Asparaginase-Based Therapy in ALL: Strategies to Increase Completion of Therapy and Minimize AEs

So my focus now will really be to talk about some of the toxicity we see with asparaginase and what are the strategies to help us increase the completion of therapy and minimize some of those adverse events.

Let’s Consider Some Patient Cases

[00:23:07]

So to start, we will consider some patient cases. I will just present them to you, and it will be presented again later.

[00:23:14]

Patient Case: 6-Yr-Old Patient With T cell ALL

Let us take our first one. This is a 6-year-old patient with T cell ALL. Initially diagnosed as they often come with a high white count of 384,000. CNS-2 on the initial diagnostic LP. This patient was treated on a COG-based regimen and received 1 dose of pegaspargase, which now would be Cal-PEG, in induction, and 46 additional doses scheduled thereafter because they were high-risk.

And so at the end of induction, the MRD was elevated, a 9.4% blast. What was noted was that during induction, when Day 4 pegaspargase was given, this patient experienced something that looked like a possible hypersensitivity reaction where they had vomiting, abdominal pain, stomachache, and a rash, but no hives were noted. So just to keep that in mind.

[00:24:11]

Pretest 1: Which of the following approaches would you recommend for this 6-yr-old patient?

So just I will throw out the first question. You do not have to answer it now, but I do want you to think about it. So which would be the following approach that you would recommend for this 6-year-old patient? Based on what you just heard, would you:

1. Check asparaginase level, activity level following this dose, and prescribe premedication at the next asparaginase dose and do therapeutic drug monitoring; or
2. Would you continue with giving pegaspargase with premedication such as H1, H2, and/or steroids; or
3. Would you switch them to intramuscular pegaspargase, anticipating that there would be less hypersensitivity compared to the IV formulation; or
4. Completely switch to a non-cross-reactive asparaginase formulation such as an Erwinia-based?

So just think about that.

[00:25:26]

Patient Case: 12-Yr-Old Patient With B-ALL

So okay, we will go to the next question. So the next case is a 12-year-old patient with B-cell ALL, came in with a high white count of 22,000. Cytogenetics, which were unremarkable, CNS1, also treated on a COG-based regimen, NCI high-risk, therefore got 4-6 doses of asparaginase post-induction. MRD was 0.15%. What was noted, though, was that when this patient went on to consolidation, the high-risk consolidation arm, they got pegaspargase or Cal-PEG on day 15, and shortly thereafter, the nurses noted that this patient had a grade 3 reaction, which manifested as a rash, abdominal pain, stomachache, but also bronchospasm and hypotension.

[00:26:22]

Pretest 2: Which of the following approaches would you recommend for this 12-yr-old patient?

And so with that, which of the following approaches would you recommend for this 12-year-old patient? Would you:

1. Continue giving pegaspargase using premedication, whether it is H1, H2, and steroids; or
2. Switch to IM pegaspargase, anticipating that you have less hypersensitivity compared with the IV formulation; or
3. Would you do C, switch completely to a non-cross-reactive asparaginase formulation, i.e., an Erwinia-based derived one; or would you
4. Completely end all asparaginase therapy; or
5. Prescribe premedication with the next dose and perform therapeutic drug monitoring?

So, go ahead and answer that.

[00:27:33]

Asparaginase: Measuring Activity

Okay, so let us talk about asparaginase and therapeutic drug monitoring. So, as many of you guys know, you know, Dr Curran talked about asparagine depletion. That is probably the gold standard to determine if the drug is doing its job. The problem is it is really hard to measure asparagine levels.

Instead, what we do is measure asparaginase activity. There are several CLIA-certified labs that can do this, and they have pretty good turnaround time, and generally accepted is actually an enzyme level is greater than or equals 0.1 IU/mL at, typically, we say at a week later to require, to fully deplete your asparagine levels.

And so, and so the nadir for these long-acting asparaginase would be 14-21 days, although when we do therapeutic drug monitoring, we check at 7 days. Often, we also check 2 weeks later, and typically, you should still see levels. If it is for the non-pegylated product, the shorter acting, it should be done at the nadir, which is about 48-72 hours after.

[00:28:50]

Asparaginase Products: Major Agent-Specific Toxicities

What are some of the toxicities that you can see with asparaginase? So I will talk about globally, some of the hypersensitivity or sensitivity-like reactions that we see. As Dr Curran mentioned, asparaginase is made from an enzyme. It is from bacteria, so it can cause immunogenicity issues, and so when that happens, your body produces antibodies, and typically, these antibodies can definitely be neutralizing. They can deplete the asparagine, and typically, what we can see is manifested as some of the symptoms that we will discuss later, which are rash and hives and angioedema, all of that, but sometimes, this can happen internally.

There is a struggle inside our body. The antibodies are produced. It is just knocking out our asparaginase, but at the same time, you do not see it. The patient looks perfectly normal, so you would never know, but they are still having suboptimal depletion of asparagine because they do not have the asparaginase to do their job, so that is what you call silent inactivation. It is actually not as common as we think. It is about 5%, but it does happen, and 1 of the ways that you can counter it and detect it is to do therapeutic drug monitoring.

Now, the other end is when you have a true hypersensitivity reaction or what we call true allergic reaction.

That is when that neutralizing antibody is produced, and it is depleting your asparaginase, and when it is produced, you actually can see the manifestations, some of it which can look like an infusion reaction, abdominal pain, nausea, vomiting. The patient has bronchospasms, has angioedema, so that is what we call a true reaction, and so that can occur, really, the number is quite varied, 10-30%, and it is definitely dependent on many factors, and 1 of them being the type of formulation, the asparaginase that is used, and again, as I mentioned, it is because asparaginase is derived from bacteria, so you have a lot of immunogenicity issues.

Because there is no cross-reactivity, as was mentioned earlier, between these E. coli first-line products and these non–E. coli, and also the recombinant, as you know, is non-E. coli. It is from Pseudomonas. You can use these second-line short-acting to still get your asparaginase depletion to replace that first-line product without, hopefully, having any further allergic reactions.

[00:31:29]

Asparaginase Products: Major Class-Specific Toxicities

And so, aside from that, there are many other side effects that you can see, adverse effects that you can see.

What we do know is that for the adverse effects that I list here, it does not matter if you use first- or second-line agents. They typically all still have the same. So, switching from 1 to the other for some of the ones that I listed here will not make a difference.

So, pancreatitis is 1 that I am sure we all have seen. I mean, it occurs, again, in a wide spectrum from 4%-8% in pediatric patients. We see it more in older patients and adolescents, for sure. They are at higher risk. We will talk in detail about each of these. This is just an overview.

You can see patients in a hypercoagulable state, and they definitely can have thrombosis, or they can actually have the opposite, which is a risk of bleeding. And so, we see that in 2-4%. And definitely, we see more clots than we do see bleeding complications.

Hepatotoxicity is actually quite common. I would say it is probably the most common toxicity that you see as an adverse effect from asparaginase products. And hyperglycemia is also 1, and that is usually not dose-limiting.

Asparaginase-Associated Hypersensitivity and Strategies to Increase Completion of Asparaginase-Based Therapy in ALL

[00:32:55]

So, going back, we will start at the top, which is to discuss some of the asparaginase-associated hypersensitivity, and what are some strategies that we can use to mitigate this.

[00:33:07]

ASNase Allergy and Inactivation

I talked about the neutralizing antibodies that are produced, and they inactivate our asparaginase chemotherapy. So, when it is a low grade, so we use different, there are different ways to grade it. Currently, it is a CTCAE version 6, and there is grade 1-5.

Grade 1 is pretty mild, and usually, what we would say is that for those with grade 1, probably we would recommend that you rechallenge, and I will talk about this more. You heard a lot about universal premedication. I think every center here probably does it. It makes us feel better that we do it.

Does it work? The data used to show that it worked, and decrease the incidence of hypersensitivity, or being able to tease out infusion reaction, and I think we all do it, but what you do need to know is that it does blunt that reaction, but it does not mitigate that actual asparaginase inactivation. It does nothing to the antibody. So, it might make you feel good, but it does not prevent the inactivation if it is truly happening, but it does help you, though, tease out if it is an infusion reaction or sign inactivation, especially if you do asparaginase drug monitoring.

[00:34:40]

Reasons for Discontinuation of ASNase in Children Aged 1-17 Yr on NOPHO ALL2008

And so, several years ago, a paper was published in Blood by the Nordic group, NOPOO AAL2008. It was actually a really large study looking at a treatment for pediatric patients age 1-17. The cohort was quite large, it was over 1400 patients, and they looked at the reasons for discontinuation, and looking at some of the adverse events that you see, clinical hypersensitivity in the main cohort, which is, I will explain the difference, 14%, almost 15% had some type of hypersensitivity. Pancreatitis was about 6%, thrombosis was pretty rare, less than 2%, hyperlipidemia, pretty rare, less than 1%.

Interesting, liver toxicity was quite rare, which is different than what we see here. And then some others. The other sub-cohort are the ones that, the N, which is over 1,115, those are the ones that they actually were able to get some therapeutic levels on, and you see pretty similar numbers, but really the point of this is that it shows you some of the adverse effects that you are seeing in this huge cohort of patients in the pediatric population.

[00:35:57]

ASNase: Hypersensitivity and Discontinuation—Expert-Recommended Best Practices

So what does a true hypersensitivity reaction look like? This is pretty severe, I am sure many of you have seen plenty of patients like this, but what should we do if we suspect a severe hypersensitivity reaction? Number 1 is that there are certain cardinal symptoms that you see that you know are real, and a true hypersensitivity reaction happens pretty fast. It is usually; you do the infusions about 100 CCs.

And you see pretty quickly, within minutes, and not only that, if a true hypersensitivity reaction, you are going to see hives, you are going to see angioedema, the patient has a hard time breathing, they have wheezing, they have bronchospasm, hypotension. That, for me, is not even questioned, but if they have maybe some flushing, maybe some abdominal pain, it is questionable. So when you see a true hypersensitivity, definitely, I think that the patient should be switched to an Erwinia-derived product so that they can complete the rest of their treatment.

And so, this is just a photo of a 15-year-old who had a severe allergic reaction.

[00:37:19]

Impact of PEG-ASNase Discontinuation or Erwinia ASNase Replacement on Outcomes in Childhood ALL

There was a recent study published by Dr Gupta in JCO in 2020, looking at the impact of discontinued asparaginase, pegaspargase, or being able to continue the patient on asparaginase therapy using Erwinia replacement, and what was the outcome? For those who are younger, you may not know, but the old, standard risk protocol was AALL0331, and the old high-risk protocol was AALL0232, so this predated even your 1131 and 1932, something like that.

But anyway, those are the old trials, and we had quite a few patients enrolled nationwide on this. And so, the incidence that was noted in terms of discontinuation for the standard risk protocol, 0331 was 12%, but for the 0231, it was pretty significant, it was 25%. And so, when he and the team looked at the disease-free survival hazard ratio for those who, in the high-risk patients on 0232, who got no further asparaginase, it was pretty high at 1.5%, however, in that group, if that high-risk group was able to replace their therapy with Erwinia, that DFS hazard ratio dropped to 1.1, so it was definitely improved. And same for the standard risk patients who did not get all of their asparaginase, you found that the hazard ratio was 1.2.

But I think that this graph here, there are actually 3 lines. We will look at the green, this is on the high-risk protocol, this is the disease-free survival of the high-risk patients on the 0232, and you see the X-axis is year, and Y is the probability of DFS. The top 2 lines, especially the green line represents patients who received all doses of asparaginase, the blue line represents those who had, for whatever reason, maybe hypersensitivity, whatnot, was then substituted with Erwinia-based, as you can see, those 2 lines are comparable, so I think this is pretty powerful data that as long as they were substituted, they had the same disease-free survival. On the other side, there was about 444 patients who missed asparaginase doses, for whatever reason, toxicity, or they were not switched, you can see that their outcome was definitely a lot poorer, and that is represented by the orange line.

[00:40:27]

COG AALL1931: M/W/F Dosing of JZP458 (RC-P) in Patients With ALL or LBL

Many of you probably also participated in the COG AALL1931, this study looked at the newer version, the recombinant Erwinia, which at that time was called RC-P or JZP458. So this study enrolled patients who were on a COG-based protocol for leukemia, and if they had hypersensitivity to the first line, at that time we had pegaspargase, then they were offered the opportunity to receive RC-P. And RC-P was dosed in different ways, it was given either intramuscular, and then later, I think the arm opened to include IV form.

And for the intramuscular, there were 3 cohorts. You had 1 cohort that received Monday, Wednesday, Friday dosing, 6 doses at the same, which was 25 mg/m², and then you had the second cohort who got it at a 37.5 mg/m², Monday, Wednesday, Friday was very equal intramuscular, and then there was a third cohort that got it 25/25 mg/m²on Monday, but on Friday to cover for the weekend, for that longer weekend, they got the increased dose of 50 mg/m².

And so the primary endpoint of the study was to look at what the response rate was, or proportion of patients who had a therapeutic level greater than 0.1 in the last 72 hours of their treatment, and then it also looked at treatment-emergent adverse events that occurred within 30 days, less than 30 days of the RC-P.

[00:42:12]

COG AALL1931: Efficacy and Toxicity of JZP458 (RC-P) in Patients With ALL or LBL

So what did the study find? It is quite interesting, and I am sure you all know the data, but just as a review.

I will review this first graph here. This, the blue represents the percent of patients who had their levels checked at the last 48, and then the orange is in the last 72 hours, and that is the serum asparaginase levels. And so I mentioned the different cohorts, and you can see here, this is cohort 1 that got it 25 mg/m² across the board on all 6 doses. If you look here, you see that, and cohort 1B is the 1 that got that sort of medium dose of 37.5 mg/m² across the board for all 6, and your cohort C is the 1 that got 25/25 mg/m², and then 50 mg/m², and cohort 4 is the 1 that got this IV.

And so if you look in the last 48 hours, everyone got therapeutic levels, right, 90-something, so it is pretty good. But I think really more importantly is, did they still sustain levels at the nadir, which was at the 72-hour, the last 72-hour? And you find that not so much in the 25 mg/m² across the board, not bad here with the 37.5 mg/m², same with the 25/25/50 mg/m², the majority of patients were able to sustain therapeutic levels, but not so much here with the IV cohort.

And so when you look at then, what were the levels of each of these cohorts? What we found was that the levels were pretty decent again in the last 48, but when you look at the true nadir, which is the last 72, that 25/25 mg/m², they were barely therapeutic at 0.16 IU/mL, and then the 37 mg/m², not so bad, at this last 72 hour, the level was 0.33, it is still pretty good. But the 1 that seemed to do better was this cohort here, the 25/25/50 mg/m², which is 0.7 even at the last 72, and you can see the IV really did not do as well.

And so what about if they are getting these doses, do we see more adverse events, side effects from the different dosing, and so this is a summary of all those AEs, and I am breaking down by the different cohorts of the intramuscular, and you can see here that across the board, cohort 1B, 1C, I would say they are all pretty comparable across the board in the evaluable patients. And so when the study looked at the modeling data, what it really gave rise to was that most likely this 25/25/50 mg/m² probably was able to give you the most therapeutic, although as you heard, this dose is also FDA-approved along with the 25 mg/m² across the board because they sustained pretty decent levels, too. So that is currently what is FDA recommended at the time for you to use if you were to switch.

[00:45:34]

Premedication and Therapeutic Drug Monitoring for Prevention of Hypersensitivity Reactions

So what about, I had mentioned universal premedication. I think, as I mentioned, a lot of us do that, but does it work? And so at the time, I think that this paper was very poignant, and it showed that yes, it does work. This is a study done by Stacy Cooper and Pat Brown. It looked at premedication, it was a retrospective study, and they did what is called pre-policy and post.

They looked at premedicating, and they premedicated with H1/H2 or steroids about 30 minutes before the infusion, and then they would check levels later, and here is what was interpreted as a therapeutic level. And what they found was that the need for substitution pre-policy was much higher in the blue, switching to an Erwinia-based therapy vs after they substituted. And reactions too, they saw less clinically significant reactions post-policy, so after they had implemented the universal premedication.

Although we mention it here, I think many of you know that there have been many, many studies since then that have shown that universal premedication maybe does not work, and so the jury is out, but I think, as I mentioned, we all do it because I think it does make us feel better, like maybe it does help.

Let’s Revisit Our Patient Cases

[00:47:04]

Patient Case: 6-Yr-Old Patient With T cell ALL

And so that being said, I would like to revisit our patient cases. And so remember the T cell ALL who got the asparaginase pegaspargase Day 4, and then had these symptoms, vomiting, stomachache, and rash.

[00:47:20]

Posttest 1: Which of the following approaches would you recommend for this 6-yr-old patient?

And the question was, this is during induction, which of the following approaches? Would you:

1. Check asparaginase levels, and still give the medication, and then do TDM;
2. Continue without TDM, but give premedication;
3. Switch to intramuscular formulation; or
4. Switch to Erwinia-based formulation.

[00:47:54]

I am not sure what you answered, but if you answered (A) bravo. So the rationale is (A) and the reason is this, is that, I will read this, but I will tell you my personal opinion.

In terms of which of the following approaches would you recommend, the majority did say, oh, can we see that again? That was really fast. Thank you.

The rationale is that, remember how I mentioned about antibodies being developed, the neutralizing antibodies. How you get antibody formation is you have to be exposed to that therapy. And so in induction, that is the first dose that they have gotten, so they really have not been exposed. It is really, really, really rare to see a true hypersensitivity reaction; therefore, we would not switch.

What is likely happening for this patient is that they probably have an infusion reaction. Some of the symptoms that you saw were pretty nonspecific, abdominal pain, a rash, which is probably some flushing, but not really what was worrisome, which was some of the other symptoms I mentioned earlier. So yes, we can continue with the next dose, but definitely would consider premedication, and also checking a level.

If you were to check a level, this patient got Day 4, check it 5-7 days later, 5-10 days later, you are going to see that it is probably therapeutic, and therefore you can continue on consolidation with the same formulation.

[00:50:16]

Patient Case: 12-Yr-Old Patient With B-ALL

And so, let us go on to our next case. So this is a patient, NCI high-risk patient, who gets a spare, who goes on to high-risk consolidation, and gets it on day 15, and shortly thereafter, in the infusion center, the nurses noted that within minutes, the patient has this, what was deemed a grade 3, with rash, stomachache, bronchospasm, they are choking, and then they have hypotension.

[00:50:50]

Posttest 2: Which of the following approaches would you recommend for this 12-yr-old patient?

In this case, what would you do? Would you:

1. Continue with this pegaspargase formulation, but use premedication for day 43 dose;
2. Should you switch to the intramuscular formulation, because you think maybe there is less hypersensitivity;
3. Switch to Erwinia-based therapy; or
4. Just stop cold turkey, no more asparaginase; or
5. Maybe next time, do premedication, no H1/H2 blockers, and do therapeutic drug monitoring.

[00:51:38]

So most of you, so pretest, you chose switching to Erwinia-based, 64%, but then posttest, 96% would do that, and that is the right answer, so it tells me you are listening.

And so the rationale is that this is really a true reaction. Again, it is happening, and as many of us know, when we see this true hypersensitivity, it happens in consolidation.

Usually, you know, first exposure to induction, typically we see on day 15. We also often see it on day 43 consol, but this is a very scary reaction, and so at that point, definitely, we would switch to the Erwinia, or the second-line short-acting formulation in order for the patient to get the rest of their therapy.

It is hard, though, unless you have gotten some drug, in terms of checking the levels, to be quite honest. If the patient just got a tiny bit, maybe, you know, it is 100 ml, and they got 5 ml, it is really difficult to measure any level. I mean, this is just anecdotally, maybe if they got 25%, it is reasonable to check, bring them back again the next day and check the level. So it really depends on how much they got and how useful is your asparaginase assay.

Let’s Consider a Patient Case

[00:53:00]

Patient Case: 18-Yr-Old Patient With B-Cell ALL

So more cases.

This is a different case, because we are going to go on to our next topic. So this is an 18-year-old female with B-cell ALL. So she gets treated with a pediatric-based therapy and includes Cal-PEG, and what was noted that, you know, a few weeks afterwards, we see that her total bili has increased and peaks at 20, but her LFTs are elevated, but not so crazy, AST of 154, ALT of 302, but make a note that the T bili is very high at 20, and over the next 6 weeks, you see that her bili and her liver enzymes start to slowly trend down to finally within normal.

[00:53:48]

Pretest 3: Which of the following approaches would you recommend for this 18-yr-old patient?

And so in this case, which of the following approaches would you take for this patient? Would you:

1. Continue the Cal-PEG at the same dose; or
2. Continue with the same pediatric-based regimen, but just omit the Cal-PEG moving forward; or
3. Now would you switch to an Erwinia-based asparaginase; or maybe
4. Just forget the pediatric, switch her back to the adult hyperCVAD to avoid further exposure to Cal-PEG.

[00:54:38]

Okay, so this is looking now at hepatotoxicity, and what do you do when you see a patient with pretty severe hepatotoxicity?

So we will talk about that. So the right answer is to continue with Cal-PEG at the same dose. Switch to Erwinia, if you remember that there was a slide that I mentioned that for hepatotoxicity, pancreatitis, and things like that, if you switch to a different formulation, it does not make a difference.

The only time that you would ever switch to an Erwinia-based therapy would be if it is hypersensitivity. So the answer is continue with Cal-PEG.

AEs and Mitigating AEs Associated With Asparaginase-Based Therapy in ALL

[00:55:15]

So with that being said, we will jump into some of the, some of the toxicities, and I will go into detail about hepatotoxicity.

[00:55:27]

Age and Asparaginase-Associated Toxicities

So there was a study that looked at some of the different toxicities, and does age matter? I think a lot of us pediatricians, we noted that there were some toxicity in our patients that were more commonly seen in adolescent young adults, our older patients and our pediatric. And so this study looked at that, did age matter?

And what it found was that, in terms of the odds ratio, as you know, if an odds ratio is 1, you cannot correlate it with that effect, but if it is positive, there is a positive correlation, if it is negative, then it is likely not to be that. For example, in terms of hypersensitivity, the odds ratio is less than 1, so what that shows you is that typically younger kids seem to have more hypersensitivity than older kids.

How about pancreatitis? We see that more, the odds ratio is greater than 1, almost 2, or above 2, actually, so that tells you that those who are older, 10-17, 18-45, tend to have more pancreatitis. Same with hyperlipidemia, the odds ratio is about 1.5, almost 2, and so the adolescent young adult and the adult patients tend to have more of that. But definitely, you see the thrombosis, that odds ratio is all the way out there, almost 8, and so definitely we would say that thrombosis is significantly higher in older patients.

[00:56:52]

Toxicity Profile in AYAs: Differences in “Young” vs “Old”

So this is a study Dr Curran had mentioned, the CALGB 10403, which is 1 of the largest trials to look at adolescent young adults with ALL, treated on a pediatric protocol. [AW2]  and this paper really nicely summarizes some of the adverse events. Grade 3/4, that you see during induction, between the AYAs in the CALGB multi-center trial vs the high-risk COG study that we participated, and the O232, the high-risk one, where our median age was 17.

You see that the older patients in the CALGB study really experienced the same adverse events, elevated ALT, hyperbili, hyperglycemia, pancreatitis, but what was noted was that they seemed to report a higher incidence of grade 3/4 in the older patients across the board for all of those, for transaminitis, even for febrile neutropenia, hyperbili, hyperglycemia, and pancreatitis. And so I think that was important data.

[00:58:03]

Common Asparaginase Toxicities: Presentation and Incidence (Pediatric vs Adult Patients)

And so that is a segue to hepatotoxicity, and as I mentioned, and that slide aptly showed, is that you see it more in older patients. And the way that hepatotoxicity manifests is that you see it with elevated bilirubin, but also elevated AST and ALT.

[00:58:24]

Pegaspargase-Associated Grade 3/4 Liver Toxicity

So in terms of the more severe grade 3/4 liver toxicity, what we will say is that to have clinical liver disease is very rare.

What you see more is the elevation in our numbers. You can see it, you do not typically see it right away. It manifests as usually weeks, even a month after, and what happens is that it does take a long time, even 6 weeks after, to see resolution. So it does take a long time to go away, but definitely it is reversible.

And so what are the risk factors for hepatotoxicity? Many studies have shown that a higher dose can cause more hepatotoxicity, as I showed you, older age, and also obesity as well, and some other factors, but those, I would say, are the main players.

So it can definitely delay your next cycle of chemotherapy, and typically, we recommend that you wait until the transaminitis and the hyperbili resolves, maybe at least goes down to a grade 2 or less before you resume it. And 1 thing I mention later is that 1 of the other risk factors, too, I think is if you have concomitant medications that are hepatotoxic, such as an azole, I think if they are on fluconazole, voriconazole, maybe you can switch to something that is less hepatotoxic.

Strategies to Increase Completion of Asparaginase-Based Therapy in ALL: Mitigating Hepatoxicity

[00:59:55]

So what are some strategies to mitigate some of the hepatotoxicity that you can see with asparaginase?

[00:01:00:05]

Mitigation of Pegaspargase-Related Hepatotoxicity

One is, is it possible to synchronize when you give PEG and dauno, especially during induction, because as you know, dauno can be mildly suppressive, but also hepatotoxic.

[01:00:19]

UKALL14 Trial in Patients Aged 25-65 Yr: Induction Toxicity

And so, I wanted to share with you a study from the UK that was published in 2017. It was a UKAAL14 trial, more of young adults and adult patients.

There were 91 patients on this trial, and on this study, they used actually 5-drug induction, and with asparaginase, the dose was lower than what we typically use, but it was given 2 times, like our T cell, on Day 4 and Day 18, and the anthracycline was given weekly on day 1, 8, 15, and 21. But what they found in this patient population was that significant hepatotoxicity, in addition to septic shock, but also bowel ischemia, and so because of that, changes were made to this protocol so that they only gave 1 dose of pegaspargase, which was on day 18, because the dauno was given weekly at the beginning, and then they embedded the asparaginase later on, around week 3-ish, but in addition to that, they also decreased the dose of dauno, and they cut it in half.

And what the study found was that the post-induction rate of death was a lot lower, 2.5% vs much higher prior to that. So that is just saying that there is potential, at least in the adult world, to kind of move the doses around.

[01:01:45]

Mitigation of Pegaspargase-Related Hepatotoxicity

And so, to be quite honest, we do not typically do that in pediatric. This is just more of completeness sake to include that, but, you know, we give our PEG on Day 4. If it is high risk, we do give our dauno on Day 1, 4, 7, weekly, 15, 22. But I think that, as I mentioned, hepatotoxicity is definitely something you see more in the adult world.

Can we also incorporate a supplement L-carnitine? Just out of curiosity, how many of you guys use L-carnitine here? Awesome, okay, great.

So, what is L-carnitine? So, for those who do not know, L-carnitine is a supplement. Endogenous L-carnitine, what it does is transport your long-chain fatty acid into the mitochondria, where it is broken down, and it produces energy and acts as a scavenger to free radicals, and in a long-winded way, it can help to mitigate some of the toxicity in hepatocytes. And so, many centers, like those who raised their hand in our center, we have been using it for quite some time as prophylaxis.

[01:02:57]

Levocarnitine for Pegaspargase-Induced Hepatotoxicity

And so, this is a couple of studies that were done, 1 was prospective, 1 was retrospective that looked at the utility and efficacy of using L-carnitine. And so, the first study is a single center, I believe, and what they found was that in 12 patients who got L-carnitine, again, very small, and the 13 who were controls who did not use it, they found that those who got L‑carnitine had a lower incidence of hyperbilirubinemia, 33%, vs 69%, in, again, a very small sample. Did not seem to make a difference, though, for the LFTs, but definitely made a difference for the hyperbili.

In this retrospective study that was multi-center, I think there was like at least ten sites that were pooled, and they looked at using it as prophylaxis, again, for their patients. And it showed that looking at whether obesity and age across the board, whether you are obese or not, whether you are young or more of an older adolescent, the blue represents those who did not get L-carnitine, this is the control sample, and the Y-axis is your hyperbilirumidinemia, you will see that those who did not get L-carnitine tend to have a higher level of bili, and especially if you were obese. And same here, if you were obese, you saw that, but also older patients also, without L-carnitine, had a higher bilirubin, but once they got the L-carnitine, it seemed to be protective, you see that in the orange bar, where their levels of hyperbili were a lot lower.

[01:04:44]

Mitigation of Pegaspargase-Related Hepatotoxicity

And so, as many of you may or may not know or are already enrolling, COG does have a current prospective study led by Iten Orjau looking at incorporating L-carnitine. For those who want to use it, not on study, it is available as a tablet or a liquid for those little ones, usually the tablet us 330 mg. Offhand, it is very well-tolerated for our patients, maybe a little fishy odor, but they do really well on it.

So what are some other strategies that we can do to mitigate hepatotoxicity? We can definitely consider, although we put the word dose reduction, I would say in the pediatric world, I would say dose capping, and there are certain populations that we would recommend for that, which many of us have done, especially for obesity, older age, where we would cap at 37, 50 as the dose.

[01:05:42]

NOPHO ALL2008: Responses to Pegaspargase in Ph-Negative ALL

And so, this is 1 study that looked at the Nordic, again, ALL2008, and it looked at response to pegaspargase in pH-negative ALL.

In this cohort, there were a lot of patients, over 1500 patients who were age 1 to 45, and what they did was that they capped the dose at 1000, so like a lot lower, 1000 IU/m², so this is a lot lower than what we use, and they did not give these patients cranial radiation. So what did they find? They found that despite that lower dose, if you look here at the overall survival, that in general, this orange line, for those aged 1-9, they still, the DFS is, not too bad, it is actually pretty good.

The highest was in the younger patients, I think, if I recall, this was 89%, and this line here, the 10-17, was about 84%, and this orange 1 was about 70-something. So despite lowering the dose, the patients still had pretty good outcome.

[01:07:04]

Pegaspargase-Associated Grade 3/4 Hyperbilirubinemia: Risk Factors

This is, again, another study to look at what are some of the risk factors that are associated with grade 3/4 hyperbili, and it looked at over 1,000 patients, and what they found is that for these patients who are given a dose of 1,000 IU/m² or 2,000 IU/m², they found that there is a higher incidence of hyperbili with a higher dose.

They found that those who are older than 45 had a higher incidence of hyperbili, and when they looked at the BMI, which I know that we have different definitions, but at the time, historically, obesity was measured by BMI, but the BMI of 30 or higher was an obese patient. More patients who were obese had hyperbili, so that is what this showed. And same here, Memorial Sloan Kettering did a very similar study, and their dose was 2,000 IU/m2. They also showed that patients who were older had a higher incidence of hyperbilirubinemia.

[01:07:59]

Pediatric Regimen With Pegaspargase Dose Modifications for Comorbidities in Adults With ALL

What are some strategies that can be done, at least in the adolescent and adult patients? In this study by Patel, published in 2021, what they did was make some changes. They modified their doses of PEG, but used still the same pediatric protocol. And so for them, the standard PEG dose was 2500 IU/m², but in the reduced model, they used 1,000 IU/m², and they switched the pred to dex, but instead of a whole month of steroids, it was broken up into 1 week at a time, Week 1, and then again at Week 3.

What they found was that the CR rate, where patients who were M1, less than 5%, was still pretty good at 77% end of induction, and they found that the induction toxicity was 40%, with the hepatotoxicity of 27%, which is less than some of the other numbers that we had seen.

[01:09:04]

Pediatric Regimen With Pegaspargase Dose Modifications for Comorbidities in Adults With ALL

I think what I will mention with this is that this is a similar study as well, and what it looked at was, again, using a pediatric protocol, but modifying the dose to be a lot lower, and lower meaning 250 IU/m², 500 IU/m², and then 1,000 IU/m², and then checking levels, and looking at their relapse-free survival.

And so I just want to, if you look at this graph here, the 250 IU/m² doses, they did not really get good therapeutic levels 7 days later. But if you look here at the 500 IU/m², and even 1,000 IU/m², the majority of patients were able to sustain therapeutic levels, and it was statistically significant, even at these lower doses. So I think this was done to see if they had less toxicity. And when they compared, if you were to give them the reduced dose, which is the 500 IU/m² or the 1,000 IU/m², vs the standard dose of 2,500 IU/m², if you look at the relapse-free survival in this cohort, it is pretty unchanged, so very similar.

[01:10:15]

Mitigation of Pegaspargase-Related Hepatotoxicity

And so, to round up this topic, it is hard for us to synchronize PEG and dauno, I think maybe you can do that more in the adult protocol, but then something that maybe in the pediatric world we can do is consider using L-carnitine. There are lots of studies now, 1 being done, but all the studies retrospectively you can find that show that this is well-tolerated, and may be able to be beneficial

Not dose-reduced, but dose-capped for certain patients, I would definitely say there is a COG standard to do for those who are older, and those who are obese, and the obesity, as you know, there are different thresholds for that.

And then, as I mentioned, try to really avoid using hepatotoxic drugs, especially during induction. If you can switch them out, that would be great.

Asparaginase-Associated Thrombosis and Strategies to Increase Completion of Asparaginase-Based Therapy in ALL

[01:11:11]

And so, I think I am rounding down to the last few. The next topic is on thrombosis, and how can we navigate that?

[01:11:18]

Common Asparaginase Toxicities: Presentation and Incidence (Pediatric vs Adult Patients)

As you may know, most thrombosis are venous, whether it is extremity, pulmonary emboli, or CNS thrombosis, occurs definitely more in adults than pediatrics.

[01:11:32]

Thrombosis

I think the incidence in pediatrics is somewhere between about 5%. And the mechanism is that it is because asparaginase is known to deplete some anticoagulation agents that include protein C, protein S, plasminogen. But I think that the main culprit is the fact that it reduces antithrombin, and that is probably the main mechanism that it causes thrombosis.

As I mentioned, it is typically venous. Some of the risk factors, which you probably know, is, as I mentioned, age, older age, can increase the risk. Obesity, having a mediastinal mass. Really, I would not say a low WC. I would say a hypercoagulable state, you know, hyperleukostasis. A high white count would probably cause it. I think an indwelling catheter can do that, too. Many of us see that, but also patients who are on OCPs or contraception can all increase the risk for thrombosis.

I think that many of us will see patients who have abnormal DIC. Unless they are bleeding or about to do a procedure, we typically do not recommend that you replace cryo if they have a low fibrinogen, unless they are symptomatic, or you are about to do an LP, because we know that that can definitely increase the risk for a clot.

[01:12:59]

Thrombosis: Treatment

And so what is the treatment? I would say the treatment is probably the same as your general treatment for venous thrombosis. However, what about, I think the question that we get asked a lot is, when do you rechallenge? Can they get asparaginase, whatever formulation of asparaginase, whether it is first or second line? I would say that if it is like an extremity, a DVT, once you start them on anticoagulation, low-molecular heparin, Lovenox, whatnot, that it is probably reasonable at a later time to resume them on asparaginase therapy again. I would say that with a pulmonary embolus, it is doable to resume, but I would not resume right away.

Typically, what we do is put them on anticoagulation, whether it is Lovenox, wait a little bit, and then a lot of us would typically do repeat imaging, see if there are collaterals, and if there is, patient's doing well, then it is reasonable to rechallenge at a later time.

However, what about cavernous sinus thrombosis or cerebral thrombosis? I think that is really challenging. We know the high mortality. I am showing you this study from the Nordic 2008 that showed that 46 patients had cerebral sinus thrombosis, and they were re-exposed. They were treated with low-molecular heparin and then re-exposed to asparaginase. And they seemed to do fine. But I think that being said, in the pediatric world, I am not as brave, and I think a lot of us are probably not as brave if our patient has a CNS clot. We probably would not rechallenge them, and I think all of us would agree on that. So I would be careful, just because of the high incidence of morbidity and mortality with CNS thrombosis.

Asparaginase-Associated Pancreatitis and Strategies to Increase Completion of Asparaginase-Based Therapy in ALL

[01:14:51]

So pancreatitis can be broken down to 2 categories. You can have, again, as I mentioned, it is seen more in adults than pediatrics.

[01:15:02]

Common Asparaginase Toxicities: Presentation and Incidence (Pediatric vs Adult Patients)

You can have 2 types of pancreatitis. One is what I call, I would not say it is insignificant, but I call it a chemical pancreatitis where a patient may have maybe just a little bit of abdominal pain, a grade 1, but an elevated level of your amylase or lipase. However, then there is actually the clinical pancreatitis where you have maybe 2 or more symptoms that I have listed below.

They have abdominal pain, nausea, or vomiting, but they also have serum levels of amylase or lipase that are elevated at least 3 times the upper limit. Or you have an imaging that shows that there is some pancreatitis or inflammation or a pseudocyst or an abscess. So that would meet the criteria for clinical pancreatitis.

I mentioned a little bit earlier, some of the risk factors would be age. Older patients tend to have higher risk. There is some data that shows that those with Native American ancestry can have a higher risk of pancreatitis and then higher doses of asparaginase as well.

So if you have a patient who has, I think we get this question a lot, who comes in with pancreatitis, typically, it is supportive care. Make them NPO, put them on IV fluids. If you anticipate it is going to be a long time, put them on TPN, analgesia. If they have fevers, then you can consider broad spectrum antibiotics.

However, it is all really supportive care. And of course, imaging, I think if you are very concerned and if there is a pseudocyst or hemorrhagic pancreatitis or abscess is when we get really worried, and we definitely would not rechallenge for that. However, really, when would you rechallenge is, again, if it is a chemical pancreatitis, mild, grade 1, maybe even a grade 2, you can consider rechallenging them.

[01:17:08]

Pancreatitis: Discontinue Asparaginase vs Rechallenge?

And if you rechallenge them, there is, for severe pancreatitis, you are going to probably see recurrence. And this study showed that there was a high incidence, a 2008 NOPHO study that a high incidence of patients, over 40% who were rechallenged did see a recurrence.

So I think for a laboratory finding, go for it, rechallenge. However, if it is severe, I would not recommend it. And would just, unfortunately, have to omit that from their therapy.

Let’s Consider a Patient Case

[01:17:50]

Patient Case: 18-Yr-Old Patient With B-Cell ALL

We will go through this real quick. 18-year-old female with B-cell ALL, and they have peak levels of asparaginase, post-asparaginase, that is T-bili that is high at 20. And over time, it gets better.

[01:18:02]

Posttest 3: Which of the following approaches would you recommend for this 18-yr-old patient?

So what would you do? Would you continue on the same dose, switch to Erwinia, Hyper CVAD, etc?

[01:18:28]

So continue with the same dose of PEG, awesome.

So pre, 79% said that, post, over 90%. And I think, as we mentioned, hepatotoxicity occurs mainly in induction. And you can see it later, but it is definitely not an indication to omit your asparaginase-based therapy. And there are lots of ways to mitigate it.