TRANSCRIPTION:

DR STOCK: It adds a lot to the pediatric regimens. It’s crucial, actually. And people from the Dana-Farber have a similar very asparaginase-intense regimen, and they’ve shown very, very clearly, they and the BFM groups have all shown very clearly that the number of doses of asparaginase, the amount that’s delivered directly correlates with outcome. And so it is a very important component of the treatment.

DR KANTARJIAN: Having said this, the French did a similar pediatric study and compared it to LALA-94. And once they start going over the age of 40, their comment is the asparaginase toxicity overweighs the potential benefit.

DR STOCK: Right.

DR KANTARJIAN: So there’s no survival benefit. There’s also a study that was done in the United Kingdom. And these people are very well versed in those pediatric leukemias, because unlike the United States, where leukemias are treated by general oncologists, in England it’s the hematologists and leukemia experts who treat the patients. And they used an induction peg asparaginase therapy with a higher-than-necessary dose of daunorubicin and they had 20% mortality during the induction. And this is a group of highly expert people. So they have reverted back to lower doses of daunorubicin, and they omitted the asparaginase over the age of 50 now.

DR LOVE: And just to clarify, Wendy, maybe you can remind us of the biology of why asparaginase works.

DR STOCK: Asparaginase is a protein synthesis inhibitor. And it basically blocks, and lymphoblasts are, in particular, very sensitive to depletion of asparagine for their normal function. And so they have a propensity to be sensitive to this drug. But it is a general protein synthesis inhibitor, because it inhibits asparagine incorporation. And so you have an enzyme that depletes asparagine, and so it’s going to have a multifaceted toxicity. And that’s probably why we see multiorgan toxicity with this drug. It’s not just depleting asparagine from the lymphoblasts. It’s depleting it from hepatocytes and from the brain, et cetera, and so we see toxicity in that sense. But lymphoblasts or lymphoid cells are particularly sensitive to asparagine depletion.

DR LOVE: And we’ll talk a little bit more about that in a minute. Charlie?

DR SCHIFFER: We had done some studies in CALGB that were not AML based, but were AML-ish, and they weren’t working. What we did then was, we sat down and essentially took one of the more intensive pediatric regimens and applied it to adult ALL, and that’s the so-called CALGB regimen.

It had a fair amount of asparaginase in there. It improved outcomes, certainly, compared to what we had seen before. At the same time, there were studies in children at the Farber that intensified asparaginase, which would have been our goal. They also tried that in adults, however, at the Farber, and it was incredibly toxic. And it became apparent that you couldn’t generally apply this to adults with ALL.

What then happened was, the regimen that we were not satisfied with but which was the standard regimen was compared historically with pediatric results. And that was in the United States and virtually every country in Europe. And what was interesting was that the difference was not in CR rate in the adolescent patients. The CR rates were approximately the same. But it was in progression-free survival. So induction may have had a role in that, but what was very likely, more important, was the ability of the pediatricians to administer postremission therapy.

As Wendy said, the more intensive, essentially more intensive asparaginase and vincristine was adopted in adults. You could do it in young adults. But as was also stated, if you go above the age of 40 in France, maybe 35 in Spain, but the point is that there is a cutoff at which the intensified asparaginase becomes much more toxic.

A lot of doctors in the United States, particularly if the patients aren’t referred, like and prefer hyper-CVAD. And there’s some merit to that in that it’s easier in the sense — adult oncologists are good at inpatient therapy. And there were blocks of inpatient therapy in hyper-CVAD, so you know where your patient is. You’re seeing your patient. And it’s less dependent on the subtleties of all of the outpatient stuff that characterize the pediatric regimens, so that that was one of those reasons, aside from the fact that the results were good, that the shift in the United States became a bit toward hyper-CVAD, simply because, although the myelosuppression was greater, there were fewer intrathecal injections and it was just easier to do.

DR LOVE: Just finishing out on the asparaginase, Charlie, what are the different preparations available and what’s seen in terms of infusion reactions and other toxicities? And how do they compare?

DR SCHIFFER: Most people use pegylated asparaginase now. Peg asparaginase is a convenience — one of the biggest conveniences is you only have to make 1 decision instead of 6, but then you’re kidding yourself, because once it’s there, it’s there. If you experience the toxicities from the peg asparaginase, liver, pancreatitis, et cetera. There are also still allergic reactions —

DR LOVE: When do they tend to occur?

DR SCHIFFER: — to peg asparaginase. Usually not with the first dose. They’re sometimes manifested by local skin reactions, for example. Everyone might get a little reaction from the injection. But if you get a big one, it’s very likely that that’s a hypersensitivity reaction. And I believe we showed a long time ago, if that happens you’re not getting asparaginase, because there are neutralizing antibodies.

DR LOVE: What do you do in that situation?

DR SCHIFFER: If there’s a serious anaphylactic-type reaction, you do the kind of stuff that you would do for that. If you have a local reaction, in general it means that you probably shouldn’t use that preparation again. Erwinia asparaginase, which, again, I think has to be administered multiple injections, right?

DR STOCK: It’s 6 doses for every dose of pegylated asparaginase.

DR SCHIFFER: Right. So that gets you back to the every-dose decision.

DR LOVE: But again, Wendy, in that situation, Erwinia usually doesn’t cause these same kind of reactions?

DR STOCK: That’s correct. It doesn’t cause anaphylactic reaction nearly — very, very rarely. And so if you have an anaphylactic reaction, you can switch to the Erwinia preparation.

The one other thing that I just wanted to mention about asparaginase that I think will help all of us in terms of our future development of that drug in adults with ALL and maybe even in children with ALL is that there is a generally available assay now that was approved within the last year to measure asparaginase levels. And so I think what we’re learning by doing that is that we’re probably giving adults too high of a dose of asparaginase. We know the dose of asparaginase that we would like to achieve in the serum from studies that were actually done at the Dana-Farber. And now we can measure that level. And so it may be possible to start with a much lower dose of peg asparaginase and achieve the same levels, and perhaps this needs to be tested — reduce some of those toxicities. But the assay is generally available. It’s a very quick turnaround. And it’s a very inexpensive assay, actually, to do.

DR LOVE: And you do it routinely?

DR STOCK: We do at our center now. We do it routinely within a week. We check at 1 week after the dose. Once the dose is in, as Charlie said, there’s not much you can do. But perhaps this way we will start with a lower dose and see if we achieve the proper level of asparaginase in the serum, at a lower dose, and maybe have less toxicity.

DR SCHIFFER: Are you measuring asparaginase or asparagine depletion?

DR STOCK: No. It’s asparaginase.

DR SCHIFFER: Is it?

DR STOCK: It’s an asparaginase assay.

DR LOVE: And are there situations where, in some way, it’s being metabolized or inactivated? And can you detect it using this assay?

DR STOCK: Yes. There are 2 things about this assay. One is, you will detect whether it’s being metabolized at a regular rate, similar to children. And we know that asparaginase metabolism changes with age. And that’s why adults have a much greater problem with it. Our metabolism isn’t as good.

The other thing that it will also detect, which Charlie alluded to, is the possibility of silent inactivation of asparaginase by the antibodies. And so if you check a level 1 week after giving the drug and the level is zero, then you know that something has happened. The antibody has inactivated the asparaginase.

DR LOVE: I’ve heard that term, “silent inactivation.” Is that because the patients are asymptomatic?

DR STOCK: That’s correct.

DR LOVE: So presumably you’re losing efficacy and not realizing it.

DR STOCK: Exactly. Exactly. It doesn’t happen very often. We don’t think it happens very often. But this assay will help us to detect that as well.

DR LOVE: And what do you do in that situation?

DR STOCK: Then again you have to change the preparation, because it’s a very specific antibody against the pegylated asparaginase. Often it’s against the pegylation of the asparaginase.

DR LOVE: The pegylation. That's interesting. I didn’t know that.

DR STOCK: It’s often. This is an area that’s still very much under study, and not all that much is known about it. But you can switch to Erwinia and then check a level to see if you get asparaginase levels.

DR LOVE: In terms of clinical side effects, what have you seen in terms of the peg versus Erwinia?

DR STOCK: The Erwinia is actually quite well tolerated, but it’s, (A), very expensive. (B), it’s been hard to obtain until recently.

And it is more complicated because it’s given several times a week. The one other thing I wanted to mention is, typically when we give asparaginase these days, we’re giving it intravenously, pegylated asparaginase, intravenously. So those skin reactions are not a way that we have, really, to monitor this anymore. And it’s thought to be better tolerated, actually, when it’s given intravenously, interestingly.

DR LOVE: That idea of looking at the level sounds really interesting. Is that being incorporated into ongoing trials?

DR STOCK: Yes. It is. I mean, the Dana-Farber had a long-term interest in studying this. And now in our future trials in the cooperative group, one of our plans is to actually monitor asparaginase levels.

Chronic Lymphocytic Leukemia (CLL)

Chronic Myeloid Leukemia (CML)

Acute Myeloid Leukemia (AML) and Acute Promyelocytic Leukemia (APL)

Myelodysplastic Syndromes (MDS)

Acute Lymphocytic Leukemia (ALL)