Thursday, January 10, 2013

Rasburicase Limbo for TLS: How Low Can We Go?

Tumor lysis syndrome (TLS) is a life-threatening oncologic emergency characterized by severe metabolic abnormalities that occur secondary to rapid lysis of malignant cells that often manifests in patients with malignancies with a high tumor burden that are highly proliferative and chemosensitive. Metabolic derangements include hyperkalemia, hyperphosphatemia, secondary hypocalcemia, and hyperuricemia, which can lead to complications such as acute renal failure and cardiac arrhythmias that if not promptly recognized and treated, can progress to seizures and death.

Hyperuricemia occurs as a result of the release and breakdown of purine nucleic acids from tumor cells that are metabolized to uric acid (UA) by the enzyme xanthine oxidase. High concentrations of UA may accumulate, causing acute renal failure as uric acid crystals may precipitate into and obstruct the collecting tubules of the kidneys. Allopurinol acts by inhibiting xanthine oxidase in order to prevent the formation of UA from its precursors (xanthine and hypoxanthine). However, with allopurinol, there is a delay in decreasing the levels of UA and it has no effect on UA that is already present in TLS.

Rasburicase is a recombinant urate oxidase that catalyzes the breakdown of UA into allantoin and hydrogen peroxide. Allantoin is nearly 5 to 10 times more soluble than UA in the urine, which will theoretically reduce the incidence of accumulation and obstruction of the renal tubules that occurs due to UA since UA levels have been shown to rapidly decline and normalize following the administration of rasburicase.

The dose of rasburicase that has been approved by the FDA is 0.2 mg/kg administered intravenously once daily for 5 days. However, because of the high cost associated with rasburicase for the treatment of hyperuricemia in the setting of TLS (nearly $35,000 for a 5-day course of treatment), alternative doses and treatment strategies of rasburicase have been investigated, specifically using lower doses of rasburicase administered as a one-time dose, to determine if the outcome of rapid reduction of UA levels can be reached, which may potentially translate to shortened length of stay in the intensive care unit and/or hospital. This is pretty relevant to our practice in the emergency department, as we would be the first resource for the patient in providing this alternative regimen.

So what do the studies show? One small case series demonstrated that a single 6-mg dose of rasburicase rapidly and effectively reduced UA levels in 10 out of 11 patients with high risk or documented TLS hyperuricemia within 32 hours when administered with concomitant therapies for TLS. The only exception was in a morbidly obese patient who required an additional 12 mg of rasburicase due to ineffective decrease in the level of UA following the administration of the 6 mg dose. Another retrospective study determined that a fixed, single 6-mg dose of rasburicase in hyperuricemic or high-risk TLS patients effectively decreased serum UA levels to less than 4 mg/dL at 3 days post-administration that was sustained in most patients at the 7-day follow up period.

The question now becomes whether we can use even lower doses of rasburicase for TLS. A recently published retrospective study evaluated the use of a single 3-mg dose of rasburicase, and medium serum levels of UA normalized within 72 hours of administration, with most patients reaching normalization at 24 hours. Another study evaluated the use of this same regimen in patients with hematologic malignancies, and determined that in those patients with UA levels that were moderately elevated but less than 12 mg/dL, administration of this fixed dose of rasburicase normalized UA levels with improved renal function occurring within 7 days of treatment; repeated dosing was necessary in those patients with UA levels greater than 12 mg/dL. Because the majority of patients in this study had multiple myeloma, which is considered low-risk for TLS compared to other malignancies, the fixed, single dose of 3 mg may be a reasonable option to use in this patient population.

More studies need to be conducted to determine the optimal strategy here for single, low-dose rasburicase for TLS hyperuricemia, but for now, I believe it is an option that we can utilize in the emergency department with consideration of the following factors:

Factors to Consider
Commentary
TLS risk level of the malignancy
·         A single dose of 3 mg may be sufficient in patients with low-risk malignancy whereas a single 6-mg dose may be necessary in patients with intermediate-to-high risk malignancy
Weight of the patient
·         Studies have been inconsistent in determining if a dose-response relationship exists in patients who are morbidly obese
Baseline UA level
·         May be necessary to re-dose if UA level continues to remain elevated 6 hours after administration of single dose
·         May consider higher initial single dose of rasburicase if the UA level is significantly elevated (> 12 mg/dL)