Pediatric-Inspired Asparaginase Regimens for Patients With Acute Lymphocytic Leukemia

Rachel Rau, MD, Attending Physician, Cancer and Blood Disorders Center
Seattle Children’s Hospital; Associate Professor of Pediatrics, Hematology/Oncology, University of Washington School of Medicine;
Principal Investigator, Ben Towne Center for Childhood Cancer Research
Seattle, WA

Asparaginase treatment is a cornerstone of acute lymphocytic leukemia (ALL) chemotherapy. This enzyme has a unique mechanism of action and toxicity profile that presents a distinct set of challenges in the clinical setting. In this article, Rachel Rau, MD, explores the use of asparaginase formulations in pediatric and adult ALL.

Q: Please provide a brief description of the unique mechanism of action of asparaginase therapy.

RAU: Asparaginase is quite distinct in terms of how it functions as an anti-
leukemic agent compared with most of our standard chemotherapies. Asparaginase is an enzyme that breaks down the amino acid asparagine into aspartic acid and ammonia.¹ Normal cells can synthesize their own asparagine and, therefore, continue to function in the absence of it. However, leukemic cells lack the machinery to form their own asparagine, and so they depend on scavenging it from their environment. When you give a person with leukemia asparaginase, the leukemic cells can’t produce proteins and they die.

Q: Can you comment on the differences between asparaginase formulations currently used in clinical practice? When do you use each formulation?

RAU: That has been a rapidly evolving landscape over the past few years. Our frontline preferred agent is asparaginase derived from Escherichia coli bacteria that has been engineered to be long-acting—it has had polyethylene glycol moieties added to that bacterial enzyme.¹ There are currently 2 FDA-approved formulations of long-acting, pegylated E coli–derived asparaginase. One is pegaspargase, which has been around the longest and has been used in most of our frontline trials over the past several decades. Currently, in the United States, that formulation is only available to individuals 22 years and older.

The other long-acting formulation is calaspargase.1 It is a pegylated
E coli–derived asparaginase with a different linker that results in a much longer duration of activity compared with pegaspargase. Pegaspargase is given no more often than once every 2 weeks, whereas calaspargase is given no more often than once every 3 weeks. Currently, calaspargase is only approved in the United States and for use in individuals 21 years or younger. Clinical trials are ongoing to examine its use in older individuals.²

If patients have a hypersensitivity reaction to one of those frontline
E coli-derived asparaginases, we have to switch them to something that they wouldn’t have antibodies to. Our available products are asparaginase derived from a different bacteria called Erwinia chrysanthemi.¹ Currently, in the United States our only Erwinia-based asparaginase therapy is recombinant Erwinia chrysanthemi.

There are only short-acting versions available of Erwinia-derived asparaginase.¹ For 1 dose of pegaspargase that lasts in the system for 2 weeks, you would have to give 6 doses of Erwinia asparaginase on a Monday, Wednesday, Friday schedule, or 7 doses every 48 hours. But we can effectively replace our long-acting asparaginase with Erwinia-based products in patients who need it.

Q: What are best practices for monitoring serum asparaginase levels?

RAU: In the United States, we now have the capacity to monitor asparaginase activity levels in patients clinically. There are 2 commercial laboratories for which these assays are available and usually, you get results back within 3 days. Best practice is to send levels 7 to 14 days after a full dose of long-acting asparaginase to ensure that they still have adequate levels.3 If the serum asparaginase levels are low at those time points, that probably indicates that the patient has silent inactivation where antibodies are neutralizing the drug, resulting in its rapid clearance from the system. Those patients are not benefitting from the drug, and that situation would prompt you to switch to the Erwinia-based asparaginase.

Certainly, if you’re giving patients premedication, it is advisable to send levels because you might have masked a hypersensitivity reaction that you could then uncover by looking at asparaginase activity levels.³ Serum asparaginase levels also should be determined for those patients who have had presumed hypersensitivity responses to judge whether these effects are related to an infusion reaction vs an antibody-mediated reaction.

The correct time to monitor serum asparaginase levels in individuals receiving the short-acting, Erwinia-based product is even less defined. A lot of institutions are not checking them at all, because that is the last line of therapy that the patient has; therefore, how those values should be used is unclear. Presumably, if a patient has multiple consecutive trough levels 48 hours after an Erwinia-based asparaginase product, this could indicate silent inactivation, prompting discontinuation.

Q: What are some of the serious toxicities associated with asparaginase therapy?

RAU: Asparaginase therapy has a unique and distinct toxicity profile compared with our other chemotherapies.¹ The first toxicity that everybody thinks about are those hypersensitivity reactions. Asparaginases are foreign-derived proteins; thus it is not surprising that our body can mount an immune response against them. True, antibody-mediated hypersensitivity reactions with our long-acting, pegylated products occur in 10% to 20% of patients.⁴

We most often give our long-acting asparaginases by intravenous (IV) infusion.1 When you give a drug by IV infusion, there is a chance of the patient experiencing an infusion reaction. An infusion reaction, simply defined, is a set of clinical symptoms that develop during or shortly after infusion of a drug. These reactions are due to the drug infusion itself and can be from a cytokine release or other mechanisms distinct from something antibody-mediated. This is relatively common with asparaginases, because they cleave asparagine into aspartic acid and ammonia, leading to a rapid increase in patients’ serum ammonia levels. As a result of this spike in ammonia, patients can get a full-body rash, nausea, vomiting, a feeling of impending doom, and vital sign changes. Infusion reactions are difficult to distinguish from allergic reactions caused by neutralizing antibodies, especially in the heat of the moment when you have a sick child in clinic with emergent symptoms. Asparaginase activity levels can help you sort that out, because really low levels would suggest that there were antibodies present to cause the reaction. If you have decent levels after that reaction, you can feel more confident that it was probably just secondary to the infusion itself. This is an important distinction because with an antibody-mediated hypersensitivity reaction, you would need to change asparaginase formulations; with infusion reactions, you can consider rechallenging with some modification to the infusion such as premedications and slowing of the infusion rate.

The next toxicity that comes to mind for most individuals is pancreatitis. This is a complication that can occur usually 10 to 14 days after the dose or the start of a course.⁵ Pancreatitis is much more common in older individuals. We see it in around 5% of the younger kids and somewhere around 10% to 15% of our adolescents and young adult (AYA) population. Pancreatitis can range in severity from transient, mild abdominal pain to fulminant pancreatitis with pancreatic necrosis, pseudocyst formation, insulin-dependent diabetes, and even death. Other than the age of the patient, there are no great ways to predict the risk for pancreatitis. There also are no great ways to prevent it. The big question after having an episode of pancreatitis, is which patients can be rechallenged? The answer to this question depends on balancing the patient’s risk of leukemic relapse with the risk of having a recurrence of pancreatitis.

The final toxicity that I will mention is liver toxicity. We see a fair amount of a distinct liver toxicity with this asparaginase, particularly during induction therapy.¹ We know that individuals who are obese are at risk for liver toxicity including really high levels of direct bilirubin.⁶ Symptoms usually manifest a couple of weeks after their first dose of a long-acting, E coli–derivedasparaginase, which is given during the first week of their first block of treatment. Strategies like capping the asparaginase dose at 1 vial for obese individuals are being explored, but we do not yet know whether that is going to solve the problem for individuals at risk.

There are some other strategies being looked at as well. We have L-carnitine as a preventative agent, which is being explored in a currently ongoing clinical trial.⁷ Delaying the dose is another strategy. Instead of giving asparagine in the first week, wait until the second or third week, when the liver may be a little more calmed from a leukemia perspective, and see if that lessens the risks.¹

Q: What is the impact of dose interruptions and discontinuations on therapeutic outcomes and future adverse events?

RAU: During recent shortages of Erwinia-derived asparaginase, we had a lot of patients who had a reaction to long-acting, E coli–based asparaginase, and we had no other options to switch to. We had to discontinue their asparaginase courses altogether, missing 1 or more of those planned during their therapy. We found that those missed doses really impacted outcomes, particularly for our higher-risk patients.8 In the Children’s Oncology Group (COG) study done by Sumit Gupta, MD, we found that NCI high-risk patients, who missed 1 or more courses of asparaginase due to toxicity or the Erwinia-based asparaginase shortage, had a 50% increase in relapse risk.⁸ Likewise, the Nordic Society for Pediatric Hematology and Oncology group showed that if you had to truncate your asparaginase therapy courses, you had an increased risk of relapse.⁹ Similar results also were shown by the Dana-Farber consortia.10 The impact of those missed courses was more than we hoped, which highlights the need to avoid drug shortages and to come up with strategies to prevent those toxicities that can be dose-limiting.

Q: How do you determine whether rechallenge vs switching formulations is the appropriate choice?

RAU:There’s only 1 indication for switching formulations, and that is a hypersensitivity reaction to E coli–based asparaginase.³ None of these other complications that we have discussed has an indication for switching from E coli–derived asparaginase to an Erwinia-based product, so the
decision then becomes if you rechallenge with asparaginase or discontinue it altogether. Pancreatitis is perhaps the toxicity where the decision of whether or not to rechallenge is most difficult. About 50% of patients who have an episode of pancreatitis will have a recurrence regardless of severity of the first episode.5 In our COG protocols, if a patient has mild grade 3 pancreatitis, meaning fewer than 72 hours of symptoms with no diabetes or pseudocyst or other severe complications, you can consider rechallenge.¹¹ If it is a more severe episode, we would advise discontinuing asparaginase. However, for all patients with pancreatitis, you must balance the risk of relapse vs the risk of recurrence of the pancreatitis.

For liver toxicity, you will almost always rechallenge. It is unlikely that you are going to get that severe hyperbilirubinemia during subsequent courses, as that tends to be most prominent during induction. Thrombosis is another potential complication that can be severe and scary, but once you have patients on a stable anticoagulant regimen and the symptoms of their initial event have stabilized or resolved, then you can rechallenge them with asparaginase.

Q: What are the key considerations to keep in mind when using pediatric-inspired regimens in adults?

RAU: That would be the toxicity profile. Many toxicities, such as pancreatitis, liver toxicity, and thrombosis, are more common as patients become older.¹ I think the exception is hypersensitivity. That seems to be pretty even across the board. Undoubtedly there is an inflection point where the risk of toxicities outweighs the benefits in terms of relapse risk, but the existing data strongly support that a pediatric-inspired regimen that includes asparaginase is beneficial in terms of relapse prevention in AYAs and even in patients in middle adulthood.

References

1. Juluri KR, Siu C, Cassaday RD. Asparaginase in the treatment of acute lymphoblastic leukemia in adults: current evidence and place in therapy. Blood Lymphat Cancer. 2022;12:55-79. doi:10.2147/blctt.S342052
2. CalPeg for newly diagnosed acute lymphoblastic leukemia (ALL). ClinicalTrials.gov. Updated August 21, 2023. Accessed January 5, 2024. https://clinicaltrials.gov/study/NCT05581030
3. van der Sluis IM, Vrooman LM, Pieters R, et al. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016;101(3):279-285. doi:10.3324/haematol.2015.137380
4. Hasan H, Shaikh OM, Rassekh SR, Howard AF, Goddard K. Comparison of hypersensitivity rates to intravenous and intramuscular PEG-asparaginase in children with acute lymphoblastic leukemia: a meta-analysis and systematic review. Pediatr Blood Cancer. 2017;64(1):81-88. doi:10.1002/pbc.26200
5. Maese L, Rau RE. Current use of asparaginase in acute lymphoblastic leukemia/lymphoblastic lymphoma. Front Pediatr. 2022;10:902117. doi:10.3389/fped.2022.902117
6. Advani AS, Larsen E, Laumann K, et al. Comparison of CALGB 10403 (Alliance) and COG AALL0232 toxicity results in young adults with acute lymphoblastic leukemia. Blood Adv. 2021;5(2):504-512. doi:10.1182/bloodadvances.2020002439
7. Roesmann A, Afify M, Panse J, Eisert A, Steitz J, Tolba RH. L-carnitine ameliorates L-asparaginase-induced acute liver toxicity in steatotic rat livers. Chemotherapy. 2014;59(3):167-175. doi:10.1159/000353402
8. Gupta S, Wang C, Raetz EA, et al. Impact of asparaginase discontinuation on outcome in childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. J Clin Oncol. 2020;38(17):1897-1905. doi:10.1200/jco.19.03024
9. Gottschalk Højfeldt S, Grell K, Abrahamsson J, et al; on behalf of the Nordic Society of Pediatric Hematology and Oncology Group. Relapse risk following truncation of pegylated asparaginase in childhood acute lymphoblastic leukemia. Blood. 2021;137(17):2373-2382. doi:10.1182/blood.2020006583
10. Silverman LB, Gelber RD, Dalton VK, et al. Improved outcome for children with acute lymphoblastic leukemia: results of Dana-Farber Consortium Protocol 91-01. Blood. 2001;97:1211-1218. doi:10.1182/blood.v97.5.1211
11. NCCN. Clinical Practice Guidelines in Oncology. Acute lymphoblastic leukemia, version 3.2023. Updated October 9, 2023. Accessed December 12, 2023. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf

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Upon successful completion of this activity, you should be better prepared to:

Discuss the use of asparaginase to treat pediatric and adult acute lymphocytic leukemia.

Identify and manage toxicities associated with asparaginase therapy.

RELEASE DATE: February 1, 2024

EXPIRATION DATE: February 1, 2025

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