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FAQ: Asparaginase in ALL
Asparaginase in AYA and Adult ALL: Expert Discussion of Frequently Asked Questions

Released: August 23, 2022

Expiration: August 22, 2023

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Key Takeaways

  • Administration of dose‑intensified pediatric regimens including asparaginase to AYA and some adult patients with acute lymphoblastic leukemia has the potential to improve disease outcomes.
  • Therapeutic drug monitoring is beneficial and cost-effective to determine if patients with mild-grade hypersensitivity to asparaginase are also having silent drug inactivation. In equivocal cases or if true grade 2-4 hypersensitivity is confirmed, patients should be transitioned to a non–cross-reactive Erwinia asparaginase product.
  • Adult patients receiving asparaginase appear to have higher risk for thrombosis and other adverse events compared with younger patients, but often these are manageable and asparaginase therapy can be continued.

Asparaginase has been a standard and integral part of pediatric regimens for treating children with acute lymphoblastic leukemia (ALL). Its success in pediatric ALL has led to its evaluation and use in adolescent and young adult (AYA) and adult populations. In this commentary, Daniel J. DeAngelo, MD, PhD; Emily Curran, MD; and Kjeld Schmiegelow, MD, answer questions on optimizing asparaginase therapy for the treatment of AYA and adult ALL that were submitted by an audience of healthcare professionals at a recent live Clinical Care Options satellite symposium held during the 2022 American Society of Clinical Conference annual meeting. 

General Considerations for Asparaginase Use

Is there an upper age limit for which you would not expose a patient to pegylated asparaginase?

Daniel J. DeAngelo, MD, PhD:
At my institution, patients with Philadelphia chromosome–negative ALL are classified by age into 3 broad categories: young adults (18-39 years of age), adults (40-60 years of age), and older adults (older than 60 years of age). At our center, all patients younger than 40 years of age are treated with a pediatric or pediatric-inspired regimen. In patients who are older than 55 years, there seems to be a marked decrease in event-free survival with these regimens compared with those who are younger, potentially attributable to differences in biologic disease characteristics between ALL of a 50-year-old patient vs that of an 18-year-old patient. There also may be an upper age limit where these types of regimens are too intense. For older adults, we use lower-intensity regimens.

Emily Curran, MD:
Based on the data, many healthcare professionals would probably say that age 50 is where the risks of asparaginase start to outweigh the benefits. However, in a single institution study, we evaluated pegylated asparaginase in patients up to age 70—so we pushed the age limit—but at reduced doses as low as 500 IU/m2 based on patient comorbidities and at prescriber discretion. Participants receiving reduced-dose pegylated asparaginase experienced fewer high-grade toxicities, but we will have to see whether or not this finding will hold up in larger studies. I still lean toward 50 years of age being the upper age limit, but it may be possible to treat some older patients with these regimens on a case-by-case basis.

Is there an upper BMI that you would feel uncomfortable dosing a patient with asparaginase?

Emily Curran, MD:
When reviewing outcomes in AYA patients up to 40 years of age treated on the CALGB 10403 pediatric‑based regimen containing asparaginase, investigators found that patients with higher BMI were more likely to have asparaginase-associated hepatic toxicities such as increased alanine aminotransferase, aspartate aminotransferase, and hyperbilirubinemia. With this in mind, I typically cap the dose of pegylated asparaginase at 3750 IU/m2, the single vial quantity, instead of increasing the dose further in patients with higher BMI values.

Daniel J. DeAngelo, MD, PhD:
I do worry about our patients with ALL and a high BMI. In the DFCI Adult Consortium Trial (06-254) evaluating pediatric-based regimens with pegylated asparaginase in AYA and adult patients with ALL, our group observed worse outcomes in patients with higher BMI, including extent of relapse and overall survival. Toxicities may play a part, but it is clearly more than that. However, the mechanisms are not known and this is an observation I still struggle to make sense of.

Management of Hypersensitivity to Asparaginase

What grade of hypersensitivity is recommended for switching to a non–cross-reactive asparaginase?

Kjeld Schmiegelow, MD:
Monitoring is key to determining whether hypersensitivity is due to a simple infusion reaction or is truly anaphylaxis. Patients who are experiencing a true hypersensitivity reaction to asparaginase generally exhibit symptoms very early on, but it is sometimes difficult to discern the mechanism behind the symptoms. If there is doubt about any patient situation or if the reaction is clearly grade 2-4 hypersensitivity, I recommend switching to a non–cross-reactive asparaginase agent. This is particularly important because with grade 2-4 hypersensitivity reactions, the asparaginase is endogenously inactivated, which results in ineffective drug administration, and we know that truncation of asparaginase therapy leads to worse outcomes.

When patients have grade 1 reactions, therapeutic drug monitoring (TDM) can be used to ensure target drug concentrations are being reached. TDM is clearly beneficial, is highly cost-effective, and enables detection of patients with silent inactivation of the asparaginase. However, if asparaginase is given by infusion and the patient exhibits symptoms very early in the infusion, you cannot just take a blood sample at that time point. You will need to wait to institute TDM at the next dose. That being said, once it is determined that target concentrations are attainable in patients with grade 1 reactions, clinical symptoms may be reduced by premedicating with antihistamine and glucocorticoid before the next asparaginase delivery or by slowing the infusion rate.

In addition, some patients may become intolerant to asparaginase, which is easily misinterpreted as hypersensitivity. However, symptoms of intolerance occur much later than those of hypersensitivity. Utilization of premedications and slower infusion rates may also mitigate symptoms of intolerance.

Regrading switching to a non–cross-reactive asparaginase formulation, how are you administering the recombinant Erwinia asparaginase formulation Rylaze? Its indication says to give it every 48 hours, but what affect would giving it on a Monday, Wednesday, Friday (M/W/F) schedule have?

Kjeld Schmiegelow, MD:
Currently, there are 2 Erwinia asparaginase products with apparently similar efficacy: Erwinase and the recombinant asparaginase formulation Rylaze. Rylaze was approved by the FDA in 2021 but has yet to be approved by the European Medicines Agency. The indicated dosing for Erwinase following pegylated asparaginase is 25,000 IU/m2 IV or IM 3 times per week, given M/W/F for 6 doses whereas the indicated dosing for Rylaze is 25 mg/m2 IM every 48 hours. Both agents have very short half-lives, so they either need to be given in large doses on M/W/F (as is the case with Erwinase) or at a lower dose every 48 hours (as is the case with Rylaze). 

If Rylaze is administered on a M/W/F schedule at the indicated dose of 25 mg/m2 IM, we know that a large percentage of patients (25% to 50%) will have subtherapeutic asparaginase levels when they are measured 3 days later on the following Monday. One solution might be to administer a higher dose of Rylaze on Fridays—but having to administer different doses on different days has the potential to become confusing for infusion nurses. So to ensure adequate drug levels when using Rylaze, it is easier to stick to the every-48-hour administration schedule, recognizing the challenge of patients needing to come into the infusion center on weekends. However, it is clear that a Rylaze dose of 25 mg/m2 IM on a Friday is insufficient.

In Europe, where we use Erwinase, TDM is performed routinely, which makes it easier to recognize the few patients who need dose increases, and we tailor their treatment strategy accordingly.

Emily Curran, MD:
My institution has an infusion center that is open on the weekends, so I administer Rylaze strictly every 48 hours.

Daniel J. DeAngelo, MD, PhD:
Our infusion center is also open 7 days per week, so Rylaze delivery is less of an issue. However, most clinics in the United States are not set up this way, so are faced with the M/W/F schedule issue. Those centers can use slightly higher doses of Rylaze on Friday or implement TDM to individualize dosing.

Management of Thrombosis With Asparaginase

How would you manage a patient who receives pegylated asparaginase and then develops a central nervous system (CNS) thrombosis?

Emily Curran, MD:
Thrombosis is one of the toxicities that most worries providers using asparaginase-containing regimens. The proposed mechanism of thrombosis is thought to be through depletion of anticoagulants such as protein C, protein S, plasminogen, and ATIII. The more typical presentation is a deep vein thrombosis (DVT) or pulmonary embolism (PE), but there is risk for cavernous sinus thrombosis. Treatment principles are consistent with those for standard venous thromboembolism management, and pegylated asparaginase can be continued safely following a DVT or PE in some cases, but I think many are hesitant to do so. Furthermore, it is not clear whether asparaginase can be safely continued with cavernous sinus thrombosis.

Kjeld Schmiegelow, MD:
We have some data that will be published soon that suggest you do not need to be more cautious regarding asparaginase rechallenge in patients with a CNS thrombosis vs in patients with other types of thromboses. In a study of the Nordic cohort, 33 children and AYA patients with ALL treated with asparaginase who experienced CNS thrombosis were re-exposed; only 2 patients experienced a second thrombosis and only 1 was in the CNS. For the latter, the symptoms and MRI were normalized at follow-up. Because our data show a low likelihood of having a second episode and considering that neurologic symptoms will normalize in the majority of patients, at our center we recommend re-exposing patients with CNS thrombosis.

Daniel J. DeAngelo, MD, PhD:
That has been the experience at our institution as well, although we have the limitation of fewer patients. We usually wait for CNS symptom resolution, not necessarily MRI normalization, before we proceed with rechallenge, and then we always proceed with anticoagulation.

Do you monitor ATIII levels in patients with ALL receiving asparaginase? What do you do for patients who have an undetectable fibrinogen level?

Emily Curran, MD:
We recently started monitoring antithrombin (ATIII) in our patients with ALL receiving asparaginase, despite that the data regarding what ATIII level should prompt repletion and whether this truly prevents complications with thrombosis and bleeding are still quite unclear. With hypofibrinogenemia, we used to replete with cryoprecipitate, but given the potential that cryoprecipitate can increase the risk of thrombosis, we avoid it unless the patient has evidence of bleeding.

Kjeld Schmiegelow, MD:
An interesting, related issue is when administering low-molecular-weight heparin as thromboprophylaxis, should ATIII be given if its levels are below 0.5 IU/mL because heparin works during that cascade? We generally recommend doing that, but again there are no data to support whether it is beneficial.

Daniel J. DeAngelo, MD, PhD:
That is an important issue because for the heparinoids to work, ATIII is necessary, but at what level? In my opinion, the cutoffs are quite arbitrary, but for therapeutic we use 0.6 IU/mL and for thromboprophylaxis we use a lower level. Historically, healthcare professionals have been frightened of hypofibrinogenemia, and my house staff continue to be. In response to our using a lower ATIII cutoff for patients on thromboprophylaxis while receiving asparaginase, I have developed a “smart phrase” in our electronic medical record that states “do not replete any cofactors” and includes my beeper number, so staff do not erroneously assume a patient is in disseminated intravascular coagulation and immediately take action based on what they think is too low of an ATIII level.

Future Directions

Are there any other improved asparaginase options coming in the future?

Kjeld Schmiegelow, MD:
There is an erythrocyte-encapsulated formulation of asparaginase under development called eryaspase. Knowing that patients form antibodies against asparaginase in the blood, a company took native Escherichia coli L-asparaginase and encapsulated it inside of donor-derived red blood cells to design a production infusion that works for several weeks. In a single-arm phase II study in patients with ALL and hypersensitivity to pegylated asparaginase on NOPHO ALL2008 or A2G-1 (N = 55), eryaspase 150 U/kg showed a significant reduction in blood asparagine levels (>100 U/L) in 54 patients aged 1-45 years, along with a reasonable toxicity profile consistent with asparaginase exposure. Furthermore, asparagine depletion was observed in the CNS but at less profound levels than with E coli L-asparaginase or even pegylated asparaginase. It may be that the erythrocyte gives a different profile of depletion resulting in less CNS efficacy, but those data are not available yet. There is also ongoing discussion about whether eryaspase can achieve full asparagine depletion, because of challenges with its accurate measurement due to leakage of some of the eryaspase into the blood. Regardless, eryaspase was shown to be a feasible therapy in this limited cohort of patients with ALL.

Eryaspase is currently being tested in patients with pancreatic cancer, so it may be that asparagine depletion plays a role in other settings. For ALL specifically, we do need a third option for the approximately 10% of patients who inactivate Erwinia asparaginase after being switched from pegylated asparaginase, so maybe this small percentage of patients could benefit from this novel agent.

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