Richter’s Syndrome In Chronic Lymphocytic Leukemia: Clinical and Laboratory Features In 119 Patients, Attempting To Identify Possible Risk Factors
Authors: Tadmor Tamar , Fineman Riva , Shvidel Lev , Bairey Osnat , Goldschmidt Neta , Ruchlemer Rosa , Rachimi Naomi Rahimi , Herishanu Yair , Yuklea Mona , Arad Ariela , Aviv Ariel , Polliack Aaron 
Published: October 2019

Abstract

Introduction
Richter's syndrome (RS) is the rare development of an aggressive lymphoid malignancy in a patient with pre-existing, or concomitant chronic lymphocytic leukemia (CLL). This complication occurs in about 5 % of patients with CLL, and the most frequent form is the development of diffuse large B-cell lymphoma (DLBCL) and less frequently Hodgkin lymphoma (HL) or prolymphocytic leukemia (PLL). Most of the available data on RS is derived from case reports or small series of patients, and only a few larger cohorts have been published.

Aim
The purpose of this retrospective study was to summarize our experience with RS in CLL, examine possible risk factors and analyze relevant demographic, laboratory and clinical parameters, including outcome.

Methods
We collected a total of 119 patients diagnosed with RS from 12 medical centers in Israel during the period 1971-2010.We then summarized clinical, demographic and some biological features related to CLL at diagnosis and examined possible risk factors for their transformation to RS.

Results
Of the 119 patients with RS, 61 % were males, 82% developed DLBCL, 14% HL and 4% PLL. In terms of ethnicity: 95% were Jews (64% Ashkenazi) and only 5 % were Arabs, which is similar to the reported data for CLL in Israel.
The median time from CLL diagnosis to development of RS was 60 months (range, 0-182 months), and the median overall survival from diagnosis of RS was 9.5 months;34 % of the cases developed extranodal RS, and the most frequent sites of involvement were the gastro-intestinal tract and bone marrow. These results further confirm that there are no established “sanctuary sites” of extranodal RS, which can develop in all tissues and organs.
None of the conventional clinical and laboratory parameters examined and evaluated as possible risk factors in CLL were able to predict transformation to RS, including: occurrence of autoimmune phenomenon during the course of CLL, spleen size, serum beta 2 microglobulin levels, degree of CD38 positivity, and the number of previous treatments given for CLL, or the prior use of rituximab in these regimens.
The only parameters, present at the time of RS diagnosis which were found to correlate with adverse prognosis, included: performance status>2 (HR- 3.45), high IPI (HR- 3.28) and high Richter score (HR-7.45). In regard to therapy for RS, patients treated with chemotherapy followed by autologous stem cell transplantation (ASCT) had a better outcome with improved overall survival (p=0.034) (Figure).

Conclusions
RS remains a heterogeneous entity. In this large series of patients none of the conventional clinical, epidemiological or laboratory parameters, often evaluated as possible prognostic factors in CLL, were associated with the risk of transformation to RS. In this retrospective study molecular genetic data were not available to examine their possible significance, as reported recently in other series.
In terms of therapy, prior treatment of CLL with rituximab – containing regimens did not appear to impact the eventual outcome of patients who developed RS. On the other hand, ASCT did significantly improve overall survival in patients who had transformation to RS.
On behalf the Israeli CLL study Group.

Disclosures:
No relevant conflicts of interest to declare.