ALL About Hypersensitivity

Speaker Introduction:

Welcome to the ALL About Hypersensitivity Podcast. 

This medical industry feature, titled “ALL About Hypersensitivity” is brought to you by Jazz Pharmaceuticals. This program is intended for healthcare professionals. I am a paid consultant for Jazz Pharmaceuticals.

I’m Sharon Bergeron, RN, BSN, CPON, and for today’s episode, I’ll be talking about hypersensitivity to asparaginase therapy in patients with acute lymphoblastic leukemia, or ALL, and lymphoblastic lymphoma, or LBL. I am a certified pediatric oncology nurse and research nurse educator at the Hyundai Cancer Institute at the Children’s Hospital of Orange County in Orange, California.

Short musical interlude

Asparaginase in ALL/LBL:

Let’s begin by discussing the role of asparaginase therapy in the standard of care for patients with ALL and LBL.

Asparaginase is an enzyme that targets asparagine, an amino acid that leukemia cells require for growth. Asparagine is needed for protein synthesis, which cells require for growth and survival. By breaking down asparagine, asparaginase deprives leukemia cells of the asparagine they rely on for growth, proliferation, and survival.^1-3

Asparaginase therapy has been a core component of multiagent treatment regimens for more than 45 years. Over time, research has shown that incorporation of asparaginase into ALL treatment protocols has improved survival estimates.^1,4

Research has also shown us the importance of patients completing their asparaginase regimen and receiving all asparaginase doses. Missing doses can negatively impact clinical outcomes, including a higher risk of relapse and lower disease-free survival in high-risk B-ALL patients.^5,6

This is why it is important to ensure patients are able to complete their asparaginase treatment regimen to help achieve optimal clinical outcomes.

Hypersensitivity in ALL/LBL:

Although the incorporation of asparaginase into ALL treatment regimens has improved survival rates, exposure to asparaginase can trigger an immune response in the body that can lead to hypersensitivity. This can happen as a result of the immune system producing antibodies in response to asparaginase.¹

Let’s review how this occurs. The development of hypersensitivity involves many immune mediators. At the cellular level, immunoglobulin E (or IgE) antibodies activate a type of immune cell called mast cells. Many of the common signs and symptoms we think of with allergic reactions and hypersensitivity, such as skin reactions, can be widely attributed to the activation of these mast cells. In cases of hypersensitivity, IgE antibodies are produced in response to asparaginase exposure. That means the next time the patient is exposed to the antigen—in this case, treated again with asparaginase—IgE antibodies can recognize asparaginase and trigger mast cell degranulation. In short, this results in an inflammatory cascade. Mast cell degranulation triggers the release of additional immune mediators, such as histamines, prostaglandins, leukotrienes, and cytokines, which in turn, trigger the activation of other immune cells. This cascade can be amplified with each time a patient is re-exposed to asparaginase, which means hypersensitivity can worsen over time with repeated dosing.^3,5,7,8

In addition to this inflammatory cascade, hypersensitivity can result in the development of neutralizing IgG antibodies that cause asparaginase to be rapidly cleared from the body. This can lower the efficacy of asparaginase due to reduced levels of asparaginase in the body.^1,5

Short musical interlude

Now, let’s discuss how this might look in a clinical setting. Hypersensitivity to asparaginase is one of the biggest challenges we face as healthcare professionals who treat ALL/LBL. This can be very scary for patients, as well as their loved ones. Because we know hypersensitivity to asparaginase is common, we routinely monitor our patients when receiving asparaginase, and we look for some of the classic signs and symptoms of hypersensitivity reactions. Hypersensitivity can affect many organ systems. So, while it can include typical signs of an allergic reaction, such as redness, swelling, and hives, it can also impact cardiovascular, gastrointestinal, and respiratory systems. Patients can have symptoms like nausea, vomiting, headache, and minor skin reactions. Symptoms of hypersensitivity that would warrant us to stop treatment and intervene are respiratory symptoms, the emergence of dry cough or severe rash, and a major dip in blood pressure. Nurses typically evaluate patients to make sure they don’t have a fever or any symptoms that may mask a potential situation like respiratory issues or complications that may become exacerbated by hypersensitivity due to asparaginase administration.^3,5,9-12

Hypersensitivity reactions can also be severe. Severe hypersensitivity reactions can include anaphylaxis and even lead to death. Because of this, it is really important for us as healthcare providers to closely monitor our patients for signs of developing hypersensitivity and quickly manage any hypersensitivity reaction that occurs during treatment. That way, if a hypersensitivity reaction does occur, we can intervene with emergency drugs that can be quickly administered. By doing this, we have all the tools to help manage or mitigate hypersensitivity.³

We know hypersensitivity to asparaginase is common. Over time, we have learned that the more doses a patient receives, the higher their risk of experiencing a hypersensitivity reaction. So while hypersensitivity reactions may not happen after the first dose, they can happen with subsequent doses and can even worsen with repeated dosing. Why does this happen? This is because patients are getting re-exposed to the antigen, or asparaginase therapy, that resulted in the development of antibodies in the first place, which is why that inflammatory cascade can be amplified and manifest as worsening hypersensitivity with repeated exposure. This is why monitoring the patient during each dose is so important.^1,3,5,13

Short musical interlude

Since we know how important it is that patients receive all asparaginase doses, how can we as healthcare providers ensure our patients are able to maintain their regimen in cases of hypersensitivity? The answer is to use an alternative type of asparaginase that comes from a different source.⁵

Asparaginase treatment regimens for ALL and LBL typically utilize long-acting E. coli-derived asparaginase. In cases of hypersensitivity upon exposure, antibodies are being developed against asparaginase that is E. coli-derived. So in order to prevent future hypersensitivity reactions, we would treat with an alternative asparaginase that is not derived from E. coli. Although hypersensitivity reactions are also associated with Erwinia asparaginase, reports indicate low rates of severe reactions above Grade 2. By switching to an alternative asparaginase, patients are able to continue their regimen without letting hypersensitivity to E. coli asparaginase result in treatment discontinuation.^5,14

Patients who develop hypersensitivity to asparaginase therapy are at increased risk of experiencing another reaction if treated again with asparaginase derived from the same source. To help maintain asparaginase activity and optimal depletion of asparagine, patients experiencing hypersensitivity should switch to an immunologically distinct asparaginase. Patients should be switched as soon as clinically possible, ideally within 48 to 72 hours, to ensure that asparaginase activity is maintained and to prevent missing a scheduled dose of asparaginase. In cases of hypersensitivity to E. coli-derived asparaginase, an alternative form of therapy would be RYLAZE^® (asparaginase erwinia chrysanthemi (recombinant)-rywn).^5,14,15

Hypersensitivity reactions can be scary for both patients and caregivers, so it is important to proactively educate patients on how we plan to address and manage any signs of hypersensitivity reactions. It is essential to communicate that we have an alternative asparaginase therapy that can replace their current regimen and allow for uninterrupted asparaginase therapy. By educating patients and staff on the availability of an alternative asparaginase we can switch to, patients are able to maintain asparaginase therapy, which we know is essential for optimal clinical outcomes.¹⁵

Longer musical interlude

Uninterrupted Asparaginase Therapy: Switching to RYLAZE

RYLAZE is the only FDA-approved Erwinia chrysanthemi-derived asparaginase that is indicated for the treatment of ALL and LBL (as a component of a multi-agent chemotherapeutic regimen) in patients 1 year and older who have developed hypersensitivity to E. coli-derived asparaginase. Because RYLAZE is Erwinia-derived, it is expected to have minimal immunologic cross-reactivity to E. coli-derived asparaginase. This can help patients continue asparaginase treatment regimens without missing doses as a result of hypersensitivity to E. coli asparaginase.^4,14,15

RYLAZE is approved for 2 different intramuscular dosing options. It can be administered every 48 hours at 25 mg/m², or it can be given at 25 mg/m² Monday morning and Wednesday morning, and 50 mg/m² on Friday afternoon.¹⁵

Approved dosing is based on the RYLAZE AALL1931 clinical study. In collaboration with the Children’s Oncology Group, this study was an open-label, multicohort, multicenter trial that evaluated the efficacy and safety of RYLAZE as part of a multiagent chemotherapeutic regimen for patients with ALL or LBL with a hypersensitivity reaction to E. coli asparaginase. RYLAZE was administered intramuscularly to 167 patients aged 1 to 25 years. The determination of efficacy was based on a demonstration of the achievement and maintenance of nadir serum asparaginase activity (known as NSAA) above the level of 0.1 U/mL by simulation. Approved dosage regimens of RYLAZE showed at least 90% could achieve and maintain NSAA levels greater than or equal to 0.1 U/mL based on simulation. Outcomes also showed a safety profile for RYLAZE that was consistent with other asparaginase therapies.^14-16

Patients who have experienced hypersensitivity should be switched as soon as clinically possible, ideally within 48 to 72 hours. Approved dose replacement information and dosing options enable introduction of RYLAZE to replace E. coli asparaginase treatments in appropriate patients, allowing them to maintain their treatment regimens and avoid therapy interruption. Treating physicians should be familiar with the recommended monitoring and dosing adjustments in the label to manage other adverse events.^5,15

To learn more about RYLAZE, please visit us at RYLAZEpro.com.

Indication

RYLAZE (asparaginase erwinia chrysanthemi (recombinant)-rywn) is indicated as a component of a multi-agent chemotherapeutic regimen given by intramuscular injection for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in adult and pediatric patients 1 month or older who have developed hypersensitivity to E. coli-derived asparaginase.

Important Safety Information

Contraindications

RYLAZE is contraindicated in patients with: history of serious hypersensitivity reactions to Erwinia asparaginase, including anaphylaxis; history of serious pancreatitis during previous asparaginase therapy; history of serious thrombosis during previous asparaginase therapy; history of serious hemorrhagic events during previous asparaginase therapy; or severe hepatic impairment.

Warnings and Precautions

Monitor for signs or symptoms of hypersensitivity reactions, including life-threatening anaphylaxis. Administer RYLAZE in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis. Discontinue RYLAZE for serious hypersensitivity reactions.

Monitor for symptoms of pancreatitis, which, if left untreated, could be fatal. Discontinue RYLAZE if severe or hemorrhagic pancreatitis occurs.

Discontinue RYLAZE for severe or life-threatening thrombosis. Provide anticoagulation therapy as indicated.

Discontinue RYLAZE for severe or life-threatening hemorrhage.

Discontinue RYLAZE and provide supportive care for grade 4 increases of bilirubin and for hepatic veno-occlusive disease.

Adverse Reactions

The most common adverse reactions (incidence >20%) with RYLAZE are abnormal liver test, nausea, musculoskeletal pain, infection, fatigue, headache, febrile neutropenia, pyrexia, hemorrhage, stomatitis, abdominal pain, decreased appetite, drug hypersensitivity, hyperglycemia, diarrhea, pancreatitis, and hypokalemia.

Pregnancy and Lactation

RYLAZE can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective non-hormonal contraceptive methods during treatment with RYLAZE and for 3 months after the last dose. Advise women not to breastfeed during treatment with RYLAZE and for 1 week after the last dose.

Before administering RYLAZE, please read the Prescribing Information and additional Important Safety Information, which can be accessed on RYLAZEpro.com.

Thank you for tuning in on today’s episode. This program was brought to you by Jazz Pharmaceuticals.