scholarly journals Control of Plasma Uric Acid in Adults at Risk for Tumor Lysis Syndrome: Efficacy and Safety of Rasburicase Alone and Rasburicase Followed by Allopurinol Compared With Allopurinol Alone—Results of a Multicenter Phase III Study

2010 ◽  
Vol 28 (27) ◽  
pp. 4207-4213 ◽  
Author(s):  
Jorge Cortes ◽  
Joseph O. Moore ◽  
Richard T. Maziarz ◽  
Meir Wetzler ◽  
Michael Craig ◽  
...  
Keyword(s):  
At Risk ◽  
Uric Acid ◽  
High Risk ◽  
Response Rate ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Hematologic Malignancies ◽  
Phase Iii ◽  
Tumor Lysis ◽  
Plasma Uric Acid

Purpose Rasburicase is effective in controlling plasma uric acid in pediatric patients with hematologic malignancies. This study in adults evaluated safety of and compared efficacy of rasburicase alone with rasburicase followed by oral allopurinol and with allopurinol alone in controlling plasma uric acid. Patients and Methods Adults with hematologic malignancies at risk for hyperuricemia and tumor lysis syndrome (TLS) were randomly assigned to rasburicase (0.20 mg/kg/d intravenously days 1-5), rasburicase plus allopurinol (rasburicase 0.20 mg/kg/d days 1 to 3 followed by oral allopurinol 300 mg/d days 3 to 5), or allopurinol (300 mg/d orally days 1 to 5). Primary efficacy variable was plasma uric acid response rate defined as percentage of patients achieving or maintaining plasma uric acid ≤ 7.5 mg/dL during days 3 to 7. Results Ninety-two patients received rasburicase, 92 rasburicase plus allopurinol, and 91 allopurinol. Plasma uric acid response rate was 87% with rasburicase, 78% with rasburicase plus allopurinol, and 66% with allopurinol. It was significantly greater for rasburicase than for allopurinol (P = .001) in the overall study population, in patients at high risk for TLS (89% v 68%; P = .012), and in those with baseline hyperuricemia (90% v 53%; P = .015). Time to plasma uric acid control in hyperuricemic patients was 4 hours for rasburicase, 4 hours for rasburicase plus allopurinol, and 27 hours for allopurinol. Conclusion In adults with hyperuricemia or at high risk for TLS, rasburicase provided control of plasma uric acid more rapidly than allopurinol. Rasburicase was well tolerated as a single agent and in sequential combination with allopurinol.

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.

Guidelines for the Management of Pediatric and Adult Tumor Lysis Syndrome: An Evidence-Based Review

2008 ◽  
Vol 26 (16) ◽  
pp. 2767-2778 ◽  
Author(s):  
Bertrand Coiffier ◽  
Arnold Altman ◽  
Ching-Hon Pui ◽  
Anas Younes ◽  
Mitchell S. Cairo
Keyword(s):  
At Risk ◽  
High Risk ◽  
Tumor Lysis Syndrome ◽  
The United States ◽  
Standards Of Care ◽  
Close Monitoring ◽  
Tumor Lysis ◽  
High Risk Patients ◽  
Patients At Risk ◽  
Risk Patients

PurposeTumor lysis syndrome (TLS) has recently been subclassified into either laboratory TLS or clinical TLS, and a grading system has been established. Standardized guidelines, however, are needed to aid in the stratification of patients according to risk and to establish prophylaxis and treatment recommendations for patients at risk or with established TLS.MethodsA panel of experts in pediatric and adult hematologic malignancies and TLS was assembled to develop recommendations and guidelines for TLS based on clinical evidence and standards of care. A review of relevant literature was also used.ResultsNew guidelines are presented regarding the prevention and management of patients at risk of developing TLS. The best management of TLS is prevention. Prevention strategies include hydration and prophylactic rasburicase in high-risk patients, hydration plus allopurinol or rasburicase for intermediate-risk patients, and close monitoring for low-risk patients. Primary management of established TLS involves similar recommendations, with the addition of aggressive hydration and diuresis, plus allopurinol or rasburicase for hyperuricemia. Alkalinization is not recommended. Although guidelines for rasburicase use in adults are provided, this agent is currently only approved for use in pediatric patients in the United States.ConclusionThe potential severity of complications resulting from TLS requires measures for prevention in high-risk patients and prompts treatment in the event that symptoms arise. Recognition of risk factors, monitoring of at-risk patients, and appropriate interventions are the key to preventing or managing TLS. These guidelines should assist in the prevention of TLS and improve the management of patients with established TLS.

Flavopiridol Administered as a Pharmacologically-Derived Schedule Demonstrates Marked Clinical Activity in Refractory, Genetically High Risk, Chronic Lymphocytic Leukemia (CLL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 341-341 ◽  
Author(s):  
John C. Byrd ◽  
Thomas S. Lin ◽  
James T. Dalton ◽  
Di Wu ◽  
Beth Fischer ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Opportunistic Infections ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Calf Serum ◽  
Potassium Phosphate ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Tumor Lysis

Abstract Flavopiridol is a broad cyclin dependent kinase inhibitor that induces p53/IL4 independent apoptosis in CLL cells. Despite potent pre-clinical activity, phase I/II studies of both a 24 and 72-hour continuous IV (CI) schedule demonstrated no activity in CLL or other cancers. Discordant binding of flavopiridol to human plasma proteins as compared to fetal calf serum prompted us to perform pharmacokinetic modeling from the Aventis-sponsored CI studies. This suggested optimal dosing would be a 30-minute IV bolus followed by 4-hour infusion. We report a mature phase I dose escalation study of flavopiridol with this schedule. We enrolled 23 pts (median age 61, range 44–84, 8 female) previously treated for CLL (median prior therapies 3, range 2–13) . At study entry, 21 pts had no response to their last therapy, 9 had intermediate risk disease, and 14 were stage III/IV. Pts received 50% of the flavopiridol dose IV over 30 minutes, the remaining 50% followed over 4 hours. This was repeated weekly 4 times on a 6-week cycle. Six pts in cohort 1 received 60 mg/m2/dose with 1 dose limiting toxicity (DLT, neutropenic fever) and 3 pts in cohort 2 received 80 mg/m2/dose. The maximally tolerated dose was exceeded in cohort 2. Acute tumor lysis syndrome (TLS) following the first flavopiridol dose was the DLT. One pt developed TLS that was controlled with aggressive medical management. The 2nd pt with TLS died with hyperkalemia before dialysis could be initiated, and on autopsy had extensive apoptosis/necrosis of diffuse intra-abdominal lymphadenopathy. No additional pts were treated at this dose, but a 3rd pt previously without TLS at the 80 mg/m2/dose developed TLS on day 1,cycle 2 at the 60 mg/m2 dose. An inpatient management plan to prevent further life-threatening TLS was initiated. We enrolled 14 additional pts. Several pts developed transient tumor lysis upon initial treatment, with increased serum potassium, phosphate, and LDH, but only 1 pt required temporary dialysis. Other manageable toxicities observed included neutropenia, anemia, thrombocytopenia, fatigue, nausea, diarrhea, and anorexia. Twenty-two patients have been followed long enough for NCI 96 response assessment. Nine pts achieved a PR (41%); 7 pts remain in remission (3–11+ months), and 2 pts relapsed at 7 and 12 months, respectively. Of the 9 responding pts, 8 were fludarabine refractory or intolerant, 8 had bulky LN (> 5cm), and 8 had del(11q) [n=6] or del(17p) [n=3] abnormalities. Additionally, opportunistic infections have not been noted to date. Eight of 9 responding pts with enlarged LN had a 50% reduction with the 1st treatment, compared to 2 of 10 who did not ultimately achieve a PR. The AUC of flavopiridol did not increase proportionally with dose, but pharmacologic data support our hypothesis that the clinical activity and toxicity of flavopiridol may be directly related to the Cmax, AUC, and Css. In summary, single agent flavopiridol given with this novel, pharmacologically modeled schedule has significant clinical activity in pts with fludarabine-refractory, genetically high-risk CLL. Further study of flavopiridol in CLL and other B-cell diseases using this pharmacokinetically modeled schedule is warranted.

scholarly journals Spontaneous tumor lysis syndrome in a patient with newly diagnosed metastatic colonic adenocarcinoma

CJEM ◽  
2017 ◽  
Vol 20 (S2) ◽  
pp. S41-S43 ◽  
Author(s):  
Ross Berringer
Keyword(s):  
Uric Acid ◽  
Tumor Lysis Syndrome ◽  
Hematologic Malignancies ◽  
Colonic Adenocarcinoma ◽  
Newly Diagnosed ◽  
Cytotoxic Therapy ◽  
Tumor Lysis ◽  
Spontaneous Tumor ◽  
Spontaneous Tumor Lysis Syndrome

AbstractAcute tumor lysis syndrome in the absence of cytotoxic therapy is an uncommon event but has been reported with hematologic malignancies. The case described below illustrates spontaneous tumor lysis syndrome in the context of a rapidly proliferating metastatic colonic adenocarcinoma. Clinicians should consider ordering phosphate, uric acid, and calcium when assessing patients with recently diagnosed or suspected malignancy.

Rasburicase Effectively Lowers Serum Uric Acid Levels in High Risk, Poor Performance Status Patients with Hematologic Malignancies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4012-4012
Author(s):  
Doris Ponce ◽  
Delong Liu ◽  
Muhammad Rasul ◽  
Nasir Ahmed ◽  
Marie Dimicco ◽  
...  
Keyword(s):  
Renal Failure ◽  
Uric Acid ◽  
High Risk ◽  
Serum Uric Acid ◽  
Performance Status ◽  
Hematologic Malignancies ◽  
Urate Oxidase ◽  
Phase Iii ◽  
Poor Performance Status ◽  
High Dose

Abstract Tumor lysis remains a significant cause of morbidity and mortality in patients with highly proliferative hematologic malignancies. Traditionally, intravenous hydration and oral allopurinol have been the mainstays of therapy. However in some patients, hyperuricemia and renal failure still occur. The resultant renal failure precludes the administration of full doses of chemotherapy and results in a poor treatment outcome. Recently we participated in a large phase III randomized trial comparing rasburicase with standard allopurinol therapy. Rasburicase is a recombinant urate oxidase that effectively reduces serum uric acid due to conversion of uric acid into allantoin, a readily excretable and soluble substance. The results of that study are reported in a separate abstract. However while the study was open, we treated 12 extremely high risk, newly diagnosed hematologic malignancy patients who were ineligible for the study with commercially available rasburicase off study. The reasons for study ineligibility were ECOG Performance Status 4 and/or expected survival of less than one month. Other baseline characteristics: Diagnosis: Burkitts ALL: 3, AML: 7, CML-BP: 1, T-ALL: 1; Age: 64 (27–85), Sex: 6M/6F; WBC: 58,000/mm3 (1.6- 245,000); LDH: 2201 U/l (1068- &gt;2500); # of preexisting comorbid medical conditions: 4 (0–7); chemotherapy: hyper-CVAD: 4, standard ara-c based rx: 5, high dose ara-C based rx: 3. Nine patients received one dose of rasburicase (0.2 mg/kg IV), 3 patients required a second dose. The median uric acid levels were: pretreatment : 9.2 mg/dl (2.8–28.6), at 24 hours: &lt;0.2 (0.2–7.5) and at 48 hours: &lt;0.2 (&lt;0.2–4.9). All patients achieved normal serum uric acid level by day 2. The median baseline creatinine was 2.6 mg/dl (0.7 – 5.6); by day seven 10 patients had a serum creatinine less than 2 mg/dl (day 7 median creatinine 0.9, range 0.4–5.5). Four patients achieved CR to chemotherapy, 5 had refractory disease and 3 had induction death. Administration of rasburicase in this extremely high risk group of patients resulted in a rapid decrease in serum uric acid levels. In many patients this allowed for preservation of or improvement in renal function and administration of chemotherapy. Although some patients had a poor outcome due to the aggressive nature of their underlying disease, 4 of 12 patients (33%) attained CR and were able to receive subsequent cycles of intensive chemotherapy without incident.

Rational use of rasburicase for the treatment and management of tumor lysis syndrome

2017 ◽  
Vol 24 (3) ◽  
pp. 176-184 ◽  
Author(s):  
Suhail A Shaikh ◽  
Bernard L Marini ◽  
Shannon M Hough ◽  
Anthony J Perissinotti
Keyword(s):  
Acute Kidney Injury ◽  
Uric Acid ◽  
High Risk ◽  
Uric Acid Level ◽  
Acid Level ◽  
Tumor Lysis Syndrome ◽  
Kidney Injury ◽  
P Value ◽  
Tumor Lysis ◽  
Conservative Group

Purpose There is a lack of high-level evidence identifying meaningful outcomes and the optimal place in therapy of rasburicase in patients with, or at high risk for tumor lysis syndrome. The primary objective of this study was to evaluate and characterize outcomes resulting from an institution-specific guideline emphasizing supportive care, xanthine oxidase inhibitors, and lower doses of rasburicase. Methods In this retrospective chart review, we compared conservative rasburicase dosing, in accordance with newly developed UMHS tumor lysis syndrome guidelines, with aggressive rasburicase in adult patients (≥ 18 years of age) with hematological or solid tumor malignancies, and a uric acid level between 8 and 15 mg/dL. The primary efficacy outcome assessed the difference in the proportion of patients achieving a uric acid level <8 mg/dL within 48 h using a one-sided noninferiority test. The principle safety outcomes analyzed included incidence of acute kidney injury and hemodialysis requirement. Results One hundred sixty-one patients met inclusion criteria and were included in the study. Within 48 h of an elevated uric acid level, treatment was successful in 97.03% of patients in the conservative group, as compared with 98.33% in the aggressive group (difference, 1.3 percentage points; 95% confidence interval [CI], −3.33 to 5.93). Furthermore, there was no difference in the proportion of patients requiring hemodialysis (2.97% vs. 10.0%, p-value 0.079), or incidence of acute kidney injury (4.0% vs. 12.5%, p-value 1.00) between the treatment group and control group, respectively. Conclusions Conservative rasburicase use was noninferior to aggressive rasburicase use in patients with or at high risk for tumor lysis syndrome.

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