This is probably a slide set that some of you have seen, generally speaking, to the advancement that we have had over time with the treatment of ALL, particularly in pediatric populations on the left. You see this amazing improvement over time from the late 1960s, where there was almost a uniform, grim prognosis of patients, to now, where the vast majority of patients survive and are cured of their disease.

And this improvement seems to be mainly impacting the younger patients. And by the time you get into your late teens and 20s, the improvements that we have seen in terms of 5-year overall survival, as you can see on the right there, seem to plateau.

And there's probably many reasons for that. Generally speaking, compliance levels off as you get older and you're able to make decisions for yourself. Tolerability to medications that is higher among children goes down as you age and you get more side effects, so you get lower doses of effective treatments. You're also more likely to have higher risk molecular features in your disease as you age.

So I think all of those things together probably impact the likelihood of success with ALL, with age.

[00:58:15]

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

And they talk about this cliff in terms of the activity and survival—activity of treatment and survival for patients following treatment. And it typically occurs in that AYA age range of 15 to 39, which is late adolescence and young adult.

And what is causing that? I brought up a few things that include the treatment approach, which may be less intensive and different, the biology of the disease which evolves with age, and certain psychosocial factors that impact us as we age.

[00:58:52]

Outcomes in AYA Patients Improved With Pediatric Regimens

AYA patients or adolescent young adult patients with ALL have better outcomes when they receive the more pediatric-inspired regimens as opposed to adult-based regimens. And this was pioneered by Wendy Stock at the University of Chicago. She's done several studies now using the CALGB cooperative group to enroll patients and study these pediatric-inspired regimens that incorporate more intensive asparaginase and steroid dosing.

And she has demonstrated that the pediatric regimens lead to markedly improved long-term overall survival advantage, as can be seen here by this Kaplan-Meier curve, and this has since been replicated by several groups, including 1 here in Boston at the DFCI.

[00:59:39]

CALGB 10403: Survival Outcomes

The CALGB-10403 is now sort of the famous AYA paper was published in Blood in 2019. The goal of this was to determine the feasibility and efficacy of a pediatric-based treatment for these younger adult patients. And the overall survival was remarkable. Three-year overall survival was around 73%, and the event-free survival was also quite remarkable at over 50%.

295 patients were enrolled, majority B-cell ALL. The median age was young at 24. The complete remission rate was exceptionally high. And importantly, the induction mortality rate was 3%.

Now, the worry you have in giving adults pediatric regimens is toxicity, and in general, the overall early mortality and treatment-related mortality with this regimen was low, when with the promising efficacy, this was quite reassuring and exciting.

[01:00:40]

Establishing the Role of Asparaginase Therapy in Patients With ALL

And an important aspect of AYA regimens is asparaginase therapy. So how do you establish that role?

[01:00:46]

ASNase: Mechanism of Action

Let's provide a brief background on asparaginase. Asparagine is a non-essential amino acid that is synthesized from aspartic acid by most of our cells. And the enzyme that does that is asparagine synthetase. ALL cells lack this enzyme, which makes them unique among the human cells, and that's good because they depend on the import of asparagine from the plasma. And when you deplete that, you make the leukemic cells uniquely sensitive and potentially target them for cytotoxicity. And that's why asparaginase is a key component of very effective therapies for ALL.

Asparaginase catalyzes the rapid deamination of asparagine to aspartic acid and just breaks it down. And pharmacologic administration of asparaginase depletes the plasma asparagine, which is the lone source for ALL cells, and as a result, leads to targeted killing of those cells.

[01:01:48]

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

And the development of asparaginase occurred in the late 1970s, several years after the incorporation of traditional chemotherapies—most of the traditional chemotherapies into ALL regimens and really has transformed the field.

[01:02:06]

NOPHO ALL2008: Responses to Pegaspargase in Ph-Negative

Here is some data. Again, age dependent-data, but this time with a focus on asparaginase. This is data from the Nordic group looking at the incorporation of pegylated asparaginase in regimens for young adults who received the therapy for their ALL. And as you can see, this too is age-dependent. The younger you are in general, the better you do with treatment that incorporates asparaginase.

[01:02:38]

Pegaspargase-Associated Grade 3/4 Hyperbilirubinemia: Risk Factors

One of the key challenges of incorporating asparaginase into treatment of ALL is unfortunately its toxicity. And it can be toxic certainly. Liver toxicity mainly manifesting as hyperbilirubinemia and transaminitis, pancreatitis, thrombosis, infusion reactions. These can be quite problematic. But you can identify individual risk parameters in patients that may increase the risk. So the dose certainly has an effect.

If you give pegaspargase at a dose of 1000 as opposed to 2000 units/m², the likelihood of liver injury is lower. Similarly, patients who are older or have a higher BMI are more likely to have liver injury as a result of exposure to pegaspargase.

[01:03:36]

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

There are recommendations that have emerged regarding addressing potential for liver injury in patients who receive pegaspargase. And these are mainly focused at reducing the standard dose from 2500 to 1000 units per meter squared, and also using dexamethasone as opposed to prednisone. Doing this did not really lead to a decrease in the remission rate at 28 days.

The induction dose was promising and liver toxicity overall was less. But nevertheless, it's important to sort of keep in mind that there is an ability to reduce the dose of pegaspargase for potentially for patients who might be at risk, such as those who have a higher BMI or older, or may have other underlying liver disease.

[01:04:27]

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

So what happens when you reduce the dose? Well, there's probably a limit. I think limiting it - decreasing the dose to 1000 or even sometimes to 500 may make sense in terms of, you know, effectively limiting asparaginase activity. Once you get below 500, you probably lose some degree of activity and efficacy.

But generally speaking, between a dose of 500 and 1000, as long as you are able to follow asparaginase activity, in general, patients seem to do well. So reduced and standard peg-asparaginase in general, in terms of relapse-free survival, as published by this group, Derman and colleagues in 2020, did not seem to reveal any difference.

[01:05:13]

Asparaginase as Part of Standard ALL Therapy

Asparaginase as a part of standard ALL therapy. Now, there are many ways you can give asparaginase in several formulations, some of which are available in the US and others that are available also in Europe.

[01:05:26]

Current Asparaginase Use in ALL

These are data that looking at the Children's Oncology Group, the DFCI team, as well as other regimens from other cooperative groups that use various formulations and different dosing over time to incorporate asparaginase into regimens.

[01:05:44]

Asparaginase: Formulations Overview      

These are the formulations that generally are available or may not be available depending on the country you're at. So E coli-derived asparaginase is still around, certainly being used outside the United States, but we do not generally have it available here.

Pegylated forms of E coli asparaginase are available in the United States, pegaspargase and calaspargase pegol, which is used as a different linker allowing for persistence of the asparaginase and effective suppression of asparagine over time.

And then Erwinia, which is available in US and Europe in intramuscular and intravenous formulations.

[01:06:30]

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

This is some data that has emerged looking specifically at calaspargase and pegaspargase in terms of the persistence of the asparaginase and this effective suppression of asparagine, as can be seen here. In general, calaspargase more effectively depletes asparagine over time. This is thought to be potentially related to the pegylated form of the succinate linker.

So this particular SS-PEG has a succinimidyl carbonate linker, which creates a more stable molecule and as a result is more effective in sort of providing a persisting response over time based on this data that was published about 10 years ago in the JCO.

[01:07:37]

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

This is some data from Erwinia asparaginase product looking at the dosing of this product, which is given on Monday, Wednesday and Friday of the week looking at different doses. The first cohort was 25 mg, the second was 37.5. And then there was a sort of a hybrid regimen, which was given 25 on Monday and Wednesday and 50 on Friday.

For the latter 2, you'd see this effective decrease of NSAA levels, which stands for nadir serum asparaginase activity. So in general, the asparaginase activity was quite good in patients who were in cohort 1b and 1c. Allergic reactions, pancreatitis, thrombosis in general were similar across the arms. And the FDA approved a recombinant Erwinia. The Monday, Wednesday dosing of 25 and 50 was added to the label.

[01:08:45]

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

There was a subsequent effort to look at dose confirmation for both intramuscular and intravenous formulations. And in general, these 2 were relatively similar in their efficacy and tolerability. New dosing was approved by the FDA, and then the European groups about a year later provided approval for the IV formulation.

[01:09:15]

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

This data is from the Children's Oncology Group looking at the activity and tolerability of recombinant Erwinia. Again, looking at these 3 dosing levels, you can see grade 3 or 4 toxicities are relatively similar between 1b and 1c. And therapy discontinuation also relatively similar with no deaths reported.

[01:09:41]

Recombinant Erwinia Asparaginase in ALL

So Erwinia asparaginase is now available in the United States. In general, 6 to doses are used to replace 1 dose of pegylated asparaginase. So the dosing is obviously different in terms of the timing and how frequent you give them.

There are current FDA-approved regimens, Monday, Wednesday, 25 mg/m² intramuscular and Friday 50 mg. And then you can also do the every 48-hour 25 mg/m², similar types of activity and tolerability.

In Europe, there is also the IV formulations.

[01:10:17]

Recombinant Erwinia Asparaginase and Premedication

Now this is an important piece. The manufacturers recommend premedication with acetaminophen histamine blockade prior to administration. But in practice there is a decent amount of variability, although the manufacturer recommendation also for calaspargase, the pegylated form is also with H1 and H2 blocker prior to administration. Again, there is a different degree of uptake of these recommendations over time.

[01:10:47]

Asparaginase Premedication

This is a table that looks at various publications that have looked at both, histamine blockade and steroids. As you can see, it's pretty much all over the map. Different folks instituting the policies before and after and seeing if there was a difference. The pediatric group published in Blood Cancer actually showed an improvement with the regimen in terms of hypersensitivity reactions, but the other groups did not.

I can tell you at our center, in terms of incorporating asparaginase, we do premedicate with both histamine blockade and steroids.

[01:11:23]

Asparaginase Products: Major Agent-Specific Toxicities

It's not only the hypersensitivity reactions which can be potentially problematic and at times can lead to hemodynamic challenges. A similarly challenging perplexity there is the development of antibodies that can be produced following asparaginase therapy. And although they may or may not produce hypersensitivity, they often cause inactivation of asparaginase and prevent its function, so leading to suboptimal depletion of asparagine.

So this can occur at full doses. It can occur at reduced doses. Certainly more likely to occur at reduced doses. And allergic reactions, they can occur up to a third of patients. But given that there is no cross-reactivity between E coli derived products and Erwinia products, the general recommendation for patients who have significant hypersensitivity allergic reactions is to use Erwinia products thereafter, to decrease the likelihood of a problem going forward.

[01:12:31]

Asparaginase Products: Major Class-Specific Toxicities

How about major class specific toxicities? So changing products within the same class does not reduce risk of recurrence. So for pancreatitis, it occurs—here it says 4% to 18%. I can tell you when this happens, it can be quite upsetting as it can be severe. Adolescents seem to be at higher risk than younger children.

And not surprisingly, patients can present with abdominal pain and elevated lipase and amylase. Risk factors are elevated age, Native American ancestry and higher doses of the asparaginase. Thrombosis or even bleeding events are also potentially problematic. They occur in 2% to 4% of patients.

Thrombotic complications can be quite severe. You can get cerebral thrombosis, pulmonary embolisms, DVTs. And they can be quite challenging.

Hepatic toxicity can happen in the form of bilirubinemia and transaminitis, as we mentioned earlier. More likely to occur in older patients and those with obesity or underlying liver disease. And hypertriglyceridemia is actually usually not dose-limiting and can be managed over time. We usually use fibrates, but at times it can be a problem.

[01:13:44]

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

So this is looking at some data with pegaspargase and calaspargase. Lower dose arm of calaspargase was terminated due to crossing predetermined response monitoring boundaries, but there was no difference in the rates of allergic reactions, pancreatitis or thrombosis between the study arms in terms of using calaspargase different doses vs pegaspargase and the likelihood of achieving deep response.

[01:14:11]

NCCN Recommendations: Treatment of AYAs With ALL

The NCCN guidelines recommend asparaginase dose capping so not go over 3750 units/m², and many times you can go much below that as we've talked about. So many pediatric centers practice dose capping at 3750.

As AYAs experience many asparaginase toxicities at much higher rates than pediatric regimens, the use of developing agents in ALL, such as blinatumomab and inotuzumab ozogamicin, the antibody-based therapies may reduce the need to give higher doses of asparaginase that cause these problems often.

[01:14:48]

ASH Recommendations for AYA ALL Receiving 1L Pediatric-Inspired (Asparaginase-Containing) Regimens

This is a pretty dense slide. Just some of the stuff is highlighted that we've already talked about. These are recommendations that have emerged from the ASH group, the hematology organization.

So ALL patients should receive pediatric-inspired regimens, particularly those who are adolescent or young adults certainly. That is the general recommendation. There is empiric dose capping and dose reductions that are reasonable strategies to mitigate toxicities. And as I mentioned, there are certain groups that you want to focus your attention on.

Prophylactic premedications are recommended to prevent hypersensitivity reactions. In patients who develop hypersensitivity reactions, the recommendation is to switch to Erwinia-based asparaginase formulations as opposed to discontinuation of asparaginase therapy. The level of that recommendation is strong.

And change of approach to therapy if there is residual MRD after 3 months of frontline therapy is recommended.

[01:15:51]

Summary of Premedication and Therapeutic Drug Monitoring for Prevention of Hypersensitivity Reactions

Here is a summary of premedication and therapeutic drug monitoring for prevention of hypersensitivity reactions. Generally speaking, premedication for asparaginase, recommendation is 20 to 30 minutes prior to dosing. Usually, as I mentioned, as histamine blockade and glucocorticosteroids are used.

Therapeutic drug monitoring is very important. And we've started to do that more and more often with pegylated asparaginase. Generally, the recommendation is a week to 2 weeks later prior to the doses. And with Erwinia because the dosing is different, to do it 2 days later prior to the next dose.

Generally, the recommendation, as I mentioned this, to monitor the serum asparaginase activity. If the levels remain low despite adequate dose, the recommendation is to change to Erwinia or to up the dose. If the levels remain up and reaction is not severe, you can rechallenge with peg-asparaginase. Again, the issue really is the question of whether there is antibody suppression of the asparaginase product.

[01:17:07]

          Posttest 1

Here's a posttest. In your current practice, which of these approaches would you implement to aid in the completion of asparaginase treatment for pediatric ALL?

Speaker: And polling is open. Please vote. And give a few more seconds for incoming responses. And we'll go ahead and close that poll and share.

Dr Fathi: Okay. Most people chose activity level following. And that is the correct answer.

Again, just to summarize, it is necessary to check enzyme activity levels following the current asparaginase dose, prescribe pre-medications, and perform therapeutic drug monitoring. Clinically, the described reaction experienced by these patients is unlikely to be a hypersensitivity reaction. However, it can lead to therapeutic levels being low as a result of antibody formation, and then the use of premedication and subsequent dosing and continuing to perform therapeutic drug monitoring would be optimal.

So with these patients in general, we premedicate check levels and make adjustments over time. That's the right approach.

[01:18:39]

Maximizing Efficacy and Minimizing Toxicity With Asparaginase Therapy

All right. The next segment, Maximizing Efficacy and Minimizing Toxicity with Asparaginase.

[01:18:45]

          Case Study

Here's another case. 21-year-old female with B-cell ALL this time presenting to your clinic. She had initially presented to the emergency department reporting dyspnea. White count was 61,000, with half of them being blasts. FISH was negative for Philadelphia chromosome and KMT2A translocation. She was started on a pediatric-inspired regimen that incorporated calaspargase pegol. Following the administration of this agent, unfortunately, a liver function test discovered a marked elevation in bilirubin as well as some transaminitis. During a 6-week period, bilirubin and liver transaminases showed a gradual trend downward within normal levels.

[01:19:29]

          Pretest 2

Here's a pretest question. Based on the current clinical evidence, what would you recommend as the optimal next step for this patient?

1. Continue with cal peg at the same dose;
2. Continue with the same pediatric-based regimen but without cal peg going forward;
3. Switch to Erwinia-derived asparaginase;
4. Switch to hyper-CVAD to avoid further exposure to cal peg.

Speaker: Polling is open. Please vote. We'll give a few more seconds for incoming responses. Go ahead and close that poll and share.

Dr Fathi: Okay. Seems like we have a mix of responses. Some say continue with cal peg. Some say give the same pediatric regimen, but get rid of the asparaginase. Some say switch to Erwinia, and some say switch to hyper-CVAD.

[01:20:36]

          Case Study

All right, let's go through the data. Before we do that, here's another case. This time a 23-year-old male patient coming in with a white count of 22,000. The CSF data shows CNS1 status. Again, this gentleman was treated with a pediatric-based regimen. At the end of induction, he had a CR, but MRD was detectable at 0.15%.

He experienced hypersensitivity following a second peg-asparaginase dose at 2500 units per meter squared IV. It was given on day 15 of consolidation and the reactions were rash, belly pain, bronchospasm and reduced blood pressure. So pretty significant.

[01:21:17]    

          Pretest 3

Here's another pretest. In your current practice, which of the following evidence-based treatment plans would you recommend as the optimal next approach for this patient?

1. Continue with pegylated asparaginase with premedication;
2. Switch to intramuscular peg-asparaginase anticipating less hypersensitivity than with IV;
3. Switch to non-cross-reactive asparaginase formulation such as Erwinia;
4. Permanently discontinue asparaginase therapy;
5. Prescribe premedication at the next dose and perform therapeutic drug monitoring.

Speaker: And polling is open. Please vote. We'll give a few more seconds. And we'll close that poll and share.

Dr Fathi: All right. Some say switch to intramuscular, actually a minority. Others say switch to non-cross-reactive asparaginase formulation with Erwinia, and others say prescribe premedication and perform therapeutic drug monitoring. I think some of this we've already talked about, but we'll again talk about this.

[01:22:33]

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

Here's some data on reasons for discontinuation of asparaginase in pediatric clinical trial that also had some adolescents. So reasons for discontinuation in terms of clinical hypersensitivity occurred in a minority of patients in 14% to 15%. And generally speaking, across all patients, about 20% to 25% of patients discontinued, but most of it was clinical hypersensitivity. Although some patients had pancreatitis, thrombosis, liver toxicity, and although liver toxicity and hyperlipidemia were quite low.

[01:23:16]

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

What can we do to increase completion of therapy and minimize adverse events?

[01:23:23]

Asparaginase: Measuring Activity and Best Practices

So it can be technically challenging to measure level of asparaginase. Instead, enzyme activity levels are generally monitored. Blood samples—at our site, we do the same. We place it on ice immediately after collection. So it's accurate. And because if you don't, there can be ongoing enzyme activity outside the body, and give you an accurate results.

Generally accepted that the enzyme activity of 0.1 units/mL is required to fully deplete asparagine levels to less than 0.1, so it's sort of a correlate. And for many years, the FDA approval of asparaginase has been based on the serum asparaginase activity. So that's what we generally follow.

And the nadir, as I mentioned earlier, is 2-3 weeks for the pegylated products and for Erwinia 2 to 3—for 2-3 hours for nonpegylated products.

[01:24:22]

Asparaginase and Therapeutic Drug Monitoring

Therapeutic drug monitoring is strongly recommended following asparaginase administration. The Children's Oncology Group guidelines are provided here. If the levels are low, the recommendation at various time points, generally a week to 2 weeks after, is to substitute with Erwinia.

The ALLTogether guidelines from Europe, similarly, substitute Erwinia asparaginase for looking at Day 7, Day 14 levels that are below certain limit guidelines that are provided here.

[01:25:00]

Recombinant Erwinia Asparaginase and Therapeutic Drug Monitoring

How about recombinant Erwinia asparaginase and therapeutic drug monitoring? There are more limited guidelines on this, though, trough levels should be monitored at that 72-hour time point, as mentioned earlier. And if it's not doing what it's supposed to do, the recommendation is to consider to switching to an every other day dosing to get the asparaginase activity optimized.

[01:25:26]

Recommendations for Managing AEs and Completing ALL Treatment With Asparaginase

How about adverse events and completing ALL treatments with asparaginase?

[01:25:32]

Age and Asparaginase-Associated Toxicities

All right. So here are some of the challenging adverse events that can emerge. And the interesting aspect of this is sort of the impact with age. Right? So certain things are more likely to occur if you get older, such as pancreatitis, hyperlipidemia and clots. Other things are less likely, such as anaphylactic reactions to asparaginase, which are more common in pediatric populations, as you can see here.

And this - this is data that emerged from a prospective database analysis of a lot of patients, 1500 patients. But the age range, importantly, just to mention is between the ages of 1-45 and not older.

[01:26:26]

Toxicity Profile in AYAs: Differences in 16-21 Yr Age Group

How about the toxicity profile differences in patients between the ages of 16 and 21 and looking at pediatric trials and adult trials? So this is interesting, right, that generally a similar age range, but pediatric studies and adult studies, markedly different.

So it may not even be the patient populations, but rather how these patients are treated and managed or evaluated or monitored over time that sort of gives us a sense of how common things like transaminitis, hyperlipidemia, bilirubinemia and pancreatitis are captured in adult trials where the median age is not too much higher than pediatric trials. They seem to occur at a much higher clip, which is an intriguing finding.

[01:27:21]

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

These are, again, the common toxicities listed here. The presentation of hypersensitivity can be allergic reaction vs silent inactivation, which is similarly problematic but more common in pediatric populations. Liver toxicity such as transaminitis and bilirubinemia more common in adults. Clots also more common in adults. And then sort of the scary manifestations are these sinus and cerebral thrombosis.

Pancreatitis also more common in adults. And if you get the necrotic variant of pancreatitis, it can be challenging and deadly and hemodynamically compromising.

Hypertriglyceridemia is also a common challenge and generally can be managed more easily, seems to occur relatively similarly among pediatric and adult patient populations. And there's also this potential CNS toxicity of fatigue and mental status change that is perhaps less appreciated.

[01:28:20]

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

In younger adults, looking at the various toxicities, particularly here in this case with a focus on liver toxicity, this was a publication by Patel and colleagues in Leukemia about 10 years ago if there is an aspect of concurrent medicines that can be similarly liver toxic.

So here we have daunorubicin, not only sort of adjusting the asparaginase dose - dose-reducing that, but also dose-reducing the daunorubicin by 50% seem to decrease the likelihood of induction death and hepatic toxicity. So I think these are aspects of management that can be considered.

[01:29:04]

Levocarnitine for Pegaspargase-Induced Hepatotoxicity

Here's another group of publications actually looking at levocarnitine for pegaspargase-induced hepatotoxicity. This is an option potentially. There seems to be a reduction in bilirubinemia and transaminitis with levocarnitine prophylaxis.

We don't typically do this here, but this is intriguing data. And perhaps this might be a way to mitigate liver toxicity perhaps in higher risk patient populations.

[01:29:41]

Pegaspargase-Associated Grade 3/4 Liver Toxicity

Grade 3 or 4 liver toxicity occurs more often after the first dose, but there is frequently no subsequent recurrence, so that's important. Clinical liver disease and persistent liver disease is uncommon. But liver injury and transaminitis can take time to resolve.

What are the risk factors for it? Higher dose, higher BMI, older age, antecedent liver disease. It can resolve and often does, but it can delay the next cycle of chemotherapy, which has its own sort of consequences.

How do we mitigate? Well, you can look at other concurrent medicines, such as anthracyclines. You can adjust the dose of asparaginase. And in patients who are fully positive, sometimes the - the challenges related to the TKIs, they get for their Philadelphia chromosome. So these are important considerations.

[01:30:45]

Common Asparaginase Toxicities: Management Approaches and ASNase Rechallenge

How about the management approaches? For hypersensitivity, we've already talked about looking at drug level monitoring and then switching formulation, the severe scenarios. With liver toxicity, dose synchronization with other medications such as anthracyclines. L-carnitine is an option in dose reduction.

You can rechallenge, though, because the likelihood of recurring episodes are - is less. Clots generally are managed with anticoagulation, and we continue to treat patients. Sometimes we dose reduce them. I've dose reduced patients and continued, so that - that is not a reason to not rechallenge.

Pancreatitis, it can be a problem, particularly if it's severe and clinical. We generally do not recommend rechallenge and the management is supportive care.

Hyperlipidemia, our general approach is diet and fibrates. And that's generally more easily managed.

[01:31:40]

Thrombosis: Treatment

The treatment of thrombosis is—the concepts are very similar to general thromboembolic management. We typically continue pegaspargase as before but at times I have reduced the dose, particularly with severe clots, I have reduced the dose to decrease the likelihood of recurrence.

It's thankfully, a severe form of clot such as cavernous sinus thrombosis is not likely. But giving the treatment with continuing anticoagulation oftentimes addresses the issue. And there's no significant difference in neurologic status between re-exposed or non-re-exposed patients.

[01:32:29]

ASNase Allergy and Inactivation

Back to hypersensitivity reactions. These are closely associated with asparaginase inactivation, as we mentioned earlier due to antibodies.

Grade 1 reactions. In general, there is some degree of uncertainty regarding what to do. 90% of patients with clinical hypersensitivity have no asparaginase activity, which is a problem, so that is an aspect. Antihistamines and steroids do not mitigate inactivation in patients. So you can address hypersensitivity, and you should. But keep in mind the issue of inactivation.

Shifting to alternative or non-cross-reactive asparaginase formulations is important. We've already talked about this just to stress this point, because 1 of these pretest questions again brought this up. So unless therapeutic drug monitoring demonstrates appropriate asparaginase activity.

[01:33:15]

ASNase: Hypersensitivity and Discontinuation—Expert-Recommended Best Practices

Asparaginase therapy should be discontinued if a DLT occurs. So if a DLT is hypersensitivity to E coli-derived asparaginase, therapy can be replaced with Erwinia. If patients then develop hypersensitivity to Erwinia-derived product, complete the treatment discontinuation. So you have to stop it if Erwinia does it to.

With DLTs, other than hypersensitivity, generally switching products doesn't really help. So we do make that recommendation for discontinuation if it's a DLT.

[01:33:54]

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

So here's some data from children between the ages of 1 and 10 from COG studies and those who are older from similar studies in adult populations. Here's data on pegylated asparaginase discontinuation over time. As I mentioned, in adults, it's much higher, about a quarter of patients have discontinuation.

And it's not only discontinuation, but intermittently missing asparaginase doses that become a challenge. There is a decrease in disease-free survival, certainly with missing asparaginase over time. So asparaginase unfortunately or fortunately is very effective and missing the doses or not getting them can impact success of treatment.

[01:34:58]

          Case Study

Let's go back to our patient cases. All right. This is the 21-year-old who presented to your clinic with dyspnea or went to the ED with dyspnea, and then came to your clinic and she did not have a Philadelphia chromosome or a KMT2A rearrangement. Got cal peg with her pediatric-inspired regimen, but then developed liver toxicity and bilirubinemia. And then over time, things got better.

Let's ask this question again. What are you going to do with this patient?

1. Continue with cal peg at the same dose;
2. Continue with the same pediatric-based regimen, but don't do the cal peg;
3. Switch to Erwinia;
4. Switch to hyper-CVAD to avoid further exposure to cal tec – cal peg rather.

Speaker: And polling is open. Please vote. We'll give a few more seconds for incoming responses. And we'll go ahead and close the poll here and share.

Dr Fathi: All right. Okay. Let's make sure. So hepatotoxicity often occurs during cal peg induction. So the right answer is A, but does not recur with subsequent cycles and is not an indication for omitting asparaginase-based treatment. Switching to a shorter-acting asparaginase treatment does not decrease the risk of hepatotoxicity. So if a patient has liver toxicity, there is no real need to switch to something else or withhold it unless it's a DLT, in which case you may need to consider doing that or you may need to dose reduce.

[01:37:01]

          Case Study

All right. This 1 is the 23-year-old male presented to your clinic. High white count, CSF, revealing CNS1 status. MRD was positive despite a remission, but the patient experienced a pretty significant hypersensitivity reaction on day 15. What are you going to do for this patient?

1. Continue with peg asparaginase with premedication;
2. Switch to IM formulation;
3. Switch to non-cross-reactive formulations such as Erwinia;
4. Permanently discontinue asparaginase therapy;
5. Prescribe premedication at the next dose and perform therapeutic drug monitoring.

Speaker: And polling is open. Please vote. We have a few more seconds for incoming responses. And we'll go ahead and close that poll and share.

Dr Fathi: Okay, good. 70% say switch to Erwinia, which is the right answer. Replacing all doses of peg-asparaginase with Erwinia-derived asparaginase optimizes treatment outcomes. Shifting to alternative non-cross-reactive asparaginase formulation is the right approach.

[01:38:34]

Expert’s Application of Asparaginase Into Evolving Clinical Practice

Application of Pediatric-Inspired Protocols in the AYA and Adult Population(s)

Application of pediatric-inspired protocols. Older patients are less likely to tolerate higher doses of steroid, and that's an obvious statement. Older patients are more likely to have mental status change, sugar issues, blood pressure issues, tachycardia and other potential complications of steroid therapy.

Older patients are less likely to tolerate higher doses of asparaginase, also not surprising. So lowering the dose to 1000 or 500 units can really help improve tolerability as long as you follow the asparaginase activity.

There is an importance to keeping cycle starts on time and assuring compliance of oral therapies. And sometimes toxicities can get in the way of this, but that's quite important. Close monitoring of patients in the clinic is essential to assess for development of adverse events such as organ injury, clots, infusion reactions.

Thrombo-prophylaxis is also important with the use of asparaginase products.

[01:39:38]

Thoughts on Assimilating New Approvals and Evolving Data Into Today’s Clinical Practice

Here are some thoughts on the assimilation of new approvals and evolving therapies. So there is always emerging therapies and their incorporation into regimens for acute leukemias, including ALL and in the AYA population particularly. And these can include tyrosine kinase inhibitors for Philadelphia-positive ALL, Philly-like ALL. They can include the bispecific T-cell engager blinatumomab. They can include antibody drug conjugates like inotuzumab over time.

And T-cell ALL also with nelarabine and other drugs such as antibodies and there are other aspects to this, right? So if you add new drugs there can be additive toxicities such as liver toxicity for example. But then there's the additional potential beneficial consideration that if you add agents that are active, you may be able to reduce the dose of drugs like asparaginase or other drugs that can cause toxicity. So there is a balancing act there.

[01:40:43]

Faculty Takeaways

Here's some takeaways. Incorporation of pediatric regimens into adult-intensive therapy has yielded impressive outcomes in ALL populations. And an important aspect of this is the incorporation of asparaginase. It remains and has always been a highly effective targeted drug for ALL.

It is very effective but has some challenging adverse events associated with it, including pancreas and liver injury, clots, and hypersensitivity reactions. A thoughtful guideline-based approach is important to prevent and manage these toxic events through laboratory assessment, physical exam, supportive measures and medications and pre-medications really with close monitoring in clinic and follow up.

Care and treatment at and coordination from larger academic centers can be helpful because there is experience with management and follow up there.

[01:41:45]

          Poll

All right. Here's a poll. Do you plan to make any changes in your clinical practice based on what you learned in today's program?

Speaker: Polling is open. Please vote. I'll give a few more seconds for incoming responses. And we'll close that poll and share.

[01:42:24]

Go Online for More CCO Coverage of Hematologic Malignancies!

Dr Fathi: Okay, great. Thank you very much for your time. And please go ahead and scan this code and follow the directions. And I'm happy to answer any questions that the team may have.

Speaker: I've got - I went ahead and launched our Zoom window for this as well. So if you'd like to just put your answer into the provided window, you can skip that QR code there. Perfect. Thank you, doctor. I was just about to ask you to go here.

[01:42:56]

Q&A

Speaker: All right. At this time, we're taking any questions you may have for Dr Fathi. Please use the Q&A function in Zoom to submit them. And while you do so, there will be 2 QR codes on the screen. There are also links in the chat panel. One will lead to the downloadable slide deck from today's presentation, and then the other will be to the program evaluation link that you will need to complete to claim your credit for attending today.

You will need to log into or create a CCO account at clinicaloptions.com, and we would encourage you to claim your credit within 30 days, as credit for today's program will expire after that time frame.

Dr Fathi, I do see a few questions. Are you able to see those? I'll be happy to read them out to you as well.

Dr Fathi: I'm on - should I stop sharing or maybe…

Speaker: You can go ahead and share. I'll just go ahead and read them to you. How about that?

Dr Fathi: All right.

Speaker: Okay. The first is do you monitor ammonia levels routinely, and if so, what thresholds prompt intervention?

Dr Fathi: Not routinely. No. If there is some degree of encephalopathy over time, we do check ammonia levels and we monitor them. Encephalopathy can also occur with asparaginase. So we don't monitor unless the symptoms become perplexing, and we ourselves are altered in terms of trying to figure out what's going on. But no, not routinely.

Speaker: The second question that is - has come in so far is, are there any strategies for patients with preexisting fatty liver disease or NAFLD?

Dr Fathi: That's a good question. There is some degree of evidence and publications that suggest that patients who have fatty liver disease, which is increasingly commonly recognized problem in the United States, have a higher risk of liver injury, following asparaginase treatment.

I think in those patients, generally speaking, I don't think asparaginase is off the table, but dose reductions and close monitoring is recommended, at least from my perspective, because they're more likely to have liver injury. And liver injury, as I mentioned, is something that does not necessarily have to recur. But once it occurs, it kind of ruins the situation. It can ruin the situation because it can delay subsequent therapies and so on.

So we - we do - I do recommend close monitoring, dose reductions of these patients so that they can tolerate treatment and benefit from it.