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).
This study reports the feasibility, safety and efficacy of CTL019 in patients treated in 2 centers from the Assistance–Publique-Hôpitaux de Paris.
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.
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.
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.