This is where we are in terms of treatment. One is initial recognition of who’s at risk. Two would be doing prophylaxis for patients who are intermediate or high risk for tumor lysis syndrome [TLS]. Where do you see the field going? What are the future directions for patients with cancer? [Comment on] prophylaxis for them against tumor lysis identification of who’s at risk or treating tumor lysis syndrome. Where do you see that headed?

It’s hard to say. There’s a lot of room for more data because this is a data-free landscape. You covered almost all the publications and abstracts on this topic. We don’t have a lot of data about the right strategy. We have limited data that help guide a lot of our clinical decision-making in terms of what uric acid level might be appropriate to give rasburicase. But we don’t have much. A lot of the recommendations for managing tumor lysis syndrome, or preventing it, are guided by expert opinion or clinical algorithms based largely on expert opinion.

What information might be helpful to have to make this less of an issue or concern for our patients? If we had good biomarkers, that could help. A lot of times, if you see a lot of patients with hematologic malignancies, you get much better at identifying if this is real TLS, is this a patient that’s high risk. Of course, there are some guidelines to help you risk stratify, but a lot of it comes with clinical experience.

Sometimes patients have hyperuricemia from their chronic renal dysfunction, and some have hyperuricemia that’s causing renal dysfunction, and that hyperuricemia is from TLS. When you have similar laboratory studies between 1 group and the other, how do we distinguish what’s TLS and what’s not? A biomarker could help us distinguish [when to] think that this is tumor lysis syndrome vs this is just hyperuricemia that’s not going to have any clinical consequence. That could be helpful.

In many ways, LDH [lactate dehydrogenase] is helpful for that. It’s not perfect, but an LDH gives you a marker of cell turnover. If that’s very high, then this looks like a patient who’s more likely to be high risk or to experience TLS as opposed to baseline renal dysfunction with some hyperuricemia. LDH is very imperfect, but a biomarker like it that was a little more specific for TLS, or at least for the underlying pathology, would certainly be helpful.

When we’re thinking about the future of monitoring and preventing TLS, there’s a link between the type of therapies that we have and the tumor type. Both of those impact the risk of TLS. If you don’t have any effective therapies for a particular malignancy, then you’re not going to see treatment-induced TLS. You might see spontaneous TLS, but you’re not going to see treatment induced.

As we get new therapies, depending on what the mechanism of actions are for those, theoretically we can get TLS across a wider number of entities. I treat hematologic malignancies only, but I’m sure many solid tumor doctors would be happy if they heard that there was some new drug for pancreatic cancer that caused tumor lysis syndrome, because that [would be] a sign that it’s working. Ultimately, we have to think about this as we develop these new drugs. Every time we’re developing a new drug in a clinical trial, we have to be aware of the underlying mechanism of action. In those clinical trials, we often add a lot of TLS monitoring because sometimes with a new drug, we don’t know if it’s going to increase the risk of TLS. For example, in the development of venetoclax, it was initially surprising that it was causing rapid tumor lysis syndrome. I’m sure there could be other drugs in the future developed for all different types of malignancies where the same thing can happen.

Ultimately, better preventive strategies will be helpful. It’s difficult to give adequate hydration to all patients. We try to, along with [giving] diuretics. But if patients have bad underlying cardiomyopathy or other cardiac issues, that can be challenging. Even though we have good antihyperuricemic drugs, such as allopurinol and rasburicase, this isn’t enough to prevent all the complications of tumor lysis syndrome. This doesn’t address the hyperkalemia, which can lead to arrhythmias. It doesn’t necessarily address the calcium phosphate deposition that can lead to renal dysfunction independent of the uric acid levels.

There are many ways we can get more information about the appropriate prevention for patients, better treatments, and better biomarkers. As we develop new drugs, we have to be cognizant that [the patients] who might be high risk for TLS might change, and it may be linked to the therapies we have.

We’ve covered a lot. Do you have any final words? Is there something in particular you want people to take away from all this?

There have been many changes in terms of how we do things. It’s true with the assessment: what’s the diagnosis, what are the features of that patient, do they have baseline renal dysfunction, do they have gout? We know we can have hyperuricemia with gout, and that could be why the uric acid is high. Is there an alternative explanation for 1 of these lab values being [abnormal]? In CLL [chronic lymphocytic leukemia], is it because all the cells died off in the tube, and that’s why the potassium level is through the roof? That’s spurious hyperkalemia.

[We have] the diagnosis and the patient specifics, and then it’s imperative which treatment you’re going to give. For a lot of our patients, that’s why they’re admitted to the hospital, because they’re not sure [what’s going on]. They’re in for monitoring to make sure there’s no TLS, no CRS [cytokine release syndrome], or other things that can happen. It’s important to screen these things out and acknowledge them, and to acknowledge that things change over time. The patient condition will change over time.

In the recent Howard modification of the Cairo-Bishop [criteria], it’s important when you see creatinine [increase] a little, if someone has a baseline creatinine of 0.6 mg/dL and the next day it’s 0.9 mg/dL, then that’s something we should probably look at. Try to make sure patients are getting adequately hydrated, they’re on allopurinol, [and on] all the things that they need to be. Use that full-team approach: pharmacists, PAs [physician assistants], NPs [nurse practitioners]. Everyone is recognizing these things. Even internal medicine doctors might [see a patient] coming in with an auto tumor lysis. All of that’s so important in terms of that team approach of making sure we’re able to get them over the hump of this initial presentation.

 We covered a lot, John. It was a great discussion. Thank you for joining me. I’m glad we could do it together, and I hope the audience found it helpful.

Videos

Closing out their discussion on tumor lysis syndrome management, James Short, MD, and John Reagan, MD, highlight unmet needs and future evolutions in the treatment landscape. 

Tumor Lysis Syndrome: Unmet Needs and Future Directions in Care 

I practice in an academic center, and so do you. Do you want to talk about how these protocols might differ between community and academic centers? Is it important to have institutional guidelines to guide our decisions in terms of who gets for rasburicase and who doesn’t, for example, or anything else involving tumor lysis syndrome diagnosis and management?

Fortunately, it’s not a very common occurrence, but it’s 1 of those things that if you don’t see it a lot, then you don’t necessarily have expertise in dealing with it. That’s probably the biggest [difference] you’d see between a community and academic medical center. If you don’t see things a lot, you might not deal with it as much. Based on the patients’ acuity, it’s important to think about this in a community center, given that we do have other treatments. You mentioned CLL [chronic lymphocytic leukemia] before. We initiate venetoclax with CLL, and you can induce tumor lysis because there’s a lot of tumor in the body, but venetoclax is so active in CLL. As we move along, you always get surprises like this. When you find 1 of these extremely effective treatments for any cancer, you have to be prepared for it.

They’ve looked at this a little bit. There was [an article in 

] in 2019 by Dr [Scott] Howard, looking at the incidence of tumor lysis syndrome in community centers. There aren’t a tremendous amount of data out there about community vs academic centers. That’s why [we should] have some pathway in place. Where are we going to [use this]? What are the guidelines for this? Who are we going to give rasburicase to? That goes back to those basic guidelines of knowing who’s at low risk for tumor lysis. [Those patients have] low tumor burden, solid tumors—most of the time, but it depends on what that treatment is because treatment efficacy for any type of cancer falls into that realm also. For B-ALLs [B-cell acute lymphoblastic leukemias] or non-Hodgkin lymphomas that are intermittent between diffuse large cell and Burkitt lymphoma, that’s where those lie.

The LDH [lactate dehydrogenase] is so useful in terms of figuring out which patients are higher risk for tumor lysis and figuring out which patients are going to need that additional prophylaxis. Looking at other things, like elevated white blood cell count, [elevated] potassium levels, or if phosphate is starting to creep up—that’s when I ask if I’m really going to use uric acid to keep the kidneys in check. When do you bring in our renal colleagues?

That’s 1 of those issues: if you’re seeing things a lot, you want to have firm protocols in place because they can happen at any place, anytime. With Epic [software], it’s a little easier in terms of sharing different protocols. You can put those in and have them ready to go. That’s the thing we should think about. If you’re in the community seeing different types of patients, it can happen with any patient at any time. We say a lot of times—not with solid-tumor patients but with small cell lung cancer—that it can happen.

You can see these patients coming in, and [there is] that oncologic emergency and need for immediate treatment. We want to make sure the patients understands. That initial recognition and assessment—who’s that patient whom I need to think about this for and probably even admit to the hospital when they’re high tumor burden. That’s where these different pathways can help us out and help lead to understanding of what’s going on with these patients.

A brief review of the differences that might be observed between tumor lysis syndrome management in an academic versus community setting.

TLS Management in Academic vs Community Centers of Care 

Could you outline any of the clinical implications of prophylaxis and those treatment options within it—when you would do and when you wouldn’t do treatment for prophylaxis?

We can just think about some of the particular considerations that we have…I think using the IV fluids and the allopurinol are pretty clear for anyone who is intermediate or high-risk for tumor lysis syndrome. I think we’re not always sure when should we be using rasburicase. So, first of all, some considerations for rasburicase. This is what we’ve talked about, that this drug is very good at rapidly reducing uric acid levels. Typically, within 4 hours you can get a significant reduction of uric acid, just after 1 dose. Actually, 1 dose is often adequate for many patients. Although certainly there are patients with very aggressive, bulky tumors with rapid turnover, where you might need to redose. You might need to redose more than once. But in many cases, actually in my experience, 1 dose of rasburicase may be all a patient needs to get them out of the danger zone where you’re worried about clinical tumor lysis syndrome.

I think other considerations when we’re thinking about giving rasburicase, for example, is it’s very important after a patient has had rasburicase to accurately measure the uric acid. You need to measure it on ice. The sample should be transported on ice because if it’s not, the rasburicase will continue to dissolve like the uric acid in the sample and you’ll get a falsely low read. So, these are just some kind of clinical things to think about when you are treating a patient with rasburicase. Now, in general, it’s a well-tolerated drug, but hypersensitivity reactions can occur. So, you need to be aware of those. One of the main things to be aware of when giving a patient rasburicase is that you can see severe hemolysis in patients with G6PD [glucose-6-phosphate dehydrogenase] deficiency. That said, tumor lysis syndrome is an oncologic emergency and we often don’t have time to test for this. We often don’t know G6PD status on the majority of our patients. So, when you’re in that situation where a patient urgently needs to get the uric acid down, I don’t stop to test for this, but certainly if a patient has a known diagnosis of G6PD deficiency, you would not want to use rasburicase because of the risk for homolysis.

In thinking about who might be higher risk for G6PD deficiency, of note it is higher in those with ancestry from Africa, Asia, Mediterranean, or the Middle East. So, you might have a little more of a suspicion in those patients, and you need to be extra careful, of course, watching all of these patients. But I think the key thing is, at the very least, if you don’t have G6PD status before giving rasburicase, at least remember that hemolysis is a potential complication. If you start to see worsening anemia in the patients after the dose, you at least immediately think of this as a potential option and then treat accordingly.

Now, as far as when do we actually give the rasburicase prophylactically? Usually, based on the studies that you had mentioned, a lot of institutions have adopted a cutoff of around 7.5 mg of uric acid as kind of a threshold. But it’s not exactly just the uric acid in and of itself. For example, there are patients who have chronic kidney disease or other causes of hyperuricemia who have elevated uric acid. It doesn’t mean we should be giving rasburicase to those patients. The way at least we have it on our formulary and the way that we practice clinically, is we consider the level of the uric acid. So again, a cutoff of 7.5 mg is often helpful. For those patients, even who have a uric acid of 7.5 mg or higher, they have to have at least 2 other risk factors to justify giving the rasburicase.

Also, this goes along with, do I really think that this is related tumor lysis syndrome, or could it just be from something else? So, those would include patients who have an elevated serum creatinine. Those patients who have a very high white blood cell count of 50,000 or higher, an elevated LDH [lactate dehydrogenase], or they have underlying high-risk disease. Like we mentioned, [that includes], very aggressive B-cell lymphoma or an aggressive acute leukemia. Now, even for those patients who have lower uric acid levels, below 7.5 mg, we still do consider it prophylactically even for those patients if they have multiple of those risk factors. If I have a patient with Burkitt leukemia or lymphoma who has an elevated LDH and a high white blood cell count and their uric acid is 7, I’m still definitely going to give that patient rasburicase before I start treatment because I’m almost certain that that patient is going to develop tumor lysis syndrome if I don’t.

Other considerations for rasburicase that are important to think about—interestingly, allopurinol and rasburicase, even though they’re both used for treatment or prevention of tumor lysis syndrome, they actually can be a little antagonistic, at least theoretically. Allopurinol can actually interfere with rasburicase activity. If possible, we like to give rasburicase first if we’re planning to do that, and then start the allopurinol afterwards. Now, this is not always feasible, unfortunately. A patient may come in and they may have already been on allopurinol, or they started allopurinol as prevention and then they start to develop tumor lysis syndrome. We often then just add the rasburicase on top of it but acknowledge that that may not be as effective as if you give the rasburicase in someone who hasn’t been exposed to allopurinol. So, ideally you give rasburicase and then start the allopurinol afterwards.

In thinking about how we’re doing all this management, hopefully we can manage all these electrolyte abnormalities and other issues, but sometimes it does come down to getting our nephrology colleagues involved. The next step after giving hydration, allopurinol, rasburicase, and all the measures that we discussed earlier, sometimes dialysis is really the only thing that’s going to clear out those electrolytes, protect the kidneys or support the kidneys through this event. It’s really just supportive care, but we typically only reserve this for patients after all of our other supportive care measures that I mentioned have not worked.

Experts James Short, MD, and John Reagan, MD, share comprehensive insight on the clinical implications of treating TLS in patients receiving therapy for cancer.

Tumor Lysis Syndrome: Clinical Implications of Prophylaxis and Treatment 

Actually leading into that…there’s very little evidence in this space— there’s not a lot of studies, but maybe talk about some of the data that can guide some of our practice and some of the things I already mentioned in terms of preventive measures for patients who might be at risk for development of tumor lysis syndrome [TLS].

Sure. So, like you said before, the key thing is keeping that urine output going and doing whatever you can to keep the urine output going. Then, like you said, with the phosphate bonders and using things like either Lokelma (Sodium zirconium cyclosilicate) or Kayexalate (polystyrene sulfonates) to try get rid of the potassium if it gets too high. But really the hallmark of TLS treatment is preventing uric acid from going up too high. The first drug that we always reach for is allopurinol. …The mechanism of action is involved in purine catabolism. Purine, if you remember back to first and second years of medical school, purine goes to hypoxanthine to xanthine, and then through xanthine oxidase it gets turned into uric acid. And what allopurinol does is, it’s a xanthine oxidase inhibitor, so it keeps things at [a normal] xanthine level. So, you’re not actually making uric acid.

The other drug that’s approved is febuxostat, which is also a xanthine oxidase inhibitor, very much the same as allopurinol. We’ll talk in a second about how all those work. But once you have uric acid, like you talked about before, our bodies can’t get rid of uric acid. Humans and higher-level primates don’t have an ability to get rid of uric acid, so what we [do is] leverage that rasburicase, which is like urate oxidase, which is what converts uric acid to allantoin and helps your body then excrete out the uric acid so you can finally get rid of it.

Those are really the hallmark treatments, giving some sort of allopurinol or febuxostat and rasburicase. Allopurinol goes back to the 1960s when it was first looked at for treatment of really elevated uric acid levels and it was found to effectively lower uric acid levels, so that became the gold standard. The initial reports for rasburicase came out of pediatric literature and, like with most things with pediatrics, was on a mg/kg basis for dosing. There was a later study by Dr [Jorge] Cortes out of MD Anderson [Cancer Center] in the 

. It was randomized and patients got randomized to either allopurinol, allopurinol plus rasburicase or rasburicase. That study showed that you were able to effectively lower uric acids much better with the addition of rasburicase. So, allopurinol was able to lower it a little bit, but rasburicase could really effectively eliminate your uric acid levels. Interestingly, in that study though, I wasn’t able to find anything in terms of renal replacement therapy or the need for that renal replacement therapy. So, that’s always something to kind of think about in the back of your mind.

Then [INAUDIBLE] oncology in 2015 did allopurinol vs febuxostat. With this study, they showed that there was really no tremendous difference in terms of uric acid levels. Once again, it was a randomized study, but there was no tremendous difference in terms of uric acid levels in these patients. And I think that’s the big take home. There were maybe some signs of cardiac issues with febuxostat populations when they get treated, but I think the big issue and the reason that we don’t usually use this drug is because of the cost. It’s an order of magnitude higher in terms of cost, so our clinical pharmacists, who are so essential in terms of helping us treat tumor lysis syndrome, usually shy away from this drug and really help us in terms of allopurinol dose and what’s an effective dosing for those patients. So these, allopurinol and rasburicase, are probably our most-used drugs for this.

James Short, MD, and John Reagan, MD, highlight guideline-indicated treatment options for patients with or at risk of tumor lysis syndrome.

Guideline-Directed Treatment Options for Tumor Lysis Syndrome

How do you think about prophylaxing these patients to prevent tumor lysis from happening in the first place?

First, what you said is so important. Theoretically, we have all the tools necessary to manage tumor lysis syndrome, but preventing it is so important. If you’re going for curative therapy and you have to pause to manage all these acute issues coming up—many of which are, at least theoretically, preventable—then that’s where the detriment to the patient may come. Not so much the tumor lysis itself, which hopefully we can manage; it will just be a transient process. But if we have to hold back on appropriate therapy for a patient, then that’s problematic. That’s very important what you discussed.

How do we prevent? First, we do need to think about risk stratification. Going back to risk factors, we don’t necessarily do the same prevention methods for everyone. For someone we consider relatively low risk for tumor lysis syndrome, like a solid tumor, nothing in particular is done. But if they’re in an intermediate risk, we have certain strategies that we do. High risk would be a little different.

Generally speaking, for anyone who’s in intermediate or high risk, we’re certainly doing hydration. Hydration is important to prevent that potential renal damage, which is what causes most of the complications. You’ll have renal dysfunction and also further buildup of electrolytes if your kidneys aren’t functioning properly. The hydration just flushes the kidneys out, preventing the buildup. Potentially, there are urate crystals, which come from the uric acid or the calcium phosphate crystals. That’s an integral part of prevention.

Some patients can’t tolerate large amounts of IV [intravenous] hydration. Maybe they have an underlying cardiomyopathy [or something else]. In those patients, diuretics can play a role because you can still give the fluids, but then you counterbalance that with diuretics. Historically people would give diuretics no matter what. Maybe people practice a little differently, but as long as someone isn’t developing fluid overload, I just hydrate. I do diuretics only if I’m concerned that I’m causing fluid overload. I don’t necessarily want to back off my hydration, but diuretics can be important to make sure you’re maintaining good ins and outs and fluid balance as you’re trying to prevent development of tumor lysis.

Of the electrolyte issues you mentioned before, particularly the elevated potassium and phosphorus, we want patients to limit this from their diet, particularly if they’re high risk or already developing tumor lysis syndrome. We want to limit potassium phosphorus intake if possible. Even when someone is initially starting on therapy, if we’re worried that they might be a little high risk for tumor lysis syndrome, we might not be as aggressive at repleting the low potassium and phosphorus as we might be in someone who we didn’t have any concern for tumor lysis.

One of the backbones of all those preventives are agents that affect uric acid levels. For anybody who’s intermediate or high risk, we’d add allopurinol. Allopurinol helps prevent uric acid buildup, but it doesn’t do anything for the uric acid that’s already there. That’s where we consider using rasburicase. Rasburicase we use for high-risk patients. Sometimes it’s a preventive measure, and sometimes we use it also for patients who’ve already developed tumor lysis. It’s very effective at rapidly dropping uric acid levels.

There are some things we don’t necessarily do prophylactically, and it’s on the border of whether you consider this in a patient who already has tumor lysis, but sometimes [we use] phosphate binders. Usually we wait to see if the phosphorus is becoming elevated, [and that’s] where we consider adding phosphate binders. Then there’s dialysis. At my institution [The University of Texas MD Anderson Cancer Center], and it differs. If you have a very high-risk patient, like 1 with a Burkitt lymphoma, who already has evidence of some clinical lysis syndrome, we may not start dialysis right away, but we’d involve our nephrology colleagues and say, “This patient is very high risk.” We’re not necessarily saying we’re going to start dialysis preventively, but we want to watch very carefully and we want to be ready. The last thing you want is to not be ready if a patient develops flora renal failure, and then you’re scrambling to do these things.

Those are all the considerations that we have when we’re starting a patient on therapy or a patient comes in with a new diagnosis of 1 of these hematologic malignancies. We want to risk-stratify them. Fluids and allopurinol are going to be the case for most patients with intermediate risk, then plus or minus rasburicase. I know we’ll be talking about the criteria that might be used, including evidence-based studies to support that.

Expert perspectives on prophylactic measures to prevent tumor lysis syndrome in patients receiving therapy for cancer. 

Prophylactic Measures to Prevent Tumor Lysis Syndrome 

It’s important that all members of the care team, who are potentially going to interact with a patient who has cancer, who might be at risk for tumor lysis syndrome, or who’s undergoing therapy, is aware of recognizing it and also what they need to do. This is an oncologic emergency if it’s severe, and we should think of it like that. This is something that patients can present in the emergency department. They’re presenting symptoms, usually in addition to everything else, but you may get their labs and they may be in spontaneous tumor lysis syndrome. Emergency doctors need to be aware of this and know what to do. They may call an oncologist who’s on call, but as far as temporizing measures and what to look out for, that needs to be done initially in the emergency center.

For institutions that are large teaching hospitals, internists and internal medicine trainees may be the ones dealing with these tumor lysis syndrome that might emerge in a patient undergoing chemotherapy. They may be aware of it before an oncologist. A lot of different people need to be aware. At our institution [The University of Texas MD Anderson Cancer Center], we have a lot of advanced mid-level providers who are the first ones on the ground monitoring patients. They need to be aware, as well as the nurses. That’s why we have a nice algorithm that walks you through in terms of risk stratification [to determine if] this meets the criteria for tumor lysis syndrome. It’s available to those who might interact with this clinical scenario.

Pharmacists are very critical, of course. I’m sure we’re going to talk about some of the medications that can be used for prevention or treatment. They’re also involved with the dosing of that and also whether it’s appropriate to do some of these medications because some of these medications can be expensive. We work with our pharmacist, and we have a formulary that helps us to decide whether it’s appropriate to use these more expensive medications.

Patients who develop severe tumor lysis syndrome—fortunately, it isn’t very common in an era where we’re much more aware of this and have good preventive measures—can develop significant renal dysfunction. Then we need to get our nephrology colleagues involved to manage the electrolyte disturbances that can come with it. It’s important to note that a broad spectrum of providers should be aware of the entity, should be aware of at least identifying it and alerting the oncologist if they’re not an oncologist. A lot of providers can interact with this and can play a major role in managing these patients, certainly when it’s in the acute, more emergent setting.

To go along with that, it’s important to note that tumor lysis syndrome—fortunately, we don’t see a lot of severe cases with the therapies and awareness we have—can cause severe complications. Talk about the outcomes related to tumor lysis and the more severe things that can happen with it.

As we talked about before, the maintenance of kidney function is paramount in this business. Renal tubular deposition of the uric acid or the calcium phosphate into the tubules and causing renal dysfunction is the rate-limiting step. That can influence your entire clinical care from then on out. If someone ends up hemodialysis dependent, it limits what you’re able to do. There are some other things too. If you end up developing arrhythmias, that can cause problems and cardiac complications later on. A lot of these are lymphomas that we often use anthracyclines for. Even if you have an AML [acute myeloid leukemia] that gets into tumor lysis trouble, that’s going to run into your anthracycline problems. Other things, such as seizures that develop with the clinical tumor lysis, are going to limit your ability to give any oral medications or any other treatments down the line. These can be damaging effects, which is why we try hard to support people through these episodes. It can also change your management. A lot of times, if we have a patient who’s in an [spontaneous] tumor lysis, you try to get that under control and maybe don’t intervene with any therapies up front.

Or you start with some single-agent cyclophosphamide for debulking or single-agent vincristine. Often a lot of the ALL [acute lymphocytic leukemia] regimens will have steroid preface [doses] built in of prednisone mg/kg [dosing] to get a lot of that tumor bulk down first. Those are important so that you’re not releasing all these toxic substances into the blood all at once. If you can manage…to keep the kidneys functioning, to keep the heart functioning normally, to not end up with complications on top of all this, that can be extremely useful for these patients and keep them on a regimen so they can get their therapies or curative therapies ordered effectively. A big problem we need to watch out for with this is that often we’re dealing with patients for whom we have a real chance of curative therapies. We want to keep them on their treatment regimens and on the treatment regimens that we know can be so beneficial to them.

Shared insight on the multidisciplinary management of tumor lysis syndrome and how treatment planning may be adjusted after it is identified. 

Role of a Multidisciplinary Healthcare Team to Manage Tumor Lysis Syndrome

Talk about some of the signs and symptoms. What are we looking for in a patient undergoing treatment to see if they have tumor lysis syndrome [TLS]?

A lot of these data came out in the 1990s, when we had more effective chemotherapies initially for tumor lysis syndrome. As you pointed out, some of it is how aggressive the tumor is, but then a lot of it is how effective your treatment is. Another thing, at least with tumors and tumor type, is that a lot of times it depends on your tumor bulk. Especially if you have bone marrow involvement, that can be another source of tumor lysis. When you have an infiltrated marrow from a leukemia which is thought to be 1.4 kg overall or if you have a marrow with over 50% blasts, that’s a patient who could also end up with tumor lysis.

The signs that you see are typically divided into 2 categories. There’s a laboratory tumor lysis syndrome, and then there are clinical criteria for tumor lysis syndrome. You probably see the laboratory criteria pretty often. When patients come in, this is something that helps you stratify who has to be admitted and watched. This is the first classification to come out, and the 1 we more commonly use. There’s a classification that happened before this, but the Cairo-Bishop [criteria] is probably the 1 that people are most familiar with. This looked at different markers of elevated uric acid levels, elevated phosphorus levels, elevated potassium, and low calcium levels.

What you’re looking for from a laboratory tumor lysis syndrome with Cairo-Bishop was uric acid more than 8 mg/dL, a phosphorus level of more than 4.5 mg/dL, a potassium level that’s over 6 mmol/L, and a correcting calcium level of less than 7 mg/dL. It’s so hard to get corrected calcium levels. Often, you’ll use an ionized calcium of less than 4.5 mg/dL. Cairo-Bishop added that if you had a 25% change from your baseline levels, that also classified you. Suddenly, if your uric acid level went up, this could become a sign of laboratory tumor lysis. I probably find that 1 most useful with your uric acid because you’ll see uric acids start to climb up a little when you have someone admitted, or you’re following them as an outpatient for some signs or symptoms of tumor lysis.

The updated Howard criteria—this was modified Cairo-Bishop criteria—removed that 25% change from baseline levels. Your laboratory levels were strictly: uric acid more than 8 mg/dL, phosphate greater than 4.5 mg/dL, potassium greater than 6 mmol/L, and the corrected calcium less than 7 mg/dL. That change was taken out—make it a little more clinically available. These levels, importantly, should happen 3 days before or 7 days after the initial initiation of a cancer directed therapy.

Added to that are any clinical criteria for tumor lysis, and these are the ones that are much scarier. The clinical criteria are cardiac dysrhythmia, or sudden death. That’s something that you can’t modify in any way, shape, or form. That could be caused by hyperkalemia. That can also be caused by hypocalcemia developing. For hypocalcemia, when those clinical signs will be a Chvostek sign, in which you tap on the side of the face and get fasciculations within the cheek.

But the 1 that we see most often in any of these is the elevation of a serum creatinine. Initially, Cairo-Bishop was more than 1.5 times the upper limit of normal for your serum creatinine, and the modified Howard did an increase in your serum creatinine above 0.3 mg/dL if you had that greater than 1.5 times the upper limit normal in terms of your serum creatinine. Once again, it’s important to understand what your patient’s baseline serum creatinine is going in and how they’re going to adequately deal with any volume shifts or release of these intracellular electrolytes and nucleic acids.

With a lot of these, both of the laboratory [criteria are used] you really want to avoid these clinical manifestations of tumor lysis syndrome. I don’t know if you have any other thoughts on that, Nick. Do you want to delve into the members of the care team, how they’re involved in monitoring and management of TLS, and what specific roles you see with each member of these teams?

You covered most of it. It’s 1 of those things where there are a lot of numbers, and it’s important. For example, at our institution [The University of Texas MD Anderson Cancer Center], we have some available algorithms because these things are complicated. As you mentioned, there’s a lot of numbers in terms of whether it meets formal criteria of tumor lysis syndrome. Those are definitely very helpful as guidance. As I said, you can pull up and plug things in and ask, does this look like real tumor lysis syndrome? It’s 1 of those things that, because you’ve treated patients with this for a while, you get a general idea and don’t necessarily have to look at those numbers. The general principle is that you’re going to see potentially elevations of potassium and phosphorus, eventually low calcium, along with an elevated uric acid. As you mentioned, the effect on the renal function is 1 of the most important things because that’s where you go from a laboratory tumor lysis to a more clinical 1. That’s where it’s more important to intervene or do additional preventive measures.

Comprehensive insight on the signs and symptoms that help lead to the identification of tumor lysis syndrome in patients receiving therapy for cancer. 

Identification of Tumor Lysis Syndrome: Signs and Symptoms 

I’m John Reagan. I’m an associate professor of medicine at The [Warren] Alpert Medical School at Brown University [in Providence, Rhode Island] and the director of hematology at Lifespan Cancer Institute at Rhode Island Hospital.

I’m Nicholas Short from [The University of Texas] MD Anderson Cancer Center in Houston, Texas. I specialize in acute leukemia, AML [acute myeloid leukemia] and ALL [acute lymphocytic leukemia]. We’re here to talk about tumor lysis syndrome. John, start with an overview of what tumor lysis syndrome is.

Tumor lysis syndrome is the destruction and release of whatever is within the cell into the blood stream. If you think about your regular chemistry panels, [let’s say] your potassium levels are very low and your sodium levels are very high. That’s because there’s a lot of intracellular potassium. One thing we find with tumor lysis syndrome is that you get release of this potassium within the cells, nucleic acids, phosphorus, and uric acid. Anything within the cell gets released out. The problem with phosphorus is that it sometimes ends up binding to that calcium and lowers your calcium levels. That’s the hallmark problem with tumor lysis syndrome: what’s inside is suddenly released and brought outside. There are some questions and risk factors that happen with tumor lysis syndrome. Nick, can you go into a little more detail in terms of those risk factors?

Some patients have what we call spontaneous tumor lysis syndrome. Oftentimes in the setting of a hematologic malignancy-leukemia or lymphoma, patients can present with these processes ongoing. The cells may be dying because they’re rapidly dividing, but tumor lysis treatment is also something that we give to patients. We give some therapy, which is a sign in some cases that it’s effective, which is good. But these cells then die as a result.

Some of the main risk factors are those hematologic malignancies, particularly leukemias and lymphomas. In general, the more aggressive you think of the malignancy, the more likely it is to cause tumor lysis syndrome. The acute leukemias—AML, ALL—are more likely than the chronic leukemias to cause tumor lysis syndrome. It’s the same for the more aggressive B-cell lymphoma, particularly Burkitt lymphoma. Those are more likely to cause it. Those can all be spontaneous. Of course, when we give treatment, 1 factor is how sensitive the underlying disease is to the treatments we’re giving. If we’re giving a very effective treatment to a very chemotherapy-sensitive leukemia or lymphoma, then that patient may be more likely to develop tumor lysis syndrome.

In 1 example, we can see what that is—for example, venetoclax in CLL [chronic lymphocytic leukemia]. This is a very effective therapy. Historically, we didn’t think CLL caused tumor lysis as much as some of these more aggressive forms of leukemia. But because venetoclax is so effective in treating CLL, we can see that. That’s why there are strategies in place when you’re treating a patient with CLL with venetoclax to do a very slow ramp-up of this.

There are other characteristics that can be associated with the development of tumor lysis syndrome. For example, if the patient has a very high LDH [lactate dehydrogenase], this is a sign of rapid cell turnover. That goes along with the more aggressive malignancies. Patients with baseline renal dysfunction are more likely to get what we would call a clinical tumor lysis syndrome and worsening renal dysfunction. We have to be very cognizant of that. In general, it’s more common when we give treatment to patients with newly diagnosed disease because they’re generally going to be more likely to have chemotherapy-sensitive disease. Unfortunately, as patients go through treatment, their disease often becomes less sensitive to the treatments that we give, and we don’t see as much tumor lysis syndrome in those cases.

Key opinion leaders James Short, MD, and John Reagan, MD, share an overview on the incidence and clinical risk factors of tumor lysis syndrome.  

John L. Reagan, MD

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