Richter's syndrome: Novel and promising therapeutic alternatives

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Abstract

Richter's syndrome (RS) is the development of an aggressive lymphoma in patients with a previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL). The incidence rate for RS is ∼0.5% per year of observation. In the presence of clinical suspicious of RS, diagnosis of transformation and choice of the site of biopsy may take advantage of 18FDG PET/CT. Molecular lesions of tumor suppression regulators (TP53), cell cycle (CDKN2A) and cell proliferation (NOTCH1, MYC) overall account for ∼90% of RS and may be responsible for its aggressive clinical phenotype. The prognosis of RS is generally highly unfavorable. However, the pattern of survival is not homogeneous and the clonal relationship between the CLL and the aggressive lymphoma clones is the most important prognostic factor. Rituximab-containing polychemotherapy represents the back-bone for induction treatment in RS. Younger patients who respond to induction therapy should be offered stem cell transplant to prolong survival.

Section snippets

Richter's syndrome

The 2008 World Health Organization (WHO) Classification of Hematopoietic Tumors defines Richter's syndrome as the development of an aggressive lymphoma in patients with a previous or concomitant diagnosis of chronic lymphocytic leukemia (CLL) [1]. The WHO Classification recognizes two distinct pathologic variants of Richter's syndrome: the diffuse large B-cell lymphoma (DLBCL) variant, which is the most frequent, and the rare Hodgkin lymphoma (HL) variant [1]. This review will focus on the

Richter's syndrome diagnosis and course

Richter's syndrome should be suspected in any CLL patient that develops rapid clinical deterioration, fever in the absence of infection, rapid and discordant growth of localized lymph nodes, and sudden and excessive rise in lactate dehydrogenase (LDH) levels. Presence of one or more of these clinical signs and symptoms is only 50–60% specific for Richter's syndrome. In the remaining cases, the histopathologic assessment results in the diagnosis of progressive CLL, prolymphocytic evolution, or

Molecular pathogenesis of Richter's syndrome

Richter's syndrome shows a biased usage of the BCR in the subset 8 configuration, suggesting that it has been selected to bind a restricted set of antigenic epitopes, and supporting a role of BCR signaling in transformation [3]. The particular aggressiveness of BCR subset 8 and its increased propensity of transform into Richter's syndrome may be explained by the strong and unlimited capacity of CLL harboring this BCR configuration to respond to multiple auto-antigens and immune/inflammatory

Chemotherapy approaches for the treatment of Richter's syndrome

Regimens commonly used to treat other B-cell non-Hodgkin lymphomas have been used to treat CLL patients with Richter's syndrome.

Regimens designed for the treatment of highly aggressive lymphomas are severely toxic in Richter's syndrome patients and remission duration is short lasting. The hyper-CVAD regimen, a fractioned cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen, induced a response in 41% (CR 38%) of patients, but the median overall survival (OS) was only 10 months.

Stem cell transplantation in Richter's syndrome

Given the short duration of response with the sole chemotherapy, both autologous and allogeneic stem cell transplantation (SCT) have been explored as post-remission therapy [9], [38]. Unfortunately, most patients (85–90%) with Richter's syndrome are unfit or do not achieve adequate response to the induction to proceed to transplant.

The European Group for Blood and Marrow Transplantation (EBMT) has retrospectively investigated the role of both, autologous and allogeneic SCT, as post-remission

Novel agents

Three aspects are in strong support of the development of novel targeted agents in the field of Richter's syndrome: i) the unsatisfactory response rates that are obtained with conventional chemo-immunotherapy, and the short response duration if not consolidated with SCT; ii) the low number of cases that can proceed to transplant because of the constraints imposed by a combination of age, poor performance status, lack donor availability and refractoriness to induction treatments; and iii) the

Summary

Suggested management of Richter's syndrome includes (Fig. 1): i) in the presence of a clinical suspicion of Richter's syndrome transformation, perform a 18FDG PET/CT and tailor the open biopsy of the index lesion according to its results; ii) if the biopsy reveals an aggressive lymphoma, establish its clonal relationship with CLL by IGHV-D-J rearrangement analysis; iii) if the CLL and Richter's syndrome are clonally unrelated, treat the disease as a de novo DLBCL; iv) if the CLL and Richter's

Conflict of interest

The author has no conflict of interest.

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