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CAR-T Meeting 2022 | Approved CAR-Ts in R/R ALL: tisa-cel and brexu-cel

Mohamad Mohty, MD, PhD, Saint-Antoine Hospital, Paris, France, comments on the use of the chimeric antigen receptor T-cell (CAR-T) therapies tisagenlecleucel (tisa-cel) and brexucabtagene autoleucel (brexu-cel) in relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Tisa-cel was originally approved in 2017 for children or young adults with R/R B-cell ALL (B-ALL) and demonstrated high rates of complete remission (CR) and measurable residual disease (MRD) negativity. More recently, the Phase I/II ZUMA-3 study evaluating brexu-cel in adults with R/R B-ALL (NCT02614066) reported impressive rates of CR with incomplete hematologic recovery (CRi). In addition, whilst the rates of cytokine release syndrome (CRS) and neurotoxicity were relatively high, only about 25% of patients experienced grade 3 or higher treatment-related side effects. The study also showed an association between the median time to peak CAR-T expansion, response to treatment and side effects. Overall, despite a relatively short follow-up, the results from this trial clearly demonstrate the efficacy and manageable safety of CAR-Ts in adult R/R ALL. According to Prof. Mohty, the next step is to evaluate these therapies in earlier lines of treatment and investigate whether they can be used with or instead of allogeneic stem cell transplantation (alloSCT). This interview took place at the EBMT-EHA 4th European CAR T-cell Meeting which was held virtually in 2022.

Transcript (edited for clarity)

The role of CAR-Ts in relapsed/refractory acute lymphoblastic leukemia is clearly a hot topic. First of all, I think we are all aware of the fact that relapsed/refractory ALL has really a dismal outcome, and we need innovation there. The good news we had now a few years ago, the approval of the first CAR-T product, namely tisa-cel in young adults and children, and this treatment allowed for a very high response rate, more than 80%, 60% complete remission in the initial studies...

The role of CAR-Ts in relapsed/refractory acute lymphoblastic leukemia is clearly a hot topic. First of all, I think we are all aware of the fact that relapsed/refractory ALL has really a dismal outcome, and we need innovation there. The good news we had now a few years ago, the approval of the first CAR-T product, namely tisa-cel in young adults and children, and this treatment allowed for a very high response rate, more than 80%, 60% complete remission in the initial studies. And when we look into the available results from the major key studies, one can clearly see some homogeneous, complete remission rates going up to more than 90%, including MRD negativity.

The most recent data in this field is about the advent and introduction of CAR-Ts in adult ALL. And this is about the KTE-X19 construct that was studied and tested in the so-called ZUMA-3 study. And in summary, this study enrolled 71 patients, 55 patients were actually treated. The median age was around 40, between 28 and 52 for the treated patients. 27% were Philadelphia chromosome-positive patients and interestingly 11% had an extramedullary disease.

The overall complete remission or complete remission with incomplete hematological recovery was 71%, quite impressive. And at time of last follow-up actually, 12 out of the 39 patients who were in CR or CRi were still in ongoing remission, nine received subsequent stem cell transplantations, and five other anti-cancer therapies. And when you look at the results of the safety and toxicity, actually they’re rather good because when it comes to the cytokine release syndrome, the incidence is 89%, but only 24% above grade 3, neurological events, 60% overall, but only 25% over grade 3. Infections rate over grade 3 was 25%. In this ZUMA-3 study, actually the median time to the peak CAR-T cell expansion in the blood was around 15 days. And actually there was a correlation between this expansion, the response, the CRS, but also neurological events. And now despite the relatively short follow-up, I think this study has paved the way to the use of CAR-Ts in adult ALL because they can induce durable remission with a manageable safety profile in a heavily pre-treated adult population with usually a bad prognosis with the other classical or best available therapies.

So clearly the field of the ALL is moving towards more and more patients receiving CAR-Ts and of course the next question is about how to move these cells in the lines of treatment towards earlier lines of treatment and maybe at some point figure out whether they can challenge the use of allogeneic stem cell transplantation, or be used as a bridge for allo. So lots of exciting questions that we need to consider in the future.

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