What is “Tumor Lysis Syndrome”?
“Tumor lysis syndrome” (TLS) is a potentially life-threatening complication. All too often I have heard from members whose local oncologists had not paid sufficient attention to this possible risk before starting chemotherapy. Once again, what you (and your doctor) do not know can kill you.
In simple terms, TLS is a risk if too many cancer cells are killed too quickly and the debris created by the dying cancer cells overwhelms your body’s garbage handling capability. As anyone who has lived through a garbage strike can tell you, things can get toxic and smelly pretty quickly once the garbage starts piling up in the streets.
One of the major components of the “garbage” created by dying cells is uric acid. Under normal circumstances your kidneys remove uric acid dissolved in your urine. Unfortunately, uric acid is only slightly soluble in water. Even when your kidneys are doing their best there is a limit to how much uric acid can be eliminated by this route. If the amount of uric acid that has to be processed overwhelms the capability of your kidneys, you are at risk of kidney damage or even kidney failure. Some of you may have had opportunity to worry about uric acid from other perspectives. “Kidney stones” are caused by precipitation of undissolved uric acid. Gout is a very painful disease associated with uric acid depositing in various joints.
Who is at risk of TLS?
Limiting our discussion to CLL patients and chemotherapy, generally speaking the folks most at risk are those with large number of tumor cells in their blood circulation, especially when they are treated with chemo drug cocktails with significant oomph. CLL cells are easiest to kill when they are easy targets out in open blood circulation, not tucked away and hard to reach in the protected environment of swollen lymph nodes and bone marrow. In other words, if your WBC (white blood cell count) is high and you are about to start treatment with common therapy options such as fludarabine or its various combinations with Rituxan, cyclophosphamide etc, you need to be extra aware of the risk of TLS. Killing CLL cells is a good thing. But you want to do it slow and easy so that your body can safely get rid of the uric acid created by dying cancer cells. What constitutes a high WBC? There are no hard and fast rules on that. In my book a WBC of 100K is high enough to worry about TLS. Your doctor may have a different cut-off point. In any case, best practices recommendation from experts is that patients should be protected against potential TLS by premedication ahead of getting therapy. Better safe than sorry, as they say.
The simplest thing you can do to protect yourself is to make sure of you are well hydrated before, during and after each cycle of therapy. In other words, drink plenty of water (not coffee or caffeinated drinks) starting about a week ahead of therapy. The logic is pretty straightforward. The more water you drink the more you will pee and that improves your ability to get rid of uric acid. It is also important to empty your bladder at regular intervals and not just cross your legs and try to “hold it” because you are busy doing something else.
Until recently the only drug available to help protect patients against TLS was allopurinol. Allopurinol is manufactured by Prometheus in the United States and marketed as “Zyloprim” by GlaxoSmithKline. In other countries other brand names are used: Allohexal, Allosig, Progout, and Zyloric.
Allopurinol is an enzyme inhibitor and in simple terms it slows down the production of uric acid. So, even if the CLL cells in your body are getting killed in record numbers in double quick time, one can hope that if you are loaded for bear with allopurinol this puts the brakes on how fast uric acid accumulates in your body. Allopurinol is taken orally and most doctors recommend that their patients start taking daily doses of it about a week ahead of start of chemotherapy. As you might guess, allopurinol is also used for treating gout and kidney stones – two diseases that are also caused by deposits of undissolved uric acid crystals in joints and kidneys, respectively.
One of the problems associated with allopurinol is that a significant percent of patients are allergic to it. My husband PC tried using allopurinol the very first time he was up for single agent Rituxan therapy. Three days after starting the drug he broke out in the most intense case of itching I have ever seen. Poor guy could not sit still even for a minute without needing to scratch! If you experience any rash or other skin discomfort, be sure to tell your doctor about it right away – and you may want to stop taking the drug while you are trying to reach the Man. “Murphy’s Law” dictates that most adverse effects seem to start on a Friday evening, when everyone has gone home for the weekend. Other and more serious adverse effects have also been reported for allopurinol. Further use of the drug was clearly a non-starter in PC’s case. The best we could do for all subsequent therapy sessions was to keep him very well hydrated, make sure he made the trip to the little boy’s room as frequently as possible and initiate therapy before his WBC reached dizzying heights. These are sensible precautions, especially if you have a history of kidney probles, or you have had kidney stones and/or gout.
Now we have a new drug on the scene that has shown efficacy in preventing TLS. Unlike allopurinol which merely slows down the production of uric acid, Rasburicase catalyses the conversion of uric acid to allantoin. And this is important because allantoin is 5 to 10 times more soluble than uric acid, so you can piss it away more effectively.
At the recent ASH conference Sanofi-aventis reported the results of a study in adult patients with hematological malignancies at high or potential risk for tumor lysis syndrome (TLS). Rasburicase (brand name “Elitek”) significantly reduced uric acid levels in the blood compared to allopurinol. The study had three arms.
- First group of patients got rasburicase at a dosage of 0.20 mg/kg each day for five days
- Second group got rasburicase at the same dosage for three days, followed by allopurinol (300 mg/day) starting on the third day and continuing for another two days.
- The last group (the control group) got only allopurinol (300 mg/day) for five days.
There were roughly 90 patients in each group, quite a large number, and that increases the credibility of the comparison. The results of the study are summarized in the article below from Cancer Network:
December 8, 2008
Rasburicase reduces tumor lysis risk in hematologic malignancies
By Walter Alexander
SAN FRANCISCO — Rasburicase (RAS) is superior to allopurinol in adult patients with hematological malignancies whose treatment puts them at high risk for developing tumor lysis syndrome or who have hyperuricemia at baseline, according to a study out of Houston’s M.D. Anderson Cancer Center.
TLS is a potentially lethal metabolic complication of chemotherapy or cytolytic antibody therapy. The prevention and management of TLS includes hydration and reduction of serum uric acid levels (SUA). Although allopurinol (AL) has long been used for TLS prophylaxis, its efficacy in controlling SUA is limited, especially due of its lack of action on pre-existing hyperuricemia. Rasburicase, an injected recombinant urate oxidase, converts uric acid into readily excretable and soluble allantoin. RAS (Elitek) is currently indicated in the U.S. for TLS-associated acute hyperuricemia in children and adolescents.
Jorge Cortes, MD, and colleagues conducted a prospective, randomized, parallel group study with three arms (RAS 0.20 mg/kg/day; RAS 0.20 mg/kg/dose days 0, 1 with an overlap day of RAS and oral AL 300 mg/day, then AL 300 mg/day on days 3 and 4; AL 300 mg day). The aim was to compare the ability of the regimens to control serum uric acid (abstract 919).
The patients (275) had high TLS or potential TLS risk and had been diagnosed with acute myeloid leukemia, lymphoma, myelodysplastic syndrome, or multiple myeloma. Treatment success was defined as a plasma uric acid level of ≤7.5 mg/dL (day 3 through 7).
Dr. Cortes reported in a poster presentation that the plasma uric acid response rate (PUAR) was superior for RAS (87% versus AL 66%, p = 0.001) with a strong trend for improved PUAR for RAS+AL (78% versus 66%, P = 0.06). No patients in the RAS-containing groups failed to control PUA. Laboratory TLS was reported in 20.7% of RAS patients, 27.2% of RAS+AL patients and in 40.7% of AL patients. Clinical TLS was reported at rates of 1%/1% and 5.5%, in the respective groups.
Overall, RAS treatment was well tolerated with most adverse events attributed to chemotherapy or to underlying disease. RAS events were uncommon, with ≤2% of grade 3/4 events, ≤1% discontinuations and no related toxic deaths. Grade 3 or higher hypersensitivity or allergic reactions were ≤1%.
“Where AL prevents the formation of new uric acid, RAS destroys uric acid. AL can take a long time because you have to wait for the already made uric acid to be cleared. RAS gets uric acid down quickly, often to undetectable levels in a day. And it stays down,” Dr. Cortes commented in an interview with Oncology News International.
“RAS is superior to AL in normalization of serum uric acid, with a faster effect, in adult patients at risk for TLS. RAS alone or followed by AL are two valid options for this patient population,” he concluded.
Availability of rasburicase therapy
Rasburicase was approved by the US Food and Drug Administration (FDA) on July 16, 2002 for the initial management of plasma uric acid levels in pediatric patients with leukemia, lymphoma and solid tumour malignancies who are receiving chemotherapy that is expected to result in tumour lysis syndrome. We hope that based on the study discussed above rasburicase will soon be approved for adult patients as well. For folks like PC who are allergic to allopurinol rasburicase is a much needed second option.
What are your chances of sweet-talking your insurance company into covering rasburicase use ahead of the FDA ruling? The cost of five days of rasburicase therapy is calculated below:
If the company still has the same pricing policy, we are looking at a cool $14K or so for an adult weighing 70kg for use of rasburicase, compared to less than two bucks for allopurinol. Anyone thinks insurance companies will be thrilled with shelling out thousands of dollars versus chump change? Wanna buy a bridge in New York?
But hey, most of us know that in life you get what you can negotiate. No harm in trying to get this approved by your insurance company (or Medicare), but be aware you will probably need your doctor to certify you are indeed a patient at high risk of life threatening TLS and allopurinol is contra-indicated in your case because of known adverse effects (hypersensitivity). And be ready to support us when it is time to do a bit of squeaky wheel patient advocacy in front of the FDA. This is a pissing contest (ahem) where we have a stake in the results. It is expected that rasburicase will come up for FDA apporoval for use in adult patients some time this year.