúció miatt a kezelést igény-lő relapsusok alkalmával ismételni szükséges a TP53-stá-tusz vizsgálatát, ugyanis a TP53-defektus gyakorisága a diagnóziskori 5-10%-ról a kemorezisztens esetekben 40%-ra, míg Richter-szindróma esetén 60%-ra nő [27,28] …”

Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

“…These findings point to a higher number of antecedent cell replications and thus a higher chance to acquire additional genetic alterations [26]. Other biological risk factors of CLL/SLL transformation to RS-DLBCL include expression of CD38 [10,14,15], ZAP-70 [10,[12][13][14][15], and CD49d [15]. Cytogenetic abnormalities, such as del(11q22.3), del(17p13), del(15q21.3), del(9p21), and/or add(2p25.3), have been also associated with RS [10,15,27].…”

“…Other biological risk factors of CLL/SLL transformation to RS-DLBCL include expression of CD38 [10,14,15], ZAP-70 [10,[12][13][14][15], and CD49d [15]. Cytogenetic abnormalities, such as del(11q22.3), del(17p13), del(15q21.3), del(9p21), and/or add(2p25.3), have been also associated with RS [10,15,27]. Heritable germline polymorphisms in BCL2 [29], CD38 [30] and LRP4 [31] have been reported to impart a higher risk for transformation, although the functional mechanisms underlying these associations remain to be determined.…”

“…Hypercalcemia, new onset of absolute lymphocytosis 5.0 3 10 9 /L, and thrombocytopenia <100 3 10 9 /L often accompany RS, but these findings are not by themselves a reliable predictor of RS [8][9][10][11][12][13][14][15][16][17][18][19].…”