Key Factors to Consider in the Management of Tumor Lysis Syndrome

For patients with aggressive malignant tumors and high tumor burden, onco- logic emergencies such as tumor lysis syndrome (TLS) emerge as a disease symptom or a treat- ment-related adverse effect.^1,2 Categorized by metabolic derangements such as hypocalcemia, renal insufficiency, and uric acid nephropathy, TLS typically occurs in patients whose tumors are chemosensitive and for whom treatment is just being initiated.¹

Several agents are available to aid in the management of TLS. However, investigators note that prevention should be a top priority for clinicians “Theoretically, we have all the tools necessary to manage TLS, but preventing it is so important,” Nicholas James Short, MD, said in a recent OncLive
Insights® program. Short is an assistant professor in the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston.

“If you’re going for curative [cancer] therapy and you must pause to manage all these acute issues coming up—many of which are, at least theoretically, preventable—that’s where the detriment to the patient may come.”

“Fortunately, it is not a very common occurrence. But it’s one of those things [where] if you don’t see it a lot, you don’t necessarily have expertise in dealing with it,” John L. Reagan, MD, said. Reagan is director of hematology
at Lifespan Cancer Institute and an associate professor of medicine at Brown University, both in Providence, Rhode Island. “That’s the biggest difference you’d see between a community [medical center] and academic medical center: If you don’t see TLS a lot, you might not be dealing with it quite as much,” he said.

Reagan also noted there are not a lot of data reflecting TLS management in the academic vs community setting. However, as agents such as venetoclax (Venclexta) have seen an uptick in use, safety awareness is key because TLS is a documented effect of the BCL2 inhib- itor.^3,4 In the OncLive Insights® series, a 6-part series on the incidence and management of TLS, Short and Reagan highlighted several key factors to recognize and promptly address before life-threatening effects such as acute kidney injury occur.^3,4

Eyes on TLS

“Essentially, tumor lysis syndrome is the destruction and release of what is [contained] within the cell into the bloodstream,” Reagan explained. “That’s the hallmark problem with tumor lysis syndrome: What’s inside is suddenly released and brought outside [the cell].”

Cellular breakdown results in the release of phosphorus, potassium, and nucleic acids that exceed the levels a kidney can process and excrete from the body.¹ Several factors are associated with the release of these cellular components. For example, nucleic acid release leads to uric acid formation, which can result in acute kidney injury following renal vasocon- striction or impaired autoregulation.¹

“There are some patients who have what we call spontaneous tumor lysis syndrome, [which is] often [seen] in the setting of a hematologic [malig- nant tumor] although not always,” Short said. He added that patients with leukemia or lymphoma typically present with these processes already in progress. “The cells are dying because they’re rapidly dividing, but TLS is also something we sometimes [cause] with our treatments.”

In addition to venetoclax, anti-CD20 monoclo- nal antibodies such as obinutuzumab (Gazyva) and rituximab (Rituxan), anti–PD-1 monoclo-
nal antibodies such as nivolumab (Opdivo) and pembrolizumab (Keytruda), and CDK inhibitors such as dinaciclib and alvocidib are associated with TLS.1,5-8 “Historically, we didn’t think of CLL [chronic lymphocytic leukemia] as causing tumor lysis [compared with] some of these more aggressive forms of leukemia,” Short said. “But because venetoclax is so effective in [managing] CLL, we see that effect, which is 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 agent.”

“In general, the more aggressive a [malignant tumor], the more likely it is to cause tumor lysis syndrome. The acute leukemias [such as] AML [acute myeloid leukemia] [and] ALL [acute lymphoblastic leukemia] are more likely than the chronic leukemias to cause tumor lysis syndrome in general,” Short said. “The same [goes] for the more aggressive [malignant tumors from] B-cell lymphoma or Burkitt lymphoma. When we give treatment, one factor [to consider] is how sensitive the underlying disease is to the [management] we’re giving. If we’re giving a very effective treat- ment to a [patient with] chemosensitive leukemia or lymphoma, then it’s more likely that patient [will] develop TLS.”

Other characteristics may be associated with the development of TLS, such as high lactate dehydrogenase levels, a sign of rapid cell turn- over. “That goes along with the more aggressive [malignant tumors]. Patients with baseline renal dysfunction are more likely to get what we call clinical tumor lysis syndrome and renal dysfunction, and we have to be very cognizant of that,” Short said.

Prophylaxis

“How do we prevent [TLS]? First, we need to think about risk stratification,” Short said, noting that prevention methods differ depend- ing on the patient’s risk status. “For someone we consider [at] low risk for TLS, such as [a patient with a] solid tumor, nothing is done....For [individuals at] intermediate risk or high risk [for TLS], we’re certainly doing hydration. Hydration is important to prevent renal damage, which is what causes most of the complications [such as] renal dysfunction and buildup of electrolytes.”

Suggestions for adequate hydration include the administration of isotonic fluid to maintain urinary output of 3 L per day.² “Some patients can’t tolerate large amounts of IV [intravenous] hydration,” Short said. He added that in those cases (eg, a patient with underlying cardiomyop- athy), diuretics can play a role. “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.”

Diet can also play a role in preventing TLS, especially with its effect on electrolytes. Eliminating potassium and phosphorus from a diet is one suggestion for patients who are at high risk for TLS, according to Short.

Uric acid buildup is a critical concern for TLS. Agents such as allopurinol and rasburicase (Elitek) are essential components to circumvent this adverse effect. “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,” Short said.

“Sometimes it’s a preventive measure, and sometimes we use it for patients who’ve already developed tumor lysis. It’s very effective at rapidly dropping uric acid levels.”

“The key thing is to keep urine output going, but the hallmark of TLS treatment is preventing uric acid from going up too high,” Reagan said. “The first drug that we reach for is allopurinol.... The mechanism of action is involved in purine catabolism. Purine, if you remember back to first and second year of medical school, goes [from] hypoxanthine to xanthine. Through xanthine oxidase, it gets turned into uric acid. And allopurinol is a xanthine oxidase inhibitor, so it keeps things at [a normal] xanthine level. You’re not actually making uric acid.”

In a study from 2010, Cortes et al demon- strated the unique mechanism of action for rasburicase that sets it apart from allopurinol in clinical practice.^9,10 “Allopurinol goes back to the 1960s when it was first looked at for [management] of elevated uric acid levels. And it was found to effectively lower uric acid levels, so that became the gold standard,” Reagan said.

Using a threshold of 7.5 mg/dL or less to signal maintenance of uric acid, investigators randomly assigned patients with hyperuricemia or at high risk for TLS to receive either rasburicase(n = 92), rasburicase plus allopurinol (n = 92), or allopurinol alone (n = 91) in the phase 3 study (NCT00230178).⁹

Response was significantly higher for those treated with rasburicase (87%; 95% CI, 80%-94%) vs those treated with allopu- rinol (66%; 95% CI, 56%-76%; P = .001).9 In terms of time to response, plasma uric acid levels were reduced to 7.5 mg/dL or less approximately 4 hours after the first dose of rasburicase vs 27 hours with allopurinol.9 Furthermore, in the combination arm, the uric acid response rate was 78% (95% CI, 70%-87%), although this was not deemed statistically significant.⁹

“That study showed that you were able to effectively lower uric acid [levels] much better with the addition of rasburicase,” Reagan said. “Allopurinol was able to lower it a little, but rasburicase could effectively eliminate your uric acid levels. The other drug that’s approved is febuxostat, which is also a xanthine oxidase inhibitor, very much the same as allopurinol. Our bodies can’t get rid of uric acid, so what we [do is] leverage that rasburicase, which is like urate oxidase, which converts uric acid to allan- toin and helps your body excrete the uric acid.”

Additional Considerations

Short highlighted that use of these agents is not a cut-and-dried guideline and that decisions for when to use prophylaxis vary. “There are consider- ations when we’re starting a patient on therapy or a patient comes in with a new diagnosis of one of these hematologic [malignant tumors]. We want to risk-stratify them. Fluids and allopurinol are going to be the case for most patients with intermediate-risk [disease], plus or minus rasburicase,” he said.

“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,” Short said. “Usually, we wait to see [whether] the phosphorus [level] is becom- ing 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], it differs [by case]. If you have a patient [at] high risk, such as one with Burkitt lymphoma who already has evidence of some clinical lysis syndrome, we may not start dialysis right away, but we’d involve our nephrol- ogy colleagues. 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.”

Reagan added that other agents to consider include phosphate binders such as sodium zirconium cyclosilicate (Lokelma) or sodium poly- styrene sulfonate (Kayexalate). Physicians can use these agents to try and eliminate potassium level if it becomes too high.

“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,” Short said, highlighting the need for interdisciplin- ary management. “The next step after giving hydration, allopurinol, rasburicase, and all the measures we discussed earlier [is dialy- sis]. 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 supportive care, but we typically only reserve this for patients after all other supportive care measures I mentioned have not worked.”

References

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3. Howard S. Tumor lysis syndrome management in community oncology settings. Blood. 2019;134(suppl 1):5875. doi:10.1182/ blood-2019-132266
4. Venclexta. Prescribing information. AbbVie Inc; 2022. Accessed February 1, 2023. bit.ly/3Jysnmy
5. Gazyva. Prescribing information. Genentech; 2022. Accessed February 1, 2023. bit.ly/3HMEomY
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8. Keytruda. Prescribing information. Merck; 2023. Accessed February 1, 2023. bit.ly/404NRNv
9. Cortes J, Moore JO, Maziarz RT, et al. Control of plasma uric acid in adults at risk for tumor Lysis syndrome: efficacy and safety
   of rasburicase alone and rasburicase followed by allopurinol compared with allopurinol alone--results of a multicenter phase III study. J Clin Oncol. 2010;28(27):4207-4213. doi:10.1200/ JCO.2009.26.8896
10. Elitek. Prescribing information. sanofi-aventis US LLC; 2019. Accessed February 1, 2023. bit.ly/3JyMelp