Diffuse large B-cell lymphoma (Richter syndrome) in patients with chronic lymphocytic leukaemia (CLL): a cohort study of newly diagnosed patients

Abstract

Nearly all information about patients with chronic lymphocytic leukaemia (CLL) who develop diffuse large B-cell lymphoma [Richter syndrome (RS)] is derived from retrospective case series or patients treated on clinical trials. We used the Mayo Clinic CLL Database to identify patients with newly diagnosed CLL between January 2000 and July 2011. Individuals who developed biopsy-proven RS during follow-up were identified. After a median follow-up of 4 years, 37/1641 (2·3%) CLL patients developed RS. The rate of RS was approximately 0·5%/year. Risk of RS was associated with advanced Rai stage at diagnosis (P < 0·001), high-risk genetic abnormalitites on fluorescence in situ hybridization (P < 0·0001), unmutated IGHV (P = 0·003), and expression of ZAP70 (P = 0·02) and CD38 (P = 0·001). The rate of RS doubled in patients after treatment for CLL (1%/year). Stereotyped B-cell receptors (odds-ratio = 4·2; P = 0·01) but not IGHV4-39 family usage was associated with increased risk of RS. Treatment with combination of purine analogues and alkylating agents increased the risk of RS three-fold (odds-ratio = 3·26, P = 0·0003). Median survival after RS diagnosis was 2·1 years. The RS prognosis score stratified patients into three risk groups with median survivals of 0·5 years, 2·1 years and not reached. Both underlying characteristics of the CLL clone and subsequent CLL therapy influence the risk of RS. Survival after RS remains poor and new therapies are needed.

Keywords: Richter syndrome survival score; aggressive lymphoma; purine analogues; stem cell transplantation; transformation.

© 2013 John Wiley & Sons Ltd.

Figures

Figure 1

Rate of Richter syndrome in the entire cohort (black solid line). Rate of Richter syndrome in those who received CLL treatment (red dashed line, initiation of CLL treatment considered time zero)

Figure 2

A: Overall Survival of all patients with Richter Syndrome B: Overall Survival of RS patients who received prior therapy for CLL compared to those who did not

Figure 2

A: Overall Survival of all patients with Richter Syndrome B: Overall Survival of RS patients who received prior therapy for CLL compared to those who did not

Figure 3

Overall Survival of all Richter syndrome patients according to the RS score *: RS score as described by Tsimberidou et al. Each of the following characteristics at the time of diagnosis of RS gets one point: ECOG performance status of 2–4, LDH >1.5× normal, PLT 5 cm and >1 prior therapy for CLL. Patients are then assigned to one of three risk groups based on their calculated RS score: 0 or 1, low risk; 2 or 3, intermediate risk; 4 or 5, high risk.