Incidence of Richter transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma in the targeted therapy era

Abstract

Richter transformation (RT) is the histologic transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). RT has devastating consequences with survival after transformation typically <1 year [1]. Estimates of RT frequency vary by study design, setting, and duration of follow-up. In several large studies from time periods when chemoimmunotherapy (CIT) was used to treat patients with CLL, RT rates have been reported between 2 and 10% after a median follow-up of 4–6 years from the time of diagnosis; these studies included patients with both newly diagnosed CLL and treated CLL [2,3,4,5,6]. Targeted therapies, including Bruton tyrosine kinase inhibitors (BTKi) and B-cell lymphoma 2 inhibitors (BCL2i), are now standard of care treatment for patients with CLL. High RT rates (up to 25%) reported in early studies with BTKi and BCL2i in relapsed CLL patients likely reflect increased RT risk among heavily pre-treated patients rather than risk due to these therapies themselves [7, 8]. Comparison of risk after specific treatment exposures from first-line clinical trials with CIT and targeted therapy arms is limited by the low numbers of RT events reported [9,10,11,12,13]. As the treatment paradigm for CLL has changed and CLL patients are living longer, we aimed to assess the current risk of developing RT and the potential impact of targeted therapies on that risk by comparing cohorts of patients with newly diagnosed CLL across different time periods.

Following IRB approval, we identified patients with previously untreated CLL in the Mayo Clinic CLL Database who were seen within 12 months of diagnosis. Only cases of biopsy proven DLBCL with histopathologic confirmation at Mayo Clinic were considered an RT event. Cumulative incidence methodology was used to display the time to development of RT, both from time of initial CLL diagnosis and from start of CLL-directed therapy, with death as a competing risk. We defined the period prior to February 2014 (FDA approval of ibrutinib for CLL) as the pre-targeted therapy era and the period after February 2014 as the targeted therapy era. Using Cox proportional hazards regression analysis, we compared the incidence of RT between patients diagnosed with CLL in the pre-targeted therapy era versus the targeted therapy era. Cox regression analysis was also used to investigate the association of effects of type of treatment exposure (time-dependent variable) on risk of RT. Statistical analyses were conducted using SAS 9.4 (SAS Institute, Cary, NC, USA).