Escalating Lymphodepletion ± Rituximab Before CD19-Directed CAR T-Cell Therapy is Safe in R/R DLBCL

Treatment with escalating doses of lymphodepleting chemotherapy comprised of fludarabine and cyclophosphamide with or without rituximab (Rituxan) prior to CD19-directed CAR T-cell therapy was safe in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to data from a phase 1 trial (NCT05052528) presented at the 2024 ASH Annual Meeting.

Additionally, using CAR T cells manufactured at a Good Manufacturing Practices (GMP) facility, a fresh, nonfrozen product was able to be administered with a vein-to-vein time of 8 days; cryopreservation was allowed when clinically indicated.

Findings showed that evaluable patients who underwent a PET/CT scan at day 90 or beyond following the infusion of CAR T-cell therapy (n = 15) achieved an overall response rate (ORR) of 86.7%, including a complete response (CR) rate of 67.7%. The 90-day progression-free survival (PFS) and overall survival (OS) rates were 86.7% and 93.3%, respectively.

Grade 1/2 cytokine release syndrome (CRS) occurred in 40% of patients, and 1 patient (6.7%) treated with a lymphodepletion regimen of 25 mg/m2 of fludarabine on days –5 to –3 plus 60 mg/kg of cyclophosphamide on day –5 experienced grade 2 immune effector cell–associated neurotoxicity syndrome (ICANS). No instances of grade 3 or higher CRS or ICANS were reported. Four patients died during the study due to disease progression (n = 3) and infection (n = 1).

“Our interim results demonstrate feasibility of point-of-care manufacturing of CD19[-directed] CAR T cells with 8-day vein-to-vein time and fresh CAR T-cell infusion,” lead study author Naseem S. Esteghamat, MD, MS, and colleagues wrote in a poster presentation of the data. “The safety of locally manufactured CD19[-directed] CAR T cells with escalating doses of cyclophosphamide and fludarabine with or without rituximab is demonstrated.” Esteghamat is an assistant professor in the Division of Malignant Hematology/Cellular Therapy and Transplantation at the University of California (UC), Davis Comprehensive Cancer in Sacramento.

Study Background and Patient Enrollment

Esteghamat and colleagues explained that although the emergence of CD19-directed CAR T-cell therapies has altered the treatment paradigm for patients with relapsed/refractory DLBCL, durable remissions will occur in only approximately 40% of patients. Additionally, fludarabine plus cyclophosphamide has been a standard lymphodepletion regimen, but prospective data regarding varying doses of these agents remain limited.

The phase 1, single-center study being conducted at UC Davis is enrolling patients with relapsed/refractory DLBCL who received at least 2 prior lines of therapy.

Six different lymphodepletion regimens are being evaluated. In all 6 arms, fludarabine is administered at 25 mg/m2 on days –5 to –3. Cyclophosphamide doses include 500 mg/m2 on days –5 to –3 (dose levels 1 and 2), 60 mg/kg on day –5 (dose levels 3 and 4), and 60 mg/kg on days –5 and –4 (dose levels 5 and 6). Patients treated at dose levels 2, 4, and 6 are also receiving rituximab at 375 mg/m2 on day –5.

All patients are receiving CD19-directed CAR T cells at a target dose of 1 x 106 cells/kg. The CAR T-cell product is manufactured at UC Davis’s GMP facility, and the agent contains a lentiviral vector, a 4-1BB costimulatory domain, and a CD3 zeta intracellular domain.

Safety of the CAR T-cell therapy with escalating doses of lymphodepletion with or without rituximab, along with the feasibility of locally manufacturing the CAR T cells, are serving as the trial’s primary end points. Secondary end points comprise ORR, CR rate, partial response rate, PFS, and OS.

At the time of this analysis, the study had enrolled 20 patients, of whom 15 were evaluable. The evaluable population had a median age of 63 years (range, 28-77), and the majority were female (n = 11). Notable morphology and molecular demographics included double-expressor lymphoma (n = 4), transformed follicular lymphoma (n = 3), and double-hit lymphoma (n = 2). The cell of origin was non–germinal center B-cell (GCB) lymphoma (n = 8), GCB lymphoma (n = 5), and unknown (n = 2). Patients had either primary refractory disease (n = 9), disease that relapsed more than 12 months after first-line treatment (n = 5), or disease that relapsed within 12 months of first-line therapy (n = 1). Disease stages included II (n = 3), III (n = 2), and IV (n = 10). Patients received a median of 3 prior lines of therapy (range, 2-8). Five patients underwent a prior autologous stem cell transplant, and 1 patient received a prior allogeneic stem cell transplant.

Enrollment is ongoing at dose level 5.

“Analysis of fresh vs frozen CAR T-cell data, [as well as] exploratory objectives including CAR T-cell persistence and T-cell subpopulations, is ongoing,” study authors concluded.

Reference

Esteghamat NS, Tuscano JM, Jonas BA, et al. A phase I study of CD19 CAR T-cells with escalating doses of lymphodepletion with or without rituximab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2024;144(suppl 1):2085. doi:10.1182/blood-2024-206680