作者
Reuben Benjamin,Nitin Jain,Marcela V. Maus,Nicolas Boissel,Charlotte Graham,Agnieszka Jóźwik,Deborah Yallop,Marina Konopleva,Matthew J. Frigault,Takanori Teshima,Koji Kato,Floriane Boucaud,Svetlana Balandraud,Athos Gianella-Borradori,Florence Binlich,Ibtissam Marchiq,Sandra Dupouy,Maria Almena-Carrasco,Matthieu Pannaux,Sylvain Fouliard,Éolia Brissot,Mohamad Mohty,Reuben Benjamin,Charlotte Graham,Agnieszka Jóźwik,Deborah Yallop,Laarni Bonganay,Lorraine Catt,Jackie Chappell,Gary Cheung,Vicky Chu,Kirsty Cuthill,S Devereux,Alan Dunlop,Rose Ellard,Farzin Farzeneh,Najeem Folarin,Elka Giemza,Shireen Kassam,Majid Kazmi,Andrea Kühnl,Jen Lewis,M.Yu. Liskova,Alice Mason,Victoria Metaxa,Ghulam J. Mufti,Helena Munro,Antonio Pagliuca,Piers Patten,Victoria Potter,Carmel Rice,Adeel Saleem,Robin Sanderson,Orla Stewart,Elias Jabbour,Nitin Jain,Emily Jones,Hagop Kantarjian,Partow Kebriaei,Marina Konopleva,Kara McGee,William G. Wierda,Jami Brown,Kevin Casey,Matthew J. Frigault,Hanno Hock,Richard Mathews,Marcela V. Maus,Meaghan A McKeown,Thomas R. Spitzer,Vesselina Toncheva,Élie Azoulay,Nicolas Boissel,Sophie Caillat‐Zucman,Karine Celli-Lebras,Emmanuelle Clappier,Raphaël Itzykson,Jérôme Larghero,Etienne Lengliné,Isabelle Madelaine,Martine Meunier,Florence Rabian,Emmanuel Raffoux,Marie-Thérèse Tremorin,Agnès Bonnin,Éolia Brissot,Anne Daguenel-Nguyen,Rémy Duléry,Tounes Ledraa,Florent Malard,Clémence Mediavilla,Mohamad Mohty,Anne Vekhoff,Takanori Teshima,Koji Kato
摘要
The prognosis for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia remains poor. UCART19, an allogeneic genome-edited anti-CD19 chimeric antigen receptor (CAR) T-cell product derived from healthy donors and available for immediate clinical use, offers a potential therapeutic option for such patients. The CALM trial is a first-in-human study evaluating the safety and antileukaemic activity of UCART19 in adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia.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 or refractory B-cell acute lymphoblastic leukaemia who had morphological relapse or a minimal residual disease level of at least 1 × 10-3 and had exhausted standard treatment options were enrolled in the study, which comprised a dose-escalation phase of up to three UCART19 doses followed by a safety expansion phase. 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 or 60 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 response assessments. The primary endpoint was incidence and severity of adverse events. Secondary endpoints 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.Between Aug 1, 2016, and June 30, 2020, 25 patients were enrolled in the study and treated 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%) from other racial or ethnic groups. Three patients developed dose-limiting toxicities (one at each dose level); one had grade 4 cytokine release syndrome and two had grade 4 prolonged cytopenias. Grade 3 or higher cytokine release syndrome was reported in six (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 prolonged cytopenia in four (16%) patients. Two (8%) patients developed grade 1 acute cutaneous graft-versus-host disease. 14 patients died, nine from progressive disease and five from infections or other complications, of which four were considered to be related to 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), duration of 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 was 13·4 months (95% CI 4·8-23·0).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 used safely to treat patients with relapsed B-cell acute lymphoblastic leukaemia.Servier.