1223 - Anti-CD19 CAR T-cell therapy for patients with Richter syndrome: A LYSA Study from the DESCAR-T Registry

Background
Richter syndrome (RS) refers to the onset of aggressive lymphoma, mostly diffuse large B-cell lymphoma (DLBCL), in patients with chronic lymphocytic leukemia (CLL). The outcome of RS patients is usually very poor with short survival (typically < 1 year) due to chemoresistance. Indeed, chemoimmunotherapy regimens used in de novo DLBCL failed to induce a significant complete remission rate (CRR) (R-CHOP, 7%; ofatumumab-CHOP, 27%) (Langerbeins et al., AJH 2014; Eyre et al., BJH 2016). CD19-targeted chimeric antigenic receptor (CAR) T-cell therapy such as axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have been transformative for patients with relapsed/refractory DLBCL. Here, we aimed to investigate the efficacy and safety profile of CD19-CAR T-cell therapy for patients with RS.

Methods
In this Lymphoma Study Association/ Lymphoma Academic Research Organization (LYSA/LYSARC) study, we conducted an analysis of the DESCAR-T registry which collects real-life data of patients treated with approved CD19-directed CAR T-cell therapies (axi-cel and tisa-cel) since July 1st, 2018 in France. We selected patients with biopsy-proven RS of DLBCL histology, treated by tisa-cel or axi-cel in either the frontline or relapse setting. Data regarding prior CLL history were collected in addition to the DESCAR-T registry data. The data cut-off was May 3th, 2023. The primary endpoint was best CRR according to Cheson IWG 2014 (Lugano Classification) after CAR-T cell infusion. Secondary endpoints were overall response rate (ORR), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytokine release syndrome (CRS) incidence and grading (ASTCT Consensus) as well as hematological toxicity (NCI CTCAE v5.0).

Results
CD19-directed CAR T-cell therapy was planned for 17 patients from November 12th, 2019 to July 26th, 2022, 15 were infused and subsequently included in the present analysis (1 patient refused the infusion and 1 was not infused due to disease progression). Median age was 61 [42-76] years and sex ratio M/F was 1.5. CLL cytogenetic features at baseline were as follows: 2/10 (20%) patients had 17p deletion, 6/9 (60%) 11q deletion and 3/7 (43%) complex karyotype. TP53 mutations were seen in 5/8 (62%) patients and 5/7 (71%) patients harbored unmutated IGHV. Median number of prior therapeutic lines for CLL before RS was 2 [0-9]. Of the 15 patients who were infused, 3 (20%) did not receive any prior therapy for CLL. Nine (60%) patients received chemo-immunotherapy, 9 (60%) had been exposed to ibrutinib including 4 (26.7%) to both ibrutinib and venetoclax (data collection ongoing for one patient).
Median time from CLL diagnosis to RS was 7 [0-22] years. Thirteen (87%) patients received ≥ 1 prior lines of therapy for RS and bridging therapy was administered to 13 (87%) patients. Evaluation for disease status prior CAR T-cell infusion revealed progression for 8 (53.3%) patients, complete response in 1 (6.6%), partial response in 3 (20%) and stable disease in 2 (13.3%) (1 patient non-evaluated).
After a median follow-up of 11.7 [0-24] months, best CRR was 40% and best ORR was 53.3%. One-year progressive free survival (PFS) rate was 40.7% and one-year overall survivor (OS) rate was 46.6%. Following CAR T-cell infusion with axi-cel (7 patients) or tisa-cel (8 patients), 8 (53.3%) patients were alive, 7 (46.6%) patients died (3 from acute toxicity with two CRS and one neurotoxicity, and 4 from disease progression). All but one (93.3%) patient presented with CRS, 5 (33.3%) with grade > 2. Tocilizumab was administered to 13 (87%) patients. Six (40%) patients had ICANS, 5 (33.3%) with grade > 3. Regarding hematotoxicity, 8 (53.3%) patients presented with grade > 2 thrombocytopenia, 5 (33.3%) with grade > 2 anemia, and 8 with (53.3%) grade > 2 neutropenia. One case of macrophage activation syndrome was reported. Five (33.3%) patients were admitted to intensive care. A total of 8 (53.3%) patients had infections.

Conclusions
CD19-directed CAR T-cell therapy showed high response rates and an encouraging survival in our series of heavily pretreated RS patients. Frequency of CAR T-cell-specific adverse events was in the range of what is observed in de novo DLBCL while severity appeared higher (Schuster et al., NEJM 2019; Neelapu et al., NEJM 2017).