CD19 CAR-T Cell Therapy Is Effective in Richter Transformation: A Multicenter Retrospective Analysis By the European Research Initiative on Chronic Lymphocytic Leukemia
Authors: Beyar-Katz Ofrat , Benjamini Ohad , Delgado Julio , Ruella Marco , Ram Ron , Grisariu Sigal , Visentin Andrea , Vandenberghe Elisabeth , Gentile Massimo , Avigdor Abraham , Shimoni Avichai , Shouval Roni , Marcus Ronit , Schuster Stephen J. , Ortiz-Maldonado Valentin , Ghilardi Guido , Paruzzo Luca , Zuckerman Tsila , Tadmor Tamar , Fineman Riva , Amit Odelia , Martinez-Cibrian Nuria , Gabrielli Giulia , Avni Batia , Minga Eva , Shem-Tov Noga , Scarfo Lydia , Yerushalmi Ronit , Nagler Arnon , Leiba Ronit , Danylesko Ivetta , Stamatopoulos Kostas , Chatzikonstantinou Thomas , Ghia Paolo , Herishanu Yair 
Published: December 2024

Introduction: Richter transformation (RT) is a devastating complication of chronic lymphocytic leukemia (CLL), associated with poor outcomes. While the progressively expanding use of CAR-T cells in the setting of large B-cell lymphoma (LBCL) is yielding encouraging results, findings regarding the response of patients with RT to this therapy are inconclusive and the need for further consolidation with allogeneic stem cell transplantation (allo SCT) has not been determined yet. Additionally, the issue of CAR-T cell treatment-related toxicity in this patient population remains unclear. The current study aimed to analyze clinical response and survival rates among patients with RT treated with CD19 targeting CAR-T cells.

Methods: This retrospective multicenter study, conducted across Europe and the USA by the European Research Initiative on CLL (ERIC) group, included all consecutive patients with RT who received CAR-T cells targeting CD19 in the participating centers between 06/2018 and 01/2024. Response rates, progression-free survival (PFS) and overall survival (OS) were assessed from the day of CAR-T infusion. CAR-T related toxicities were reported by ASTCT criteria.

Results: The study included 54 patients with RT treated with anti-CD19 CAR-T cells (investigational products: n=29, 54%; tisagenlecleucel: n=20, 37%; axicabtagene ciloleucel: n=4, 7%; lisocabtagene maraleucel: n=1, 2%). The median age at CAR-T cell product infusion was 62.6 (range 41-82) years. The ECOG performance status (PS) prior to lymphodepletion was 0-1 in 39 (72%) and 2-3 in 15 (28%) patients. Mean prior lines of CLL treatment were 2 (range, 0-8). The majority of patients (35/52, 67%) had previously received Bruton tyrosine kinase inhibitors. Bridging therapy was administered to most patients (n=36, 67%). Lymphodepletion consisted of fludarabine with cyclophosphamide in 46/52(85%) and bendamustine in 8 (15%) patients. The overall and grade 3-4 cytokine release syndrome (CRS) were documented in 47 (87%) and 10 (21%) patients, respectively. Immune effector cell-associated neurotoxicity syndrome (ICANS) of any grade was diagnosed in 12 (22%) patients, with high-grade ICANS found in 5 (42%) of them. Among the infections identified in a total of 22 patients (41%), bacterial infections were most common (71%). Seven patients (13%) underwent allo SCT following CAR-T cell infusion. Among these, four patients (57%) died, with 3/4 due to transplant-related toxicities and 1/4 due to progressive disease. The overall response rate was 65%, with complete response (CR) achieved in 46% of patients at 1 month and in 50% at 3 months following CAR-T cell infusion. With a median follow-up of 20.2 (range, 2-57) months, median OS was 14.4 months (95% CI = 8.8-19.2). PFS rates at 6 and 12 months were 56% (95% CI = 42%-70%) and 41% (95% CI = 27%-56%), respectively. The median PFS was 24.6 months (95%CI=16 - 32) for patients achieving any response (CR+PR) compared with 1.2 months (95% CI= 0.92 - 1.6) for patients with stable disease/progressive disease.

In the univariable analysis, mortality was found to be significantly associated with high ECOG PS (2-3) at the time of CAR-T cell infusion (p &lt;0.001), the development of ICANS (p = 0.027) and lack of response 1 month following CAR-T cell infusion (p=0.001). Multivariable analysis revealed that the two latter factors remained statistically significant. There was no significant difference in response rates among patients harboring genetic aberrations such as deletion 17p, 13q, 11q, trisomy 12, TP53 mutations or IGHV mutational status. CAR-T cell related toxicity was more frequently observed in patients with a high disease burden, defined according to the lactate dehydrogenase (LDH) level prior to CAR-T cell infusion [150 (131-193) vs 274 (222-359) mU/ml, p &lt;0.001].

Conclusions: The current study demonstrates clinically significant response rates and manageable toxicity in patients with RT treated with investigational as well as commercially available CAR-T cell products. These findings could potentially pave the way for new treatment paradigms in the management of this high-risk and challenging patient population.