CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy for Adults with B-Cell Acute Lymphoblastic Leukemia (B-ALL): A Large Real-World Series from Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) (2022)

Background CD19-directed genetically modified T-cell immunotherapy represents a breakthrough treatment for relapsed and refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and has been used significantly over the past four years since it was approved by the EMA. Initially, tisagenlecleucel was approved for the treatment of patients up to 25 years of age with B-ALL that is refractory or in second or later relapse. More recently, commercial and academic CD19 CAR-T cells have been used in adult patients. The European Society for Blood and Marrow Transplantation (EBMT) received a regulatory qualification from the European Medicines Agency for using its patient registry to support post-authorization safety studies. The EBMT CAR-T cell Registry was developed to collect long-term safety and efficacy information on recipients of cellular immunotherapies and is used as a post-marketing study in the real-world setting. Methods Patients aged 18 years or older who received a first infusion of CD19 CAR-T cells for B-ALL between 2018 and May 2021 were included. Clinical data from the EBMT registry were analyzed for baseline information. Efficacy and safety data were presented for patients with a median of 1 year of follow-up. Results Baseline and comprehensive information were available for 118 patients with a median follow-up of 12.4 months (95% CI, 11.6-16.2). The median age was 23.8 years (range, 18.2-67.1). Sixty-for percent were male and 63.9% had a Karnofsky score ≥90. Seventy-one percent received CAR-T cells for Philadelphia chromosome-negative (Ph-) B-ALL and 29% for Ph+ ALL (63 data missing). Most patients (82%) were not in complete remission (CR), 3% were in CR1, 7% were in CR2 and 8% were in ≥CR3. Twenty-seven percent of the patients had not received a previous allogeneic hematopoietic cell transplant (allo-HCT), 58% had received one allo-HCT, and 14% two allo-HCTs. More than 80% of CD19 CAR-T cells were commercial. Lymphodepletion regimen was mostly an association of fludarabine and cyclophosphamide (98%). Almost 88% of the patients developed a cytokine release syndrome (CRS), starting at a median of 3 days post-treatment (range, 0-27) (1/3 data msising). CR was obtained in 91% of patients. Overall survival at 12 months was 88.9% for patients who received CAR-T cells in CR, and 61.9% for non-CR patients. Leukemia-free survival at 12 months was 65.8% for patients in CR, and 38.7% for non-CR patients. Relapse incidence at 12 months was 34.2% in CR patients and 57.2% in non-CR patients. Cumulative incidence of non-relapse mortality at 12 months was 0% in CR patients, and 4% in non-CR patients. Forty-six patients died. Recurrence of the original disease was the main cause of death (79%), while infections represented 4.7% (n=2) of the deaths, and 9.3% (n=4) of deaths were cell therapy related. Conclusions The EBMT registry offers access to real-world data on a continental scale, in this analysis focusing on the treatment of adult patients with B-ALL treated with commercial or academic CD19 CAR-T cells. Such large multicenter and multinational real-world evidence demonstrates the feasibility of CAR-T cell therapy at a larger scale. The results were in line with those from registration trials evaluating approved and commercial products. Interestingly, in this real-life setting, up to 18% of the patients were in CR at time of CAR, paving the way for the use of CAR-T cells earlier in consecutive lines of therapy.