Incorporating Asparaginase Therapy Into Clinical Practice: Current and Future Clinical Practice

for the final part of the program, tasked with talking about incorporating asparaginase therapy into clinical practice, both current and future. The future's a lot, so I will get into that a little bit.

[01:19:18]

Optimal Asparaginase Therapy Selection and Management for Individual Patients With ALL

And just to go over the objectives, talk about current use of asparaginase in upfront pediatric ALL trials. Talk a little bit about how we got there, and then maybe a little bit about what might be coming for the future, basically because we have a lot of new agents. And so as we incorporate those into our practice, what does that mean for asparaginase therapy?

Talk about some guidelines, bringing that into care, specifically looking at premedication and therapeutic drug monitoring. And then a little bit on the application of pediatric protocols, which I think we have already touched on some for AYA patients.

[01:19:50]

Current Asparaginase Use in ALL

So current asparaginase use in ALL depends a little bit on where you practice at.

And so for COG centers, if you are an NCI standard-risk patient, you get 2 doses of asparaginase, long-acting asparaginase, 1 in induction, and 1 in delayed intensification. If you are a high-risk B-ALL or a T-ALL patient, you get 1 in induction, 6 post induction for a total of 7 doses.

For the Dana-Farber consortium protocols, their strategy for asparaginase is a little bit different. You do get the 1 dose in induction, but then there is a 30-week consolidation phase of therapy where the goal is continuous asparaginase depletion. And so what that means is for the Cal-PEG, they get ten doses of Cal-PEG every 3 weeks over a 30-week period.

St. Jude's total therapy is similar to COG, but not identical. They get 2 doses in induction. And then low-risk patients will get 2 post induction, and standard-risk or high-risk patients will get 10 post induction for a total of 12 doses. So more asparaginase exposure than COG.

And then adults, and I will not wade into the variation of practice in the adult world, but the E1910 study, which incorporated blinatumomab, had 2 induction and 2 post-induction doses of long-acting asparaginase as part of that protocol.

[01:21:01]

Calaspargase

So calaspargase, which is now the only long-acting asparaginase that us pediatric people have access to, was approved by the FDA in 2018 based on 2 clinical trials that we will go through for the treatment of pediatric ALL from 1 month to 21 years.

In December 2023, that formulation, which was sparingly used before, became the only formulation available for this age ring of patients. We talked a little bit about the differences, a longer half-life and a more stable molecule leading to a longer shelf life. The half-life for Cal‑PEG is 16 days, and the half-life for pegaspargase is 5.7 days. So in that sense, quite a longer exposure.

[01:21:43]

COG AALL07P4: Pharmacokinetics of Calaspargase and Pegaspargase in Newly Diagnosed High-Risk B-cell ALL

So COG did a study comparing pegaspargase to calaspargase, the AALL07P4 study. And so on the left part is asparaginase activity.

And you can see for the first couple weeks after exposure to a dose of asparaginase, both pegaspargase and 2 different doses of calaspargase that were investigated, standard 2,500 units/m², and then a lower 2,100 units/m² dose have the same pharmacokinetic profile. And then as you get 2 and a half weeks to 20 days in, you can see the pegaspargase patients start to have asparagase activity that is not considered to be therapeutic at less than 0.1, and then oppositely on this graph, you can see asparagine levels, and the blue line there is pegaspargase. And you can see at Day 18-20, that starts to really increase, while it still stays pretty low for both the calaspargase doses.

[01:22:40]

COG AALL07P4: End-of-Induction Response and Adverse Events With Pegaspargase and Calaspargase

And so, looking at response on this study, the first thing I want to point out is that for the lower calaspargase dose, the 2,100 units/m², you can see in terms of both MRD at the end of induction and rapid early response, the outcomes were a little bit worse in that group. And while they were not statistically significant, they did meet predetermined stopping rules for that study, so that lower-dose arm was closed on that study. For both pegaspargase and calaspargase at standard dosing, these outcomes in terms of MRD and rapid response were pretty similar, and there was no difference between some of the major asparaginase toxicities, such as hypersensitivity, thrombosis, and pancreatitis between any of the arms on this study.

[01:23:20]

DFCI 11-001: Efficacy and Safety of Pegaspargase and Calaspargase in Childhood ALL

A second study was done comparing pegaspargase to calaspargase by the Dana-Farber Consortium, and you can see on the pharmacokinetic chart here, pretty similar, very, very similar rates of asparaginase activity early on after the dose, and then between days 18-25, the pegaspargase activity drops off. And so when you looked at patients on day 25 using 0.1 units per mL as a cutoff, 88% of patients that got Cal-PEG were still therapeutic, while only 17% of patients that got pegaspargase were therapeutic. Again, no differences in some of the major toxicities that we look for in pegaspargase, and again, outcomes looking at  overall survival were very similar, basically hovering around 95% for both arms of the study.

So based on these 2 studies is how calaspargase got FDA-approved. It is now the only long-acting asparaginase patients for pediatric patients.

[01:24:11]

AALL1931: Phase II/III Trial of Recombinant Erwinia Asparaginase in ALL

This was mostly already shown, just sort of touching on most centers now use the Monday, Wednesday, Friday 25/25/50 mg/m² dosing schedule, and on that schedule, 90% of patients will have a trough dose at hour 72 that is therapeutic.

And here on the right, we are again reviewing the toxicity, really kind of standard levels of asparaginase-associated toxicity for these patients. And so recombinant Erwinia was approved in June of 2021, and then the Monday, Wednesday, Friday with the Friday 50 mg/m² dose was added to the label in 2022.

[01:24:49]

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

And so again, this slide has already been shown, but I just want to circle back. I got to feel a little bit old when it was mentioned that the new generation of pediatric oncologists are not familiar with O232 and O331, which were open when I was a fellow.

But 25% of the patients on the high-risk study did not complete their asparaginase therapy, and those patients had a 50% higher risk of relapse. And so maybe the goal of the future of asparaginase is to use less of it. We do have to ground ourselves that it is still a very important medicine and make sure that we study it very carefully in clinical trials. So future.

And so as we look to adding blinatumomab for most of our patients, ways in the pediatric community to add inotuzumab, part of that is going to be getting rid of, hopefully, some of the rest of the chemotherapy. And so in the adult study, I mentioned earlier that they get 4 doses of pegaspargase as part of that E1910 study. On the CALGB 10403 study, which mimicked pediatric high-risk study, patients got 7 doses on that. So for people that use the E1910, that is a reduction in total asparaginase exposure for adult patients.

St. Jude is currently doing a phase II study for their high-risk B-cell patients that incorporates blinatumomab and inotuzumab, and 1 of the goals of that study is to reduce the total amount of asparaginase that patients get. And then COG for the high-risk B-cell patients looking at reopening the 1732 study with blinatumomab, still randomizing to inotuzumab, with patients that get into getting only half of consolidation in DI, which would reduce total asparaginase doses from 7 to 5 on that trial.

[01:26:20]

Poll 3: What premedication strategy do you use for your patients receiving calaspargase?

So now we will get back into a poll before we get to some of the rest of the stuff. So for this question, there is not really a standard of care, so we were just kind of curious of what people were doing. And so, what premedication strategy do you use in your clinic for patients receiving calaspargase?

1. No premeds;
2. H1 plus H2, so like benadryl and famotidine;
3. H1 and steroids;
4. H2 and steroids; or
5. All 3.

Kind of expected that there is a range, and at least 1 person answered for each of those things that they used that strategy. And so we will kind of go through that.

[01:27:12]

Poll 4: What premedication strategy do you use for your patients receiving recombinant Erwinia ASNase?

Okay, the next question is looking at the same thing basically for Erwinia. And so there is again not really a standard for the way people do this, just kind of curious what people are doing in their practice.

So, again, varying answers, but still a little bit different than for Cal-PEG with I guess notably no premedication being answered more often on this one, which I kind of expected.

[01:27:47]

Calaspargase Administration and Premedication

So the manufacturer's recommendation for calaspargase for premedication is both an H1 and an H2 blocker given 30-60 minutes prior to administration. The data on this has been mixed, and all the data is from mostly single center retrospective analysis.

And so practice across institutions, as we just kind of proved in this room, is highly variable looking at COG centers. And so there was a poster at ASH that surveyed COG centers, and most of them use Benadryl or H1 blocker, two-thirds use an H2 blocker, and just over 50% use steroids. Certainly, nowhere in there to pick out a standard of care.

[01:28:30]

Asparaginase Premedication

And if you look at the data, I know we showed earlier Stacy Cooper's data from Johns Hopkins where they instituted premedication, and it looked amazing. And a lot less patients needed Rylaze, and that was statistically significant. A couple other groups have looked at it retrospectively, and so there was a study that looked at both Seattle and Children's Hospital of Los Angeles who both used different strategies.

And you can see by the data here, no real change in the rate of hypersensitivity reactions. And then CHOA in Atlanta looked at their retrospective analysis, 2 different strategies, 1 using all 3 medicines, and again, no real change in the incidence.

So while the data from Johns Hopkins was super promising, I do not think anyone has really been able to show after that, that it makes a huge difference, hence the wide variety of practice patterns.

[01:29:20]

Recombinant Erwinia Asparaginase and Premedication

And so for recombinant Erwinia, the manufacturer's recommendations, again, an H1 and an H2 blocker. They also recommend acetaminophen, which I do not think a lot of people actually do, 30-60 minutes prior to presentation.

And so I would say practice here, as we saw, is also variable, probably more so than it is for calaspargase, and for the reason that we are doing this 3 times a week, 2 weeks in a row, 6 times, that is a lot of premeds, that 30-60 minutes starts to add up when you are doing all those doses, and so it is more time in clinic. And the toxicity profile, it does not seem to be any worse. And so, like we showed here, 50% of people do not premedicate. I think a lot more centers do not premedicate for recombinant Erwinia than they do for calaspargase.

[01:30:03]

Poll 5: How do you use therapeutic drug monitoring (TDM) for your patients receiving calaspargase?

And so last poll question, how do you use therapeutic drug monitoring for your calaspargase patients?

1. No TDM;
2. Check it after one week;
3. Check it after two weeks;
4. Check it both after one week and two weeks; or
5. Other, because there can be a lot of different strategies.

Okay, so there we go. Quite a bit of variety there. Most common answer was 1 week after dose, which I will confess, that is what we do in our practice.

[01:30:52]

Asparaginase and Therapeutic Drug Monitoring

Therapeutic drug monitoring. So easy to say therapeutic drug monitoring is strongly recommended following asparaginase administration. It’s a little bit harder to say exactly how that looks in practice. So there are COG guidelines in their protocols.

If you check it an hour to a day, which I do not think many people do commonly in their practice, anything less than 0.5, they say, is a reason to switch. If you check it at 1 week, anything less than 0.3 is suggested a reason to switch. And then at 14 days, anything less than 0.1, you should switch formulations.

In Europe, there is an ALLTogether group that contains most of the European countries, including the UK, that are doing ALL protocols, and their guidelines are different than the COG guidelines. So they check at Day 7 level. If that is less than 0.1, they recommend switching. And they check at day 14 if they are using pegaspargase, day 21 for calaspargase, and if that level is below the level of detection, they recommend switching. So even within those 2 prominent consortiums, there is a little bit of a disagreement in exactly how that is used in practice.

[01:31:55]

Recombinant Erwinia Asparaginase and Therapeutic Drug Monitoring

Even harder is TDM for recombinant Erwinia asparaginase. And so guidelines are limited. I think most people agree that trough levels should be measured at some point, but exactly how to do that, and since there is not really a switch for recombinant Erwinia, what to do if your level is too low.

I think the easiest thing to say is that you should probably try to monitor this at the 72-hour time point, which logistically may have some issues, and if that level is less than 0.1, then probably recommend going to an every-other-day dose if that is something that is feasible to your clinic. Fortunately, based on the data, 90% of patients will still have good levels, so hopefully that is okay. However, that is kind of where we are at for that.

[01:32:35]

Treatment of AYAs With ALL

And then lastly, talking about the treatment of AYAs with ALL, there are some ASH draft recommendations out there that, as we have discussed, kind of recommend that pediatric-inspired asparaginase-containing regimens, such as the CALGB 10403, be used for AYA patients, as opposed to non-asparaginase-containing regimens like hyper CVAD.

There are NCCN guidelines for adults that recommend capping your dose at 375 units for adult patients. In the pediatric practice, that is not a formal recommendation. Some centers choose to cap doses for obese patients because they are worried about hepatotoxicity, but that is not something that is universally practiced.

And then as we talk about the future of treatment, knowing that AYAs in adult patients experience a lot of the side effects of asparaginase more so than younger patients, even more important to look at how do we reduce asparaginase exposure as we introduce new agents into practice.

Putting It All Together: Sharing Best Practices Across the Global Community

[01:33:31]

And so that kind of concludes this part of the talk.

A Quick Survey

[01:33:37]

Poll 6: Do you plan to make any changes in your clinical practice based on what you learned in today’s program?

There is a quick survey. And so, do you plan to make any changes in your clinical practice based on what you learned today?

[01:34:10]

Poll 7: Please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education.

And then 7 is, please take a moment to text in 1 key change that you plan to make in your clinical practice based on this education.

All right, thank you for answering that.

And now we will go on to the question-and-answer session. And I know there are already a few questions that have been put into the magic iPad over here.

Q&A

Dr Curran: So the virtual question was, are protocols specific for B-cell and T-cell ALL?

Dr August: I can speak from a COG standpoint is that, yes, we do have separate B-cell and T-cell protocols. I think with blina, it is going to be hard to have both of them on the same study because blina, in theory, does not work for T-cell because it does not express CD19. And also TALL, I think most people are incorporating nelarabine into their protocols.

So as far as asparaginase is concerned, T-cell and B-cell are analogous in their asparaginase exposure. I think the last COG trial, 1231, actually had 2 extra doses, but there was no real evidence that those helped and maybe a little bit of evidence that those caused more toxicity. And then with calaspargase, you cannot give it day 4 and day 18. So those are just removed from what most people are doing.

Dr Curran: Okay. The next question is, what is the prognosis of a patient who has hypersensitivity? I am going to say, I think this is hypersensitivity from asparaginase. And I assume this is also maybe without being able to replace.

Dr Huynh: So probably just hypersensitivity to both. Can we go back to that? Okay.

So what is the prognosis of a patient with hypersensitivity to both? Probably it means first-line and the second-line Erwinia-based. And so I think you can extract that if it is the prognosis is not bad just because they have hypersensitivity, but I think the issue is if they are not able to get asparaginase therapy. I think we show the data from Dr Gupta that patients where asparaginase was completely omitted, tend to have a worse outcome. That being said, I think anecdotally, I have had patients where for whatever reason, they just could not have it, and they are still doing okay. However, I think on a global level, you can extract the data that because they are not getting all of their asparaginase treatment, they tend to have a worse survival.

Dr August: How did obese patients respond to pegasparaginase-associated grade 3/4 hyperbilirubinemia?

Dr Curran: I can take this because we see this quite a bit. I think the chances of a long-term liver toxicity from pegasparaginase when you get that hyperbilirubinemia, you do not typically see long-term liver toxicity. However, the issue is, again, that you have to delay the subsequent cycles of chemotherapy.

I will, I guess, let you guys talk about obese, but I will just quickly say for us in our young adults who are obese, we always cap. And sometimes we do actually dose reduce. Because we know they are at higher risk, we actually will give them a dose of 1000 IU/m².

However, I do not know if you guys want to speak about pediatric patients.

Dr Huynh: I think in general, as we have mentioned, that it is recommended in the pediatric protocols to cap the dose at 3750 IU/m². However, I think, just for me, I wonder if we can push the dose even further. I think maybe that is my dream, is to see, moving forward, can we do studies?

Some of the studies I presented, they were giving doses of 1,000 IU/m², but I do not know if I would go that low. Can we push it down to 2000 IU/m², and will we see still efficacious levels and still good survival, but less toxicity?

I think that is where maybe we can start pushing the envelope in future studies.

I do not know what you think?

Dr August: I do not have anything to add to that.

Dr Curran: There are a question commenting on encephalopathy and ammonia levels. Is there any practical advice?

Dr August: I have seen reactions that are associated with elevated ammonia levels, like patients kind of turning red and getting GI symptoms. I think our response to that has just been to slow down the infusion. And to be honest, we now practice a slowdown of infusion, and I think see that a lot less.

However, I do not know if anyone else has seen encephalopathy.

Dr Huynh: There is so much to talk about. So for those who do not know, the high ammonia level is because when you give the IV formulation, you get a rapid breakdown of glutamine and asparagine, which releases ammonia levels, so you see that high uptick.

And so you can measure the ammonia levels. I think in general, I do not know that we have seen such significant encephalopathy, but I think the treatment would be, as Keith said, you can slow down their infusion, see if it helps. However, if a patient is symptomatic, I think a lot of us would admit them and give them fluids and lactulose and try to bring that level down.

It is usually reversible. I do not think they have long-term sequelae from that.

Dr Curran: All right, and then I think the last 1, I think it is commenting on the patient experience when they have pancreatitis or thrombosis, and I assume their reaction to it. I will say, my patients, because when they get pancreatitis, I do not ever rechallenge. If they have a central venous thrombosis, I also do not rechallenge, and that can be very stressful for the patients.

I think hopefully with some of these newer agents, like blinatumomab, we can try to mitigate some of that risk of not getting it, but it can be very stressful. I do not know if you guys have other thoughts.

Dr Huynh: Yes, so I think we had mentioned about when do you rechallenge, but it is stressful, Especially, you see pancreatitis in our population, especially the AYA, it can be pretty severe. They end up in the ICU, septic shock, you name it, right, hemorrhagic pancreatitis, and I think it is tough when you tell the family they cannot get it. It makes us nervous, too, that they cannot get it anymore. So I think when you can rechallenge, I think it is ideal if it is not so severe. If it is not such a significant clot, I definitely would try. However, if it is severe, I would not rechallenge and hope, really hope that they get all the rest of the treatment.

Keith?

Dr August: There is also the opposite. There is being afraid of not getting it, but also, if you have got moderate pancreatitis, lipase went up, you were in the hospital for a few days with pain, working through that, and my thought, and I guess I have been successful in the 2 or 3 cases that this has, is to push through, and it is worked out well. However, certainly, there is a lot of anxiety because that is not a great experience for patients.