Patients that are at high risk for tumor lysis really need to be admitted to the hospital for very close monitoring. We need to get labs every 6 hours, maybe every 8. If you ask our pediatric colleagues they want to get labs every 4 hours. Obviously, there is limitations in how fast you’re going to get your labs back and being able to address those labs. In our practice we usually use q [every] 8 hours but that being said, you can’t do every 8 hour labs as an outpatient. So patients need to be admitted.

Contrast that to our intermediate or lower risk, many of these patients don’t need laboratory monitoring that closely and can be monitored as an outpatient. Definitely low-risk patients are monitored as an outpatient. Intermediate risk—it depends on which expert you ask and which guidelines you look at, but in our practice our intermediate-risk patients are treated as an outpatient. Just to give you a picture of what an intermediate-risk patient looks like, this would be a patient getting R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone] for diffuse large B-cell lymphoma. As you know, we don’t admit every single one of those patients for q-8 hour laboratory monitoring of tumor lysis. We are monitoring these patients as an outpatient.

I think the most important thing to know about tumor lysis syndrome is that it is a life-threatening syndrome. So we all need to be educated about it, whether you’re at an academic center treating hundreds of patients per year, or at a community center treating only a couple patients that are at risk for tumor lysis per year. I think it’s very important to have institutional guidelines that outlines who is at high risk, who needs labs very frequently, what labs should we be ordering for these patients, what are the signs and symptoms, what prevention strategies should we be using and what treatment strategies should we be using? This should all be outline in an institutional guideline so that we have a uniform practice no matter who is treating this patient. Whether it’s oncologist X or oncologist Z, or the interns with PharmD’s who are treating the patients. I think everyone needs a uniform approach and a common strategy so that we’re not recreating the wheel every single time we have a new patient with tumor lysis. Also, when you treat in a uniform fashion and standardize the approach it’s going to be safer for the patient.

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Closing out his discussion on tumor lysis syndrome, Anthony Perissinotti, PharmD, BCOP, shares practical advice on its identification and management. 

Practical Advice on the Management of Tumor Lysis Syndrome 

When I have a patient that I’m worried about tumor lysis syndrome, whether it’s for prevention or treatment, I start everybody on allopurinol. I will start them on 300 mg twice a day at least initially for a day or two to load them up. Then I transition them to 300 mg daily. For patients that are at very high-risk or their uric acid is already quite high, I just continue them on 300 mg twice a day. This has been the standard of care since the 1960s. I usually continue it until I no longer feel that they are at risk for further tumor lysis. Usually this takes a couple days after they are complete of their chemotherapy. To make it easy sometimes I just tell our interns send our patient home with 7 days of allopurinol and that usually does the trick.

There’s another xanthine oxidase inhibitor, febuxostat, which is a little bit more potent than allopurinol. There was this trial, called the FLORENCE trial [NCT0172452], that showed febuxostat could lower uric acid a little bit quicker than allopurinol. There’s some debate about whether that is true or not, and whether it was just an underdosing of allopurinol. That being said, when I have a patient who I’m worried about their uric acid but I’m not quite worried enough that I want to pull out rasburicase, that’s a patient who I might consider using febuxostat. I use 120 mg daily and again, similar to allopurinol I start before chemotherapy and I continue it past the period of their risk.

As far as rasburicase, rasburicase has been studied in randomized controlled trial published in [the

] by [Jorge] Cortes [, MD, Georgia Cancer Center] back in 2010, so we’ve had this data for quite a while. We’ve learned a lot of the use of rasburicase since this trial and one of the things we’ve learned is understanding that we can use fixed dosing. I typically will use 3 mg for most patients when their uric acid rises. I don’t use it for prophylaxis, I use it for treatment and I use it when I see the uric acid is inappropriately high. Many guidelines and many institutional practices use rasburicase the second they see the uric acid jump above 8 mg/dL, then they give rasburicase. I don’t usually use one laboratory value at one moment in time to decide on therapy. I’m a bit more methodical about it. I’m thinking about what’s the patients trends, what’s the patients risk, how much fluid have they received, how much fluid can I continue to give. It’s a lengthy thought process before just saying, “Oh the uric acid is 8 mg/dL I’m going to give rasburicase.” I typically watch the trends. There are levels of uric acid that I do say the uric acid is this and I automatically give rasburicase. Usually when their uric acid is above 15 mg/dL I don’t even think about it and I just give rasburicase.

It brings up a question that is admitted and their uric acid is, say, 20 mg/dL, so it’s at a very dangerous level that can lead to renal failure and the need for dialysis. It’s an open question of should you wait to give rasburicase and do G6pd deficiency testing, because patients can get hemoglobinemia. In my practice I don’t wait. If I have an emergency where I need to get the uric acid down immediately, I’ll give them a small dose, 3 mg or 6 mg, and I’ll monitor the patient very closely. Now if I have time, I certainly will consider G6pd deficiency testing in patients with Mediterranean decent or northern African descent. If they fit the phenotype, I’ll consider it if time allows, but if time doesn’t allow, I’ll give them rasburicase regardless of that testing. Again, my approach is probably a little bit more conservative than others. It really just comes down to the cost of the medication and also my comfort level with monitoring patients very closely and knowing that I can pull the trigger at any moment to get their uric acid down to essentially zero the second that I’m worried about the patient.

Another contentious debate among experts is, do you use rasburicase by itself, or can you combine it with a xanthine oxidase inhibitor like allopurinol? Part of the concern is that some believe that if you give allopurinol you’re going to increase hypoxanthine and xanthine and if you give rasburicase you’re going to continue to see very high levels of hypoxanthine and xanthine. Which can cause xanthine nephropathy. This is not a proven disorder so I am not worried about xanthine nephropathy, especially when I’m giving patients 200 ml/hour of normal saline. So to me it’s not a big issue.

The other thought is that some believe that giving the combination is just pointless because you are giving rasburicase. If the uric acid is going down to zero why do you even need more agents to reduce the uric acid or prevent the uric acid from going up. I think in the world of using fixed dosing, there are many patients who do require multiple doses of rasburicase. So at our institution, our thought process is to potentially to prevent additional need for giving more and more doses of rasburicase, because we probably are under-dosing some patients, if we use the combination we might be able to prevent the uric acid from rising again. Again, it’s a debate. I’d say if you ask one expert, they’ll say the combination is fine, you ask another expert and they’ll say absolutely not because you’re going to potentially increase their risk for renal failure.

Guideline-directed treatment strategies available to patients with identified tumor lysis syndrome. 

Tumor Lysis Syndrome: Treatment Armamentarium

There are many different approaches to prophylaxis of tumor lysis syndrome and it really depends on the risk of the patient. I’ll just describe high-risk patients because low-risk patients probably don’t need much prophylaxis at all. Intermediate-risk patients for the most part, I’m approaching them similarly to our high-risk patients. I start everyone on a xanthine oxidase inhibitor, regardless of what their uric acid level is. So I start them on allopurinol. I also start them on fluids, 100 to 150 ml per hour. I watch their electrolytes. If I have to go up, I have to go up. If they are getting fluid overloaded, I’ll give them Lasix [furosemide]. If their uric acid looks great in a day I’ll bring down the fluids, but at least I start on 100 to 150 ml for most patients. Certainly patients with cardiac disorders, heart failure, I might be a little bit more ginger with their fluids. I start [those] before starting chemotherapy.

I don’t start a phosphate binder as prevention I wait for the phosphorus to go up. I also don’t start rasburicase prophylaxis even in high-risk patients. Now this is a contentious debate. I think many experts would disagree with me and many guidelines would suggest all high-risk patients should get rasburicase regardless if the uric acid. I don’t use it as prevention I use it as treatment. It’s a very effective medication and if you’re monitoring patients labs every 6 hours or even 8 hours and you see that uric acid start to rise rapidly you can instantaneously give them rasburicase and the uric acid will go down to zero and so for that reason I don’t use it for prevention.

For the prevention and treatment of tumor lysis syndrome, there is no better strategy than to hydrate patients. Hydrating means giving them normal saline. Decades ago we thought that potentially alkalizing urine to make it more basic could help tumor lysis because the uric acid was more soluble. Now that we have very effective uric acid lowering agents that’s no longer the case. It’s less of a debate now whether you choose a sodium bicarbonate vs normal saline. I use normal saline. The field has moved in the direction of using normal saline because with an alkaline urine your phosphorus and your calcium phosphorus can actually become less soluble and therefore deposit more inside the kidneys. So we use normal saline to prevent and tumor lysis. It’s by far the most effective way to prevent and treat tumor lysis.

For prevention I generally will start a patient 100 too 150 ml per hour of normal saline and I adjust as needed. For treatment it’s much higher, 200 to 300 ml per hour. The goal here is not necessarily hypervolemia, our goal is to keep a patient euvolemic because what we’re trying to do is just flush out all of the electrolytes. There are times a patient can get fluid overloaded and it’s very important to monitor for this because we don’t want our patients to have flash pulmonary edema. So we provide our patients with diuretics as well.

I think one thing that no one ever talks about for prevention is debulking the patient. Starting things like steroids or hydroxyurea or even doing luciferases to pull off hundreds of thousands of blood cells. Trying to debulk that patient so that when you do start definitive therapy the disease burden is much less that it was 2, 3, 4 days ago while you were waiting for a definitive diagnosis. So I think debulking is very important for the prevention of tumor lysis as well.

Of course, we limit potassium in patients’ diets at least 24 or 72 hours around chemotherapy. I don’t use phosphorus binders for the prevention of tumor lysis but I will use it when my patient’s phosphorus starts to rise, as treatment. There are a number of phosphorus binders out there. There’s sevelamer, there’s calcium based, lanthanum based, and aluminum based drugs. I typically just used Sevelamer. It’s probably the weakest of all the binders but it’s what I tend to use. The way these drugs tend to work is they bind to phosphorus in your stomach, so it’s binding dietary phosphorus. They don’t work all that well because when you think about it the phosphorus is actually being released in your bloodstream not from your gut. So It might help prevent you absorbing more phosphorus, but really it’s the fluids that are going to get rid of your phosphorus. In worst-case scenarios if we can’t deal with the phosphorus with our fluid and our phosphate binders, that’s when we have to get a nephrologist on board to pull off these electrolytes with dialysis.

There are also agents that can help lower potassium, which in general we’re treating hyperkalemia just like you would on any other unit, but this is probably the most important electrolyte to monitor because this is the one that can cause sudden cardiac death and arrhythmia. We want to pull out our insulin and dextrose as soon as feasible based off of how high their potassium [levels] are. Essentially you’re just pushing potassium into the cell with the insulin and then you use dextrose to prevent hypoglycemia from the insulin.

Then we have our uric acid—lowering agents like allopurinol or febuxostat. These are our xanthine oxidase inhibitors, they prevent the conversion of xanthine and hypoxanthine to uric acid. Then we have rasburicase which is an enzyme that helps convert uric acid that has already been made or is being released from the cells. It converts uric acid to a molecule called allantoin. Allantoin is much more water-soluble and you are able to excrete it through your kidneys a lot easier than uric acid. Uric acid can clog the kidneys and cause renal failure.

An overview of the prophylactic strategies that may be utilized to reduce the likelihood of tumor lysis syndrome.

Tumor Lysis Syndrome: Prophylactic Strategies 

As a pharmacist, I first received training as a student on my rotations. We had topic discussions on tumor lysis syndrome especially when we start patients on chemotherapy we would discuss that patient case with my mentors and preceptors. I further had more knowledge during my first- and second- year residencies, where again mentors taught me their experience with tumor lysis syndrome. And, of course, I did my own readings. After that point it was really all independent [learning].

I’m on services every single day of the week so I see the highest of high-risk patients for tumor lysis syndrome every single day. So I see the trends, I see what patients go through, I see all the lab abnormalities. I try to just gain more experience by watching my patients and watching their trends. From there what I do to further my education is studying the trends. I might start a new initiative or a new treatment strategy. I’ll do sort of a pre- and post-analysis to understand whether or not I improved patents outcomes with that. I think doing research really pushed me to what I like to think of myself as an expert at this point.

It’s really best practice to train everybody around you. I want to empower others on my team, my attendings, my fellows, other residents to be able to monitor for, treat and prevent tumor lysis syndrome. While I’m on service I educate the interns and everyone on the team during rounds to know what they should be expecting when we start a new patient on chemotherapy. I’ve also created institutional guidelines so that they can refer to those when I’m not around so that they are able to properly prevent and treat and of course monitor for tumor lysis syndrome.

Expert perspective on the role of a pharmacist in managing patients with identified tumor lysis syndrome. 

Role of a Pharmacist in Managing Tumor Lysis Syndrome 

Tumor lysis syndrome [TLS] is an oncologic emergency that can be life threatening. It's an urgent diagnosis that we have to monitor for when patients are getting chemotherapy. Essentially what happens is when malignant cells that respond to therapy and the intracellular contents get released into the blood stream. The intracellular contents are generally potassium, phosphorus, and then nucleic acids, which can turn into uric acid. There are 2 general definitions that we use, 1 is the Cairo-Bishop criteria and the other is the Howard criteria.

The signs and symptoms of tumor lysis syndrome, I like to break them down into either laboratory or clinical. Laboratory tumor lysis syndrome is characterized by hyperkalemia, hypophosphatemia, hyperuricemia. You see a secondary hypo-low calcium, and this is because the calcium ends up binding with the phosphorus and the phosphorus just overwhelms the calcium and the calcium drops. So those are some of the laboratory findings. We also have the clinical tumor lysis syndrome signs and symptoms which is what we're trying to prevent. The laboratory abnormalities often are OK, but we really want to try to prevent clinical tumor lysis syndrome because this is where things can become more life threatening and cause end-organ damage. So some things that we can see are cardiac arrhythmias, we can see hypotension, heart failure, and renal failure that leads to oliguria, muscle cramps, tetany seizures, syncope and sudden death.

The malignancies that tend to cause tumor lysis syndromes are those that are fast dividing or rapidly growing malignancies or very high bulk tumors. Also disease states that are very responsive to therapy. Some examples are going to be our acute leukemias, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL). Then some of our lymphoid tumors such as Burkitt lymphoma, a very fast dividing, very responsive disease state. Diffuse large B-cell lymphomas, especially the more aggressive one like double-hit which have rearrangement in 

. We can see also some of our T-cell lymphomas that can be proliferative and very responsive and thus cause tumor lysis syndrome. There is some that believe that some of our solid tumor malignancies can also cause tumor lysis syndrome because there are again some things that are very responsive and fast dividing like our small cell lung cancers. Also our germ cell tumors.

Within pediatrics indeed they also see acute leukemias, but they can also see neuroblastoma, which is again, quite proliferative and responsive to therapy. Actually pediatrics, for whatever reason, their TLS tends to be a little bit more robust. Probably due to the fact that their malignancies are rapidly responsive to therapy as opposed to adults. Besides disease states we do worry about some drugs that can increase patients risk for tumor lysis. I think one of the newest drugs that should be implicated with TLS is venetoclax. This is especially true when we use venetoclax for lymphoid disease states, specifically chronic lymphocytic leukemia [CLL]. Our patients with CLL, cells are primed for death because they have an overactivation of BCL2. And when you add a BCL2 inhibitor like venetoclax you can see profound and robust tumor lysis syndrome. So we have many mitigation strategies to help prevent that from happening.

Anthony Perissinotti, PharmD, BCOP, highlights associated risk for tumor lysis syndrome and identifies signs and symptoms. 

Anthony Perissinotti, PharmD, BCOP

Articles

Practical Advice on the Management of Tumor Lysis Syndrome

Tumor Lysis Syndrome: Treatment Armamentarium

Tumor Lysis Syndrome: Prophylactic Strategies

Role of a Pharmacist in Managing Tumor Lysis Syndrome

An Overview on Tumor Lysis Syndrome in Cancer Care