Safety of CAR-T Therapy, Tisa-cel, for DLBCL | Christian Chabannon, MD, PhD | #ASH24

Good morning. Thank you for having me. My name is Christian Chabannon. I'm a French hematologist working at the Institute Paoli-Calmettes Comprehensive Cancer Center in Marseilles in the southeastern part of France. And yesterday, I had the opportunity to speak on behalf of the European Society for Blood and Marrow Transplantation. And my topic was to  present the preliminary results of a post-authorization safety survey that was conducted by EBMT, along with Novartis, to look at the safety and efficacy profiles of tisagenlecleucel, or tisa-cel.

This is an autologous CAR T-cells targeting CD19, first in class, approved in Europe in the summer of 2018. And we've collected data on a series of 610 patients treated with tisa-cel for relapsed refractory diffuse large B-cell lymphoma. So I described all the needed organization to collect data across several hundred transplant and cellular therapy programs that operate across many European countries and member states how we comply with the European Global Data Protection Regulation to enable the registry to transfer pseudonymous data to the registry and to use it for secondary use with partners such as pharma companies.

Getting to the core of my presentation, this is a large series that largely confirms the efficacy and safety profile of tisa-cel in real world condition, which are significantly different from the patient population that was included in the original registration trial. So this is quite reassuring that even in very  heterogeneous conditions, in terms of a patient care and conditions to deliver the treatment, we still have the very same efficacy as was seen in the registration trial and the manageable toxicity profile. So we do have three autologous CAR T-cells targeting CD19 that have now been approved in Europe. Tisa-cel was as mentioned, along with axi-cel, was the first one to get approval. It was approved in third line and beyond, and later on, there was a three publications describing the results of randomized trials in second line. And unfortunately for tisa-cel, the results were not positive in the billing that trial. So the difference, the main difference at the moment, between tisa-cel and axi-cel or liso-cel is that tisa-cel cannot be used in second line for diffuse large B-cell lymphoma. In third line, there are some data coming from retrospective studies, in particular from the French de Cartier registries, suggesting that axi-cel may be somewhat more efficacious, however, at the expense of increased toxicities.

So we don't have direct comparisons between CAR-T cells, which prevent any robust conclusion on one being better than the other. But it's a physician's choice, and many physicians would pick a tisa-cel in third line, especially for frail or older patients, because the toxicity profile may be a bit more favorable than with axi-cel. The common side effects are quite similar, to side effects seen  with all medicinal products in this class. So this includes the well-known cytokine release syndrome, which is an inflammatory response when the CAR-T cells destroy tumor cells, the neurotoxicity, ICANS, where the physiopathology underlying ICANS is less well understood than for CRS chronic myelotoxicity in a significant fraction of patients and then rarer side effects that can occur in the middle term. One peculiar concern is the issue of secondary malignancies, because last year in the US, there were reports of secondary malignancies, occurring after CAR T-cell therapies. And the special concern is the discovery in a small number of patients of T-cell malignancies, raising the question of whether the CAR-T cells themselves may turn malignant 

To get to the point,I think there is little evidence that that can be the case. Most secondary malignancies that happen after CAR T-cell therapies may also be the consequences of the prior therapies. Chemo agents, combinations that have been delivered to the patients before they receive CAR-T cells. So there was a warning both by the FDA and EMA that, you know, we should be cautious. We should keep looking at those patients in the middle to long term. But the overall risk benefit ratio was not modified by this. EBMT has not received notifications of T-cell lymphoma.

There was a recent case published by European groups that we are trying to collect more information on. And, again, yeah, this is something of concern, but that shouldn't prevent using CAR-T cells for patients in need of it. One of the questions, that very important question is access to CAR T-cells treatment. There are a number of contributors that can delay access to CAR T-cells treatment. And this includes some factors that are related to hospital organization, such as how do hospitals that do not have access to CAR-T cells refer their patients to those tertiary care hospitals that do provide access to CAR-T cells? We need to have a quick, timely referral. There are some technical issues, like how much time does the manufacturer need to manufacture the CAR-T cells, release it, ship it back to the hospital. There are now new techniques in cell manufacturing that may reduce what we call the vein-to-vein time. And, of course, the elephant in the room are all the costs, direct and indirect cost associated with CAR T-cell therapies and the burdens, the financial burdens that is on different countries having access to CAR-T cells in low-income countries, for example, is an issue. If we look at Europe, CAR T-cell treatment have been adopted quite rapidly. We have now more than 10,000 patients in the registry. But if you look at the different countries, it's not absolutely equal. And in some countries, access is easier than in others.