Allogeneic off-the-shelf chimeric antigen receptor (CAR) T-cells “showed evidence of antileukemic activity” in heavily pretreated patients with relapsed or refractory B-cell acute lymphoblastic leukemia, according to results from a phase I study.
Reuben Benjamin, MBBS, FRCPath, PhD, of King’s College London, and colleagues conducted the first-in-human CALM study, which evaluated UCART19, an allogeneic genome-edited CD19-directed CAR T-cell product derived from healthy donors. UCART19 “offers a potential therapeutic option” for immediate use in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, who typically have poor prognoses, according to the study’s investigators.
Dr. Benjamin and colleagues conducted the open-label study at eight centers in France, the United Kingdom, the United States, and Japan. The study comprised 25 patients aged 16 to 70 years who had CD19-positive relapsed or refractory B-cell lymphoblastic leukemia and had “exhausted standard treatment options,” according to the researchers. The median patient age was 37 years, 56% of patients were male, 68% were White, 8% were Black, 8% were Asian, and 16% were from other racial or ethnic groups. All patients had morphological relapse or a minimal residual disease level of at least 1 × 10-3.
Patients underwent lymphodepletion with fludarabine 30 mg/m2 per day intravenously for three days and cyclophosphamide 500 mg/m2 per day intravenously for three days, with or without alemtuzumab 1 mg/kg, 40 mg/kg, or 60 mg/kg for five days. The study involved a dose-escalation phase of up to three UCART19 doses, followed by a safety expansion phase. The patients received UCART19 doses of 6 × 106, 6-8 × 107, or 1.8-2.4 × 108 total CAR T-cells intravenously.
The study’s primary endpoint was the incidence and severity of adverse events. Secondary endpoints included the overall response rate (ORR), duration of response, relapse-free survival (RFS), progression-free (PFS) survival, and overall survival (OS).
The ORR was 48% (95% CI, 28-69) at a median follow-up of 12.8 months. The median OS was 13.4 months (95% CI, 4.8-23), while the median PFS was 2.1 months (95% CI, 1.2-2.8). The duration of response and median RFS were 7.4 months (95% CI, 1.8 to not calculable).
Grade 3 or higher cytokine release syndrome occurred in six patients, while grade 3 or higher neurological toxicity occurred in one patient. Grade 3 or higher infections occurred in seven patients, and grade 4 prolonged cytopenia occurred in two patients. Grade 1 acute cutaneous graft-versus-host disease occurred in two patients.
Dose-limiting toxicities, including grade 4 cytokine release syndrome and grade 4 prolonged cytopenia, occurred in three patients, one at each dose level. Death due to progressive disease occurred in nine patients, while five patients died from infections or other complications, with four of those deaths deemed related to UCART19, lymphodepletion, or both.
“UCART19 had a manageable safety profile and showed evidence of antileukemic activity in heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia,” Dr. Benjamin and colleagues concluded. “This study shows that allogeneic off-the-shelf CAR T-cells can be used safely to treat patients with relapsed B-cell acute lymphoblastic leukemia.”
Benjamin R, Jain N, Maus MV, et al. UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial. Lancet Haematol. 2022. doi:10.1016/S2352-3026(22)00245-9