Multi-centre real-world outcome of patients with Richter transformation receiving CD19-directed commercial CAR T-cell therapy in Australia.

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Abstract Aim: Richter transformation (RT) is an uncommon (2-10%) complication of chronic lymphocytic leukemia (CLL), most frequently manifesting as diffuse large B-cell lymphoma (RT-DLBCL, 90-95%). It is associated with complex genetic aberrations and poor prognosis, with a median overall survival (OS) of 12 months. Patients with RT-DLBCL were not eligible for the pivotal ZUMA-1 and JULIET trials. In Australia, public funding permits CAR T-cell therapy for patients with RT-DLBCL, offering a unique opportunity to assess real-world outcomes in this high-risk group. Here we report outcomes of CAR-T therapy for RT-DLBCL from 6 Australian centres that participate in the Australian CAR-T Real-World Consortium. Methods: We identified 28 patients with histologically confirmed DLBCL with either concurrent or antecedent CLL diagnosis, who underwent apheresis for commercial CAR T-cell therapy (axicabtagene ciloleucel [axi-cel] or tisagenlecleucel [tisa-cel]) between Jan 2024 and Mar-2025. Baseline characteristics include age, sex, del(17p)/TP53 status, CLL-related cytogenetic or molecular abnormalities, clonal relationship, presence of CLL by flow cytometry in either blood or bone marrow prior to apheresis, lymphodepletion, post-CAR T-cell treatment, prior CLL or RT-DLBCL therapies, and response to bridging treatment. Primary endpoints were 12-month progression-free survival (PFS) from apheresis (intention-to-treat, ITT, population) and from infusion. Secondary endpoints included one-month overall response rate, overall survival (OS) from infusion, maximum grades of cytokine release syndrome (CRS) and immune-effector cell associated neurotoxicity syndrome (ICANS). Results: Of the 28 patients who underwent apheresis (19 intended axi-cel & 9 tisa-cel), 24 proceeded to infusion (17 axi-cel & 7 tisa-cel). In all four patients that did not receive infusion the primary reason was progressive disease. The median age was 64 (range 34-81) years. Most patients had prior CLL diagnosis (N=21; 75%). Of the 11 patients with known clonal relationship, all had clonally related RT. Del(17p) or TP53 mutations were present in 46% of patients. Of 18 patients with prior information, five had complex cytogenetic. Prior exposure to BTK and BCL2 inhibitors were reported in 43% and 39% of patients, respectively. Only 11% had prior autologous stem cell transplant. In most cases (59%), disease did not respond to bridging therapy. The one-month overall response rate was 75% which included 54% CR. Severe CRS and ICANS (grade 3) were uncommon (both 8%). With a median follow-up of 18.4 months, estimated 12-month PFS and OS rates were 47% and 61%, respectively. Of the 8 patients with disease response to bridging therapy, the 12-month PFS was 72.9%. The actuarial 24-month OS rate was estimated at 44.4%. Four patients had relapsed disease after 12 months from CAR T-cell infusion. Progressive disease was the leading cause of deaths (7 out of 11). Notably of the 19 infused patients who had peripheral blood or bone marrow flow cytometry data, 13 (68%) demonstrated absence of the CLL clone within first year post-infusion. Conclusions: In this multi-centre real-world cohort of RT-DLBCL patients, CAR T-cell therapy demonstrated encouraging efficacy and manageable immune toxicities, comparable to de novo DLBCL. These findings support CAR T-cell therapy as a treatment option for patients with RT-DLBCL. The encouraging outcomes for the small number of patients with favourable response to bridging therapy suggests that development of novel bridging strategies to CAR-T may be beneficial.

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