Acute Tumor Lysis Syndrome during Oral Fludarabine Treatment for CLL – a Rare Event that Might Be Observed More Frequently in the Future

Accessible online at: www.karger.com/onk Fax +49 761 4 52 07 14 E-mail Information@Karger.de www.karger.com Cheson reviewed 6,137 patients with CLL treated with fludarabine and found an incidence of TLS in 0.33% of the patients [2]. TLS has also been observed in CLL patients treated with oblimersen, flavopiridol, high-dose corticosteroids, and rituximab [3–6]. TLS is caused by the lysis of malignant cells by cytotoxic chemotherapy, leading to a rapid release of intracellular contents into the blood stream including potassium, phosphate, and purines from the breakdown of nuclear proteins. Secondary hypocalcemia, hyperkalemia and hyperphosphatemia lead to gastrointestinal disturbances, neuromuscular effects and cardiovascular consequences. Purines are catabolized to hypoxanthine, then xanthine, and finally in the liver to uric acid by the enzyme xanthine oxidase. The precipitation of excess uric acid contributes to impaired renal function; acute renal failure represents the most frequent and serious clinical consequence of TLS-related hyperuricemia [7]. Risk factors include the type of malignancy, some tumor-related factors, such as high numbers of circulating tumor cells and a large tumor burden, the presence of individual factors, such as preexisting renal insufficiency, and the type and intensity of anticancer regimen used [7]. A literature survey in 2003 reported 5 cases of intravenous fludarabine-induced TLS in patients with CLL that occurred within the first week of initiation of therapy [8]. However, the 20 cases reported by Cheson in 1998 were not accounted for in this survey [2]. Since then some other case reports have been published but they are rare because most of the patients at risk received allopurinol prophylaxis. It is probable that the incidence is higher, most cases not being reported anymore. Since allopurinol prophylaxis is available for oral use in Europe, only one case of oral fludarabine-induced TLS was described [9]. The patient, which had been treated with oral fludarabine 40 mg/m2 daily for 5 days, developed 2 episodes of acute TLS 17 and 15 days after starting fludarabine for the Tumor lysis syndrome (TLS) with acute renal failure is a very rare complication of oral fludarabine therapy in patients with chronic lymphocytic leukemia (CLL). Calvo-Villas et al. [1] report in this issue of ONKOLOGIE the second published case of such a complication, alerting clinicians to this potentially lifethreatening syndrome that may occur in patients with CLL after fludarabine given intravenously or orally. Treatment with rasburicase and hydration is recommended in front of such a patient but prophylactic measures for patients with high risk of TLS are easy and should be done in all patients. Fludarabine is a frequently used purine analogue in the treatment of patients with CLL. It has been demonstrated to be superior to regimens based on alkylating agents in inducing clinical and hematologic remissions in both treated and previously untreated patients. Today it is mostly used in regimens like FC (fludarabine plus cyclophosphamide) or FCR (fludarabine, cyclophosphamide, and rituximab). Fludarabine alone is usually prescribed in elderly patients where these regimens might be too toxic. Although TLS and its life-threatening complication, acute renal failure, is a well-known safety problem, reports of TLS in CLL patients treated with fludarabine remain anecdotal, probably because this side effect is easily prevented. Unlike TLS occurring in lymphoma patients treated with chemotherapy, TLS after fludarabine in CLL patients usually occurs with some delay after the first day of treatment, and may be observed up to 7 days after treatment. It only occurs in patients with high a number of lymphocytes in the blood, however, no threshold was defined, or in patients with high tumor mass during the first cycle of therapy. It is easily prevented with administration of allopurinol from day 1 to 10 of the first cycle in high-risk patients. Finally, this event is specific for CLL patients and was not described in other lymphoproliferative disorders where fludarabine may be used, such as follicular lymphoma, mantle cell lymphoma or Waldenström’s macroglobulinemia. It is probably a rare event: Acute Tumor Lysis Syndrome during Oral Fludarabine Treatment for CLL – a Rare Event that Might Be Observed More Frequently in the Future