ASH 2023 | Brexu-cel in adults with R/R B-ALL: a real-world outcomes collaboration

The quick background is that adults with relapsed refractory B-cell ALL still experience poor outcomes despite a lot of progress in recent years. I think newer agents like blinatumomab or inotuzumab have proven revolutionary with regard to the development of new immunotherapies, but still, the duration of remission that we achieve with those agents is probably not as long as we had hoped. 

Now, brexu-cel came along in late 2021, as the first FDA-approved CAR T-cell product targeting CD19 approved for adults with relapsed or refractory B-cell acute lymphoblastic leukemia. This was on the basis of a study called ZUMA-3, which was published in The Lancet by Bijal Shah and colleagues. That study infused 55 patients. They saw a response rate of around 70%, and on the basis of those results, the drug was approved for use by the US FDA. Shortly after the drug hit the market, there began watercooler conversations, essentially, from docs in the field about how this drug was actually performing when deployed on the ground. And so we, myself and Lori Muffly from Stanford, decided to form a real-world outcomes collaborative to to study the performance of brexu-cel when used on-label. And so we began this effort about a year and a half ago, and we started asking our friends, first of all, and then the referral pattern grew and grew to, you know, form data-sharing agreements with our institutions and to pool our data together, in a HIPAA compliant way, to see if we can understand the performance of this drug when deployed in the real world. 

And so we showed results from the first 76 patients earlier this year at ASCO. We didn’t have quite as many patients as we wanted, we didn’t have long enough follow-up, but we’ve thankfully been able to let the effort mature a bit, and on Monday at ASH, I’ll be presenting sort of the top-line results from this collaborative that includes data from 189 patients, with a median follow up of 11.4 months for survivors.

The patient characteristics first and foremost, these were heavily pretreated patients, individuals who we studied had a median of four prior lines of therapy. More than half of patients had seen prior blinatumomab, more than 40% had seen prior inotuzumab, and 41% had received prior transplantation. 

In terms of the results. So, we saw high rates of complete remission. We saw CR rate of about 90%. And if you break down by measurable residual disease, or MRD status, within those complete remissions, of those 90% of patients that responded, about 80% of those remissions were MRD-negative remissions. Everyone uses different methodologies for measuring MRD, but for the most part, all of the patients in this collaborative received a combination of clonoSEQ, PCR for receptor gene rearrangements, or flow cytometry for MRD. 

So the response rates were high, and we also noticed that toxicity patterns were notable as well. The majority of patients, close to 75%, will experience some grade of cytokine release syndrome, or CRS. The good thing, though, is that it appears that most CRS is low grade. Things were a little more mixed for neurotoxicity or ICANS, immune effector cell-associated neurotoxicity syndrome, so we use ICANS for short. And although there were about 30%- 40% of patients who experienced no ICANS whatsoever, there was a significant portion, about one-third of the cohort, a little less actually, who experienced high-grade three/four neurotoxicity, and that’s a significant toxicity signal that we noticed. 

And then a few other just points of interest. There was a subset of about 35 patients who went into their pre-CAR-T disease assessment with active central nervous system involvement of their disease. We were interested in this relatively small population, in particular, because they would have been excluded from the trial based on the presence of CNS involvement of disease, and we were actually starting to detect a signal that brexu-cel may be capable of clearing that leukemic CNS infiltration alone in the absence of other therapies, but we have to study that a little bit more. 

And then, in terms of our ability to identify predictors of response and factors associated with superior or inferior progression-free survival, we were able to perform uni and multivariate analysis to identify these predictors. And so I’ll highlight that in terms of factors, both prior treatments and disease and patient characteristics that seem to be associated with superior progression-free survival, I would highlight that Ph-positive disease biology, the receipt of prior stem cell transplantation, and individuals who had consolidation or maintenance therapy after CAR-T tended to do better. Whereas, at least in univariate analysis and not confirmed in multivariate, higher disease burden, individuals who received prior inotuzumab, or individuals who received bridging therapy tended to do worse. 

This was a large cohort of patients, close to 190, with eight and a half months of follow-up for all patients and 11.5 months of follow-up for survivors. Our six-month progression-free survival was 60% at six months and 50% at a year. And so we do think that even in the absence of some kind of consolidation or maintenance therapy, which we believe tends to do better for our patients, there is a signal for, you know, durable remissions of about 40% of individuals who receive brexu-cel as a bit of a destination therapy and who do not get subsequent treatments afterward. And so our hope is that, as we allow this data set to mature, we can actually tease out further the influence of consolidation and maintenance therapies, the easiest being, of course, TKIs for Ph-positive disease. But then the question becomes, well, when it comes to things like more chemotherapy or stem cell transplantation, which are more invasive and carry larger morbidity and mortality, are those ultimately going to be worth it for relapse prevention? 

So there are some questions that we were able to answer with this abstract, but I think, excitingly, there are even more questions that we were able to identify that we would like to address further in the future.