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105 Randomized Clinical Trial of Rasburicase Administered as a Standard Fixed Five Days Dosing Vs a Single Dose Followed by as Needed Dosing in Adult Patients with Hematologic Malignancies at Risk for Developing Tumor Lysis Syndrome

Oral and Poster Abstracts
Oral Session: Lymphoma: Therapy with Biologic Agents, excluding Pre-Clinical Models: Uncommon Lymphomas and Supportive Care
Sunday, December 6, 2009: 5:00 PM
R02-R05 (Ernest N. Morial Convention Center)

Saroj Vadhan-Raj, MD1, Luis Fayad, MD2, Michelle Fanale, M.D.3, Barbara Pro3*, Alma Rodriguez3*, Frederick Hagemeister3*, Kandice Ames, RN4*, Carlos E. Bueso-Ramos, MD5, Xiao Zhou, MD, PHD4*, Peter McLaughlin3*, Nathan Fowler3, Jatin Shah, MD3, Felipe Samaniego, MD3, Anas Younes, MD3, Larry Kwak, MD, PHD3* and Jorge Romaguera, MD3*

1Cytokines & Supportive Oncology, Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, TX
2Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX
3Department of Lymphoma/Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX
4Cytokines & Supportive Oncology, M.D. Anderson Cancer Center, Houston, TX
5Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Tumor lysis syndrome (TLS) is a potentially life threatening complication resulting from massive lysis of malignant cells and most frequently observed in patients with rapidly proliferating, bulky, and chemo-sensitive malignancies. The prevention and management of TLS includes hydration and reduction in the levels of serum uric acid by drugs that decrease production or increase excretion of uric acid. Rasburicase is a recombinant urate oxidase that rapidly reduces the levels of uric acid by enhancing the conversion of existing uric acid into allantoin which is more soluble in urine than uric acid. Rasburicase is approved in the USA for the treatment of pediatric patients at high risk for developing TLS, to be administered at a dose of 0.15 to 0.2 mg/kg once daily for 5 days. Although, activity has been seen with lower doses and shorter duration of treatment, the optimal dosing of rasburicase has not been established for adults. The purpose of this study was to evaluate the efficacy of rasburicase (0.15 mg/kg) administered as a single dose followed by as needed (max 5 doses over 5 days) as compared to standard fixed 5-days dosing in patients with hematologic malignancies at risk for TLS. The patients were stratified based on their risk for TLS and randomized 1:1 to rasburicase administered as a single dose followed by as needed (Arm A) or fixed daily dose x 5 days (Arm B).  Sixty six patients were enrolled; 20 had > 2-fold LDH levels and 9 had above-normal serum creatinine. 64 patients received at least one dose of rasburicase and were evaluable for response [24 high risk with mean baseline uric acid levels, 9.8 (7.6–16.1 mg/dL) and 40 potential risk with uric acid, 5.3 (2.4-7.4 mg/dL)]. All patients normalized their uric acid levels at 4 hours after the first dose; 83% to an undetectable level (<0.7 mg/dL). On Arm B (fixed 5-days dosing), all patients (n=34, 100%) had a sustained response, as defined by the normalization of uric acid levels in 48 hours and its maintenance within normal range for 6 days. On Arm A, all except for 4 patients (all 4 high risk for TLS) had a sustained response (26 of 30, 87%) to a single dose of rasburicase. Four of 11 patients from the high risk group required a second dose around day 4 for uric acid levels >7.5 mg/dL. Serum creatinine normalized in all patients by day 5. The treatment was well tolerated, except for one incident of methemoglobinema and hemolytic anemia in a patient found to have G6PD deficiency. Since high uric acid levels have been associated with elevated cytokine levels, we examined the effects of treatment on plasma cytokines. At baseline, high risk patients showed increased TNF-α and IL-6 plasma levels. There was a marked decrease in the plasma levels of TNF-α (from mean 14.2 to 6.4 pg/ml, p<0.0001), and IL-6 (from 11.2 to 8 pg/mL, p=0.05) during treatment.
Conclusion: Rasburicase is a highly effective uricolytic agent for prevention and management of TLS. This study demonstrates that it is feasible to decrease the duration of administration of rasburicase at the approved dose of 0.15 mg/kg. The majority of patients responded to a single dose of the agent, and only a small subset at high risk for TLS required a second dose.

Disclosures: Vadhan-Raj: Sanofi Aventis: Honoraria, Research Funding. Off Label Use: Rasburicase is indicated for the initial management of plasma uric acid levels in pediatric patients with leukemia, lymphoma, and solid tumor malignancies who are receiving anti-cancer therapy expected to result in tumor lysis and subsequent elevation of uric acid. The approved administration dose, route, and schedule are 0.15-0.20 mg/kg IV infusion for 5 days, respectively..

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