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Asparaginase as the Cornerstone for ALL Chemotherapy
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ABIM MOC: maximum of 0.25 Medical Knowledge MOC point

Physicians: Maximum of 0.25 AMA PRA Category 1 Credit™

Released: July 29, 2025

Expiration: January 28, 2026

Emily Curran
Emily Curran, MD

Asparaginase as the Cornerstone for ALL Chemotherapy

 

survival has really improved for pediatric patients with ALL over the past several decades, with survival previously less than 10% and now greater than 90%. And I think, as we all saw at ASH, I think even higher now, really impressive overall survival.

 

[00:07:33]

 

Chemotherapeutic Agents and Steroids Used in Treatment of Children With ALL: Timeline of Approvals  

And this really occurred in part because of a lot of the drugs that have been around for a long time that were introduced in the 50s and 60s, many of which are still part of the ALL regimens that we use today. All of these look very familiar. And including asparaginase, which was approved in 1978. And if you think back to that curve, really, there was this big improvement in survival around the 70s. And I think that was some of these drugs as well as the incorporation of asparaginase. So this has really become a key component of our treatment for ALL.

 

Role of Asparaginase in Cellular Metabolism in Leukemia  

 

[00:08:11]

 

And so we will kind of go over why that is important, but also how you mitigate some of the toxicities.

 

So, but first off, I think it is important to kind of understand how asparaginase works, especially if there are any trainees in the room, because sometimes it is a black box. However, it is important to understand so that you can help think about what the toxicities are and how to mitigate those.

 

[00:08:32]

 

ASNase: Mechanism of Action  

And so the way that asparaginase works is, so asparagine is a non-essential amino acid. It can be exogenous and used by the normal cell or the tumor cell. However, in addition, asparagine can be synthesized from aspartic acid using asparagine synthetase by a normal cell. So you have got these 2 different sources, the exogenous asparagine, but also the normal healthy cell can make its own asparagine if they do not have the exogenous source.

 

The tumor cell, on the other hand, uses the exogenous asparagine, but it actually lacks that asparagine synthetase, so it cannot make its own. And so what happens is, with asparaginase, what it does is it takes that exogenous asparagine and it converts it into aspartic acid, as well as ammonia, which we may be talking about later on as far as side effects. So it converts it into aspartic acid, so you have a decrease in the amount of the exogenous asparagine.

 

However, that does not matter for the normal healthy cell because the normal healthy cell just takes that aspartic acid, uses its asparagine synthetase, and makes asparagine. However, that tumor cell because again, it cannot make its own, when there is no exogenous asparagine around, it cannot make its own, and so therefore, it dies. And so this is really kind of, in a way, a targeted therapy because it preferentially kills the ALL cells because they are not able to make their own asparagine, but the normal healthy cells are able to survive.

 

[00:10:21]

 

Asparaginase: Formulations Overview  

There are several different formulations of asparaginase. One of the older ones is this E. coli–derived asparaginase, the native asparaginase.

 

This is no longer available in the United States, but it is 1 of the drugs that is oftentimes given in other countries, particularly low-income countries.

 

[00:10:45]

 

What we have here in the United States is the pegylated form of this native E. coli asparaginase. That includes pegaspargase, as well as calasparagase.

 

[00:10:57]

 

PEGylation  

 

These 2 drugs are actually the pegylated form of the E. coli asparaginase. The pegylation that is added on increases the size and molecular weight, but that improves the pharmacodynamics and pharmacokinetics of this agent. It has a longer half-life, which, importantly for the patients, means it does not have to be given quite as often.

 

[00:11:23]

 

Pegylated ASNase Products  

 

That is kind of the mainstay of our asparaginase here, at least in the United States.

 

There are 2 different forms, as I think probably most people in this room are aware. One is the pegaspargase, which it has this polyethylene glycol moiety that is added to the asparaginase with an (SS) linker. This 1 has been around for longer.

 

It was FDA-approved in 1994. It has a longer half-life, again, than this E. coli asparaginase. Therefore, it lasts for about 2 weeks, so you just have to give a dose every 2 weeks as opposed to 6 doses every other day with the E. coli asparaginase.

 

Cal-PEG is the newer formulation, which uses that same E. coli enzyme, the same polyethylene glycol moiety, but it has a different linker. This has an (SC) linker that is more stable than the previous linker. This was approved in 2018 for patients up to age 21, and is now the only product that can be given in that age range.

 

Now, again, for our patients above the age of 21, we are still utilizing the PEG-asparaginase. So if many institutions have, treat patients within, you know, under and above age 21, so many institutions do have both of the formulations.

 

This 1, the Cal-PEG, has a longer half-life than the PEG-asparaginase, so it can be dosed every 3 weeks and every 2. I think when this first came out, we were all struggling, at least in the adult world, struggling with how exactly we interchange these 2 using our current protocols, but I think moving forward, a lot of the pediatric and some of our young adult protocols are accounting for this.

 

[00:13:13]

 

Asparaginase: Formulations Overview  

 

In addition to the pegylated form, there is also an Erwinia-derived asparaginase product. The 1 that is currently available in the United States is the (recombinant)-rywn asparaginase.

 

[00:13:27]

 

Recombinant Erwinia Asparaginase in ALL  

 

That 1, because it is Erwinia and not the E. coli, it can be, I think probably everybody in this room knows, and as we will talk about later, it can be used for patients who have hypersensitivity to the other formulations of asparaginase, the E. coli-derived asparaginase. This 1 is shorter acting, so you have to use 6 to 7 doses for every dose of the pegylated formulation.

 

There are 2 different regimens that are currently FDA-approved, every 48 hours, to make it easier on the patients, as well as for centers where they do not have their infusion suites open on the weekend. It can also be given Monday, Wednesday, and Friday with the lower dose of 25 mg/m2 on Monday and Wednesday, but then the higher dose on Friday of 50 mg/m2 with the goal of getting you through the weekend until the next week.

 

Treatment Outcomes in ALL - Pediatric Patients vs AYAs

 

[00:14:28]

 

So that is asparaginase. Now I am going to flip a little bit because again, I am an adult oncologist, I am going to talk a little bit about the pediatric vs the adolescent and young adult population. And I think this is important because even if you are a pediatrician, and you say, I never see adult patients, there are some differences even among our young adult patients as far as the asparaginase toxicity.

 

[00:14:55]

 

Survival Gap in ALL: AYAs vs Children  

 

And so, historically, AYAs, they are generally considered to be the age range of about 15-39. And unfortunately, they have worse outcomes than the pediatric patients. And so again, there is this beautiful improvement in survival among our pediatric patients with ALL.

 

And you can see here on the right, while there has been this gradual improvement in survival among the younger patients, if you look at the bottom here in the orange, the patients age 20‑29, we really have not seen the same improvement in outcomes as we have in our younger patients.

 

[00:15:32]

 

ALL: 5-Yr Relative Survival Rates From 2015-2021—All Stages By Age, Both Sexes, All Races/Ethnicities  

 

People have sometimes called this the survival cliff that happens when you go from age 15 to age 16. All of a sudden, there is this drastic drop-off in survival, and that does continue as you get older, that continued drop-off in survival.

 

There has been a lot of work and a lot of really smart people trying to understand why this happens. You know, there is a lot of data that our AYA population has a different disease biology. So these patients are more likely to have high-risk disease. So it is probably part of the reason that they do not do as well.

 

Psychosocial factors, you have got these patients who go from living with their parents, getting full support to all of a sudden now living on their own, trying to hold down their first job while they are also getting their treatment, not having health insurance. So that definitely plays a role as well.

 

However, I think for the purposes of today, I think 1 of the really important things is that there are also differences in treatment approach. When you go from your 18-year-old to your 19-year-old, there can be very, very major differences in treatment.

 

[00:16:41]

 

Outcomes in AYA Patients Improved With Pediatric Regimens  

 

So this is now a very old study done by my mentor, Dr Wendy Stock, as well as Jim Nachman at the University of Chicago back in 2008. And here they looked at patients aged 16-20 who were treated either on a pediatric protocol, so this time it was the CCG, or 1 of the adult protocols, so that is the CALGB. And you can see that despite being matched for age, the patients who were treated on the pediatric trials did significantly better than those treated on an adult regimen. Now granted, this is a retrospective analysis, it is not controlled, but it does go to show that perhaps there are some differences in how patients do when they are treated with different regimens.

 

[00:17:32]

 

CALGB 10403: Survival Outcomes  

 

This actually led to now the prospective trial, also done by Dr Stock, of CALGB 10403, where it looks like when we look retrospectively, patients do better when they are treated with a pediatric regimen. However, is this actually feasible? Is it truly efficacious if we do this in a prospective manner?

 

And so this was a trial, a cooperative group trial, with almost 300 patients, mostly B-cell ALL. AYAs, the average age was 24, who were treated with a pediatric-based protocol. So this is based on the COG-0232 backbone, with some modifications for young adults.

 

And what they found was that not only was the induction mortality and overall treatment-related mortality low, but the overall and event-free survival was better, significantly better than the historic controls.

 

Comparison Between Pediatric and Adult Regimens in ALL  

 

[00:18:35]

 

Prospective Trials of Pediatric-Based Regimens in AYAs and Adults With ALL  

 

And so this has really become kind of the standard of care for our young adult patients with ALL. And this was replicated both within the United States as well as throughout the world.

 

And they found very similar results with event-free survival in the 50-60%, as well as overall survival of around 60-70%, which, again, to the pediatricians in this room, may not sound that great, but for us, it was really very impressive and a huge improvement over what we had in the past. So this has really kind of become the standard, or many would argue that this is the standard of care regimen for young adults with ALL.

 

[00:19:15]

 

Regimens Used in AYA Patients With ALL  

 

However, I think what I would like to point out here, and I would urge some of our pediatric colleagues to reach out to your adult colleagues and help them, is that this does not actually happen in real life.

 

And I can say it is still not really happening in real life, that our young adult patients are getting a pediatric-based regimen. And so this is a nice study done by Dr Lori Muffly. This is an older study now.

 

And so you can argue whether or not it will hold true with some of the newer data. However, what she did was she looked at California residents, AYAs, age 15-39, who were with newly diagnosed ALL, and just looked at where they were treated and what they were treated with. And what she found was the minority of patients were treated at a pediatric institution.

 

So that is the smaller piece of the pie chart here. You can see, but if you were a young adult, pediatric, or if you were a young adult, and you went to a pediatric institution, you 100% of the time received a pediatric-based regimen. If you went to an adult institution, which made up the majority of the patients, so most patients ended up going to an adult institution, less than a fourth of them received a pediatric regimen.

 

And again, this is an older study.

 

This preceded the, the 10403 results were not published until I think 2018. So it would be great to look at this again and see if this has changed. I will tell you that I think it has changed a little bit, but from getting referrals and speaking to colleagues, I do not think it has changed that drastically. I think in general, our young adults are getting more adult-based regimens.

 

[00:21:17]

 

Comparison Between Pediatric and Adult Treatment Regimens in ALL  

 

And so I think 1 of the questions, and I could talk for another hour on this, but why is that? What is the difference? Why are these patients not getting pediatric-based regimens? And I think that is part of the reason we are here is that when we talk about the adult regimens, these tend to be very myelosuppressive. So the side effects of these are you drop the counts.

 

Oftentimes these patients are in the hospital, they get neutropenic fevers, they get infections. These are all things that as an adult oncologist, we are good at. We know what to do. We can manage neutropenic fever, no problem. It is not scary to your average leukemia doctor. However, when you look at the pediatric regimen, that is less myelosuppression, but you have more of these drugs that maybe people are not as used to, you get more intrathecal chemo. However, also importantly, you get more asparaginase. And a lot of the toxicity in these pediatric regimens, particularly in our young adults, are asparaginase-related.

 

And I think that that is part of the huge driving reason that adult oncologists are not giving these pediatric-based regimens. And so I think understanding how to mitigate this, working with, if you were a pediatric oncologist, working with your adult colleagues to try to help mitigate some of these toxicities is going to be very important as we move forward.