Richter's Transformation after CD-19 Directed CAR-T Cells for Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Introduction Approximately 5-10% of patients with chronic lymphocytic lymphoma (CLL) will develop transformation to a more aggressive lymphoma, usually diffuse large B-cell lymphoma (Richter's transformation, RT). The median overall survival after transformation is less than one year. It remains difficult to predict which patients will transform although there is a correlation with poor risk features of CLL, like del17p/TP53 mutation and Notch1 mutations among others. While data emerging from trials of CD19-directed CAR-T cells (CD19CART) in CLL are showing promising results in the relapsed/refractory setting, there appears to be an emergence of RT in some cases even when there is no measurable residual CLL. For instance, in the phase 1 portion of the TRANSCEND CLL 004 trial, in the monotherapy arm with lisocabtagene maraleucel (n=23), 5 RT cases emerged subsequently and 3 of these had no recurrent CLL or MRD conversion to positive [Siddiqi T, et al. ASH 2020]. Four of these RT events were in patients who had progressed on both ibrutinib and venetoclax. Here we describe patients who developed RT after receiving CD19CART for CLL at City of Hope. Methods A retrospective chart review was performed to identify RT emergence and to analyze key factors surrounding the development of RT after CD19CART for CLL at City of Hope. Patient characteristics were assessed including age, sex, prior number of treatments, CLL FISH panel, mutational analysis, time on BTK inhibitor therapy, response to CAR T cell therapy, time to RT after CD19CAR T cell therapy, and outcomes after RT. Pathology samples from RT were assessed for CD19 expression and will be assessed for PDL-1, MYC, SYK, ZAP70, AKT, ERK expression by IHC or flow cytometry. Results A total of 7 out of 27 patients have been identified who received CD19CART for CLL at City of Hope and subsequently relapsed with RT [Table 1]. The median age at the time of CD19CART was 66 years (range, 54-68) and median number of prior therapies was 5 (range 4-7). All patients had features associated with high risk CLL prior to CD19CART: 5/7 had del17p; 3/7 had TP53 mutations, 2/7 had NOTCH1 mutations, and 1/7 had SF3B1 mutations. Most patients, 6/7, achieved an objective response to CD19CART with 4/7 undetectable minimal residual disease to a level of