Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter’s Transformation: An International Multicenter Retrospective Study

Background:

Aggressive lymphoma, most commonly large B-cell lymphoma (LBCL), arising in the setting of chronic lymphocytic leukemia (CLL) is known as Richter’s transformation (RT), and is associated with poor outcomes. CD19 CART has revolutionized the treatment (tx) of LBCL, with durable responses for patients (pts) with relapsed/refractory disease. Pts with RT have been excluded from most major CD19 CART trials. Therefore, there is limited data describing outcomes of pts with RT receiving CD19 CART

Methods:

We conducted an international multicenter retrospective study of pts with RT who received CD19 CART approved for hematologic malignancies at 9 academic centers. RT was defined as pts with LBCL with preceding or concurrently diagnosed CLL. We collected pt, disease, and tx characteristics. Progression-free survival (PFS) and overall survival (OS) were measured from date of CD19 CART infusion and estimated using the Kaplan-Meier method. Cox regression model was used to associate prognostic factors with PFS and OS. Response was assessed by Lugano criteria.

Results:

62 pts were included. Median age at CD19 CART infusion was 65 (range: 27-80). Median prior lines of therapy for CLL or RT were both 2 (CLL range: 0-10, RT range: 0-7). 52 (84%) pts previously received a Bruton tyrosine kinase inhibitor (BTKi) or BCL2 inhibitor (BCL2i) for CLL or RT. Median Ki-67 on pathology sample was 80% (range: 40-100), median SUV on brightest lymph node (LN) on PET-CT was 15.0 (range: 3-50.6), median size of largest LN was 3.8cm (range: 0-16), and median LDH prior to CD19 CART was 244 (range: 96-2878, ULN range: 190-271). Median time from apheresis to CD19 CART infusion was 33 days (range: 24-100), and 52 (84%) pts received bridging therapy. 40 (65%), 14 (23%), 7 (11%), and 1 (2%) pts received axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), lisocabtagene maraleucel (liso-cel), and brexucabtagene autoleucel (brexu-cel), respectively.

Overall response rate was 65%, with 29 (47%) and 11 (18%) pts attaining complete response (CR) and partial response (PR), respectively. After a median follow up of 24.1 months (mos) from CD19 CART infusion, the median PFS was 4.7 mos (95% CI: 2.3-6.9), and median OS was 8.5 mos (95% CI: 5.1-32.5) (Figure). Median duration of response was 14.5 mos (95% CI: 4.0-NR), with a median not reached (NR) (95% CI: 13.1-NR) for pts who achieved a CR, and a median of 2.3 mos (95% CI: 1.0-3.3) for pts who achieved a PR. Among 39 pts who died, 28 (72%) died due to progression of disease (PD), and 11 (28%) died for other reasons including 8 infections (4 COVID), 1 septic shock, 1 stroke, and 1 respiratory failure. The cumulative incidence of non-relapse mortality at 12 mos was 13% (95% CI: 6.2-23.4). 3 pts in a CR underwent allogeneic stem cell transplantation, 2 were alive at last known follow up (3.9 and 24.2 mos post-transplant), and 1 pt died from PD 21 mos post-transplant. 55 (89%) pts had CRS, with 9 (15%) grade ≥3 events. 43 (69%) pts had ICANS, with 23 (38%) grade ≥3 events.

On univariable analysis, increasing Ki-67 and LDH were found to be associated with worse PFS and OS, and attaining a CR with CD19 CART was found to be associated with improved PFS and OS. On multivariable analysis, increasing Ki-67 and LDH, and greater number of prior lines of therapy for RT were independent prognostic variables for worse PFS and OS, and attaining a CR was associated with improved OS. All other variables, including type of CD19 CART product received, were not correlated with PFS or OS (Table).

Conclusions:

We report findings from the largest cohort of pts with RT who received CD19 CART. Of note, 84% of pts were exposed to either BTKi or BCL2i for the tx of CLL or RT. RT remains a disease of unmet need, as the median OS was 8.5 mos in this study. However, there is some progress made as historically the median OS for patients with RT previously treated with BTKi is 4 mos (Kittai et al AJH 2023). Given higher number of prior therapies is associated with worse OS, earlier use of CD19 CART in the RT disease course may be warranted. Our data support the use of CD19 CART for pts with RT, with durable disease control in a subset of pts, however there is clear room to improve and develop better therapies. Given observed high response rate to CD19 CART, along with most pts experiencing early relapse, allogeneic stem cell transplantation at response should be considered. Prospective clinical trials evaluating CD19 CART with novel agents for RT are currently ongoing.