Activity Transcript

Michael J. Burke, MD​: Hello and welcome today's program. My name is Dr Michael Burke, and I'll be the moderator of this session. I'm a professor of pediatrics at Children's Hospital of Wisconsin in Milwaukee, Wisconsin. I lead the leukemia efforts directing the leukemia and lymphoma program at our hospital. Today we'll be joined by 2 other faculty, one being Sandy Kurtin, who's a PhD and clinical assistant professor of medicine, adjunct clinical professor of nursing, and director of advanced practice in clinical integration at the University of Arizona Cancer Center in Tucson, Arizona, as well as Elise Janssen-Koning, who is a nurse practitioner at the Princess Máxima Center for Pediatric Oncology in Utrecht, the Netherlands. So, welcome to them both.

So today we'll be reviewing some case studies of patients with acute lymphoblastic leukemia (ALL) who are experiencing asparaginase-associated toxicity. And before we do, let's briefly review the role of asparaginase therapy in the management of patients with ALL, in which asparaginase-associated toxicities we are referring to.

So asparaginase has an essential role in all of ALL treatment. Asparagine is an essential amino acid that's critical for protein synthesis. Lymphoblastic leukemia cells cannot synthesize this amino acid, due to the absence of an enzyme, asparagine synthetase, which we ourselves have within our cells. So therapies that contain asparaginase treat ALL by hydrolyzing asparagine to aspartic acid and ammonia, thereby it depletes the tumor cells of their supply of asparagine. Also, this degradation allows for an ammonia spike, so it's very common, as well as expected, to see elevated ammonia levels when the use of asparaginase.

We know that continuous and prolonged asparagine depletion blocks tumor cell proliferation and induces tumor cell death, ultimately improving outcomes in ALL. And pediatric patients with ALL who complete at least 26 weeks of asparaginase therapy, as outlined in the Dana-Farber Cancer Institute Consortium studies, where they used consecutive weeks of asparaginase depletion, that patients will have superior outcomes if they hit that 26-week timepoint, compared with those who receive fewer weeks of therapy.

So as you can see on this table, there are a number of different asparaginase products that range from short-acting to long-acting, long-acting being PEGylated. And the next table shows the pharmacokinetics, that the short-acting asparaginase have a half-life of hours compared with the PEGylated formulations, which have half-life of days, and as many as 16 days for the intravenous (IV) Cal-PEG.

So asparaginase has a number of associated toxicities. A couple of these we're going to particularly highlight in today's presentation. Some of these toxicities are ones that have higher incidence, such as hypersensitivity, which depending on the formulation and the number of doses one receives can be as high as 20% to 30% hypersensitivity rates. Whereas toxicities such as hemorrhage or thromboembolism, pancreatitis, can be much less, in the under 10% rate. But as you can see, pancreatitis and hypersensitivity and thromboembolism, high ammonia which can lead to encephalopathy, hepatotoxicity. Not only elevations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), but also of bilirubin, can be quite significant, particularly in adolescent young adults, in adults or those that are obese, giving hyperbilirubinemia to the degree that other chemotherapies like vincristine and anthracyclines can no longer be given based on the hepatic metabolism and risk for increased toxicity of those agents. Hyperglycemia and hyperlipidemia are also a little more common in adolescent adults and adults than pediatrics, but there are a number of toxicities that be seen with all the formulations of asparaginase, both the short-acting and long-acting, and we'll discuss in a little more detail some of these as we go forward.

So the guidelines for asparagine-associated adverse events depend on the particular toxicity. There's been a number of consensus expert recommendations for the identification and management of asparaginase hypersensitivity and silent inactivation in particular. Managing toxicities with asparaginase space therapies in adult ALL, there's a summary of an European Society for Medical Oncology (ESMO) Open Cancer Horizons round table discussion available, as well as the National Comprehensive Cancer Network (NCCN) guidelines under ALL, which provides guidelines for these toxicities. However, in all these guidelines that are available, the management of these asparaginase adverse events, very few of them target the nurse audience specifically. Therefore, we're going to go through a couple of case vignettes and to highlight how the role of nursing and approaching these toxicities can be managed.

So with that, I'm going to hand this off to Elise, who's going to walk us through a case of Amanda, an 11-year-old girl who experienced hypersensitivity due to asparaginase therapy. So thank you, Elise.

Elise Janssen-Koning, MSc, BN​: Thank you. Amanda is diagnosed with pre-B ALL since almost 2 months, and she already received 3 doses of peg-asparaginase, which started as an induction without any problems, and until now she had an adequate therapeutic asparaginase activity. And while administrating the fourth dose, she's suffering with complaints. What we see with her that within the first minutes of administration, she's not feeling well. Her airway is free, she's breathing 50 times a minute, she has normal breathing sounds and no signs of dyspnea. She does receive oxygen through a non-rebreather mask. Her heart rate is 104 times a minute, with a normal capillary refill. Her hands are feeling cold, her feet are slightly cold, and she has a blood pressure is 104/91. She's responding, but she's not in a normal way. She has a higher temperature of 38.2. On her skin are no hives or rash, and at this moment she starts vomiting.

So when we listen at the case, we can imagine, maybe there's hypersensitivity. And when we look at the definition, the National Cancer Institute says it's an exaggerated response by the immune system to a drug or to other substance, and reactions can range. And when we look specifically to the hypersensitivity to asparaginase, we can define 3 types of hypersensitivity. The first one is an allergic reaction, the second silent inactivation, and the third is an allergic-like reaction. And when we look at all 3 of them, I will mention then the first, the allergic reaction, is an adverse local or general response from exposure to asparaginase, and which is characterized by flushing rash, urticaria, a drug fever, dyspnea, symptomatic bronchospasm, edema, hypotension, and/or an anaphylaxis. And it's accompanied by inactivation of asparaginase activity. So then you can say that even a grade one allergic reaction can also be accompanied by inactivation. So that's important to realize.

The second one is silent inactivation. And there you see patients who don't have clinical allergy, but when you look at asparaginase trough levels, which are preferably measured in 2 independent samples, in general you can say that their trough level is lower than the lower limit of quantification. So there is no asparaginase activity.

And the third one is an allergic-like reaction. So there's an intolerance with symptoms such as vomiting, a stomach ache, or a rash, and these patients have normal asparaginase activity levels if we do continue the infusion. So when you look at real allergies, they often occur at the first drops, while the allergic-like reaction occurs later during the infusion. So there's the question of how we can distinguish between those two.

And when we look at the allergic-like reaction comparing to the real allergic reaction, I already mentioned that the time where the problem starts is relatively late after the start when you look at an allergic-like reaction, where there's multiple times a direct reaction after the start of the infusion when you look at the real allergic reaction. In all cases we found antibodies from antiasparaginase, when there's a real allergic reaction, but we couldn't differentiate between the severity. They're all grade 2 medium severity when you look at the patients, and the symptoms are pretty much the same. They can of course distinguish, but it's difficult to distinguish just looking at the symptoms. So what we really do need to distinguish is the therapeutic drug monitoring (TDM). You need to see the asparaginase activity. Because in an allergic-like reaction, we can continue asparaginase if the patient clinically tolerates the dosing, but when there's a real allergic reaction, there's a need to switch the formulation or to stop the asparaginase treatments.

So when we look back at the case of Amanda, we need to find out whether we already can say if you know what kind of hypersensitivity we see in her case. And as I already mentioned, we need to see the asparaginase activity. So that's the information we need to mention what kind of hypersensitivity we see, because therapeutic drug monitoring is useful to distinguish between those two, because also patient with a low-grade allergy can have neutralizing antibodies and thereby an activity level of zero. And also TDM is useful to ensure a therapeutic asparaginase level.

And when you summarize the hypersensitivity reaction and the switching guidelines, you can say when there is an allergy, you see the symptoms on a patient, and you find inactivity, and then there's a reason to switch. And that's also the case when there are signs of inactivation, because we don't see any symptoms on the patient, but we do know that there's inactivity. So when you do give asparaginase, it won't have an effect on your patient, so there's a reason to switch. And when you compare it to an allergic-like reaction, and we do see symptoms on the patient, but we don't see in activation, so there's no reason to switch to another brand or dosing schedule.

And when we look back at Amanda, we can see that after stopping the infusion and providing antihistamine, hydrocortisone, and epinephrine, she really feels better. She needs to be admitted to the hospital because of a fever and neutropenia, but when we look back at the start trough level of the asparaginase at the fourth dose, we found that there is a level of zero. So in this way I think we can say that there isn't an allergic-like reaction, but it's a real allergic reaction.

And then we need to know, why is it so important to switch patients to an alternative asparagine therapy? And as already mentioned by Dr Burke, the patients who are not receiving their planned asparaginase doses have worse outcomes, as you can see in this graph, that the outcome for patients who receive all dose of asparaginase is higher than the ones who missed doses. And also in other research we found that patient with a suboptimal asparaginase treatment, they had an increased relapse risk. So that's really important to distinguish between a real allergy and an allergic-like reaction, and to switch patients to continue the asparagine treatments.

All right, that leads back to pre-medication and/or a longer infusion rate, because does pre-medication help prevent an allergic reaction? And I'm wondering how you look back at this point, Dr Burke.

Dr Burke: Sure. This is a really good question. A number of protocols are starting to include pre-medication as a means to decrease the adverse reaction to asparaginase products. I think before the time of TDM, at least within the children's oncology group studies, this was spoken strongly as discouraged, to do any pre-medication, because we did not have a way to monitor activity. But with the advent of TDM and measuring asparaginase activity levels, pre-medication has become more prevalent.

But I think to your point, pre-medication will not eliminate an allergic reaction, or the development of antibodies, but it can minimize the symptoms that a patient may experience with asparaginase, whether it's an allergic-like reaction or allergic reaction. And so I think that if someone uses pre-medication, it's critical that they use TDM to make sure that they're not completely, I guess, masquerading the development of antibodies and turning it into a silent inactivation.

The same can be said about longer infusion rates. This can be done particularly for our infusion reactions to help minimize those, very similar to other protein therapeutics that are given to patients, that may have a reaction if you stop the infusion and then slow the rate and give it over a long period of time, oftentimes it's more tolerable. So the same has been shown with asparaginase, to give it over 2 hours is more tolerable than 1 hour, even diluting it with normal saline has been shown some hospital practices to help minimize adverse reactions. But just to remember that none of these will eliminate the development of antibodies, and antibody inactivation is what we're really concerned about. And so if pre-medication is being done, TDM I think she should be done with that.

So I'm curious, Sandy, what your practice is or what thoughts you might have on both pre-medication and/or longer infusion rates.

Sandra Kurtin, PhD, ANP-BC, AOCN, FAPO​: Sure. So I would say that everything you said absolutely applies. I think from just a pure nursing perspective, and also the critical need to continue dosing, and I don't do pediatrics, I do young adults and adults, is the experience of a infusion reaction, regardless of whether it's allergic or just an infusion-related reaction, can often deter patients from wanting to receive subsequent doses, because it's frightening to them. I think from a nursing perspective, the idea of giving a drug with a high probability of hypersensitivity without pre-meds is also very uncomfortable.

But to your point, and also I think very importantly, there aren't other therapies that we give where the TDM is so integral to detecting efficacy. So there are some really important concepts just purely from a nursing perspective for those nurses that are actually administering the drugs to understand the rationale. I think in the United States, at least in the young adult and adult settings, there has been a move, even in the NCCN guidelines and other guidelines, to incorporate, to your point, premedication, but emphasizing the need for that TDM when you do that, because otherwise you may be masking silent inactivation.

Ms Janssen-Koning: Yeah, thank you. I can really see your points, and we do also see it in children. We use now pre-medication and the longer infusion rate after truncation combined with TDM. And my next question for you is how to see your patients when he or she starts vomiting during infusion, because there are also symptoms like hyperammonemia that we can also see patients vomiting. In what way do you distinguish between a real allergic reaction and hyperammonemia, and why and how do you continue or stop your infusion?

Dr Burke: Yeah. These are great questions, because one, a patient has an adverse reaction during asparaginase infusion, and you don't really know what it is necessarily. It could be an allergy, it could be an infusion reaction, it could be a hyperammonemia contributing to this. So stopping the infusion is probably the best thing to start with, just to have a better sense of what's going on. If the patient had not been pre-medicated, it's an opportunity to give medication, I should say, anti-allergy medication, if the symptoms of the patient warrants this. But sending off a serum ammonia level would be quite helpful, depending on how quickly it's run in your laboratory, is how beneficial the results are.

But hyperammonemia can masquerade as allergy or infusion reaction, because it can cause nausea and vomiting, which are very common with high ammonia levels, as well as headache and irritability, anxiety and rash, although the rash is not urticarial. So that's a good description or a good way to differentiate between the two is, urticarial rash is really consistent or speaks to allergy. Other rashes that you can see with infusion reaction or hyperammonemia tend not to be urticarial or hives. But ammonia is something that can be mitigated with therapies that will lower the ammonia levels in patients, both oral and IV medications, as well as slowing the infusion rate will allow the liver to handle the high ammonia levels a little more easily than when the infusion's given over a shorter period of time.

Sandy, do you have anything else to add to that?

Dr Kurtin: No, not a lot. I do think that this isn't terribly common, but really important to evaluate. In the young adult and adult population, we have had patients where this happens after they go home or the next morning, and they may be just thinking that it's what everybody gets with chemotherapy, nausea, vomiting, headaches, and may or may not call and tell us this. So I will say, we can't help you if you don't tell us. So very important just to educate the patients to contact their clinical team with any of these symptoms, so that we can intervene, and in those cases have them come in and draw an ammonia level, if it's not happening on site, actually during their infusion. We do most of this in the outpatient setting, so they're not in the hospital and not accessible. They are in the clinic and will be going home.

Ms Janssen-Koning: All right. Thank you all for looking back at my case and help me discuss the points I wanted to mention.

Dr Burke: All right. Thank you, Elise. We're now going to move to a second case. This is the case of James. He's a little bit older, a 26-year-old man, who experienced thromboembolism due to asparaginase therapy, and Sandy's going to walk us through this case.

Dr Kurtin: Sure. So this is James. He's 26 years old. He presents to the emergency department with cervical adenopathy, bruising, headaches, bone pain, and chest pressure. So obviously lots of possible etiologies for that. They go ahead and do scans and see widespread adenopathy. He has a biopsy of the cervical node, which is terminal deoxynucleotidyl transferase (TdT)-positive, also has a bone marrow biopsy showing 6.9% lymphoblasts. And so he actually has a diagnosis of T-cell lymphoblastic lymphoma, which we treat in the same way that we treat ALL, and we also use pediatric inspired regimens in what... He would be considered AYA, adolescent and young adult, goes up to age 35. And so we use pediatric-inspired regimens to treat these patients.

So he's treated on a regular regimen, a pediatric-inspired regimen, which includes the typical drugs. daunorubicin, pegaspargase, vincristine, and prednisone, and presents for follow-up after being treated in the inpatient setting. He's discharged and presents with right arm pain and swelling. Turns out this is on the same arm where he has a peripherally inserted central catheter (PICC) line that was put in for administration of his chemotherapy. So we send him off for a Doppler ultrasound, which reveals a catheter-related deep vein thrombosis. So in this case we consider this a... There's a identified cause for the clot, so it's provoked, basically, not unprovoked. He's got lymphoma, lymphoblastic leukemia, and he's got a line.

We are going to treat him, and in this case we do this as an outpatient. For these patients, low molecular weight heparin and then transition to direct oral anticoagulants. You can start with direct oral anticoagulants depending on the severity. This is a pretty large clot, so we want to get it stabilized. We're going to make sure he doesn't have additional clots. So we're going to do a chest computed tomography (CT) to evaluate for a pulmonary embolism (PE), and that is negative for James.

So I think in this case it's important to understand that patients receiving asparaginase compounds are at a greater risk for thromboembolism. This happens most often in the early phases of treatment where they have active disease, they're getting chemotherapeutic agents, in some cases they're in the hospital, which by itself is another risk factor. I think it's important to evaluate other risk factors. Do they have a history of a clot? Are they diabetics? In the setting of older patients, coronary artery disease, all the things that we typically think of as risks for clotting.

The other thing, and we didn't really focus on this, but some of these patients can develop hypofibrinogenemia, so low fibrinogen levels, and we treat that if it's severe with cryoprecipitate. So in the setting of a clot, we're going to really evaluate the risks and benefits of cryoprecipitate administration to correct that fibrinogen level, because essentially you're giving clotting factors. So really understanding that also platelet counts that may be diminished because of the other components of the regimen, and giving concurrent anticoagulants, need to be considered. So this can be a little tricky to navigate, but it is something that we do see in these patients.

The other very important thing to distinguish in terms of what you're going to do with the asparaginase is if it is a central nervous system (CNS) clot or a non-CNS clot. And so we typically continue therapy, we treat the clot, but it is not by itself a reason to discontinue the asparaginase unless it is a CNS thrombosis and more severe in its grade.

So we have James, who now has been anticoagulated, his swelling and pain have improved. So once the symptoms have resolved, we are going to go ahead and get him started back on treatment with his asparaginase, but monitor very closely all the things that I just described, and continue to very closely monitor his counts basically to include the fibrinogen. If you're using certain direct oral anticoagulants, you're going to consider measuring the antithrombin III levels, just to make sure that you are in a therapeutic range. We don't use warfarin in these patients, just because it's very difficult to regulate, and so generally we stick with the direct oral anticoagulants.

And I'll turn it back over to you, Dr Burke, to see what your thoughts are about thromboembolism. And are they as common in kids, I guess I would say, in pediatrics?

Dr Burke: Thank you, Sandy. It's a very important toxicity that we need to be aware of. The incidence within pediatrics is lower than adults. I just want to second your point about the importance of continuous asparaginase therapy despite a history of thrombosis.

I think one of the advantages of the scheduling of the pegylated asparaginase is oftentimes, by the time the patient is due for the next asparaginase, the clot may have significantly been reduced. So it's not typically the case that you have a significant clot when you need to give another dose of asparaginase. That can happen, but most of the times in my clinical practice, they've had a clot earlier on, they've been treated with anticoagulation, the clot is resolving, and by the time they're due for asparaginase again, either the clot is no longer present or it's very, very minor. But in cases where it's, like you mentioned, a CNS clot, where it's life-threatening, then you know may likely need to hold and forgo that asparaginase dose, and then consider whether making that up or not.

Dr Kurtin: Great. The one thing that I'll add about the direct oral anticoagulants is, these are oral compounds and they are very unforgiving. So if you miss doses, you will re-clot. And so I think that's, from a nursing perspective, really critically important to educate, again, the patients and their families about how critically important it is to not miss doses for their anticoagulants.

Elise, what about... Do you have something you'd like to add relative to thromboembolism or hyperfibrinogenemia?

Ms Janssen-Koning: I don't have anything to add, just to confirm that we do see it as well in children, and that we do continue asparaginase combined with anticoagulant therapy, and it's real necessary to do so, and all children do well with it, even with the subcutaneous injections.

Dr Kurtin: Great. So Dr Burke, I'll turn it back to you to wrap up our discussion.

Dr Burke: Thank you both, Sandy and Elise. That was great, and particularly bringing those 2 cases, highlighting some of the more common toxicities. So I think really in summary here, there's a myriad of toxicities associated with asparaginase products. We spoke of hypersensitivity, and thromboembolism as well. But reminding you all that pancreatitis and hepatotoxicity, hyperglycemia, and hyperlipidemia are also ones we see.

So ultimately these toxicities can be significant and somewhat common, depending on the age and where they are in therapy. But with the right management and steps, these patients can continue their asparaginase therapy and hopefully receive the great outcomes that we would anticipate with treating patients today.

So with that, I'd like to thank both Sandy and Elise for joining me, and all of you for joining this session, to learn more about how nurses can manage these acute toxicities of asparaginase therapy. And thank you.

This transcript has not been copyedited.