Davids Discusses Risk Factors in Managing Tumor Lysis Syndrome

Matthew S. Davids, MD, MMSc

Director, Clinical Research

Division of Lymphoma

Dana-Farber Cancer Institute

Associate Professor of Medicine

Harvard Medical School

Boston, MA

Targeted Oncology^TM: What is tumor lysis syndrome (TLS)?

DAVIDS: TLS is a cascade of pathophysiologic events that can lead to multiorgan failure or even sudden death. The classic electrolyte abnormalities include hyperuricemia, hyperphosphatemia, hyperkalemia, and hypocalcemia, and eventually clinical uremia can develop in the setting of high uric acid.¹

As the tumor cells lyse, some of the early changes seen are efflux of potassium out of the cells; the release of nucleic acids, which can break down into uric acid through purine catabolism leading to hyperuricemia; and hyperphosphatemia.

This is often seen in hematologic malignancies. As this process is evolving, we can also see an elevation in lactate dehydrogenase [LDH], which can be an early indicator of TLS.¹ If left untreated or if it is very severe even in the face of treatment, it can lead to more significant electrolyte abnormalities such as severe hyperkalemia and cardiac arrhythmias. When uric acid precipitates in the kidneys, it can cause acute renal failure, which can further precipitate other issues. Calcium phosphate imbalance can further exacerbate that too. Fluid resuscitation is very important because fluid depletion can induce a variety of symptoms and in the worst of cases put patients at risk for sudden death.

What is TLS risk assessment? What are the recommendations for prophylaxis?

Most solid tumors do not have a high risk of TLS, with certain exceptions. So when we’re talking about TLS risk, we’re usually talking about hematologic malignancies. Most indolent lymphomas such as follicular lymphomas, Hodgkin lymphoma, and so forth, fall into the low-risk category, particularly if they don’t have a circulating component, the white blood cell count [WBC] is less than 25, and the LDH is not particularly high.²

However, I think it’s therapy-dependent because with venetoclax [Venclexta] we have observed some TLS in mantle cell lymphoma [MCL]. As we get into the intermediate-risk category, we start to think about more aggressive non-Hodgkin lymphomas. Some [patients with] Burkitt lymphoma can be intermediate risk too, although I tend to think of them as more in the high-risk category. Lymphoblastic lymphomas, or variants of acute lymphoblastic leukemia [ALL], can either be intermediate or high risk depending mostly on the tumor burden. If the WBC count is lower or the lymph node size is smaller, the risk is a bit lower. Then we have some chemotherapy-sensitive bulky solid tumors that can fall into this intermediate-risk category, such as germ cell tumors, neuroblastoma, and small cell lung cancer.²

The high-risk category has a greater than 5% chance of TLS. These include Burkitt lymphoma, ALL, particularly when the WBC count is greater than 100 or if they’re coming in with a high baseline LDH, perhaps suggesting some spontaneous TLS even before starting treatment. Those are the patients we’re worried about, particularly if they have bulky lymph node disease.²

What are the TLS risk factors?

We have the disease-related factors, and these are tumors that have rapid cellular proliferation, have high tumor burden, or are sensitive to cytoreductive therapy. We are particularly worried when it’s disease that is causing renal issues—for example, renal infiltration by the lymphoma that’s impairing renal function, or compressive lymphadenopathy such as bulky retroperitoneal lymphadenopathy that’s causing hydronephrosis or urinary tract obstruction.²

High bone marrow involvement can be a hidden factor. Sometimes we get a little bit thrown off if we see a patient who doesn’t have a lot of circulating disease, but they may have a packed bone marrow, and if it is sensitive to treatment, they can still have TLS, even with a normal WBC count.

Splenomegaly is kind of interesting as it’s been one of the less predictable [factors] over the years.² I’ve had a patient with MCL who had normal-sized lymph nodes, a minimally elevated lymphocyte count, but a huge spleen, and had very significant TLS when starting treatment. So that’s something to keep an eye on.

There are also the patient-related factors. Do they have other comorbidities, [such as] preexisting renal disease? Are they diabetic and already have renal disease from that? Are they already [dealing with] uremia for various reasons? [The focus should be] on pretreatment for hyperuricemia or hyperphosphatemia and keeping patients’ volume replete to avoid hypovolemia or hypotension.

Acidic urine may contribute [to TLS]. Congestive heart failure [CHF] can be very challenging here, because these are patients we need to flood with fluids, and if they already have CHF that can make it very difficult. Older patients, especially in my population of patients [with CLL (chronic lymphocytic leukemia)], are at risk, both in terms of their lesser ability to tolerate fluid loads and their poorer renal function.³

Treatment-related factors, of course, matter as well. How intensive is the cytoreductive therapy? Is this a single-agent chemotherapy vs combination approaches? This will, of course, vary across diseases. Are they inadequately hydrated during cytoreductive therapy? Do they have a need for other ongoing agents that are nephrotoxic, which could further put them at risk? As with venetoclax, you don’t necessarily need to be using multiagent chemotherapy regimens to see TLS; it depends on how sensitive the tumor is to a particular drug, and it may just be 1 targeted agent. If it’s a very effective targeted agent, the TLS risk could be high.³

What factors put patients at high risk of TLS?

Most of these patients probably will be admitted to the hospital for very close monitoring when they’re getting their first cycle of treatment. They are going to be [patients with] Burkitt lymphomas, especially if they have an LDH that’s elevated at baseline; ALL or acute myeloid leukemia [AML] with high WBC counts; lymphoblastic lymphoma with a high LDH; certain T-cell leukemias or lymphomas, which I find to be a little bit more unpredictable as some of them are, as we know, very unresponsive to treatment. However, others can cause TLS, and diffuse large B-cell lymphoma tends to fall in the middle.⁴

I’ve noticed anecdotally that [patients with] transformed lymphomas with a high LDH may be at a little bit more risk. Certainly, patients with bulky tumors are at a higher risk, although we treat patients with bulky DLBCL who don’t have TLS. So that remains, I think, a little bit of a mystery.

There is also MCL, especially if they’re coming in with spontaneous TLS or bulky tumors.⁴ For CLL, it was surprising to us when it happened, because with all our prior chemotherapy-based approaches to [managing] CLL, we had not seen TLS as a major problem. Suddenly, when we came in with the venetoclax-based treatment, particularly for those patients with CLL who had bulky lymph node disease or those who had an elevated lymphocyte count, we realized very quickly that the risk of TLS was high, particularly with the dosing schemes that were used early in the drug’s development.

What selected therapies are associated with an increased risk of TLS or uric acid elevation?

Radiation therapy and steroids can carry some risk, but not super-high [risk]. Several antineoplastic systemic therapies can lead to TLS, and it varies by disease and by treatment. There have been cases of TLS reported with bendamustine [Treanda], but not that common, and blinatumomab [Blincyto], certainly in the ALL setting. The proteasome inhibitors, such as bortezomib [Velcade] and carfilzomib [Kyprolis], are also not super common but we can see it, and dasatinib [Sprycel], although not as much. There is also doxorubicin, of course, as a component of multiagent chemotherapy regimens.⁵

There have been scattered case reports of some laboratory TLS-like changes with ibrutinib [Imbruvica], but I’ve used a lot of ibrutinib at this point and I’ve almost never seen that, so it’s certainly rare. We don’t use lenalidomide [Revlimid] that much in CLL, but those of you who are treating [patients with] myeloma, I’m sure, have more experience with it than I do. In CLL, you can see TLS when you start lenalidomide, but it certainly is not common.

Obinutuzumab [Gazyva] is one that I wanted to highlight because I think it gets overlooked. It is becoming a more commonly used anti-CD20 monoclonal antibody in CLL, and we see TLS commonly in those first couple of doses. It’s something that wasn’t on my radar until a couple of years ago when I started checking laboratory results 6 to 8 hours after they started the infusion, and then also 24 hours later, and I saw quite a few patients with electrolyte changes. Usually, it was not frank clinical TLS, but I usually intervene when I see the laboratory changes, so maybe I’m avoiding clinical TLS in some patients. Others are venetoclax…and then vincristine, rituximab [Rituxan], usually as part of complex regimens with multiple different agents.⁵

What criteria are used to define TLS?

One of the more commonly used ones is the Cairo-Bishop criteria, and this is useful in terms of thinking about the intrinsic tumor-related risk factors as well as the patient-related risk factors.⁶ For the tumor-related factors, you should ask, “Is it proliferating quickly? Are they high-risk cancers? What’s the bulk of disease? How sensitive is it to the treatment?”

For patient-related factors, you should ask, “What are their pretreatment electrolytes looking like? Did they come in with some spontaneous TLS to begin with? Do they have some preexisting nephropathy or other comorbidities of the kidneys? Do they have oliguria, for example? Are they inadequately hydrated?”⁶

These are some of the factors, but what’s useful from the Cairo-Bishop classification is that you have this distinction between laboratory and clinical TLS. We see laboratory TLS more commonly, both in the clinical trial setting and outside of clinical trials. I won’t go through details of all the different electrolyte abnormalities, but, in essence, to meet these criteria you must have 2 or more of these abnormalities 3 days prior and up to 7 days after the initiation of cytotoxic therapy.

So this captures those patients with spontaneous laboratory TLS prior to starting treatment, and those patients who [may develop] TLS during the first 3 days of treatment. Either you have 2 or more of those laboratory abnormalities or you have a 25% change from baseline analysis in any 1 of the analytes.⁶ In the venetoclax program, there were a fair number of cases of laboratory TLS. Most of these are patients who don’t have any clinical sequelae at all, and it is just something that we see in the laboratory results.

Some patients have interventions that help to keep them in that category of laboratory TLS and not evolve into the more serious category of clinical TLS. For clinical TLS, you have to have laboratory TLS to start with and 1 or more of the following: a creatinine that’s 1.5 times the upper limit of normal, cardiac arrhythmia, seizure, or sudden death related to TLS.⁶

What are some clinical manifestations of TLS?

Generally, within the first 12 to 72 hours is the highest risk time frame for the clinical manifestations of TLS. Patients can develop symptoms that reflect the underlying metabolic abnormalities, such as gastrointestinal symptoms, weakness, lethargy, hematuria, cardiac dysrhythmias, seizures, muscle cramps, and even tetany or syncope.⁷

How does hypouricemic therapy work to prevent TLS symptoms?

Purine catabolism leads to hypoxanthine, which is converted by xanthine oxidase into xanthine, so that’s one of the steps at which allopurinol can block. Allopurinol can then block the conversion of xanthine into uric acid itself. Moreover, urate oxidase is what breaks down uric acid, and that moves into allantoin, which can be easily excreted. So that’s where rasburicase [Elitek] acts to break down the uric acid directly into allantoin very quickly so it can be excreted from the kidneys.

What are some complications of TLS?

Renal dysfunction can lead to uric acid nephropathy, nephrocalcinosis, obstructive nephropathy, or rarely xanthine nephropathy in the setting of allopurinol therapy. Hyperphosphatemia is associated with secondary hypocalcemia, renal failure through precipitation in the kidneys, which leads to additional clinical sequelae such as seizures or heart rhythm abnormalities.

Hyperkalemia, of course, can initially cause [electrocardiogram (ECG)] changes, but eventually arrhythmia, or paresthesia, weakness, and myalgia. Hypocalcemia itself can cause ECG changes and arrhythmias as well as paresthesia and muscle cramps, [and] in more severe cases tetany.^6,7

What are some other TLS prevention measures?

TLS management is clinical judgment based, but the most important thing is prevention, so starting prophylaxis before the initiation of therapy is helpful whenever that’s possible. For patients whom you’ve identified as being at a lower risk, just watching and seeing how they do and then [managing] TLS if it evolves is a reasonable strategy. But you need to monitor laboratory results and their fluid status and have a low threshold to initiate IV [intravenous] fluids. You may even think about allopurinol prophylaxis in these patients because there’s usually not too much downside if they tolerate allopurinol and don’t develop a rash or another complication.^2,4

The intermediate-risk patients have a 1% to 5% risk of TLS. This is where you want to start doing the IV hydration. Some guidelines would suggest even 3 L/m² per day. You certainly want to start these patients on prophylactic allopurinol or equivalent, ideally 2 to 3 days before starting the treatment. Vigilantly monitor laboratory parameters and fluid status. You may think about using rasburicase as an antihyperuricemic prophylactic agent, particularly for patients who come in with an elevated uric acid [level]. If you have a patient already on allopurinol and fluids, and hyperuricemia is beginning to develop on treatment, that’s where rasburicase can be very helpful to quickly turn that around.^2,4

The high-risk patients have a greater than 5% chance of TLS. These are patients who, generally, you should treat in the inpatient hospital setting with aggressive IV hydration. This is where you want to think about prophylactic rasburicase to get that uric acid level down before starting treatment and, again, vigilantly monitor laboratory parameters and fluid status.^2,4 You will have the occasional patient you come across, if you test, who has glucose-6-phosphate dehydrogenase deficiency, and these are patients you can think about [giving] allopurinol instead of rasburicase, even in high-risk disease.⁴

Looking at urine output is very helpful, and in the inpatient setting you can closely monitor that. In the low-risk patients, encourage oral hydration. In the high-risk patients, give them a lot of normal saline solution at an aggressive rate and then look for urine output of at least 2 mL/kg/hr or 100 mL/hr as a good benchmark.⁸

What study data support the use of rasburicase?

There was a phase 3 study [NCT00230178] of rasburicase for control of plasma uric acid levels in adults who were at high risk for TLS. [Basically, the patients had] either active leukemia or lymphoma [and] were randomized in a 1:1:1 fashion to just traditional allopurinol starting before the cancer therapy; allopurinol plus rasburicase; or rasburicase alone, given at the 0.2 mg/kg/day dosing that’s FDA approved, all for 5 days.⁹

The primary end point of this study was the uric acid response rate, which was the proportion of patients with plasma uric acid levels of less than or equal to 7.5 mg/dL from days 3 to 7 after the initiation of therapy. Secondary end points were pharmacokinetic parameters. They identified high-risk patients based on [factors] including a high baseline uric acid level, an aggressive leukemia or lymphoma, or even high-grade MDS [myelodysplastic syndrome].⁹

There were approximately 90 patients in each arm. It is an older study, a little over a decade old, and was published in the Journal of Clinical Oncology in 2010.⁹ The response rate was highest in the rasburicase-alone arm, interestingly, and similarly high with rasburicase plus allopurinol, but a little bit lower. The allopurinol-alone arm had a lower uric acid response rate. I think all of us who have used rasburicase know how quickly this drug works.

The uric acid [level] drops dramatically within the first day when you use rasburicase; whereas, with allopurinol, it slowly drifts down over time as patients are on allopurinol for longer, but it doesn’t lower uric acid to close to zero like rasburicase [does]. The authors concluded that some of the treatment-related differences in plasma uric acid response rates were preserved in the high TLS risk or high uric acid baseline subgroups.

The incidence of TLS and renal events from the study was compared across the different arms. Interestingly, the rates of clinical TLS were similar because it was quite uncommon, just 3 or 4 cases in each arm. Laboratory TLS was significantly less in both the rasburicase-containing arms, at the 21% and 27% range compared with allopurinol, where it was 41%. Of course, the uric acid levels were lower in the [patients treated with] rasburicase. The other ones did not differ as much, although, interestingly, hypocalcemia seemed to be a little bit higher in the allopurinol-only group. The actual risk of renal events and the rates of increased blood creatinine and renal failure didn’t differ much across the different arms.⁹

_REFERENCES

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_{4. Cairo MS, Coiffier B, Reiter A, Younes A; TLS Expert Panel. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149(4):578-586. doi:10.1111/j.1365-2141.2010.08143.x}

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_{7. Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26(16):2767-2778. doi:10.1200/JCO.2007.15.0177}

_{8. Goodrich A. Advanced practice perspectives on preventing and managing tumor lysis syndrome and neutropenia in chronic lymphocytic leukemia. J Adv Pract Oncol. 2021;12(1):56-70. doi:10.6004/jadpro.2021.12.1.5.}

_{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}