Transcript
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Dr. Gupta: Children with standard risk ALL, acute lymphoblastic leukemia have really been one of the moderate success stories of medicine in the past 50 years. We've gone from what was a universally fatal disease to one in which 85 to 90% of children can now expect a cure, and that's a really wonderful number for the community. But in the last 15 or 20 years, we really haven't seen any progress in that number. There have been a number of trials both here in North America and abroad that have attempted to change different types of traditional chemotherapy, intensify traditional chemotherapy in an effort to improve that number even higher. But those have generally not worked.
Dr. Rau: And so 1731 knew that we would need some different strategy. We couldn't just add more cytotoxic chemotherapy to the existing backbone to make really any further progress. And so we knew we would likely need an agent with a distinct mechanism of action and a non-overlapping toxicity profile. In the time we were designing the trial, there were emerging data mostly from relapse and refractory B-ALL patients suggesting that blinatumomab, which is an immunotherapeutic agent, which engages the patient's own T cells to eliminate the lymphoblastic B cells, that it looked like it was a safe agent and was showing a very promising efficacy signal. And so we incorporated that as our investigational agent into this trial. 1731 enrolled most children with NCI standard risk B-ALL, which is categorized as children who are between the ages of one and 10 at the time they're diagnosed and have a white blood cell count less than 50,000 at the time of diagnosis, is the most common subset of pediatric ALL that we care for in the clinic.
These patients were treated with our standard three-drug induction regimen. At the end of which they were assigned to one of three groups based on their expected risk of relapse. Patients with a very low expected risk of relapse were called standard risk favorable, and that group does so well with chemotherapy alone that they weren't eligible for our randomization. They were non-randomly assigned to standard therapy. Children with a relatively high risk of relapse were called our standard risk high group, and a vast majority of those patients were eligible for randomization to either an intensified chemotherapy backbone alone or that same chemotherapy backbone plus two cycles of blinatumomab. And then in our intermediate group, they were called standard risk average, and that group of patients were mostly also eligible for randomization. There was a small subset of them who were MRD negative by a very sensitive assay called Next Generation Sequencing or clonoSEQ. And those kids also do really well with standard chemotherapy alone. So they too were non-randomly assigned to standard treatment. But all other standard risk average patients were eligible for randomization to either our standard intensity chemotherapy or that same chemo plus two cycles of blinatumomab.
Dr. Gupta: Like all randomized controlled trials, we had a data safety monitoring committee who had pre-planned interim efficacy analyses. And so our very first one of those analyses was planned to occur when we hit 40% of our expected number of events over the trial. So that happened in June of this year. And after examining the data, the Data Safety Monitoring Committee actually recommended that randomization be terminated and that the results be disseminated essentially because blinatumomab ended up being a home run. So for example, in that standard risk average group, those children who received chemotherapy only had a three-year disease-free survival of 90%, whereas those same children who received chemotherapy and blinatumomab together had a disease-free survival of 97.5%. And then in an analogous way in the standard risk high group that Rachel described, the children who received chemotherapy alone had a disease-free survival of 85%, whereas those who received chemotherapy and blinatumomab together had a disease-free survival of 94%. So really in the end, what treatment with blinatumomab did was actually take the outcomes of that standard risk, average and standard risk high group and made them as high as what we previously had considered our most favorable groups. So it really converted these high risk relapse groups into very low risk relapse groups. Now, like any agent, it's not without risk as well. And so there was a side effect profile that we were looking at as well.
Dr. Rau: Yeah, and there are two main known target toxicities of blinatumomab. Number one is called cytokine release syndrome. It's essentially when you start to break down the malignant B cells, they release substances that can cause fevers and hypertension and other symptomatic issues in the patients. We saw very low rates of that in our patient population, which wasn't surprising since they come in, they have a very low amount of leukemic cells in their body at that time. So less than 1% of patients per cycle had severe cytokine release syndrome. Blinatumomab can also cause specific neurotoxic events including seizure and encephalopathy, and we saw also low rates of those, and most of the ones we saw were also not of a severe grade. We also have very close infectious toxicity monitoring in the context of 1731, and we didn't see any difference in the rates of infectious complications in the standard risk high patients.
But in our standard risk average patients randomized to receive blinatumomab, we saw increased rates of grade three plus sepsis and catheter related infection. Some of that was during the blinatumomab cycles themselves. So about 3% of patients per cycle would have one of these infectious complications. But most of the difference was actually because of increased rates of infections in the chemotherapy courses that followed blinatumomab up to a year after you finished of your blinatumomab therapy. So the effect was pretty long lasting. Luckily, we didn't see significant differences in the rates of severe grade four or fatal grade five infections, which were overall very rare in our randomized cohort. So overall, the trial demonstrated in a randomized manner that the addition of blinatumomab to risk adapted chemotherapy significantly improves the disease-free survival of NCI standard risk ALL patients of average or higher risk of relapse. Overall, it's a well-tolerated agent with the known toxicity profile of cytokine release syndrome and neurotoxicity being quite rare, but the infectious complications were higher amongst our standard risk average population.
But overall, the results support that blinatumomab added to risk adapted chemotherapy is really now a new standard for NCI standard risk B-ALL patients. I think more broadly speaking, there's been data presented at ASH and other meetings and published now just in the last couple of years, demonstrating that in newly diagnosed patients, the addition of blinatumomab to chemotherapy improves outcomes for infants with B-ALL adults with B-ALL. And now this trial in children with NCI standard risk B-ALL, and the one group that really hasn't been formally studied in is another population called NCI high risk B-ALL. And that's a population heavily enriched for adolescents with BALL, but it's very reasonable to extrapolate from our standard risk high population and the young adults treated on a recent study by the ECOG-ACRIN group because those therapeutic plans and the expected outcomes are very similar to the NCI high risk population. So really overall now the bulk of the available data suggests that blinatumomab is a standard component of therapy for most patients with B-ALL.
Dr. Gupta: So I think one of the things that we've been asking ourselves, it's learning these results is, I mean, that they're so spectacular not to exaggerate, but what do we do now? And I think one of the things that we're really excited about in the future is Blinatumomab seems to be such an effective agent at preventing relapse that the sort of natural question is, do we actually need all of that chemotherapy? Remember, as Rachel had said, this trial added two cycles of blinatumomab without removing any of the chemotherapy. So I think that's really the direction that not just the children's oncology group, but that other groups are going to start thinking about as well, is what can we start to safely take away? It's a really hard question when you have these kind of excellent outcomes, and it's going to take a lot of consultation within the community and also with parents and caregivers.
But I think that's probably the really exciting next step. I think one of the other things that it's been really striking over the last little while as well is as amazing as these results are and as effective as blinatumomab seems to be, it obviously does zero good if you can't actually access it. This is a drug that is delivered in 28 day continuous infusions. And so if you are family with limited resources or who lives in a remote or rural area, there are really big challenges in how to get it. And so I think it's incumbent on us as a community and as a society to also make sure that when we have these type of incredibly effective interventions, that we actually also put effort into making sure that access is prioritized as well. And that's even without thinking about the global context, the majority of children with ALL don't live in countries like Canada, the US, Australia, and New Zealand, where this trial was conducted.
So thinking about that I think is crucial as well. And then I think the last thing we always want to talk about, but maybe as well we're the lucky ones who co-led this and who are here to be able to talk about it, but there are literally hundreds and hundreds of people who helped conduct this trial. Again, even without mentioning the 215 sites across those four countries who actually enrolled children on this trial. Again, even without mentioning all the parents who at the worst moment of their lives actually somehow managed to consider the option of going on a clinical trial.