iwAL 2019 | iwAL 2019: CAR-T & cellular therapies in AML and ALL

Noelle Frey:
Hi. So, I’m Noelle Frey, and I’m here with Doctor Wendy Stock, and Doctor Bianca Santomasso, and we just finished an interesting session here talking about improving outcomes for patients with acute lymphoblastic leukemia. And I just want to first start with Wendy. You went over today the tremendous improvements that we’ve made in older, younger patients, patients who are treated by adult physicians with an adolescent/young adult protocol, and the data that you summarized from a recent cooperative group study was inspiring. But as you pointed out, we can still do better. And so, in your opinion, going forward how can we continue to improve on treatment outcomes for these young adults with ALL?

Wendy Stock:
Yeah. Thanks, Noelle. Well, I think that one of the big issues is, as we talked so much about it at this meeting, was how we might be able to potentially improve outcomes without increasing toxicity. Because in the young adult population, the intensive regimen was quite toxic, although the mortality rate was not any higher than expected. No higher than predicted from the pediatric studies. So, what we’re planning to do as we move forward is we’re planning to incorporate some of the new agents in different centers, different studies. In the United States, a study led by Doctor Dan DeAngelo for the Alliance, and the entire US cooperative group mechanism is going to be incorporating inotuzumab into frontline treatment to see whether we can early eradicate MRD, minimal residual disease, and thus improve outcomes since that’s been one of the most important prognosticators for outcome. And we believe that adding inotuzumab to frontline treatment will make a difference. That’s our hypothesis, and we’re going to be testing it in a randomized phase three trial using the backbone that was already so successful at improving event free and overall survival.

Noelle Frey:
Great, great. One of the newer therapies that we talked about today in our session was CAR T-cell therapy, specifically targeting CD19 for patients with relapsed and refractory ALL. And I was able to present some of the highlights, and the good outcomes, and Bianca had the opportunity to go on the flip side, and talk about some of the toxicities. As a neurologist, you’ve been able to witness neurotoxicity in CAR T-cell recipients first hand in addition to cytokine release syndrome. And I was really impressed with one aspect of your talk today, which was to describe and report on a new grading scheme that thought leaders have developed. I was wondering if you can tell us how you think that might improve the progress of the field going forward.

Bianca Santomasso:
Right. Thanks, Noelle. I was very pleased that we were all able to come together, and put together this grading scheme. One of the problems was that in the early trials that were done, there were several different grading schema that were used both for cytokine release syndrome, and neurologic toxicity. Especially for neurotoxicity, as you know, having treated these patients, as well. It’s hard to know what the significant events are, and there’s a lot of subjectivity to the grading when you’re talking about an encephalopathy. So, there was the importance both of figuring out what are the important symptoms we need to capture, and then also specifically how to grade the encephalopathy component. And so, I think that we built on some of the early steps. So, obviously, there was the CAR-tox working group had put together kind of a preliminary step. Though, some of those aspects were a little bit cumbersome, you know, requiring CSF opening pressure, and measuring papilledema. But they did have an initial kind of pare down, ten question exam that you can do at the bedside, basically asking orientation questions, following commands, naming, writing, and then in attention, counting backwards.

Bianca Santomasso:
And with that ten-point scale, ten being the perfect score, and then zero being not a good score, you can get a sense of how encephalopathic that patient is. We do know from our studies at Memorial Sloan Kettering, we had a phase one trial where we saw that difficulty with language, specifically expressive aphasia was one of the first severe symptoms. So, it can be an early clue, kind of like a vital sign check that can be done to help any practice provider be alert to the fact that this patient is probably developing toxicity.

Bianca Santomasso:
So, I think that really just it will help harmonize the grading, which will then help inform what to do about the patients. It’s not clear that steroids always need to be given at the same intensity, or even at all, but I think we first have to start by making sure you and I are talking about the same thing. So, I was very pleased. And again, I think it’s a starting point, and there’ll be room for improvement, but we needed something.

Noelle Frey:
Yeah, no. I think it’ll be very helpful. There’s so many investigators doing small, and now larger trials, and just to be able to define the problem in a way that we make interventions, and different trials that can really correlate with outcomes that we’re all on the same page about. So, I think that’s a big step forward in the field. And as you said, it’s great everybody agreed on a system.

Bianca Santomasso:
Yes. Well, and the other thing is that we’re dealing now not only with CAR T-cells, but with other immune effector cell types, as well, and obviously the bispecific antibodies where you can see a similar constellation of symptoms. So, the idea is that this grading would not just be CAR T-cell specific, but any immune effector cell grading. And so, it’s actually called the immune effector cell consensus criteria for that reason.

Noelle Frey:
Wendy, I wanted to ask you another question. So, I think one of the things you highlighted in your talk today is the importance of a very effective drug to treat ALL, which is PEG-asparaginase, or an asparaginase based medications. You commented on it’s an important drug, and there’s a differential ability for patients to tolerate it. Do you mind summarizing some of those factors?

Wendy Stock:
Sure. I think that what we have seen, and one of the most challenging pieces of giving asparaginase are its longer term toxicities, both immediate and several weeks, and sometimes several months, actually, in duration. And the most problematic in the adult population has been the liver toxicity that occurs. There’s also an encephalopathy, actually, interestingly, that occurs in these patients, especially as we age. And we know that this drug gets more difficult to administer once patients are over the age of 15 to 16 years of age. Part of that maybe the body mass index, the increasing obesity because we’ve been dosing that drug based on body size, and body weight. And so, if you give these high doses, perhaps that’s the reason that these toxicities are so profound. In addition, it causes steatosis in the liver, and liver toxicities are … asteatotic livers are increasing with age, and with obesity.

Wendy Stock:
So, we have trouble with that drug. There are many side effects of the drug, but as I said, the one that causes the most consternation among clinicians, and patients, is the liver toxicity, along with this feeling of malaise that the patients have. And so, my hope is that perhaps by giving lower doses of the drug over time, and maybe individualizing the dose based on levels of asparaginase, which can now be measured in a commercial test, we can then tailor the dose of asparaginase appropriately, so that we still get asparaginase levels that are therapeutic, as defined by previous studies, and yet minimize the toxicities. And from some pilot studies that have been done, it looks like that might be the case. Interestingly, in Europe, they tend to use lower doses even in the pediatric population than we’ve used in the United States. And as you know, they have outstandingly good outcomes. So, that’s my hope about trying to make it a more tolerable drug because you’re absolutely right. It is such an important drug in terms of efficacy in the population of patients with ALL.

Noelle Frey:
That’s great. It’s a drug I have a lot of respect for, which is a way of saying I fear it in some ways. Are the cooperative group studies measuring drug levels?

Wendy Stock:
Yeah. So, in our new study, we’ve reduced the dose uniformly, not dramatically. I think we could’ve gone down lower, but we were trying to be conservative. We don’t want to lose the beneficial effect that we have, and these studies need to be done prospectively. But in this study, prospectively, we are going to be measuring levels, and so, we’ll get an idea of how high we are, and maybe how we can maybe go down. And whether or not later we’d have to test whether that truly does correlate with less toxicity.