1. Managing Tumor Lysis Syndrome
Anas Younes, MD
Chief, Lymphoma Service
Memorial Sloan Kettering Cancer Center New York, New York

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3. Faculty Anas Younes, MD Chief, Lymphoma Service
Memorial Sloan Kettering Cancer Center New York, New York
Anas Younes, MD, has no real or apparent conflicts of interest to report.

4. Overview

5. Tumor Lysis Syndrome: Overview
Rapid breakdown of cancer cells releases intracellular contents
Phosphorous
Potassium
DNA    uric acid
Contents are released too quickly for the body to remove them, causing metabolic abnormalities
Hyperuricemia
Hyperkalemia
Hyperphosphatemia
Secondary hypocalcemia
May occur spontaneously or as a result of antineoplastic therapy
TLS is a result of the rapid breakdown of cancer cells, usually in response to effective treatment.[1] Clinical concerns with TLS stem from the release of phosphorus and potassium and the breakdown of DNA to produce high levels of uric acid. These chemicals, when released quickly into the blood, can cause metabolic abnormalities and subsequent clinical manifestations, including the potential for acute renal failure. Patients may experience hyperuricemia from elevated levels of uric acid, hyperkalemia from elevated potassium, and hyperphosphatemia from elevated phosphorus. The high levels of phosphorus can also lead to precipitation of calcium, potentially resulting in secondary hypocalcemia.
TLS may rarely occur spontaneously, but most often, it occurs as a result of effective anticancer therapy—the more effective the treatment, the greater the chance of TLS. In this module, I discuss the identification of patients at high risk for developing TLS, current prevention strategies in high-risk patients, and treatment options for TLS.
1. Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:
Slide credit: clinicaloptions.com
Coiffier B, et al. J Clin Oncol. 2008;26:

6. Frequency of TLS by Tumor Type
Burkitt lymphoma
Lymphoblastic lymphoma
Acute leukemia
Common
Low-grade lymphoma
Breast carcinoma, small-cell lung cancer
Seminoma
Uncommon
Medulloblastoma, neuroblastoma, colorectal carcinoma, Merkel cell carcinoma
TLS, tumor lysis syndrome.
The prevalence of TLS varies, depending on the tumor type, the type of anticancer treatments used, and the use of prophylactic procedures. Certain tumor types have a higher risk of TLS in response to therapy.
Historically, hematologic malignancies with a high proliferative rate where malignant cells accumulate in the blood and lymph nodes had the highest prevalence, and included Burkitt lymphoma, lymphoblastic lymphoma, and acute leukemias. On the other end of the spectrum were solid tumors, including colorectal cancer, Merkel cell carcinoma, medulloblastoma, and neuroblastoma. However, these patients are normally not considered at risk for TLS and prophylaxis is not given. In addition, rare cases of TLS have been reported in patients with low-grade lymphomas, breast carcinoma, small-cell lung cancer, and seminomas.
However, with the advent of more effective therapies, some hematologic malignancies like CLL, historically considered as being at low risk for developing TLS, have seen an increase in TLS with the use of newer agents such as venetoclax or ibrutinib.
Case reports
Barton JC. Cancer. 1989;64: Boisseau M, et al. Eur J Cancer. 1996;32: Chasty RC, et al. Br J Hosp Med. 1993;49: Dillman RO. Cancer Metastasis Rev. 1999;18: Dirix LY, et al. Cancer. 1991;67: Hussein AM, et al. Am J Clin Oncol. 1990;13: Lorigan PC, et al. Ann Oncol. 1996;7: Stark ME, et al. Cancer. 1987;60: Tomlinson GC, et al. Cancer. 1984;53: Vogelzang NJ, et al. JAMA. 1983;249:
Slide credit: clinicaloptions.com 6

7. Complications of TLS PO3- 4 Ca2+ PO3- 4 Ca2+ Cardiac arrhythmia
Hyperphosphatemia:
release of intracellular
phosphates
Hyperkalemia:
release of intracellular
potassium
PO3- 4
Ca2+
Release of DNA
(nucleic acids)
TLS, tumor lysis syndrome.
Multiple adverse events are associated with TLS, including hyperkalemia, hyperphosphatemia, and hyperuricemia.[2] Hyperkalemia (excess potassium) is usually the first laboratory abnormality with TLS and may lead to cardiac complications, including arrhythmia and cardiac arrest. Hyperphosphatemia (excess phosphate) leads to formation of calcium phosphate, which results in hypocalcemia as well as precipitate formation in the renal tubules. Hypocalcemia can contribute to hypotension, tetany, muscular cramps, and cardiac arrhythmia along with hyperkalemia. The calcium phosphate precipitates, along with urate crystallization from excess uric acid created by the breakdown of the cellular DNA released during TLS, can lead to acute kidney injury (AKI) and renal failure if left unchecked.
AKI is common in hospitalized patients, affecting approximately 5% to 7% of patients. The incidence can be higher in critically ill patients, especially in the presence of infection and sepsis. Permanent kidney injury is common after AKI, and AKI independently contributes to mortality.
A related concern is respiratory complications, typically due to treatment of TLS—and not TLS itself. Patients require high levels of IV fluids for hydration, and if the patient has underlying cardiac or renal disease, excess hydration may lead to fluid overload and resultant respiratory complications.
2. Cammalleri L, Malaguarnera M. Rasburicase represents a new tool for hyperuricemia in tumor lysis syndrome and in gout. Int J Med Sci. 2007;4:83-93.
PO3-
Hypoxanthine 4
Uric acid
crystals
Ca2+
Xanthine
Cardiac arrhythmia
Calcium phosphate 
precipitates
Xanthine oxidase
Acute renal failure

8. Acute Kidney Injury AKI is common: 5% to 7% of hospitalized pts
As high as 40% in critically ill pts (particularly with sepsis)
Permanent kidney injury is common after AKI
AKI independently contributes to mortality
No effective therapy for AKI exists, so prevention is the key to improving outcomes
TLS occurs predictably in certain subsets of cancer pts, and there is often the opportunity for early intervention to protect the kidneys
AKI, acute kidney injury; TLS, tumor lysis syndrome.
AKI is common in hospitalized patients, affecting approximately 5% to 7% of patients. The incidence can be higher in critically ill patients, especially in the presence of infection and sepsis. Permanent kidney injury is common after AKI, and AKI independently contributes to mortality.
A related concern is respiratory complications, typically due to treatment of TLS—and not TLS itself. Patients require high levels of IV fluids for hydration, and if the patient has underlying cardiac or renal disease, excess hydration may lead to fluid overload and resultant respiratory complications.
Xue JL, et al. Clin J Am Soc Nephrol. 2006;17: Waikar SS, et al. J Am Soc Nephrol. 2006;17: Ostermann M, et al. Crit Care Med. 2007;35: Bagshaw SM, et al. Nephrol Dial Transplant. 2008;23:
Slide credit: clinicaloptions.com

9. TLS: Progression Lysis of tumor cells Laboratory TLS Clinical TLS
TLS, tumor lysis syndrome.
TLS can be divided into 2 categories: laboratory and clinical. As numerous tumor cells begin to lyse after anticancer therapy is administered, asymptomatic laboratory TLS develops. If laboratory TLS remains undetected and untreated, it can lead to the clinical manifestations mentioned above.
Because the clinical manifestations of TLS can be life threatening, prevention and/or early detection is key.
Clinical TLS
Slide credit: clinicaloptions.com

10. Cairo–Bishop Definition of TLS
Laboratory TLS
Clinical TLS
Element
Value
Change From Baseline
Uric acid
≥ 8.0 mg/dL
25% increase
Potassium
≥ 6.0 mEq/L
Phosphorus
≥ 4.5 mg/dL
Calcium
≤ 7.0 mg/dL
25% decrease
Laboratory TLS plus any of the following:
Creatinine ≥ 1.5 x ULN
Cardiac arrhythmia or sudden death
Seizure
TLS, tumor lysis syndrome; ULN, upper limit of normal.
The most widely used diagnostic criteria and classification of TLS is the Cairo–Bishop definition of TLS, based on the 3 major biochemical changes: hyperkalemia, hyperphosphatemia, and hyperuricemia as well as secondary hypocalcemia.[3]
Laboratory TLS is defined as having at least 2 of metabolic abnormalities within 3 days before or 7 days after initiation of chemotherapy. Based on these classifications, hyperuricemia is defined as a uric acid level ≥ 8 mg/dL, hyperkalemia is a potassium level ≥ 6.0 mEq/L, and hyperphosphatemia is a phosphorus level ≥ 4.5 mg/dL. Secondary hypocalcemia, caused by hyperphosphatemia, is defined as a calcium level ≤ 7.0 mg/dL.
In addition, any increase of uric acid, potassium, or phosphorous levels > 25% from baseline is also considered to be laboratory TLS, even if the specific values listed are not reached. For example, if a patient’s baseline uric acid level was 2.0 mg/dL and increased by 25% to 2.5 mg/dL, although it does not reach 8.0 mg/dL, this increase would still qualify as laboratory TLS. It is not merely the absolute numbers that are important, but how each patient’s individual laboratory values change over time.
The effects of laboratory TLS may lead to abnormal liver or renal function and clinical TLS. Clinical TLS is defined as laboratory TLS plus creatinine levels ≥ 1.5 mg/dL of the upper limit of normal, cardiac complications including arrhythmias or cardiac arrest, or seizures from low calcium levels.
3. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004;127:3-11.
≥ 2 of the listed metabolic abnormalities within 3 days before or 7 days after initiation of treatment
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Cairo MS, et al. Br J Haematol. 2004;127:3-11. 10

11. Risk Assessment

12. Cancer-Related Risk Factors for TLS
Bulky tumors
Large tumor mass
Organ infiltration
Bone marrow involvement (leukemias are bulky)
Highly proliferative tumors: LDH is a marker
Chemosensitive tumors
Burkitt lymphoma
Lymphoblastic lymphoma
Acute leukemias
LDH, lactate dehydrogenase; TLS, tumor lysis syndrome.
As clinicians begin to understand more about how to manage TLS, it is becoming increasingly important to be able to identify patients at high risk for developing TLS.
Cancer-related risk factors for TLS have been identified.[4] The type of tumor, the tumor bulk, and the proliferative potential of the tumor (measured using LDH level) are important risk factors. In general, the larger the tumor mass, the higher the risk for tumor lysis. The tumor type also matters; for example, large, bulky, follicular lymphoma has a lower risk of TLS than does large, bulky Burkitt lymphoma. The sensitivity of the tumor to the anticancer treatments available also plays a large role, so tumor bulk and treatment efficacy contribute to the tumor-related risk factors.
In addition, organ infiltration and bone marrow involvement increase the risk for TLS, especially for patients with leukemia.
4. Howard S, Pui CH. Pitfalls in predicting tumor lysis syndrome. Leuk Lymph. 2006;47:
Slide credit: clinicaloptions.com
Howard S, et al. Leuk Lymph. 2006;47: 12

13. Pt-Related Risk Factors for TLS
Pt factors
Gout
Chronic renal insufficiency
Hypertension
Presentation
Hyperuricemia
Dehydration
Diminished urine output
Acute renal insufficiency
Acidic urine
TLS, tumor lysis syndrome.
In addition to the cancer-related risk, patient-specific factors can also increase the risk of TLS. These factors include age; patients with decreased fluid intake, dehydration, or diminished urine output due to decreased appetite, nausea, or vomiting; and preexisting renal dysfunction or other comorbidities.
These patient-specific factors may not actually increase risk for TLS, but if TLS does develop, they have increased risk for complications of TLS. For example, underlying cardiac disease or chronic renal insufficiency increase the risk of TLS complications and not necessarily the risk of developing TLS.
In other words, serious complications of TLS are a greater concern in patients who are more fragile or have preexisting conditions than in an otherwise healthy person. However, prevention and management of TLS are similar in both situations.
Slide credit: clinicaloptions.com
Howard S, et al. Leuk Lymph. 2006;47: 13

14. TLS Guidelines: Risk Stratification
Low Risk
Intermediate Risk
High Risk
ALL
WBC < 50,000/μL
WBC 50, ,000/μL and
LDH < 2 x ULN
WBC ≥ 100,000/μL or
LDH ≥ 2 x ULN
AML
WBC < 25,000/μL
WBC 25, ,000/μL or
WBC ≥ 100,000/μL
Burkitt lymphoma/
leukemia --
Early stage and
Advanced or early stage
with LDH ≥ 2 x ULN
CLL if treating with
venetoclax
All LN < 5 cm and
ALC < 25,000/μL
Any LN 5-10 cm or
ALC ≥ 25,000/μL
Any LN ≥ 10 cm or
LN ≥ 5 cm and ALC ≥ 25,000/μL
DLBCL
LDH ≥ 2 x ULN and
nonbulky disease
LDH ≥ 2 ULN and
bulky disease
Indolent lymphomas
LDH < ULN
LDH ≥ ULN
ALC, absolute lymphocyte count; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML-CP, chronic-phase chronic myeloid leukemia; DLBCL, diffuse large B-cell lymphoma; LDH, lactate dehydrogenase; LN, lymph node; MM, multiple myeloma; TLS, tumor lysis syndrome; ULN, upper limit of normal; WBC, white blood cell.
During the past few year, there have been multiple articles published with recommended guidelines for TLS risk stratification for hematologic malignancies.[1,5-7] Although each recommendation varied slightly, in general, patients with high bulky disease, high tumor burden, advanced phase, and high LDH have the highest risk of TLS. In non-Hodgkin lymphomas, the risk of TLS is highest in patients with Burkitt lymphoma and B-cell acute lymphoblastic leukemia. Diffuse large B-cell lymphoma generally confers intermediate risk, although patients with LDH ≥ 2 times the upper limit of normal and bulky disease are at high risk of TLS, and patients with indolent lymphomas are at low risk for TLS.
For some other tumor types, the risk of TLS is better correlated with the disease burden, that is, white blood cell counts in the peripheral blood. For example, in acute lymphoblastic leukemia a white blood cell count > 100,000/μL represents high risk, 50, ,000/μL is intermediate risk, and patients with ≤ 50,000/μL are at low risk. Acute myeloid leukemia is similarly risk stratified.
For patients with CLL, the TLS risk stratification was recently updated following the approval of venetoclax.[8] The highest risk for TLS in patients with CLL is in patients who are planning treatment with venetoclax and have lymph nodes that have enlarged to > 10 cm, or which are at least 5 cm with absolute lymphocyte counts > 25,000/μL. For high-risk CLL, we patients typically are admitted for hours for observation and hydration before starting venetoclax. Even so, venetoclax dosing must be slowly escalated from 20 mg, and patients still require careful monitoring.
In addition to venetoclax, other novel and targeted agents carry an increased risk of TLS. In a recent review, the incidences of TLS were 8.3% and 8.9% in 2 trials of venetoclax in CLL, and 10.0% in trials of CAR T-cells for B malignancies and obinutuzumab for non-Hodgkin lymphoma.[9] TLS rates up to 15% were seen with dinaciclib in the treatment of acute leukemias, and in this setting, the rate with alvocidib (with cytarabine and mitoxantrone) was 53%.
1. Coiffier B, Altman A, Pui CH, et al. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008;26:
5. Abu-Alfa AK, Younes A. Tumor lysis syndrome and acute kidney injury: evaluation, prevention, and management. Am J Kidney Dis. 2010;55(5 suppl 3):S1-S13.
6. Mughal TI, Ejaz AA, Foringer JR, et al. An integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome. Cancer Treat Rev. 2010;36:
7. Mirrakhimov AE, Voore P, Khan M, et al. Tumor lysis syndrome: a clinical review. World J Crit Care Med. 2015;4:
8. Venetoclax [package insert]. North Chicago, IL: AbbVie; 2016.
9. Howard SC, Trifilio S, Gregory TK, et al. Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review. Ann Hematol. 2016;95:
MM, CML-CP, CLL if treating with alkylating agent, MM, and solid tumors typically considered low risk.
Coiffier B, et al. J Clin Oncol. 2008;26: Mirrakhimov AE, et al. World J Crit Care Med. 2015;4: Venetoclax [package insert]
Slide credit: clinicaloptions.com

15. Managing TLS: Summary Minimal Risk Low Risk Intermediate Risk
High Risk
Clinical TLS
No prophylaxis indicated
Prophylaxis:
hydration ± allopurinol
Daily lab tests
Prophylaxis:
hydration + allopurinol; consider rasburicase
Lab tests every hrs
Prophylaxis:
hydration + rasburicase
Lab tests every 6-8 hrs
Cardiac monitoring
Prophylaxis:
hydration + rasburicase
Lab tests every 4-6 hrs
Cardiac monitoring in ICU
ICU, intensive care unit; TLS, tumor lysis syndrome.
Without data from randomized, prospective clinical trials, the choice and timing of TLS prophylaxis is different at each institution. However, prophylaxis and monitoring for TLS should be based on each patient’s risk for developing TLS. This table summarizes current best practices for prophylaxis of laboratory and clinical TLS. For each risk group, hydration is critical, whereas the use of prophylactic medications, allopurinol and rasburicase, along with the frequency of laboratory testing are based on the risk of TLS or if clinical TLS develops.
Patients at low risk for TLS should receive hydration and undergo daily laboratory monitoring for development of TLS. Some clinicians may consider prophylactic treatment with allopurinol for these patients as well. Patients with intermediate risk for TLS should receive adequate hydration along with allopurinol and laboratory monitoring every 8-12 hours. Some clinicians may consider prophylactic treatment with rasburicase for these patients as well.
Patients who may be at higher risk for TLS should receive careful monitoring in addition to the prophylactic measures. These patients are first admitted to the hospital for observation and hydration and then monitored during the active therapy for hours. These patients will often be given a dose of rasburicase before initiating treatment. For high-risk patients or those who develop clinical TLS, cardiac monitoring is also necessary.
Monitoring patients for TLS includes assessing sodium, potassium, chloride, calcium, carbon dioxide, blood urea nitrogen, uric acid, serum creatinine, LDH, and phosphorus levels once or twice daily (depending on risk) throughout treatment and then as clinically indicated thereafter.
Based on these guidelines, we will now discuss the optimal use of allopurinol and rasburicase in clinical practice.
Slide credit: clinicaloptions.com
Howard SC, et al. N Engl J Med. 2011;364:

16. Prevention of AKI in Pts at Risk of TLS
Hydration: achieve high urine output
Manage hyperuricemia
Monitor for hyperkalemia and symptomatic hypocalcemia
Do not treat asymptomatic hypocalcemia, as it increases risk of calcium phosphate precipitation
Manage hyperphosphatemia
AKI, acute kidney injury; TLS, tumor lysis syndrome
Slide credit: clinicaloptions.com 16

17. Hyperuricemia as a Result of TLS
Adenosine
Guanosine
Inosine
Guanine
Hypoxanthine
Xanthine
Uric acid
Allantoin
Allopurinol
Urate
Oxidase
Deaminase
Nucleosidase
Crystals
Inhibition
Catalysis
Cell death and nuclear breakdown release large quantities of purines which are converted to uric acid and excreted in the urine
TLS, tumor lysis syndrome
As discussed, AKI due to urate crystal deposition is one of the core concerns in patients at risk of TLS.[10] This graphic demonstrates the steps by which nuclear purines are converted to uric acid, resulting in urate crystals and AKI. To mitigate this risk, hydration is essential. In addition, hyperuricemia is managed with allopurinol and/or rasburicase, which have different mechanisms of action.
Allopurinol blocks the conversion of xanthine to uric acid, which reduces the formation of uric acid and the incidence of TLS.[11] By contrast, rasburicase catalyzes the oxidation of free-form uric acid to allantoin. Allantoin is much more soluble than uric acid and is easily metabolized by the kidneys, thus reducing the potential for damage caused by uric acid crystal formation.
10. Chasty RC, Liu-Yin JA. Acute tumour lysis syndrome. Br J Hosp Med. 1993;49:
11. Arrambide K, Toto RD. Tumor lysis syndrome. Semin Nephrol. 1993;13:
Arrambide K, et al. Semin Nephrol. 1993;13:
Chasty RC, et al. Br J Hosp Med. 1993;49:
Goldman SC, et al. Blood. 2001;97: Howard S, et al. In: Childhood Leukemias. 2nd ed
Slide credit: clinicaloptions.com 17

18. Management of Hyperuricemia: Xanthine Oxidase Inhibitors
Prevent the metabolism of xanthine and hypoxanthine into uric acid
Reduces the formation of uric acid and the incidence of TLS
Most effective when used hrs prior to initiation of cytotoxic therapy
Allopurinol: primary agent to correct hyperuricemia for decades
Adverse events: hypersensitivity reactions and rash
Drug interactions: mercaptopurine, thiazide diuretics, antibiotics
Most effective at alkaline pH; however, alkaline pH increases calcium phosphate deposition in the kidneys
Febuxostat: not FDA approved for use in TLS
TLS, tumor lysis syndrome.
For decades, allopurinol, a xanthine oxidase inhibitor, has been the primary agent used to manage hyperuricemia.[12,13] It is most effective when used hours prior to initiation of cytotoxic therapy. Adverse events include hypersensitivity reactions and rash. Drug interactions are a concern, particularly regarding mercaptopurine, thiazide diuretics, and antibiotics. Although allopurinol is most effective with an alkaline pH, this alkalinity increases calcium phosphate deposition. Another xanthine oxidase inhibitor, febuxostat, is approved in Europe for use in TLS, but not in the United States.[14,15]
Because allopurinol decreases production of uric acid, it is more effective in preventing hyperuricemia compared with decreasing preexisting high levels of uric acid.
12. Cairo MS. Clin Lymphoma. Prevention and treatment of hyperuricemia in hematological malignancies. 2002;3(suppl 1):S26-S31.
13. DeConti RC, Calabresi P. Use of allopurinol for prevention and control of hyperuricemia in patients with neoplastic disease. N Engl J Med. 1966;274:
14. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353:
15. Tamura K, Kawai Y, Kiguchi T, et al. Efficacy and safety of febuxostat for prevention of tumor lysis syndrome in patients with malignant tumors receiving chemotherapy: a phase III, randomized, multi-center trial comparing febuxostat and allopurinol. Int J Clin Oncol. 2016;21:
Cairo MS. Clin Lymphoma. 2002;3:S26. Davidson MB, et al. Am J Med. 2004;116: DeConti RC, et al. N Engl J Med. 1966;274: Becker MA, et al. N Engl J Med. 2005;353: Allopurinol [package insert]
Slide credit: clinicaloptions.com 18

19. Management of Hyperuricemia: Rasburicase
Derived from a cDNA clone isolated from Aspergillus flavus and synthesized in Saccharomyces cerevisiae
Significantly reduced risk of hypersensitivity reaction compared with nonrecombinant urate oxidase
Contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency
Risk of hemolytic anemia and methemoglobinemia
The recombinant enzyme rasburicase was derived from Aspergillus flavus and is synthesized in Saccharomyces cerevisiae yeast.[16] Rasburicase significantly reduces the risk of hypersensitivity reaction compared with nonrecombinant urate oxidase. However, it is contraindicated in patients with G6P dehydrogenase deficiency as it carries a risk of hemolytic anemia and methemoglobinemia.
16. Ribeiro RC, Pui CH. Recombinant urate oxidase for prevention of hyperuricemia and tumor lysis syndrome in lymphoid malignancies. Clin Lymphoma. 2003;3:
Slide credit: clinicaloptions.com
Ribeiro RC, et al. Clin Lymphoma. 2003;3: 19

20. Uric Acid Reduction With Rasburicase in Adults With or at Risk for Hyperuricemia
Dosing every 12 hrs allowed for first 72 hrs of chemotherapy
Median number of doses: 2 (prophylaxis; range: 1-7) and 3 (treatment; range: 1-9)
Rasburicase 0.2 mg/kg/day IV for 1-7 Days 12
Baseline
Post treatment
10.8 10
N = 338 8
Uric Acid (mg/dL) 6
4.8 4
Rasburicase is an effective therapy at reducing uric acid levels in adults with or at risk for hyperuricemia. In a study by Jeha and colleagues,[17] patients with cancer presenting with or at risk of acute
hyperuricemia and TLS were assessed (adults N = 338) after rasburicase was given as prophylaxis against or as treatment for hyperuricemia. Results showed that in either clinical scenario, the use of rasburicase effectively decreased uric acid levels to 0.7 mg/dL (P < .001).
17. Jeha S, Kantarjian H, Irwin D, et al. Efficacy and safety of rasburicase, a recombinant urate oxidase (Elitek), in the management of malignancy-associated hyperuricemia in pediatric and adult patients: final results of a multicenter compassionate use trial. Leukemia. 2005;19:34-38. 2
0.7*
0.7*
Prophylaxis
Treatment
*P < .001
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Jeha S, et al. Leukemia. 2005;19:34-38. 20

21. Uric Acid Levels (mg/dL)
Rasburicase vs Allopurinol in Adults With Hematologic Malignancies at Risk for TLS
Drug-related AEs infrequent in all groups and primarily immunoallergenic in nature: rasburicase, 4%; rasburicase + allopurinol, 5%; allopurinol, 1%
No life-threatening AEs or deaths occurred 8
Rasburicase
Rasburicase + allopurinol 7
Allopurinol 6 5
Uric Acid Levels (mg/dL) 4 3 2
AE, adverse event; TLS, tumor lysis syndrome.
Cortes and colleagues[18] conducted a study comparing rasburicase with allopurinol in adults with hematologic malignancies who were at risk for TLS. These curves representing uric acid levels show that rasburicase, with or without allopurinol, is highly effective in quickly reducing uric acid levels. The curves show a sharp drop in uric acid from nearly 6 mg/dL at baseline to < 1 mg/dL within 4 hours of rasburicase administration.
Since allopurinol reduces the formation of uric acid instead of depleting uric acid that is already present, the effect of allopurinol is a more gradual decrease in uric acid levels. It can take 6-7 days to reach the nadir with allopurinol and the level of uric acid does not decrease as dramatically as with rasburicase. Although both drugs are commonly used in sequence, there does not appear to be much value to using both.
18. Cortes J, Moore JO, Maziarz RT, et al. 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. J Clin Oncol. 2010;28: 1 1 2 3 4 5 6 7
4 hrs
Days
Slide credit: clinicaloptions.com
Cortes J, et al. J Clin Oncol. 2010;28:

22. Rational Use of Allopurinol and Rasburicase to Manage TLS in Adult Pts
Recommendations from M. D. Anderson TLS guidelines algorithm[1]
Intermediate Risk
High Risk
Monitor labs
daily during tx,
then as clinically indicated
Uric Acid ≥ 7.5 mg/dL
Ensure adequate hydration
Allopurinol mg PO every 8 hrs
Increased hydration to maintain urine output
1 dose rasburicase, repeat if clinically indicated
Single dose of rasburicase
Recommendations from University of Michigan guidelines[2]
Intermediate Risk
High Risk
Uric Acid ≥ 9 mg/dL
TLS, tumor lysis syndrome; tx, treatment
The FDA and the European Medicines Agency recommend a dosing range for rasburicase of mg/kg/day for 5 days. However, several studies have demonstrated that a shorter treatment period or a lower dosage might have similar efficacy.[19] A TLS expert consensus panel recommended that a single dose of rasburicase ( mg/kg), repeated only if clinically necessary, is sufficient in patients who are at high risk for TLS.[20,21] This may help physicians to optimize use of this highly effective but expensive treatment.
As mentioned earlier, since there have been no large, prospective, randomized trials, each institution has adopted their own guidelines for managing TLS. This slide shows 2 such guidelines, one from the M. D. Anderson Cancer Center and one from the University of Michigan that was recently published. Both of these guidelines recommend a single dose of rasburicase for patients with high risk of TLS, in line with the consensus panel recommendation, although the specifics differ slightly.
M. D. Anderson Cancer Center recommendations suggest adequate hydration and allopurinol for intermediate-risk patients or increased hydration to maintain urine output and 1 dose rasburicase for high-risk patients. This prophylaxis should be followed by daily lab monitoring during treatment and then as clinically indicated. If a patient experiences uric acid levels ≥ 7.5 mg/dL, and additional dose of rasburicase is recommended.
The University of Michigan guidelines also suggest adequate hydration and allopurinol for intermediate-risk patients, but for high-risk patients, recommendations include adequate hydration and allopurinol with 1 dose rasburicase if uric acid ≥ 12 mg, or consider 1 dose rasburicase if uric acid is 9-12 mg. Again, if a patient experiences uric acid level increases during monitoring, an additional dose of rasburicase can be used. These guidelines differ somewhat from the M. D. Anderson experience in that the dose of rasburicase differs based on the concentration of uric acid: if a uric acid level of 9-15 mg/dL are reported, rasburicase 3 mg IV should be used while if the uric acid level is > 15 mg/dL, 6 mg of IV rasburicase can be considered.
While these guidelines may differ in their specific techniques, the key theme is that patients at increased risk of TLS should receive adequate hydration and prophylaxis, with ongoing monitoring of the important laboratory values to assess TLS. If laboratory TLS does occur despite prophylaxis, additional rasburicase treatment can help mitigate development of clinical TLS and organ damage.
19. Galardy PJ, Hochberg J, Perkins SL, et al. Rasburicase in the prevention of laboratory/clinical tumour lysis syndrome in children with advanced mature B-NHL: a Children's Oncology Group Report. Br J Haematol. 2013;163:
20. Cairo MS, Coiffier B, Reiter A, et al. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol. 2010;149:
21. Vadhan-Raj S, Fayad LE, Fanale MA, et al. A randomized trial of a single-dose rasburicase versus five-daily doses in patients at risk for tumor lysis syndrome. Ann Oncol. 2012;23:
Ensure adequate hydration
Allopurinol 300 mg/day PO
Ensure adequate hydration
Allopurinol 600 mg Day 1, 300 mg BID Days 2-3, then 300 mg/day
1 dose rasburicase if uric acid ≥ 12 mg/dL, consider if 9-12 mg/dL
After
24 hrs
9-15 mg: rasburicase 3 mg IV
> 15 mg: rasburicase 6 mg IV
All pts should continue allopurinol and hydration
1. M. D. Anderson Cancer Center. Tumor lysis in adult patients
2. Shaikh SA, et al. J Oncol Pharm Pract. 2017;[Epub ahead of print].
Slide credit: clinicaloptions.com

23. Venetoclax Monotherapy in CLL: Dose Escalation
Phase II trial in pts with R/R CLL with del(17p) confirmed by central lab
ECOG PS ≤ 2; creatinine clearance ≥ 50 mL/min; no major organ dysfunction
PO, QD dosing increasing weekly with risk-based prophylaxis to mitigate tumor lysis syndrome
Wk 5
Wk 4
Wk 3
CLL, chronic lymphocytic leukemia; ECOG, Eastern Cooperative Oncology Group; PS, performance status; R/R, relapsed/refractory.
As mentioned previously, venetoclax is an oral, selective Bcl-2 inhibitor that directly induces apoptosis (ie, independent of P53) and has recently been approved for treatment of patients with del(17p) CLL after first-line therapy. However, venetoclax has been associated with a substantial 3% to 9% risk of TLS in patients with CLL.[22] In the phase II clinical trials of venetoclax in del(17p)-positive relapsed/refractory CLL, a stepwise dosing approach was developed to minimize the number of patients who develop TLS.[23,24]
22. Howard SC, Trifilio S, Gregory TK, et al. Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: a systematic review. Ann Hematol. 2016;95:
23. Seymour JF. Effective mitigation of tumor lysis syndrome with gradual venetoclax dose ramp, prophylaxis, and monitoring in patients with chronic lymphocytic leukemia. Ann Hematol. 2016;95:
24. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17:
400 mg
Wk 2
200 mg
100 mg
Wk 1
50 mg
20 mg
Slide credit: clinicaloptions.com
Stilgenbauer S, et al. Lancet Oncol. 2016;17:

24. Risk-Based Management Plan for TLS in Venetoclax Clinical Trials
All pts receive allopurinol ≥ 72 hrs prior to first dose; continue up to 5 wks based on ongoing risk
Admit to hospital before first venetoclax doses of 20 mg and 50 mg; include oral uric acid reducer and IV fluids
Intensive lab monitoring (chemistry, hematology) in first 24 hrs; chemistry labs at 48 and 72 hrs
TLS Risk
Disease Characteristics
Management Plan
Incidence,
n (%)
Low risk
No bulky adenopathy
ALC < 25 x 109/L
Dose increases after 50 mg administered as outpatient
19 (18)
Int risk
Bulky adenopathy: ≥ 5 cm and < 10 cm or
ALC: ≥ 25 x 109/L
Dose increases after 50 mg administered as outpatient if creatinine clearance > 80 mL/min
43 (41)
High risk
Bulky adenopathy: ≥ 10 cm
bulky adenopathy: ≥ 5 cm and ALC ≥ 25 x 109/L
Prophylactic rasburicase (0.2 mg/kg) administered prior to 20-mg dose
Prophylactic reductions for potassium, inorganic phosphorus and/or uric acid above ULN were considered
Risk reassessed prior to each dose increase; for pts remaining at high risk, intensive prophylaxis measures continued
45 (42)
ALC, absolute lymphocyte count; Int, intermediate; TLS, tumor lysis syndrome; ULN, upper limit of normal.
In addition to the stepwise dosing, risk-based TLS prophylaxis was also used to minimize clinical TLS. In the pivotal phase II study, all patients received allopurinol prior to the first dose, and this could be continued for up to 5 weeks depending on risk.[24] All patients were admitted to the hospital before venetoclax was started for the 20-mg and 50-mg doses and were given an oral uric acid reducer and IV hydration.
After the 20-mg and 50-mg dosing, a risk-based management plan was outlined for these patients receiving venetoclax. Patients at low risk were allowed outpatient dose increases after 50 mg, and patients at intermediate risk of TLS were allowed dose increases as an outpatient after the 50 mg dose if their creatinine clearance was at least 80 mL/min. Patients with high risk also received prophylactic rasburicase prior to the initial 20-mg dose, along with prophylactic reductions for potassium and inorganic phosphorus, if needed. Risk of TLS was reassessed for these patients prior to each dose increase, and if the patient remained at high risk, inpatient prophylaxis measures continued.
Using this approach, there were no incidences of grade 1/2 TLS, 5% of patients experienced grade 3 TLS, and no patients experienced grade 4/5 TLS.
Although we have mostly discussed management of hyperuricemia, other electrolyte imbalances may also occur.
As mentioned, hyperkalemia can result in cardiac complications and patients should be assessed for symptoms related to hyperkalemia, such as fatigue, weakness, and so on. Patients with electrocardiogram changes or elevated potassium levels should be monitored for arrhythmias and other cardiac complications during treatment. Potassium levels can be managed through a careful review of the patient’s medications, implementation of a low-potassium diet, and ensuring IV fluids do not contain potassium.
Hyperphosphatemia can contribute to kidney injury as well as create hypocalcemia. This electrolyte imbalance can be managed through dietary phosphate restriction and administration of oral phosphate binders. However, IV calcium should not be used unless hypocalcemia is symptomatic as this approach may increase the risk of calcium phosphate precipitation and subsequent kidney injury.
TLS is a serious medical complication of cancer therapy. Identifying patients at risk for TLS can allow for proper prophylaxis and management to reduce the risk of serious complications. As such, prophylaxis and monitoring for TLS should be based on the individual patient’s risk for developing TLS.
Although hydration is critical regardless of risk, the use of prophylactic allopurinol and/or rasburicase, along with the frequency of laboratory testing, should be based on the risk of TLS. If clinical TLS develops, close monitoring with early intervention with rasburicase with or without allopurinol can mitigate long-term complications and minimize poor outcomes for patients.
24. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17:
No grade 1/2 TLS; 5% experienced grade 3 TLS; no grade 4.5
Slide credit: clinicaloptions.com
Stilgenbauer S, et al. Lancet Oncol. 2016;17:

25. Go Online for More CCO Programs on Novel Agents for Hematologic Malignancies!
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