Findings from the phase 1 CALM study evaluating the allogeneic genome-edited anti-CD19 chimeric antigen receptor T-cell product UCART19 show it can be safely used for patients with relapsed or refractory B-cell acute lymphoblastic leukemia.
Heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) who were administered UCART19 had a manageable safety profile and demonstrated evidence of antileukemic activity, according to findings from the phase 1 CALM study (NCT02746952).1
This trial is the first completed study of an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product being evaluated in adult patients with relapsed or refractory B-cell ALL.
Findings from this study seem promising as among a cohort of patients with high tumor burden and rapidly proliferative disease, the objective response rate (ORR) was 48% (95% CI, 28-69).
“It is encouraging that 48% of the entire cohort, and 55% of those who received lymphodepletion with fludarabine, cyclophosphamide, and alemtuzumab, had a complete response or complete response with incomplete hematologic recovery. The response rate was highest at the lowest UCART19 dose level [67% at dose level 1 vs 42% at dose level 2 vs43% at dose level 3]. Notably, the treatment approach was most homogeneous at dose level 1, with all patients treated at the same site, where they received an identical lymphodepletion dosing schedule and UCART19 from the same batch,” wrote study authors in findings published in The Lancet Hematology.
CALM is a phase 1, open-label study which was conducted at 8 centers across the United States, France, the United Kingdom, and Japan. The trial was made up of a dose-escalation phase which administered patients up to 3 doses of UCART19 followed by a safety expansion portion of the study.2
Patients were enrolled in the study if aged 16-70 years with CD19-positive relapsed or refractory B-cell ALL. Those enrolled were required to have had morphological relapse or a minimal residual disease level of at least 1 × 10–3, used all other standard treatment options, have an estimated life expectancy ≥ 12 weeks, and an ECOG performance status of 0-2.
In the trial, those enrolled underwent lymphodepletion with fludarabine at 30 mg/m2 per day intravenously (IV) for 3 days and cyclophosphamide at 500 mg/m2 per day IV for 3 days with or without alemtuzumab (Lemtrada) 1 mg/kg or 40 mg or 60 mg over 5 days. Patients also were given doses of UCART19 at 1 of 3 doses, including 6×106, 6-8×107, or 1.8-2.4×108 total CAR T cells IV. This was then followed by safety evaluation and disease response assessments.
Investigators determined dose-escalation by the frequency and severity of dose-limiting toxicities (DLTs) at each dose level. DLTs were defined as an adverse event (AE) or abnormal laboratory value observed in the first 28 days following administration of UCART19 which was considered to be related to the CAR T-cell product.
The primary end point of the trial was to examine the incidence and severity of AEs and secondary end points included the overall response rate (ORR), duration of response (DOR), relapse-free survival, progression-free survival (PFS), and overall survival (OS).
A total of 25 patients were enrolled between August 1, 2016, and June 30, 2020, all of whom were treated with UCART19. Among those enrolled, the median age was 37 years (interquartile range [IQR], 28-45), 14 patients (56%) were male and 11 (44%) were female. There were 17 (68%) patients who were White, 2 (8%) who were Black, 2 (8%) who were Asian, and 4 (16%) from other racial or ethnic groups.
The median number of previous lines of therapy received by patients was 4 (IQR, 3-5), and included inotuzumab ozogamicin (Besponsa) in 8 (32%) patients and blinatumomab (Blincyto) in 12 patients (48%). Eighteen patients (72%) underwent prior allogeneic hematopoietic stem-cell transplant, the median time between enrolment and UCART19 infusion was 9 days (IQR, 8-13), and the median blast percentage in bone marrow prior to lymphodepletion was 33% (12-69).
In the dose-escalation portion of the trial, 6 patients were treated at dose level 1 of UCART19, 6 at dose level 2, and 7 at dose level 3. The maximum tolerated dose was dose level 3 while the recommended dose was determined to be dose level 2 based on a combination of a similar safety profile across dose levels, UCART19 expansion kinetics, and antileukemic activity. In the expansion phase of the study, another 6 patients were given 6-8×107 cells.
Findings showed that after a median of follow-up of 12.8 months (interquartile range [IQR], 2.8–24.8), ORR was 48% in 12 of the 25 patients (95% CI, 28-69). Both the DOR and the median relapse-free survival were 7.4 months (95% CI, 1.8-not calculable), and the PFS was 2.1 months (95% CI, 1.2-2.8). Additionally, the OS was 13.4 months (95% CI, 4.8-23.0).
At each dose level, 1 patient developed DLTs. One of these patients had grade 4 cytokine release syndrome (CRS) while the other 2 had grade 4 prolonged cytopenias. Another 6 patients (24%) reported having grade 3 or higher CRS, and 1 patient (4%) had grade 3 or higher neurological toxicity.
Regarding safety, there were 7 patients (28%) who had grade 3 or higher infections, and 4 patients (16%) with grade 4 prolonged cytopenia. Another 2 patients (8%) developed grade 1 acute cutaneous graft-versus-host disease.A total of 14 patients in the study died with 9 as a result of progressive disease and 5 from infections or other complications. Among those 5 patients, four were linked with UCART19, lymphodepletion, or both.
Overall, findings from this study demonstrate that the use of allogeneic off-the-shelf CAR T cells can be safe when treating patients with relapsed B-cell ALL.