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
Authors: Kramer Anne Marijn , Baird John H. , Srinagesh Hrishikesh , Egeler Emily , Levine Kendall , Brown Annie K. , Mavroukakis Sharon , Cunanan Kristen , Su Yi-Jiun , Agarwal Neha , Hamilton Mark P. , Bharadwaj Sushma , Arai Sally , Johnston Laura , Lowsky Robert , Meyer Everett H. , Negrin Robert S. , Rezvani Andrew R. , Shizuru Judith , Mikkilineni Lekha , Hosoya Hitomi , Shiraz Parveen , Sidana Surbhi , Weng Wen-Kai , Kennedy Vanessa E. , Smith Melody , Dahiya Saurabh , Davis Kara L. , Ramakrishna Sneha , Schultz Liora Michal , Tunuguntla Ramya , Feldman Steven A. , Muffly Lori , Mackall Crystal L. , Miklos David B. , Frank Matthew J. 
Published: December 2024

Introduction
In a Phase 1 academic clinical trial (NCT04088890), 38 participants with LBCL, who relapsed after CAR19, were treated with CD22-directed CAR T-cells (CAR22, firicabtagene autoleucel). Here, we report updated outcomes after a median follow-up of ≥3 years. We also report long-term complications including causes of non-relapse mortality (NRM) and rates of prolonged cytopenia and infections.
Methods
In this single-center, dose-escalation Phase 1 trial, we administered CAR22 intravenously at two dose levels (1 and 3 million CAR22-positive T cells/kg) to adult patients (aged ≥18 years) who had relapsed after CAR19 therapy or had CD19-negative large B-cell lymphoma. The primary endpoints 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 (i.e., the recommended Phase 2 dose, RP2D). This study is registered with ClinicalTrials.gov (NCT04088890) and is active but closed for enrollment.
Results
At the data cutoff on July 15th, 2024, 38 patients had been enrolled, with a median follow-up of 36.7 months (range 20.2-56.8 months). 37 patients had progressed after CAR19 and the median prior lines of therapy was 4 (range 3-8). The overall response rate (ORR) and complete response rate (CR) were 68% and 53%, respectively (Frank MJ, et al., Lancet 2024). The recommended Phase 2 dose (R2PD) was established at 1 million CAR22-positive T cells/kg. For this cohort of 29 patients treated at the RP2D, the median DOR was 23.2 months (95% CI, 9.2- not estimable) and not reached for those who achieved a best response of CR. At data cutoff, responses were ongoing in 47%. Median progression-free survival (PFS) and overall survival (OS) were 3.0 (95% CI, 1.6-NE) and 25.7 months (95% CI, 9.18 - not estimable), respectively. The estimated 3-year PFS was 30% (95% CI, 17%-53%) and 3-year OS was 47% (95% CI, 32%-70%). At the RP2D, no grade 3 CRS or ICANS occurred.
When studying all 38 enrolled patients, twenty-seven PFS events occurred, of which 22 were due to lymphoma progression- 20 within 12 months, and 2 between 1-2 years post-CAR22. Second primary malignancies were diagnosed at a median of 30 months after infusion (range 8-39 months) in 4 patients (11%), all were treatment related myeloid neoplasms (tMDS/AML). These 4 patients received a median of 4 prior lines of therapy. A total of 6 NRM events (16%) occurred, 3 with 1-year post-CAR22, 1 between 1-2 years, and 2 after 2 years (latest occurring at 56 mo post-CAR22). Of the 6 NRM 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 tMDS/AML. The 3-year cumulative incidence of death after disease progression was 45% and the 3-year risk of non-relapse mortality 14%.
In responding patients, cytopenias (neutropenia, thrombocytopenia) ≥ grade 2, at 1- and 2-year milestones, were present in 2 of 14 and 0 of 10, respectively. Infections requiring hospitalization 6 months after infusion or later, were present in 4/18 patients. IVIG treatment 3 months after infusion or later was required in 10/18 patients.
Conclusions
CAR22 provides durable remissions and long-term survival in CAR19-progressing LBCL patients. Late progression or lymphoma-specific death was uncommon, suggesting a curative potential for these patients. The long-term safety profile is manageable, though it reflects the heavily pre-treated cohort, particularly regarding the risk of tMDS/AML. This risk warrants lifelong follow-up of these patients and underscores the need to study this therapy in earlier lines of treatment, given its favorable safety and response profile.