Richter syndrome: molecular insights and clinical perspectives

Abstract

Richter syndrome (RS) represents the clinico-pathologic transformation of chronic lymphocytic leukaemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). The clinical definition of RS is heterogeneous, and encompasses at least two biologically different conditions: (i) CLL transformation to a clonally related DLBCL, that accounts for the majority of cases; (ii) development of a DLBCL unrelated to the CLL clone. In clonally related RS, the pathogenetic link between the CLL and the DLBCL phases is substantiated by the acquisition of novel molecular lesions at the time of clinico-pathologic transformation. RS is not a rare event in the natural history of CLL, since the cumulative incidence of RS at 10 years exceeds 10%. Prompt recognition of RS is known to be clinically useful, and may be favoured by close monitoring of CLL patients harbouring clinical and/or biological risk factors of RS development. Conventional risk factors that are independent predictors of RS development at the time of CLL diagnosis include: (i) expression of CD38; (ii) absence of del13q14 and (iii) lymph node size 3 cm. Other risk factors of RS development include CD38 genotype and usage of specific immunoglobulin variable genes. The molecular pathogenesis of RS has been elucidated to a certain extent. Acquisition of TP53 mutations and/or 17p13 deletion is a frequent molecular event in RS, as it is in other types of transformation from indolent to aggressive B-cell malignancies. Additional molecular alterations are being revealed by genome wide studies. Once that transformation has occurred, RS prognosis may be predicted by the RS score, based on performance status, LDH, platelet count, tumour size and number of prior therapies. Depending on patient's age and RS score, the therapeutic options for RS may range from conventional immunochemotherapy to allogeneic bone marrow transplantation.

Molecular history of Richter syndrome: origin from a cell already present at the time of chronic lymphocytic leukemia diagnosis

“…[1][2][3][4] Despite morphologic and phenotypic similarities, 4 the ID status of IGHV genes of clonally unrelated RS differed from that of both clonally related RS and de novo DLBCL with a non-GC phenotype. In fact, all clonally unrelated RS harbored ID and were characterized by a significantly higher mutation frequency (median: 1.18 Â 10 À3 range: 0.42-1.61 Â 10…”

“…[1][2][3][4] The role of antigen in promoting CLL transformation to RS is supported by the recent observation of a high prevalence of stereotyped B-cell receptors in CLL transforming to RS, and by the documentation of biased usage of immunoglobulin heavy variable (IGHV) genes, including IGHV4-39.…”

Successful Allogeneic Hematopoietic Stem Cell Transplantation in a Young Patient with Richter Syndrome Presenting with Chronic Lymphocytic Leukemia and Diffuse Large B-Cell Lymphoma with Different Cell Origins

“…Depending on the patient's age and the RS score, the therapeutic options for treating RS range from conventional immunochemotherapy to alloHSCT. However, intensive immunochemotherapies utilized for high-grade non hodgkin lymphoma (NHL) or (ALL) have not been found to be effective for RS, demonstrating a median survival time of less than one year (3)(4)(5). On the other hand, in a nonrandomized comparison of two RS cohorts, the estimated overall survival rate at three years was 75% among patients who received alloHSCT after achieving a complete remission (CR) or partial remission (PR), compared to 27% among those who responded to the initial therapy but did not receive alloHSCT (6).…”

“…The clinical outcomes of RS are generally poor with a median survival time of less than one year, even when intensive chemotherapies effective for high-grade nonHodgkin's lymphoma or acute lymphoblastic leukemia (ALL) are applied (3)(4)(5). Additionally, as most RS patients are elderly, allogeneic hematopoietic stem cell transplantation (alloHSCT) is applicable in limited cases only (6).…”

Histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

“…Among patients with newly diagnosed CLL/SLL, the annual incidence rate of DLBCL is 0.5%; whereas among patients who have received treatment for CLL/SLL the annual incidence rate of DLBCL is 1% [15]. Up to 10.7% of all CLL/SLL patients progress to DLBCL (RS-DLBCL) [11,12,14,15,[20][21][22][23] (Supporting Information Table I). The incidence rate for DLBCL reported in the literature is highly variable, likely attributable to many factors including the heterogeneity of the patient population studied, duration of clinical follow-up, and diagnostic criteria used to define development of DLBCL (clinical/imaging vs. biopsy-proven).…”