Management of hyperuricemia in adults with or at risk of tumor lysis syndrome

In addition to hematologic malignancies, solid tumors may result in TLS as a response to chemo(bio)-therapy or radiation/chemoradiation therapy or spontaneously. In adults, solid tumors that have been associated with TLS include, but are not limited to, breast cancer, lung cancer (especially small cell lung cancer), gastrointestinal stromal tumor, germ cell tumor, hepatocellular carcinoma, melanoma, malignant pheochromocytoma, ovarian cancer, colon cancer, and renal cell carcinoma.19–21 Table 1 presents a list of recent reports of TLS in adults with hematologic malignancies or solid tumors.22–41 Although TLS is less common in patients with solid tumors than in those with hematologic malignancies, its onset and progression in patients with solid tumors often are less predictable.19 Consequently, patients with TLS from solid tumors tend to have worse prognoses.19 In patients with solid tumors, TLS may develop days or even weeks after initiation of chemotherapy, providing no or limited opportunity for effective prophylaxis. Thus, for patients with solid tumors, heightened awareness of and vigilance for TLS are necessary to ensure appropriate and timely management of TLS.

The importance of such timely management of TLS is illustrated by several case studies. In one such case, a 55-year-old man with advanced hepatocellular carcinoma developed acute renal failure, hyperkalemia, and hyperuricemia 30 days after the initiation of treatment with the oral tyrosine kinase inhibitor sorafenib (Nexavar). The patient eventually died of multiple organ failure, despite treatment with hyperhydration, administration of the maximal daily dose of allopurinol, and use of emergency hemodialysis.37

Another fatal outcome of TLS was reported for a 62-year-old man with metastatic colon cancer and a 10-year complicated history of treatments. The patient, who had extensive lung metastases, hyperuricemia, and elevated serum LDH and creatinine concentrations at baseline, developed severe TLS within 2 days of receiving bevacizumab (Avastin) with combination chemotherapy and eventually died of acute renal failure.34

Furthermore, a rare case of spontaneous TLS occurred in a patient with Crohn’s disease who developed plasmacytoma while being treated with immunosuppressants. The patient experienced extreme hyperuricemia (a PUA level of 44 mg/dL) and died of the consequences of acute oliguric renal failure, despite hyperhydration, alkalinization, treatment with maximal doses of allopurinol followed by rasburicase, and hemodialysis.39

According to current TLS management guidelines, patients with multiple myeloma or rapidly growing solid tumors and an expected rapid response to therapy are considered to be at intermediate risk of TLS. However, the risk of TLS in patients with solid tumors is increased by the presence of bulky disease (masses or lymph nodes > 10 cm),17 unfavorable host baseline characteristics (such as renal insufficiency and baseline hyperuricemia),17 and the presence of liver metastases.19 According to relatively recent case reports, TLS occurred in two adult patients with hepatocellular carcinoma undergoing transarterial chemoembolization36 and in a 58-year-old man with metastatic melanoma and bulky liver metastases, who developed TLS within 24 hours after receiving intra-arterial infusion of cisplatin and embolization therapy.42 TLS from palliative radiotherapy, although rare, also has been reported; two fatal cases include a 74-year-old man with diffuse large B-cell lymphoma43 and a 52-year-old man with non-small cell lung cancer.38

Chemo(bio)therapy regimens associated with risk of TLS

The availability of new agents (either as monotherapy or in combination regimens) with high tumor response rates is expected to increase the risk and incidence of TLS. Even for hematologic malignancies with a relatively low incidence of TLS, such as chronic lymphocytic leukemia (CLL), the risk of TLS may increase with the growing use of novel agents that are highly effective inducers of apoptosis.44

In CLL associated with WBC counts of 10,000–100,000 cells/µL, fludarabine therapy (as monotherapy or combination therapy) confers intermediate-risk status (for TLS), according to current TLS management guidelines.17 Current US prescribing information for rituximab (Rituxan), which together with fludara¬bine (± cyclophosphamide) constitutes the standard treatment backbone for previously untreated CLL,45 contains a black-box warning for TLS when rituximab is given for the treatment of NHL.46 A warning for TLS also has been issued for the use of bendamustine (Treanda) for CLL.47 Alvocidib (flavopiridol), a cyclin-dependent kinase inhibitor in clinical development (phase II studies) for the treatment of adults with relapsed CLL, has been associated with a high incidence of TLS, particularly in patients with WBC counts > 200,000 cells/µL.48,49 Finally, lenalidomide (Revlimid) was associated with TLS and a tumor flare phenomenon in patients with CLL in phase II clinical studies.50

A number of case reports have associated imatinib (Gleevec), bortezomib (Velcade), and thalidomide (Thalomid) with the development of TLS in adults. Administration of imatinib led to TLS in two patients treated for ALL and in one patient treated for CML.23 Bortezomib and/or thalidomide caused TLS in several patients treated for multiple myeloma.31,51–54 TLS also is common in patients receiving chemotherapy for acute adult human T-cell lymphotrophic virus-1–associated T-cell leukemia/lymphoma (ATLL). Fatal TLS recently occurred in an obese 57-year-old woman with ATLL, in the background of systemic lupus erythematosus, after chemotherapy with high-dose prednisone and adjusted doses of cyclophosphamide and doxorubicin.33