Clinical Characteristics and Outcomes of Chronic Lymphocytic Leukemia Patients with Richter Transformation

Introduction: Richter transformation (RT) refers to transformation of chronic lymphocytic leukemia (CLL) to an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). Most studies on the management of RT were either small retrospective series or early phase non-randomized trials before the era of novel agents. The natural history, prognostication and optimal treatment of patients with RT remain undefined. Here we report the clinical characteristics and outcomes of a large series of RT from a single center. Methods: Biopsy-confirmed RT (limited to non-Hodgkin lymphoma) diagnosed from 4/1993 to 4/2018 were identified from the Mayo Clinic CLL database. Clinical characteristics, treatment information and follow-up data were abstracted by chart review. Overall survival (OS) was defined as time from RT diagnosis to death from any cause and analyzed using the Kaplan-Meier method. Statistical analysis was done in SAS 9.4. Results: A total of 204 patients with CLL who developed RT were identified. The median age at CLL diagnosis was 62 years (range 22-85), and 148 (73%) were male. The median time to transformation was 4.7 years (range 0-34.5). Prior to RT, 68 (33.3%) patients received no treatment for CLL, 109 (53.4%) received chemoimmunotherapy (CIT) only, and 27 (13.2%) received at least one novel agent (idelalisib, ibrutinib, or venetoclax) for CLL. The median lines of CLL therapy prior to RT was 2 (range 0-13). The median age at RT diagnosis was 69 years (range 30-88). Pathology of RT was DLBCL and high grade B-cell lymphoma in 193 (94.6%) and 11 (5.4%) patients, respectively. The median LDH was 306 IU/L (range 99-9000). 62/125 (49.6%) patients had bulky disease (≥ 5 cm), and the median PET SUVmax was 13.9 (range 2.9-30.0). 45/131 (34.4%) patients had del(17p) or TP53 mutation, 12 (9.2%) had del(11q), 21 (16.0%) had trisomy 12, 27 (20.6%) had del(13q), and 25 (19.1%) had normal FISH. The CLL and RT were clonally related in 12/21 (57.1%) patients. For the transformed lymphoma, cell of origin by Han's algorithm was germinal center B cell-like (GCB) and non-GCB in 31/100 (31.0%) and 69/100 (69.0%) patients, respectively. EBV was positive in 14/52 (26.9%) patients. The median Ki-67 was 80% (range 10-100). Myc and Bcl-2 were positive by IHC in 31/43 (72.1%) and 83/103 (80.6%) patients, respectively; 27/56 (48.2%) were double-expressors. MYC, BCL2, and BCL6 rearrangement was positive by FISH in 18/68 (26.5%), 10/34 (29.4%), and 4/31 (12.9%) patients