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Treatment with a novel, optimized, hinge dual CD19/CD20–directed CAR T-cell therapy was safe and elicited high response rates, particularly when administered following autologous stem cell transplant (ASCT), in patients with relapsed/refractory B-cell lymphoma, according to findings from a phase 1/2 trial presented at the 51st Annual EBMT Meeting.
At the data cutoff date of December 5, 2024, the best overall response rate (ORR) among all enrolled patients (n = 51) was 84%, which included a complete response (CR) rate of 52% and a partial response (PR) rate of 32%. Moreover, at a median follow-up of 10.4 months, the median progression-free survival (PFS) and overall survival (OS) were not reached. Estimated 1-year PFS and OS rates for all enrolled patients were 74.0% (95% CI, 60.0%-84.2%) and 86.0% (95% CI, 72.8%-93.1%), respectively. Moreover, for those who achieved an ORR at 3 months, the estimated 1-year PFS and OS rates were 85.4% (95% CI, 70.3%-93.2%) and 97.4% (95% CI, 83.2%-99.6%), respectively.
“Our results show that the optimized hinge CD19/CD20 CAR T-cell therapy… delivered durable remissions with a safe profile in patients with relapsed/refractory B-cell lymphoma,” lead study author Jiaqi Guo, of the Department of Hematology at Tongji Hospital, Tongji Medical College, in Wuhan, China, and colleagues, wrote in a poster presentation of the data.
Rationale and Study Overview
The efficacy of CD19-directed CAR T-cell therapy in relapsed/refractory BCL is often limited by CD19 antigen loss. Although recent studies suggest that targeting 2 antigens simultaneously can overcome CD19 relapse in this setting, the combination of CD19- and CD20-directed CAR T-cell therapy has not been fully explored.
To address this, a series of dual CD19/CD20–targeted CAR T-cell agents were designed, and preclinical comparative analyses confirmed that the optimized hinge tandem CD19/CD20 CAR T-cell therapy outperformed other structures in both in vitro and in vivo studies.
Accordingly, a multicenter, open-label, single-arm, study evaluated the novel therapy in a cohort of patients with relapsed/refractory B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL, n=39), Burkitt lymphoma (n=4), follicular lymphoma (n=4), marginal zone lymphoma (MZL, n=2), and mantle cell lymphoma (MCL, n=2). Starting in July 2022, patients were recruited from the hematology departments of Tongji Hospital, Shanxi Bethune Hospital, and the Fourth Hospital of Hebei Medical University.
Among all patients who received tandem CD19/CD20 CAR T-cell infusion, the median age was 51 years (range, 28-74). Prior to enrollment, 86.3% of patients had stage III/IV disease, 68.6% had undergone third-line or later treatment, 7.8% had previously received ASCT, and 15.7% (8/51) had prior CAR-T therapy.
Additional Subgroup Analysis Insights
Additional findings from subgroup analysis showed that patients who received ASCT followed by the tandem CD19/CD20 CAR T-cell infusion achieved a higher CR rate of 83.3% compared with 34.4% among those who received the infusion alone. Notably, a trend toward improved 1-year PFS and OS was observed among patients who underwent ASCT plus the CAR T-cell infusion vs the CAR T-cell infusion alone. The PFS and OS rates in the ASCT plus CD19/CD20 CAR T-cell therapy group were 83.0% and 94.1%, respectively; these rates were 69.4% and 81.5% in the CAR T-cell therapy–alone group.
Spotlight on Safety and Pharmacokinetic Data
Regarding safety, grade 1/2 cytokine release syndrome (CRS) was observed in 54.9% of patients, and 2.0% experienced grade 3 CRS. No cases of grade 4 CRS occurred. Grade 1/2 immune effector cell–associated neurotoxicity syndrome (ICANS) was observed in 4.0% and 2.0% of patients, respectively. The most common grade 3/4 adverse effects (AEs) were neutropenia (100%), thrombocytopenia (58.8%), and infection (19.6%); other grade 3 to 4 AEs were relatively rare in this cohort.
Notably, grade 5 AEs associated with CAR T-cell infusion included CRS (59%), ICANS (6%), pyrexia (59%), skin rash (18%), increased alanine aminotransferase levels (18%), increase aspartate aminotransferase levels (205), increased gamma-glutamyl transferase levels (25%), thrombocytopenia (78%), neutropenia (100%), hypotension (8%), hypoalbuminemia (35%), hypokalemia (14%), hyponatremia (25%), hypocalcemia (27%), tachycardia (47%), diarrhea (16%), and infections (25%).
CAR-T cell expansion peaked primarily between days 7 to 14 post infusion. The median peak CAR-T copy number was 62,808.5/µg gDNA (95% CI, 14,943-82,286/µg gDNA) in patients who achieved a CR vs 20,856.65/µg gDNA (95% CI, 3,035-86,743/µg gDNA) in those who did not achieve a CR (P = 0.34).
Reference
Guo J, Zhou X, Luo H, et al. The optimized hinge CD19/20 CAR-T showed durable efficacy in patients with relapsed/refractory B-cell lymphoma: Interim results from a multicenter phase I/II trial. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025. Florence, Italy. Abstract A082.