Among patients with large B-cell lymphoma (LBCL) progressing after CD19-directed CAR T-cell therapy, treatment with CD22-Directed CAR T-cells provided durable remissions and long-term survival after 3 years, according to 3006 follow-up data from a phase 1 trial presented at the 66^th ASH Annual Meeting.

The single-center, dose-escalation phase 1 trial enrolled adult patients (aged ≥18 years) who had relapsed after CD19-directed CAR-T therapy or who had CD19-negative LBCL. CD22-directed T-cells were administered intravenously at 2 dose levels: 1 and 3 million CAR22-positive T cells/kg).

The primary end points of the trial were the feasibility of manufacturing, safety assessed by the incidence and severity of adverse events and dose-limiting toxicities, and the determination of the maximum tolerated dose (recommended phase 2 dose).

At the data cutoff on July 15th, 2024, 38 patients were enrolled, with a median follow-up of 36.7 months (range, 20.2 to 56.8 months). 37 patients had progressed after CD19 CAR-T therapy, and the median prior lines of therapy was 4 (range, 3 to 8). 

The overall response rate (ORR) was 68% and the complete response rate (CR) was 53%. The recommended phase 2 dose was established at 1 million CAR22-positive T cells/kg.

Among the cohort of 29 patients treated at the recommended phase 2 dose, the median duration of response (DOR) was 23.2 months (95% CI, 9.2 to not estimable [NE]) and not reached for those who achieved a best response of CR. At data cutoff, responses were ongoing in 47% of patients. 

Median progression-free survival (PFS) was 3 (95% CI, 1.6 to NE) months and overall survival (OS) was 25.7 months (95% CI, 9.18 to NE). The estimated 3-year PFS and OS were 30% (95% CI, 17% to 53%) and 47% (95% CI, 32% to 70%), respectively. No grade 3 cytokine release syndrome (CRS) or ICANS occurred at the recommended phase 2 dose.

Among all 38 patients enrolled, there were 27 PFS events reported, of which 22 were due to lymphoma progression: 20 within 12 months and 2 between 1 to 2 years after treatment with CD22 CAR T-cells.

Second primary malignancies were diagnosed at a median of 30 months after infusion (range, 8 to 39 months) in 4 patients (11%), all were treatment-related myeloid neoplasms. These 4 patients received a median of 4 prior lines of therapy.

A total of 6 non-relapse mortality events (16%) occurred, 3 within 1-year post-CAR22, 1 between 1 to 2 years, and 2 after 2 years (latest occurring at 56 months post-CAR22). Of the 6 non-relapse mortality events, 1 was secondary to infection, 2 had treatment unrelated cardiac events, 1 died from unknown causes after being lost to follow-up, and 2 patients died due to progression of treatment-related myeloid neoplasms. The 3-year cumulative incidence of death after disease progression was 45% and the 3-year risk of non-relapse mortality was 14%.

In responding patients, grade ≥2 cytopenias (neutropenia, thrombocytopenia) 1- and 2-year milestones, were reported in 2 of 14 patients and 0 of 10 patients, respectively. Infections requiring hospitalization 6 months after infusion or later, were present in 4 of 18 patients. IVIG treatment 3 months after infusion or later was required in 10 of 18 patients.

In conclusion, treatment with CD22-directed CAR T-cells provides durable remissions and long-term survival in in patients with LBCL progressing after CD19-directed CAR-T therapy. Late progression or lymphoma-specific death was uncommon, suggesting a curative potential for these patients.

Source:

Kramer AM, Baird JH, Srinagesh H, et al. CD22-Directed CAR T-Cell Therapy for Large B-Cell Lymphomas Progressing after CD19-Directed CAR T-Cell Therapy: Continued Durable Remissions at 3-Year Follow-up. Presented at the 66th ASH Annual Meeting & Exposition; December 7-10, 2024; San Diego, California. Abstract 69