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Article Dans Une Revue Blood Année : 2022

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 April 29th, 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 6th, 2020 to March 2nd, 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.

Dates et versions

hal-04020852 , version 1 (09-03-2023)



Hedi Bensaber, Emmanuel Bachy, David Beauvais, Remy Dulery, Thomas Gastinne, et al.. Anti-CD19 CAR T-Cell Therapy for Patients with Richter Syndrome: A Lysa Study from the Descar-T Registry. Blood, 2022, 140 (Supplement 1), pp.3803-3804. ⟨10.1182/blood-2022-158807⟩. ⟨hal-04020852⟩
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