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 1^st, 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 April 29^th, 2022. 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 14 patients from January 6^th, 2020 to March 2^nd, 2022, 12 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 60 years (range, 42-76) and sex ratio M/F was 2. CLL cytogenetic features at baseline (when available) were as follows: 2/8 (25%) patients had 17p deletion, 6/8 (75%) 11q deletion and 3/6 (50%) complex karyotype. TP53 mutations were seen in 4/7 (57%) patients. 4/6 (67%) patients harbored unmutated IGHV. Median number of prior therapeutic lines for CLL before RS was 2 (range, 0-9). Of the 12 patients who were infused, 3 (25%) did not receive any prior therapy for CLL. Seven (58%) patients received chemo-immunotherapy, 7 (58%) had been exposed to ibrutinib including 5 (42%) to both ibrutinib and venetoclax. Median time from CLL diagnosis to RS was 7 years (range, 3-22). Ten (83%) patients received ≥ 1 prior lines of therapy for RS (median 3, range 0-3) and bridging therapy was administered to all but one patient. Evaluation for disease status prior CAR T-cell infusion revealed progression for 7 (58%) patients, complete response in 1 (8.3%), partial response in 2 (16.7%) and stable disease in 1 (8.3%) (1 patient non-evaluated).

Following CAR T-cell infusion with axi-cel (5 patients) or tisa-cel (7 patients), best CRR was 42% and best ORR was 50%. Ten (83%) patients presented with CRS, 3 (25%) with grade > 2. Tocilizumab was administered to 9 (75%) patients. Five (42%) patients had ICANS, 3 (25%) with grade > 3. Regarding hematotoxicity, 6 (50%) patients presented with grade > 2 thrombocytopenia, 5 (42%) with grade > 2 anemia, and 7 with (58%) grade > 2 neutropenia. One case of macrophage activation syndrome was reported. Three patients were admitted to intensive care. A total of 5 (42%) patients had infections. After a median follow-up of 1.6 months (range, 0-23), 8 (67%) patients were alive, 4 (33%) patients died (2 from CRS and 2 from disease progression).

Conclusions CD19-directed CAR T-cell therapy showed high response rates 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). Larger cohort with longer follow-up and prospective trials are warranted to confirm these observations.

Bachy:Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, Sanofi: Honoraria; Roche, Gilead, ADC Therapeutics, Takeda, Novartis, Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen, BMS: Research Funding; Hospices Civils de Lyon: Current Employment. Beauvais:Gilead: Honoraria. Dulery:Kite/Gilead: Other. Gastinne:Gilead/Kite, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel, participation in a data safety monitoring board or advisory board. Houot:Bristol-Myers Squibb, Celgene, Gilead Sciences, Incyte, Janssen, Kite, MSD, Novartis and Roche: Honoraria. Guieze:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astrazeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie, Beigene, Janssen, Gilead, Roche, AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees.