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
Mené sur 25 patients atteints d'une leucémie lymphoblastique aiguë à cellules B réfractaire ou récidivante (durée médiane de suivi : 12,8 mois), cet essai de phase I évalue la dose maximale tolérée et l'efficacité, du point de vue du taux de réponse globale, de la durée de la réponse, de la survie sans récidive, de la survie sans progression et de la survie globale, de UCART19, une immunothérapie allogénique par lymphocytes CAR-T anti-CD19 provenant de donneurs non malades
Background : The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemiaremains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor(CAR) T-cell product derived from healthy donors and available for immediate clinicaluse, offers a potential therapeutic option for such patients. The CALM trial is afirst-in-human study evaluating the safety and antileukaemic activity of UCART19 inadult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. Methods : This phase 1, open-label study was conducted at eight centres across France, the UK,the USA, and Japan. Adult patients aged 16–70 years with CD19-positive relapsed orrefractory B-cell acute lymphoblastic leukaemia who had morphological relapse or aminimal residual disease level of at least 1 × 10–3 and had exhausted standard treatment options were enrolled in the study, which compriseda dose-escalation phase of up to three UCART19 doses followed by a safety expansionphase. Patients underwent lymphodepletion with fludarabine (30 mg/m2 per day intravenously for 3 days) and cyclophosphamide (500 mg/m2 per day intravenously for 3 days) with or without alemtuzumab (1 mg/kg or 40 mg or60 mg over 5 days) and received UCART19 doses of 6 × 106, 6–8 × 107, or 1·8–2·4 × 108 total CAR T cells intravenously, followed by safety evaluation and disease responseassessments. The primary endpoint was incidence and severity of adverse events. Secondaryendpoints were the overall response rate, duration of response, relapse-free survival,progression-free survival, and overall survival. This trial is registered with ClinicalTrials.gov (NCT02746952) and is complete. Findings : Between Aug 1, 2016, and June 30, 2020, 25 patients were enrolled in the study andtreated with UCART19. Median duration of follow-up was 12·8 months (IQR 2·8–24·8).Median age was 37 years (IQR 28–45). 14 (56%) patients were male and 11 (44%) female.17 (68%) patients were White, two (8%) Black, two (8%) Asian, and four (16%) fromother racial or ethnic groups. Three patients developed dose-limiting toxicities (oneat each dose level); one had grade 4 cytokine release syndrome and two had grade 4prolonged cytopenias. Grade 3 or higher cytokine release syndrome was reported insix (24%) patients and grade 3 or higher neurological toxicity in one (4%) patient.Grade 3 or higher infections occurred in seven (28%) patients, and grade 4 prolongedcytopenia in four (16%) patients. Two (8%) patients developed grade 1 acute cutaneousgraft-versus-host disease. 14 patients died, nine from progressive disease and fivefrom infections or other complications, of which four were considered to be relatedto UCART19 or lymphodepletion, or both. After a median of follow-up of 12·8 months(IQR 2·8–24·8), overall response rate was 48% (95% CI 28–69; 12 of 25 patients), durationof response and median relapse-free survival were 7·4 months (95% CI 1·8 to not calculable),progression-free survival was 2·1 months (95% CI 1·2–2·8), and overall survival was13·4 months (95% CI 4·8–23·0). Interpretation : UCART19 had a manageable safety profile, and showed evidence of antileukaemic activity in heavily pretreated adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. This study shows that allogeneic off-the-shelf CAR T cells can be usedsafely to treat patients with relapsed B-cell acute lymphoblastic leukaemia.