PS943 SAFETY AND EFFICACY OF TISAGENLECLEUCEL (CTL019) IN B ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN AND YOUNG ADULTS: ROBERT DEBRÉ AND SAINT LOUIS HOSPITALS EXPERIENCE
Authors: Dourthe M.E. , Cabannes‐Hamy A. , Yakouben K. , Fabian F. , Chaillou D. , Chevillon F. , Dhédin N. , Lesprit E. , Naudin J. , Roupret‐Serzec J. , Parquet N. , Brignier A. , Guérin V. , Lainey E. , Caye‐Eudes A. , Cavé H. , Clappier E. , Mathis S. , Caillat‐Zucman S. , Azoulay E. , Dalle J.‐H. , Madelaine I. , Larghero J. , Boissel N. , Baruchel A. 
Published: June 2019

Background:Relapsed/refractory B acute lymphoblastic leukemia (B‐ALL) treatment remains a major challenge. Tisagenlecleucel (CTL019) is a chimeric antigen receptor T cell‐ therapy that reprograms autologous T cells to target CD19+ leukemia cells. This “living drug”, manufactured for each patient, has obtained a marketing authorization in 2018 in the EU for patients under 26 years old in refractory B ALL, in second relapse or more or in first relapse after allogeneic hematopoietic stem cell transplantation (HSCT).Aims:This study reports the feasibility, safety and efficacy of CTL019 in patients treated in 2 centers from the Assistance–Publique‐Hôpitaux de Paris.Methods:Eligible patients were patients included in sponsored‐clinical trials (n = 16) or treated within the French compassionate program (n = 18) with an apheresis performed between mars 1, 2016 and February 15, 2019.Results:As of February 15, 2019, 34 patients referred from 20 french centers were screened and benefited from an apheresis. Twenty‐nine patients were infused with CTL019 at a median age of 13.2 y (range, 4.8–29.2) after fludarabine‐cyclophosphamide based lymphodepletion. Out of 34 patients, 23 (67%) had a prior history of allogeneic SCT. Median number of relapses before apheresis was 2 (range, 1–5). Two patients presented with a primary refractory ALL. Among the 5 patients who did not receive CAR T cells infusion 3 died of progressive disease, one died of septic choc and one was excluded because of age. Out of 29 patients 2 were non‐evaluable for efficacy: one for fatal cytokine release syndrome (CRS) 6 days after CAR T cells infusion, one for insufficient follow up. Among the 27 patients evaluable after one month all were in CR/Cri, 25 (92.6%) being MRD negative. Median relapse free survival (RFS) and overall survival (OS) were not reached with a median follow up of 7.2 months (range, 0.2–30.6). The 18 month‐OS probability is 82.6% (95%CI, 53.2%>94.4%). Eight patients relapsed: 3 CD19+, 4 CD19‐, 1 of undetermined status. Four deaths were reported: 3 due to progressive disease and 1 being associated to a CRS (grade 5). Sixteen patients experienced a CRS (≥ grade 3: n = 12) with a median time of 4 days after CTL019 infusion (range, 0–8): 1/6 patients <10 years and 15/23 patients ≥ 10 years. ICU level care was required for 14 patients (48%). Nine patients received tocilizumab, 4 patients siltuximab and 7 patients corticosteroids. Currently 6 neurological events have been reported, all completely reversible except one (fatality in combination with grade 5 CRS). Two patients received a second CAR T cells infusion at 5 and 7 months of the first one due to B cell recovery at 3 and 4 months after first infusion. No expansion neither B‐cell aplasia was observed in these 2 cases. One patient relapsed 4 months after the second infusion. Of note 2 patients, including the only patient who died of adverse event, were older than 26 years of age, and would note fit the current FDA/EMA indications of tisagenlecleucel. No patient underwent allogeneic HSCT while in remission after CAR T cells infusion.Summary/Conclusion:CTL019 confirms its efficacy in a cohort of patients heavily pretreated for refractory or relapsed B‐ALL without additional therapy after remission. The toxicity profile underlines the need of a strong collaboration between intensivists, neurologists and hematologists to successfully manage these patients.