1123 - Anti-CD19 Chimeric Antigen Receptor T-cell therapy for Richter’s Transformation: A 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. Anti-CD19 Chimeric Antigen Receptor T-cell therapy (CART) has revolutionized the treatment of LBCL, with impressive durable responses for patients with relapsed/refractory disease. Patients with RT have been excluded from most major anti-CD19 CART clinical trials. Therefore, there are minimal available data describing outcomes of RT following anti-CD19 CART.

Methods:
We conducted a multicenter retrospective analysis of patients with RT who received anti-CD19 CART currently approved for hematologic malignancies at 7 academic centers in the United States. RT was defined as patients with LBCL with preceding or concurrently diagnosed CLL. We collected patient, disease, and treatment characteristics. Progression-free survival (PFS) and overall survival (OS) were measured from date of anti-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 by individual investigators.

Results:
Fifty-five patients were included. Median age at the time of anti-CD19 CART infusion was 64 years (range: 27-78). Median prior lines of therapy for CLL or RT were both 2 (CLL range: 0-10, RT range: 0-7). Forty-nine (89.1%) patients 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 14.5 (range: 3-50.6), median size of largest LN was 4.1cm (range: 0-16), and median LDH prior to anti-CD19 CART was 249 (range: 140-2828). Median time from apheresis to anti-CD19 CART infusion was 33 days (range: 24-100), and 45 (81.8%) patients received bridging therapy. 35 (63.6%), 13 (23.6%), 6 (10.9%), and 1 (1.8%) patients received axi-cel (axicabtagene ciloleucel), tisagenlecleucel (tisa-cel), lisocabtagene maraleucel (liso-cel), and brexucabtagene autoleucel (brexu-cel), respectively.
Overall response rate was 61.9%, with 25 (45.5%) and 9 (16.4%) patients attaining complete response (CR) and partial response, respectively. After a median follow up of 27.5 months from anti-CD19 CART infusion, the median PFS was 3.45 months (95% CI: 1.81-6.94), and median OS was 8.5 months (95% CI: 4.80-25.4) (Figure). Among 34 patients who died, twenty-four (70.6%) died due to progression of disease, and 10 (29.4%) died for other reasons including 7 infections (4 COVID), 1 septic shock, 1 stroke, and 1 respiratory failure. The cumulative incidence of non-relapse mortality at 12-months was 17.1% (95% CI: 8.3-28.6). Three patients in a CR underwent allogeneic stem cell transplantation, two were alive at last known follow up (3.9 and 24.2 months post-transplant), and 1 patient died from progression of disease 21 months post-transplant. Forty-eight (87%) patients had CRS, with 9 (16.3%) grade ≥3 events. Thirty-seven (67.2%) patients had ICANS, with 22 (40%) grade ≥3 events.
On univariable analysis, increasing Ki-67 and LDH were found to be associated with higher risk of progression and death. On multivariable analysis, increasing Ki-67, increasing LDH, and greater number of prior lines of therapy for RT were independent prognostic variables for worse PFS and OS. All other variables, including type of anti-CD19 CART product received, were not correlated with PFS or OS (Table).

Conclusions:
We report the largest cohort of patients with RT who received anti-CD19 CART. This was a heavily pretreated cohort with a median prior lines of therapy for CLL or RT of 2, and 89% of patients were exposed to either BTKi or BCL2i agents. RT remains a disease of unmet need, as the median OS was 8.5 months in this study. However, there is some progress made as historically the median OS for patients with RT previously treated with BTKi is 4 months (Kittai AJH 2023). Given higher number of prior therapies is associated with worse OS, earlier use of anti-CD19 CART in the RT disease course may be warranted. Our data support the use of anti-CD19 CART for patients with RT, with durable disease control in a subset of patients. Given observed high response rate to anti-CD19 CART, along with most patients experiencing early relapse, allogeneic stem cell transplantation at response should be considered. Prospective clinical trials evaluating anti-CD19 CART with novel agents, including BTKi, for RT are currently ongoing.