Updates in the Treatment of Adults With Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia - Episode 2
An oncologist specializing in the treatment of patients with B-ALL discusses the study design, efficacy, safety, and two-year updated results of the phase I/II ZUMA-3 study evaluating brexucabtagene autoleucel in adult patients with R/R B-ALL.
Highlights From the Two-Year Follow-Up Results of the ZUMA-3 Trial
Jae Park, MD: So, the ZUMA-3 Trial, clinical trials of first Phase Two clinical study of looking at a Brexucabtagene in adult patients with Relapsed Refractory B-cell ALL. And just to remind ourselves, Brexucabtagene is CD19 targeted CAR T-cells, so these are autologous CAR T-cells from the patients themselves. And genetically engineered to express CD19 - CD19 targeted CAR with the Brexucabtagene, and they are conditioning chemotherapy, that's consisting of Fludarabine and Cyclophosphamide. And there's a single infusion, one-time infusion of the Brexucabtagene cells, so this was again Phase Two Study of adult patients, Relapsed Refractory Disease expressing CD19. It did enroll for a variety of different patient populations relapsed after a bone marrow transplant, primary refractory patients, multiple relapse patients, given the nature of the disease and the trials, the median lines of the therapy was three and four. So you know that these are relatively heavily pretreated patients, about half the patients were exposed to prior Blinatumomab or Inotuzumab, and about 40 to - 40% of the patients had a prior stem cell transplant, and for relapse disease they received Brexucabtagene. So again, heavily pretreated patients, but this was a Phase [00:06:00] Two single-arm study. And with this study, there was a remarkable response rate. So 70% CR and CRi combined rate, and these are typical response rate that we are now used to seeing with a single use CAR T-cell therapy for both pediatric young adults patients as well as adult ALL patients. So those are quite encouraging results in the initial report that was published in Lancet. Then there are some toxicities as we all are aware by now, that are associated with the CD19 targeted CAR T-cells. One is Cytokine Release Syndrome, and the other one is neurological side effects with neurotoxicity. And there are a variety different rates, but the severe ones are grade three and higher CRS and neurotoxicity rates in quarter of the patients. But these are largely reversible and then manageable side effects, and then we are as clinicians, are getting much better at predicting or anticipating the side effects and intervening early. That is shown to be effective in ameliorating or mitigating these potentially severe side effects. So these are again manageable side effects that we are seeing with these patients, but 18% of these patients went to stem cell transplant after receiving CAR T-cell therapy. And we still do struggle as to what to do after the - after these patients do achieve the CR and CRi. The responses, and in this particular study about 20% went to transplant, and duration of remission, when they analyze the data with - by either censoring or not censoring for transplant, did not appear to be seemingly different. But again, these are not a prospective study, kind of been trying to answer the question of whether we should go to transplant or not. So that still remains a somewhat of a difficult question, but at the end of the day, the data does show that there are a subset of the patients who are able to maintain the duration of remission after single infusion of a CAR T-cells. At ASCO this year in 2022, and there was an updated data for the two-year follow-up, so now we have a little longer-term follow-up from the initial - the data report from the Phase Two studies. And then what it's showing is that the - these remission rates up here just stayed similar to kind of what the initial report was, as well as the duration of remission. So about 30% of the patients are still in continuous remission at the last follow-up, and the median follow-up was about - just over a year, about 14 or 15 months on this study. So that is encouraging that in a day, there are maybe a sign of a plateau of the curve showing the long-term durable remissions, at least in subset of the patients. And then hopefully we can figure out a little bit more, as to who are these patients that were able to maintain and enjoy durable remissions. We do know the disease burden does play a very important role in maintaining a good long-term efficacy, so lower the disease burden, the better the long-term outcome. From our prior data from MSK, and then I think similar data have been shown through the other studies too. So that may be one of the important factors to look at.
So Brexucel, we know from the data that certainly haven't been applicable. There's strong data to support for those patients who have either Inotuzumab or Blinatumomab exposure. Blinatumomab has obviously, because it's approval in the MRD setting, some of these patients are receiving Blin in the MRD, or the frontline setting with CR1 in the first relapse. So a lot of patients are being exposed, about 40 to 50% of patients have been exposed to date. If they relapse afterwards, then the patient - choices are typically either Inotuzumab or CAR T-cells. And then if we're worried about again, the liver disease and potential toxicity of the VOD, then one may consider the Brexucel kind of as a - either as a bridge to therapy or hoping to avoid their - avoid transplant as a standalone therapy as well too, while the question remains relatively unanswered. So, I think these patients who have either – and the Blinatumomab exposed afterwards in relapse, I think the Brexucel could be considered. And certainly, those had put both Inotuzumab and Blinatumomab, I think the CAR T-cell therapy has been studied, and it does have - is shown to be effective in that setting as well. The other setting that I mentioned earlier that the patients who had a prior transplant, I think in these patients are always very challenging, because a long-term remission duration or a potential for cure, is low without the second transplant typically. And there's where the CAR T-cell therapy, while we may not know yet whether this could be curable approach, but certainly have a more durable approach for the duration of remission, so these are the patients that are also considered for the CAR T-cell therapy. The other patient population may be the patients with Extramedullary Disease or active CNS disease, or CNS1 or CNS2. We now have good data for the safety and efficacy, the CAR T-cell therapy is effective in eradicating the CNS disease for those patients who are refractory to intrathecal chemotherapy. I think this may also practice though, could be an option and then also Extramedullary Disease where data is a little bit lacking for the Blinatumomab, although Inotuzumab does seem to work well in this setting. So that they are - the patients do have options between Ino, or CAR T-cells in this setting.
Transcript Edited for Clarity