Mato Examines Tumor Lysis Syndrome Risk and Hyperuricemia Management

Case-Based Roundtable Meetings SpotlightCase-Based Roundtable Meetings Spotlight: September 2022
Pages: 74

Anthony Mato, MD, discusses the case of a 76-year-old man with stage IV chronic lymphocytic leukemia.

Anthony Mato, MD, MSCE 

Director, CLL Program 

Memorial Sloan Kettering Cancer Center 

New York, NY

Anthony Mato, MD, MSCE

Director, CLL Program

Memorial Sloan Kettering Cancer Center

New York, NY

Targeted Oncology™: What is the pathophysiology of tumor lysis syndrome (TLS)?

MATO: TLS is considered a potential life-threatening oncologic emergency. It is a cascade of pathophysiological events initiated when tumor cells are rapidly destroyed, either spontaneously or in the setting of treatment, that can lead to multiorgan failure. The major concerns are renal dysfunction, cardiac dysfunction, [and] neurological dysfunction, all of which can lead to sudden death.1

The rapid destruction of cells can lead to expelling of their intracellular contents into the bloodstream and one can develop abnormalities including hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, and uremia or renal dysfunction.1

The consequences of these electrolyte abnormalities—for example, the efflux of potassium, an important intracellular cation—can lead to hyperkalemia that can directly cause dysrhythmia. That’s probably the most concerning one that we see in patients when we have effective cancer-directed therapies. Of course, you can also have release of nucleic acids directly related to purine catabolism and that can lead to hyperuricemia, which can subsequently lead to precipitation of uric acid crystals, leading to acute renal failure. Subsequently, acute renal failure can lead to electrolyte abnormalities like hyperkalemia. They’re all interconnected.

Renal failure can also be secondarily caused by calcium phosphate crystal deposition as well, which can also lead to hyperkalemia and cardiac dysrhythmia. Hyperphosphatemia can also lead to hypocalcemia with intratissue crystallization of calcium phosphate crystals, which can have neurological consequences. Taken together, it’s not just 1 abnormality, but each of these electrolyte abnormalities can play into one another to magnify and worsen the outcome for patients.

How is risk assessed for TLS? What are some risk factors?

Patients are stratified based on TLS risk, high risk being defined as greater than 5% risk, intermediate being 1% to 5%, and low risk being less than 1%. The breakdown focuses on the different lymphomas and leukemias and how to determine what the risk of TLS is. For example, CLL is not defined as high risk, although I might argue that patients with extremely bulky disease who were treated with very sensitive therapies would be considered high risk, but certainly the use of biologic or targeted agents in CLL puts patients at an intermediate risk for TLS, particularly the targeted therapies.2 Each tumor type—be it Burkitt lymphoma, acute lymphocytic leukemia [ALL], or acute myelocytic leukemia [AML], high [WBC] counts, high LDH, bulky disease, and lymphadenopathy—will elevate patients into either an intermediate-risk or a high-risk category.2

The risk factors for TLS are broken down into the 3 categories of disease risk factors, patient-related factors, and treatment-related factors. Disease risk factors include rapid cellular proliferation, potentially marked as elevated LDH; high tumor burden, so bulky tumors with an elevated WBC count; sensitivity to cytoreductive therapy, probably one of the most important ones because the better the therapies we have, the faster acting they are and the more likely the body is overcome by the electrolyte intracellular contents; renal infiltration or outflow tract obstruction by tumor; bone marrow involvement, again as a measure of bulk of disease; and splenomegaly as a measure of bulk of disease.2,3

The patient-related factors are preexisting factors like renal dysfunction and uremia, for example. If your kidney is not great to begin with, of course that’s a problem. Other factors include if patients have pretreated hyperuricemia or hyperphosphatemia, particularly in the setting of spontaneous TLS; hypovolemia or hypotension; acidic urine, which would facilitate crystallization of uric acid; congestive heart failure; and older age.2,3

The treatment-related factors include the intensity of the cytoreductive therapy, whether you’re giving 1 agent or combination, and this is disease specific according to the tumor type; inadequate hydration during cytoreductive therapy—I just got a call about a patient whose uric acid was up a little bit, so I gave them a bolus of fluids; and the concurrent use of nephrotoxic drugs.2,3

To me, any Burkitt lymphoma has an incredibly high risk for TLS. This is sort of the textbook scenario where patients present with spontaneous TLS or TLS with glucocorticoids requiring dialysis before they start therapy.4 I think in pediatrics they would have a dialysis catheter placed before they began Burkitt-specific therapy because the risk was so high.

In ALL and AML, particularly with a high WBC count, there’s a connection between the degree of leukocytosis and TLS risk. Lymphoblastic lymphoma with an elevated LDH, T-cell leukemia, or lymphoma [are high risk too]. I think diffuse large B-cell lymphoma [DLBCL] is intermediate risk, but the risk is particularly higher if the LDH is elevated or there’s bulky disease. Mantle cell lymphoma in the leukemic phase of the disease with elevated LDH and bulky tumor is high risk. CLL with bulky disease as evidenced by enlarged lymph nodes, spleen and/or an elevated lymphocyte count is high risk, particularly if you’re using CD20-directed antibodies such as venetoclax [Venclexta].4

Of course, one can see TLS with any of the therapies including radiation or steroids, but cytotoxic chemotherapy is probably the most common cause and includes agents like bendamustine [Treanda]; blinatumomab [Blincyto]; bortezomib [Velcade]; carfilzomib [Kyprolis]; dasatinib [Sprycel]; doxorubicin [Adriamycin]; ibrutinib [Imbruvica], which I would consider probably low risk; lenalidomide [Revlimid]-based therapy; methotrexate; obinutuzumab [Gazyva], which I would consider high risk; vincristine [Oncovin]; and rituximab [Rituxan].5

How is TLS defined and diagnosed?

There is a distinction between clinical and laboratory TLS as per the Cairo-Bishop classification. I’ve already touched on the intrinsic tumor-related risk factors such as high cell proliferation rate, high-risk cancers, large tumor burden, chemosensitivity, and the patient-related factors including pretreatment electrolyte and/or renal dysfunction, preexisting nephropathy, oliguria, acidic urine, nephrotoxins already on board, and inadequate hydration.

The definition of TLS can be broken down into 2 components, laboratory and clinical. Laboratory TLS requires 2 or more of the following abnormalities within 3 days prior to or up to 7 days after the initiation of a cytotoxic therapy. The cutoffs are uric acid greater than or equal to 8 mg/dL; potassium greater than or equal to 6 mEq/L; phosphate greater than or equal to 6.5 mg/dL for children, but a little bit lower threshold for adults at 4.5 mg/dL; calcium less than or equal to 7 mg/dL; or a 25% change from baseline in any of the above.6

As an example, in the patient about whom I got a call, the nurse said to me the potassium is normal at 4.2 mEq/L, but to me that’s not super helpful. I also want to know what the baseline was. If they started out at 3.2 mEq/L, that’s a problem. If they started out at 4.1 mEq/L, that’s not a problem. You also need to look for trends. Clinical TLS can occur in any patient with laboratory TLS plus 1 or more of the following: creatinine 1.5 times the upper limit of normal, which is an immediate change; cardiac arrhythmia; seizure; or sudden death.6 Outside of the creatinine bump, the other abnormalities that define clinical TLS are considered life threatening.

What is the rationale for hypouricemic therapy?

Allopurinol [Zyloprim], for example, interferes with purine metabolism and inhibits xanthine oxidase. Normally when you think about purine catabolism, the end point is uric acid, which is a poorly soluble end product that can easily precipitate in the kidney. I think we’re the only mammalian species [that doesn’t] have urate oxidase, which is the rasburicase [Elitek] product.

All other mammals will degrade uric acid to allantoin, which is soluble and easily excreted in the urine, but we don’t have that, so that’s where rasburicase comes into play. It’s an infusion enzyme [that] can break down uric acid in the bloodstream to allantoin, which is then easily excreted in urine.

I don’t fully understand why from an evolutionary perspective, but we somehow lost our ability to break down uric acid. Of course, hyperuricemia leads to renal dysfunction including uric acid nephropathy, nephrocalcinosis, obstructive nephropathy, and xanthine nephropathy, which is due to allopurinol therapy, so it is a consequence of the preventive strategy for TLS.4,6

Hyperuricemia can lead to secondary hypocalcemia, which causes renal failure, seizures, and then dysrhythmia. Hypocalcemia can make [patients] quite sick. One can also have electrocardiogram [ECG] changes, dysrhythmia, paresthesia, muscle cramps, and tetany. Hyperkalemia, which I think we understand best, can change the ECG and can cause dysrhythmia, paresthesia, weakness, and myalgias.4,6 There are a lot of different clinical issues here, but we’re focusing on how to intervene in 1 problem, which is hyperuricemia that can lead to renal dysfunction.

The prevention guidance for TLS is stratified by the estimated risk for an event. Low risk is less than 1%, and the strategy is watch and wait, which may be appropriate, although you should still think about vigilant monitoring of laboratory parameters and fluid status and having a low threshold for IV [intravenous] fluid infusion and allopurinol prophylaxis.2,4 I think for most of the diseases we’re talking about, we’re comfortable starting allopurinol and providing IV fluids including in leukemias and high-grade lymphomas regardless of the risk.

Intermediate risk is 1% to 5% risk. One is supposed to do aggressive IV hydration of approximately 3 L/m2 per day. This essentially results in patients getting 1.5 L to 3 L of IV fluids daily. Other prophylactic strategies include allopurinol and vigilant laboratory monitoring. Rasburicase can be thought about as an initial hypouricemic agent in place of allopurinol, particularly in certain patients.2,4

High risk is a risk of greater than 5%. Fluids are given aggressively. One might want to think of prophylactic rasburicase as the standard of care. Of course, you must make sure the patient is not G6PD deficient before you do that. Do vigilant monitoring of laboratory values and fluid status. Allopurinol can be substituted for rasburicase if the patient is G6PD deficient.2,4 Hydration is most important. It trumps any of these drugs. If you hydrate a patient well, you’re going to dilute the electrolytes and cause increased urine output, excreting electrolytes more effectively and minimizing crystallization.

The IV fluid dose for high-risk TLS is generally normal saline at 2500 mL/m2 /d to 3000 mL/m2 /d. Never alkalinize the urine. It’s malpractice. The individual patient’s tolerance and comorbidities must be taken into consideration. Obviously, you’re not going to give 3 liters to a patient who’s in heart failure or a patient who’s on dialysis when they’re not due for dialysis at that time. Consider the medical history. Normal saline is the mainstay of hydration, not Lactated Ringer’s solution, and not alkalinized fluid, which will cause precipitation of calcium phosphate in the kidneys and kidney failure.2,4

What data support the use of rasburicase as an antihyperuricemic agent? There was an interesting study [NCT00230178] of more than 180 patients who received either weight-based rasburicase for 5 days, rasburicase and allopurinol combined, or allopurinol as a monotherapy.

Anticancer therapy was initiated 4 hours to 24 hours after the first antihyperuricemic agent dose and then patients were stratified by their risk for TLS.7 Participants in this study had to be adults; have an ECOG performance status of up to 3, so they could have some poor performance status; have acute leukemia or lymphoma; or be at high risk of TLS. The primary end point of the study was lowering of uric acid, so this was not meant to be a trial with a clinical end point but a laboratory end point. There’s an intent-to-treat group, a high-risk group, and a hyperuricemic group. The rasburicase monotherapy strategy was probably the most effective at lowering hyperuricemia, followed by the combination, then the allopurinol monotherapy.

There’s a dramatic reduction in uric acid values in either of the arms where the rasburicase was included, but not so great for allopurinol, even if this was started a few days before the initiation of the anticancer therapy. The lowest rate of hyperuricemia, as one would predict, was with the rasburicase followed by the combination, and then the allopurinol as a monotherapy [Figure7]. Interestingly, this didn’t translate into a difference in clinical TLS. It was 3% vs 4% vs 3%, for the rasburicase, allopurinol monotherapy, and combination arm, respectively. But the rasburicase monotherapy did result in a lower rate of laboratory TLS of 21% vs 41% for allopurinol vs 27% for the combination.

For laboratory TLS, one must have 2 or more abnormalities to meet the definition. So hyperphosphatemia or hyperuricemia by itself is not enough. By minimizing the hyperuricemia, you’re essentially removing that as a variable and that decreases the laboratory events. None of these strategies translated into a very high risk of clinical TLS, thankfully, so they were all effective in that regard. Of course, we don’t know the management per se for each of these arms and whether it was different in the setting of these electrolyte abnormalities, but it didn’t translate into a difference in clinical TLS.

Acute renal failure was a little bit higher in the combination arm at 5% vs 2% for the other arms. Renal failure or renal impairment was a little bit higher in the combination arm at 9% vs 4% for rasburicase alone vs 2% for allopurinol alone. The increase in creatinine was a little lower in the rasburicase arm at 8% vs 10% for the other arms, although I doubt this has any statistical significance.7

The drug-related adverse events [AEs] were 4% in the rasburicase arm vs 5% in the allopurinol arm and 1% in the rasburicase to allopurinol arm.7 This is interesting to me because I would have thought allopurinol was even more toxic than this. In my own practice I have seen issues with skin such as rash, and I see liver dysfunction quite frequently, but it wasn’t seen here as frequently as I would have expected. I think the take-home from this is that all of these were well tolerated, and AEs were relatively rare.

When should a physician consider prophylaxis for TLS?

Based on the NCCN [National Comprehensive Cancer Network] B-cell lymphoma guidelines for TLS, one should consider prophylaxis for patients with the following risk factors: Burkitt or lymphoblastic lymphoma, and occasionally DLBCL; anyone who presents with spontaneous TLS; elevated WBC count, meaning leukemic-phase disease; bone marrow involvement, meaning stage IV disease; preexisting elevated uric acid; ineffectiveness or intolerance of allopurinol; and renal disease or renal involvement by tumor.8

TLS is best managed if anticipated and treatment is started prior to chemotherapy and the centerpiece of treatment includes vigorous hydration and management of hyperuricemia, frequent monitoring of electrolytes, and aggressive correction of electrolyte abnormalities.

How is TLS prophylaxis used in patients being treated with venetoclax? Venetoclax is indicated in AML and CLL. The WBC count should be less than 25 × 109 /L prior to venetoclax initiation and one might want to use cytoreduction to get a patient there. Prior to the first dose you should give prophylaxis with adequate hydration and antihyperuricemic agents and continue during the ramp-up phase. Assess blood chemistry and correct preexisting electrolyte abnormalities.

The recommendations for monitoring blood chemistry for TLS are at predose, 6 to 8 hours after each dose, and 24 hours after final dose. For patients with risk factors, consider additional measures, including increasing the frequency of laboratory monitoring or reducing the starting venetoclax dose.9 In 2 different trials, the TLS rate after venetoclax is relatively low, at 1.1% (all laboratory TLS) and 5.6% (4 clinical events, 2 of which were deaths). But this is not a regimen that’s immune from risk of lifethreatening TLS.

The NCCN guidelines for TLS monitoring for inpatient treatment strongly recommend doing it during cycle 1, especially through dose escalation. Patients may need hospitalization even beyond cycle 1. There are recommendations as per label, whether you’re giving venetoclax with a hypomethylating agent or low-dose cytarabine during the dose escalation. The recommendation is treatment with allopurinol or other uric acid–lowering agents until no further risk.

For proliferative disease, monitor blood chemistry every 6 to 8 hours. If within the normal limits, recheck once daily and continue monitoring. After the first several days if you think the risk is lower, you can back off on the frequency of the laboratory monitoring, and then aggressively monitor and manage electrolyte imbalances.10

There are NCCN guidelines for TLS prophylaxis in CLL, which has not been considered a big deal from a TLS perspective historically. However, because of the rapid responses with agents like venetoclax, it’s now an issue. Prophylaxis should be considered for patients receiving venetoclax, chemoimmunotherapy, lenalidomide, or obinutuzumab; patients with progressive disease after a small molecule inhibitor; bulky lymph nodes; spontaneous TLS; elevated WBC count; preexisting uric acid elevation; or renal disease or renal involvement by tumor.11

The majority of participants would also start hydration. I’m guessing if you consider the patient high-risk, you would do it in the hospital. I think they have bulky disease. One could be concerned about the renal dysfunction and the uric acid, so I would probably admit such a patient. There is a risk stratification for TLS when venetoclax is used for CLL based on tumor burden. Low tumor burden is when all lymph nodes are less than 5 cm and WBC count is less than 25 × 109 /L. Medium tumor burden is any lymph node between 5 cm and 10 cm or WBC count greater than 25 × 109 /L, and high tumor burden is any lymph node greater than 10 cm or any lymph node greater than 5 cm and WBC count greater than or equal to 25 × 109 /L.9

Low-risk patients get oral hydration and allopurinol, although IV hydration is never wrong. Medium-risk patients can get IV or oral hydration, although I always give them IV and allopurinol. The high-risk patients should be getting IV hydration between 150 mL and 200 mL per hour and then allopurinol or consideration of rasburicase, particularly if the uric acid is elevated.9

The frequency of monitoring laboratory changes depend on the risk status. Low and medium risk will have predose monitoring, then 6 to 8 hours after each dose, and 24 hours post final dose particularly on weeks 1 and 2 of the escalation. I tend to be conservative and do it throughout the escalation. Then high-risk patients have laboratory monitoring [before] dose, then after 4 hours, 8 hours, 12 hours, and 24 hours, particularly on weeks 1 and 2 as you’re debulking these patients and escalating dose from 20 mg to 50 mg. When you get to 100 mg, 200 mg, and 400 mg, you still do laboratory monitoring at 8 hours and 24 hours post dose.9

The TLS rate in clinical trials for venetoclax in CLL or small lymphocytic lymphoma with the 5-week ramp-up is relatively low at around 5%, but certainly 2% to 3% for each trial. Most of these events are laboratory events. In the escalated 2-week-to-3-week ramp-up, there’s a 13% risk.9 There are very few patients with CLL who must have an escalated ramp-up due to concern of clinical proliferative disease.

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