CAR-T Meeting 2024 | Improving survival outcomes and optimizing CAR-T therapy in patients with DLBCL

So in my talk today, I’ll be talking about four main areas where we’re trying to improve outcome in terms of survival from CAR T-cell therapy.

So initially that’s identifying patients at the outset who may become eligible for CAR T-cell therapy. So that’s looking at high-risk factors at first-line diffuse large B-cell lymphoma management. So that’s patients for example, that have a high tumor metabolic volume or a poor performance status. It’s been documented and shown in trials that those patients are at higher risk of relapsing. Also, we know from the original studies from David Kurtz et al. that looked at the levels of ctDNA, we know those patients that have higher level of ctDNA at baseline are more likely to relapse. So, they’re both prognostic factors that we can look at from the outset. Also, during the management of first-line DLBCL, we know that interim PET scanning is predictive of relapse, if positive at interim-PET2 or interim-PET4. So they are all factors that we can look at during the management of first-line DLBCL patients that might predict relapse in the future, and therefore consideration for second-line CAR T-cell therapy.

The next point from the talk is really looking at those patients with refractory or early relapsed DLBCL, so within 12 months of initial therapy, about quick referral to CAR T-cell therapies and consideration for CAR-T. And the most important thing really is considering all patients for CAR T-cell therapy despite their age or their co-morbidities. We know from data that patients up to 89 can benefit from CAR T-cell therapy with no difference in outcome compared with those patients 65 and above, and also that patients with comorbidities have very good response rates, but those with moderate or severe hepatic, renal or cardiac impairment do have a poorer overall survival. This really indicates that rehabilitating patients prior to CAR T-cell therapy, so improving their co-morbidities and maximizing their organ function improves their outcome and they can still then be eligible for CAR T-cell therapy.

Thirdly, looking at patients, how we can optimize them for CAR T-cell therapy in terms of debulking their disease. So we know that patients with bulky disease do poorer with CAR T-cell therapy in terms of their outcome and in terms of developing adverse events. So lots of strategies now look at bridging using radiotherapy or chemotherapy and steroids to reduce tumor bulk prior to CAR T-cell therapy.

And finally just looking how we can maximize the outcomes in terms of reducing adverse events, and this is mainly based on predicting patients who are going to develop bad adverse events. That tends to be patients that have a poor performance status, so again prehabilitation is important, but also those patients that have refractory disease or a high LDH. So it’s really talking about how we can earlier prevent those adverse events or manage them better. I think what is important is having individualized protocols for patients who have CAR T-cell therapy, so those patients at higher risk of CRS and neurotoxicity can be preemptively treated with tocilizumab and steroids, for example.

So it’s really just looking broadly at how we can improve survival outcomes by looking at each component of the CAR T-cell pathway. And I think one of the really important things is the quick referral. Once a patient is identified as eligible for CAR-T, shortening the time to which they get CAR T-cell infusions. So there’s American data looking at the brain to vein time, so this is really when you think about CAR T-cell therapy for a patient and then the time to which they actually get infused. Looking at that data, patients that were treated promptly, so within 17 days, had a much better outcome than those patients that would treated over a longer pathway, so over 37 days. So there’s really maximizing the treatment pathway in terms of referral from centers to the CAR T-cell center; maximizing the communication between different teams so that patients don’t progress prior to CAR T-cell therapy and actually receive their infusion.