Single 6-mg dose of rasburicase: The experience in a large academic medical center

2018 ◽  
Vol 25 (6) ◽  
pp. 1349-1356 ◽  
Author(s):  
Mary Nauffal ◽  
Robert Redd ◽  
Jian Ni ◽  
Richard M Stone ◽  
Daniel J DeAngelo ◽  
...  
Keyword(s):  
Uric Acid ◽  
Lactate Dehydrogenase ◽  
Serum Creatinine ◽  
Medical Center ◽  
Academic Medical Center ◽  
Tumor Lysis Syndrome ◽  
Urate Oxidase ◽  
Baseline Serum ◽  
Tumor Lysis ◽  
Blood Ph

Background Tumor lysis syndrome is an oncologic emergency due to the release of tumor cell contents, leading to metabolic derangements. Rasburicase, a recombinant urate oxidase, catabolizes uric acid. At our institution, we administer a single 6-mg dose of rasburicase to patients who are at risk for tumor lysis syndrome. We aimed to assess the efficacy of single 6-mg dose of rasburicase and explore risk factors associated with rasburicase failure. Methods We report results in 92 adult patients who had a baseline uric acid greater than 7.5 mg/dL and received a single 6-mg dose of rasburicase for the management of tumor lysis syndrome. Responders were defined as those whose uric acid was less than or equal to 7.5 mg/dL within 24–36 h of rasburicase administration. The primary end point was response based on uric acid level. Secondary end points included response to rasburicase in association with lactate dehydrogenase, serum creatinine, calcium, phosphorus, blood pH, and oncologic diagnosis. Results Median age was 65 years and 70% were men. Most patients had leukemia (32%) or lymphoma (40%). Eighty-seven of 92 patients (95%), who received single 6-mg dose of rasburicase, achieved a uric acid less than 7.5 mg/dL within 24–36h of dosing. Body mass index was similar between responders and non-responders: 28.6 kg/m2 vs. 26.6 kg/m2, respectively, p = 0.6. Baseline lactate dehydrogenase levels were similar between the groups: 756 U/L vs. 892 U/L, respectively, p = 0.33. Blood pH values documented within 24 h of first dose of rasburicase were also similar between the two groups (n = 30; 7.33 vs. 7.34 respectively, p = 0.6). However, median baseline uric acid was lower in responders than non-responders: 12.3 mg/dL vs. 17.3 mg/dL, respectively, p = 0.012. Baseline serum creatinine and creatinine clearance were similar between responders and non-responders (2.2 mg/dL vs. 3.95 mg/dL; p = 0.12 and 29 mL/min vs. 16 mL/min; p = 0.11, respectively). Conclusions Higher baseline uric acid levels were observed in patients who did not respond to the first rasburicase dose. In our study, uric acid levels normalized in 95% of patients after a single 6-mg dose of rasburicase indicating that a single 6-mg dose of rasburicase may be sufficient to manage tumor lysis syndrome, for most patients.

The value of low, fixed, single dose rasburicase in the prevention and treatment of tumor lysis syndrome.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e18558-e18558
Author(s):  
Bharadwaj Ponnada ◽  
Saadvik Raghuram ◽  
Sanketh Kotne ◽  
Pavithran Keechilat
Keyword(s):  
Uric Acid ◽  
Single Dose ◽  
Low Dose ◽  
Medical Center ◽  
Day Treatment ◽  
Tumor Lysis Syndrome ◽  
Urate Oxidase ◽  
Fixed Dose ◽  
Tumor Lysis ◽  
Prevention And Treatment

e18558 Background: Rasburicase is a recombinant urate oxidase drug approved by the US FDA for the management of hyperuricemia in Tumor Lysis Syndrome (TLS). Recommended dose of 0.2 mg/kg/day for 5 days is expensive and the benefit of extended schedule compared to a single fixed dose of 1.5 mg is not known. Methods: This is a retrospective cohort study done at a tertiary medical center including 165 (144 adult and 21 pediatrics) patients admitted between January 2013 and December 2018. We analyzed the efficacy of single low dose rasburicase 1.5 mg irrespective of bodyweight in adults and in children a dose of 0.15 mg/kg (maximum 1.5 mg) intravenously over 30 min for prevention and treatment of TLS and subsequent doses were given based on clinical and biochemical response. Plasma samples for uric acid were collected at baseline, 6–24 hrs, 48 hrs post-rasburicase, and daily during treatment. The primary outcome was achieving a uric acid level less than 7.0 mg/dl after a single dose of rasburicase in the groups. Secondary outcomes included need for repeat rasburicase doses, and a cost analysis. Results: Children accounted for 12.1% (n = 20) and adults 87.9% (n = 145). The median ages in pediatric and adult groups were 7.9 years and 54 years respectively. Rasburicase was used prophylactically in 35 (21.2%), for laboratory TLS in 105 (63.6%) and for clinical TLS in 25 (15.2%) patients. SDR prevented laboratory/clinical TLS in 89% of the prophylactic group and prevented clinical TLS in 72% of the laboratory TLS group. However, 92%(n=23) of the patients with clinical TLS required more than one dose rasburicase. The average total monthly cost of rasburicase was reduced by 96% ($2850 to $114) after adoption of the above protocol. Conclusions: Single low dose rasburicase is a highly economical and clinically effective way of managing patients with TLS and could serve as an alternative to the 5-day treatment. This dose, therefore, balances cost and efficacy of treatment.

A Predictive Model for Tumor Lysis Syndrome in Acute Myelogenous Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 883-883
Author(s):  
Anthony R. Mato ◽  
Brett E. Riccio ◽  
Li Qin ◽  
Daniel Heitjan ◽  
Alison Loren ◽  
...  
Keyword(s):  
Uric Acid ◽  
Predictive Model ◽  
Acute Myelogenous Leukemia ◽  
Tumor Lysis Syndrome ◽  
Myelogenous Leukemia ◽  
Predictive Score ◽  
Baseline Serum ◽  
Tumor Lysis ◽  
Acute Myelogenous ◽  
Sensitivity Specificity

Abstract Tumor lysis syndrome (TLS) is defined by the metabolic derangements of hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia in the setting of rapid tumor destruction. In acute myelogenous leukemia (AML), TLS management and prophylaxis is largely based on data derived from the non-AML patient population. To characterize the association between AML and TLS, a retrospective cohort analysis was conducted to estimate TLS incidence and identify TLS predictive factors. At our institution, all AML patients routinely receive allopurinol and intravenous fluids for TLS prophylaxis during induction chemotherapy. An understanding of the incidence and risks of TLS may allow us to tailor our treatments and avoid unnecessary toxicities. To estimate TLS incidence during induction we examined Cr, PO4, K, and uric acid in 194 AML patients aged 18–86 undergoing induction chemotherapies between 1998 and 2003. Nineteen patients (9.8% 95% CI 5.2% – 15%) developed TLS within 8 days of initiation of therapy as defined by either (i) doubling of baseline serum creatinine in association with hyperphosphatemia (PO4 > 5 mg/dL), hyperuricemia (UA > 7 mg/dl), or hyperkalemia (K >5 mmol/L) in 6 patients or (ii) a stable Cr with elevations in two of the above electrolytes in 13 patients. We examined several parameters hypothesized in the literature to be TLS predictors. In univariate analysis, elevated pre-chemotherapy values for uric acid (UA) (p=.0003), Cr (p=.0025), LDH (p=.0001), WBC (p =.0058) male sex (p =.0064), and CMML (p=.0292) were significant. In multivariate analysis, pre-chemotherapy LDH (p=0.01, OR 3.01, 95% CI 1.5–6.2) and UA (p =0.01, OR 2.00, 95% CI 1.4–2.8) remained significant TLS predictors. We then performed a second logistic regression using re-coded versions of LDH and UA based on the quantiles of the initial pre-chemotherapy values. Based on the odds ratios for LDH and UA we constructed a scoring algorithm by assigning weights to these predictors in a 1:2 ratio. Entitled The Penn Predictive Score of Tumor Lysis Syndrome (PPS-TLS), the score is defined as follows: LDH score = 2 if LDH ≥ 2416 mg/dL, 1 if LDH ≥ 721 mg/dL and LDH < 2416 mg/dL, or 0 if LDH < 721 mg/dL, UA score = 4 if UA ≥ 5.2 mg/dL, 2 if UA ≥ 2.8 mg/dL and UA < 5.2 mg/dL, or 0 if UA < 2.8 mg/dL. (Normal range for LDH and UA 313 to 618 mg/dL and 3.0–7.5 mg/dL respectively). The total score is the summation of the pre-chemotherapy LDH and UA scores for the subject. The median PPS-TLS score for our patients with TLS is 5 (Range 3–6). Table 1 describes the sensitivity, specificity, and positive likelihood ratio (LR +) for each PPS-TLS score The PPS-TLS represents, to our knowledge, the first predictive model for TLS in AML. This analysis may lay the groundwork for the development of the first evidence-based guidelines for TLS monitoring and management in AML. We are currently designing a study to assess the external validity of this predictive model. Table 1: Sensitivity, Specificity and LR for PPS-TLS Scores Score 0 1 2 3 4 5 6 Sensitivity 1 1 1 1 0.89 0.63 0.42 Specificity 0 0.08 0.21 0.40 0.67 0.85 0.96 LR+ 1.0 1.1 1.26 1.67 2.7 4.2 10.5

Low-Dose Recombinante Urate Oxidase (Rasburicase) Is Effective in Treating Hyperuricemia in Patients with Hematologic Malignancies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3123-3123 ◽  
Author(s):  
S. Trifilio ◽  
A. Evens ◽  
L. Gordon ◽  
S. Singhal ◽  
M. Tallman ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Tumor Lysis Syndrome ◽  
Ideal Body Weight ◽  
Hematologic Malignancies ◽  
Chronic Hemodialysis ◽  
Urate Oxidase ◽  
Close Monitoring ◽  
Hematopoietic Stem ◽  
Baseline Serum ◽  
Baseline Serum Creatinine

Abstract Hyperuricemia is a commonly seen in patients with hematologic malignancies and high tumor burden, and is a major feature of tumor lysis syndrome (TLS). Hyperuricemia is conventionally treated with hydration, urine alkalinization, and allopurinol. Allopurinol inhibits the conversion of hypoxanthine to xanthine, and xanthine to uric acid (UA) by inhibiting xanthine oxidase. It has no direct effect on existing UA in the serum. Rasburicase lowers UA rapidly to very low levels at the approved dose of 0.15–0.2 mg/kg daily for 5 days by converting UA to allantoin which is excreted rapidly. Despite this dramatic effect on UA, rasburicase has not been shown to have any beneficial impact on survival in patients with hematologic malignancies. We administered 0.2 mg/kg ideal body weight rasburicase to an obese hyperuricemic patient (actual 120 kg, ideal 60 kg). Serum UA declined from 11 mg/dL to 1.4 mg/dL in 3 h and 0.4 mg/dL in 11 h. The serum UA level remained low for several days and a second dose was not needed. After seeing this dramatic and sustained response, variable low rasburicase doses were used in patients with malignant diseases with close monitoring of biochemical parameters (Trifilio et al, ASH 2004). Here, we present our experince with the use of a single 3 mg dose of rasburicase in 42 adult patients receiving chemotherapy or undergoing hematopoietic stem cell transplantation for hematologic malignancies. In addition to rasburicase, allopurinol and other supportive therapy including hydration were also administered. Serum UA levels (baseline 6.4–16.4 mg/dL, median 9.7) had declined by 12–95% (median 43%) 24 hours after rasburicase administration. Figure Figure The baseline serum creatinine was 1.0–8.6 mg/dL (median 2.1), and that 24 hours after rasburicase administration was 0.7–8.0 mg/dL (median 2). The median change in creatinine was a decline of 10%. Except for 3 myeloma patients who were already on chronic hemodialysis, renal impairment did not progress to hemodialysis in any patient - and substantial renal function improvement (at least 50% decline in serum creatinine) was seen in all patients with a baseline serum creatinine of ≥ 3 mg/dL. Based on the Red Book rasburicase cost of $387 for a 1.5 mg vial, the amount of money saved ranged from ~$10,000 to ~$30,000 per patient. Our data suggest that rasburicase is effective at a fraction of the recommended dose. A formal randomized comparison of low- and conventional-dose rasburicase is warranted to see if the recommended higher dose offers any clinical benefit.

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.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 105-105 ◽  
Author(s):  
Saroj Vadhan-Raj ◽  
Luis Fayad ◽  
Michelle Fanale ◽  
Barbara Pro ◽  
Alma Rodriguez ◽  
...  
Keyword(s):  
Uric Acid ◽  
Single Dose ◽  
High Risk ◽  
Serum Creatinine ◽  
Plasma Levels ◽  
Pediatric Patients ◽  
Tumor Lysis Syndrome ◽  
Hematologic Malignancies ◽  
Tumor Lysis ◽  
Tnf Α

Abstract Abstract 105 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.

Superiority of Rasburicase Versus Allopurinol on Serum Uric Acid Control in Adult Patients with Hematological Malignancies at Risk of Developing Tumor Lysis Syndrome : Results of a Randomized Comparative Phase III Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 919-919 ◽  
Author(s):  
Jorge Cortes ◽  
Karen Seiter ◽  
Richard Thomas Maziarz ◽  
Meir Wetzler ◽  
Michael Craig ◽  
...  
Keyword(s):  
At Risk ◽  
Uric Acid ◽  
Adverse Events ◽  
Serum Uric Acid ◽  
Hematological Malignancies ◽  
Tumor Lysis Syndrome ◽  
Urate Oxidase ◽  
Phase Iii ◽  
Tumor Lysis ◽  
Phase Iii Study

Abstract Tumor lysis syndrome (TLS) is a potentially lethal metabolic complication of chemotherapy or cytolytic antibody therapy usually seen in patients with hematologic malignancies, especially those malignancies with a high proliferative rate, large cellular burden and/or sensitivity to chemotherapy. The prevention and management of TLS includes hydration and reduction of serum uric acid (SUA) levels. Although Allopurinol (ALLO) has had longstanding use for TLS prophylaxis, its efficacy in controlling SUA is limited, especially due of its lack of action on pre-existing hyperuricemia. Rasburicase (RAS), a recombinant urate oxidase, effectively reduces SUA due to conversion of UA into allantoin, a readily excretable and soluble substance. RAS has significant activity in the initial management of TLS-associated acute hyperuricemia in pediatric populations, and is currently indicated in the US for this condition in children and adolescents. A prospective, randomized, controlled phase III study was conducted in adult pts to compare the efficacy in SUA control of RAS (0.20 mg/kg/d, IV) days 1–5, versus RAS+ALLO (RAS 0.20 mg/kg/d, IV days 1–3 plus oral ALLO 300 mg/day days 3–5) versus ALLO alone (300 mg/d) days 1–5. 280 pts (275 evaluable) with hematological malignancies at high or potential risk for TLS were enrolled. 92 pts received RAS, 92 pts received RAS+ALLO, and 91 received ALLO. Treatment arms were well balanced in terms of demographics, baseline characteristics, TLS risk, and percentage of pts with baseline hyperuricemia. The SUA response rate - defined as normalization of SUA (≤ 7.5mg/dl) at days 3–7 was 87.0% in the RAS arm, 78.3% in the RAS+ALLO arm and 65.9% in the ALLO arm. RAS was superior over ALLO (p=0.0009) in the overall study population as well as in pts at high risk TLS (89.0% vs. 62.8%, p=0.0012), and in pts with baseline hyperuricemia (89.5% vs. 52.9%, p=0.0151). The time to control SUA in hyperuricemic pts was 4.1 h in the RAS arm and 27 h in the ALLO arm. The mean SUA area under the curve (AUC) results indicated that there was an 8.4-fold increase in UA exposure in the ALLO arm compared to the RAS arm. There were no significant differences in the incidence or severity of adverse events, serious adverse events or deaths. The majority of RAS and/or ALLO-related adverse events were grade 1 and 2, and most of these events were hypersensitivity-related reactions. No cases of anaphylaxis, methemoglobinemia or hemolysis were observed with RAS treatment. In conclusion, RAS is superior to ALLO in normalization of SUA, with a faster effect, in adult pts at risk for TLS. RAS alone or followed by ALLO are two valid options for this patient population.

scholarly journals Spontaneous Tumor Lysis Syndrome in Blastoid-Variant Mantle Cell Lymphoma: Considerations for the General Internist

2020 ◽  
Vol 8 ◽  
pp. 232470962094470 ◽  
Author(s):  
Vishal Patel ◽  
Robert Case
Keyword(s):  
Uric Acid ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
General Internist ◽  
Tumor Lysis ◽  
Spontaneous Tumor ◽  
Mantle Cell ◽  
Spontaneous Tumor Lysis Syndrome

Spontaneous tumor lysis syndrome (SPTLS) is a rare phenomenon that can manifest in rapidly proliferating hematological malignancies and solid tumors prior to initiating cytotoxic therapy. We encountered a patient who originally presented with diffuse lymphadenopathy, abdominal distention, and dyspnea, who had laboratory abnormalities suggestive of SPTLS. His peripheral flow cytometry and lymph node biopsy revealed blastoid-variant mantle cell lymphoma. Prior to initiating chemotherapy, acute kidney injury (AKI) and uric acid had improved with intravenous fluids and the initiation of allopurinol. However, after beginning chemotherapy, the patient developed a second AKI concerning for tumor lysis syndrome (TLS). He went on to have renal recovery and did not require renal replacement therapy. With the exception of case reports, there is limited evidence to guide general medicine clinicians who encounter cases of SPTLS. Expert-based guidelines are available to guide use of rasburicase, an uricase enzyme, before initiation of chemotherapy for certain malignancies when risk for TLS is considered high. Despite these guidelines, the role of rasburicase in preventing AKI remains controversial after inconclusive results in a meta-analysis. The causative relationship between uric acid and AKI in TLS is based on a mechanism of tubular obstruction. There are also mechanisms by which uric acid may cause AKI without tubular obstruction related to acute hyperuricemic nephropathy. Further characterization of the role of uric acid in causing AKI in patients without tubular obstruction may identify new mechanisms of injury and offer insight into new treatment strategies.

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