Parameters of long‐term response with CD28‐based CD19 chimaeric antigen receptor‐modified T cells in children and young adults with B‐acute lymphoblastic leukaemia

Abstract

Summary CD28‐based CD19 chimaeric antigen receptor‐modified (CAR‐)Tcells were recently FDA‐approved for adult acute lymphoblastic leukaemia (ALL). We report long‐term outcome of 37 children and young adults treated with autologous CD19 CAR‐T cells. The complete remission rate was 86%, of which 71% were polymerase chain reaction (PCR) minimal residual disease (MRD)‐negative, 14% were MRD‐negative by flow cytometry, and 14% were PCR MRD‐positive. 26 patients proceeded to subsequent haematopoietic stem cell transplant (HSCT). 11 patients had a CD19‐postive relapse (eight post HSCT and three without) and one had a CD19‐negative relapse. All relapse events occurred within two years from cell therapy. With a median follow‐up of three years, the median event‐free survival (EFS) is 17 months and the median overall survival (OS) is not reached. The three‐year EFS is 41% and OS is 56%. Patients with >5% blasts in the bone marrow prior to lymphodepletion had an inferior EFS. All patients with a PCR MRD‐positive result at day 28 had relapsed after CAR‐T‐cell therapy. A prior HSCT did not significantly affect outcome, but a consolidative transplant after achieving remission improved long‐term results. Overall, prelymphodepletion disease burden and molecular MRD negativity following CAR‐T cells are predictors of long‐term outcome following CD19 CAR‐T‐cell therapy for ALL.

Long-term outcomes following CAR T cell therapy: what we know so far

“…Data from these studies confirm the excellent initial CR rates ranging from 62% to 86%, with the majority of these being deep minimal residual disease (MRD)-negative remissions 18,[42][43][44][45][46][47][48][49][50][51][52][53] . Median event-free survival (EFS) durations varied between studies, which probably reflects the fact that most studies included a substantial and variable fraction of patients (13-88%) who received consolidative allogeneic HSCT while in remission 18,[42][43][44][45][46][47][48][49][50][51][52][53] . This approach obscures the interpretation of the ability of CAR T cells alone to elicit a curative response.…”

“…Data are now available from multiple long-term follow-up studies of the efficacy of CD19-targeted CAR T cell therapy in patients with B-ALL 18,[42][43][44][45][46][47][48][49][50][51][52][53] . A total of 12 studies provide data on the outcomes of patients with a minimum median follow-up duration of 1 year (range 1-4.8 years) 18,[42][43][44][45][46][47][48][49][50][51][52][53] (Table 2).…”

“…Data are now available from multiple long-term follow-up studies of the efficacy of CD19-targeted CAR T cell therapy in patients with B-ALL 18,[42][43][44][45][46][47][48][49][50][51][52][53] . A total of 12 studies provide data on the outcomes of patients with a minimum median follow-up duration of 1 year (range 1-4.8 years) 18,[42][43][44][45][46][47][48][49][50][51][52][53] (Table 2). Data from these studies confirm the excellent initial CR rates ranging from 62% to 86%, with the majority of these being deep minimal residual disease (MRD)-negative remissions 18,[42][43][44][45][46][47][48][49][50][51][52][53] .…”

“…A total of 12 studies provide data on the outcomes of patients with a minimum median follow-up duration of 1 year (range 1-4.8 years) 18,[42][43][44][45][46][47][48][49][50][51][52][53] (Table 2). Data from these studies confirm the excellent initial CR rates ranging from 62% to 86%, with the majority of these being deep minimal residual disease (MRD)-negative remissions 18,[42][43][44][45][46][47][48][49][50][51][52][53] . Median event-free survival (EFS) durations varied between studies, which probably reflects the fact that most studies included a substantial and variable fraction of patients (13-88%) who received consolidative allogeneic HSCT while in remission 18,[42][43][44][45][46][47][48][49][50][51][52][53] .…”

“…Overall, these data suggest that a cure is possible without consolidative allogeneic HSCT in some paediatric patients treated with tisagenlecleucel. Data from four studies have detailed the outcomes of paediatric patients who received other CD19-targeted CAR T cell products, achieved a CR and did not proceed to consolidative allogeneic HSCT 42,47,49,50 . These studies showed a rate of relapse from CR in non-consolidated patients of 68-100% 42,47,49,50 .…”