Tumor Lysis Syndrome The most common disease-related emergency encountered by physicians caring for children or adults with hematologic cancers When tumor cells release their contents into the bloodstream, either spontaneously or in response to therapy- leading to the characteristic findings of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia Electrolyte and metabolic disturbances- progress to clinical toxic effects- including -renal insufficiency, -cardiac arrhythmias, -seizures, and -death due to multiorgan failure Laboratory tumor lysis syndrome : Requires that two or more of the metabolic abnormalities occur within 3 days before or up to 7 days after the initiation of therapy Clinical tumor lysis syndrome: Laboratory tumor lysis syndrome is accompanied by an increased creatinine level, seizures, cardiac dysrhythmia, or death. IN MALIGNANCIES –high proliferative rate, –large tumor burden, –high sensitivity to treatment- Initiation of cytotoxic chemotherapy, Cytolytic antibody therapy, Radiation therapy, Sometimes glucocorticoid therapy alone Rapid lysis of tumor cells!!!!! Releases massive quantities of intracellular contents: K+ , phosphate, and nucleic acids

1. TUMOUR LYSIS SYNDROME
DR DIBYAJYOTI PRUSTY
Senior Resident
Dept. of Clinical Haematology
SCB Medical College, Cuttack
#Blood
Basics

2. Introduction
 The most common disease-related emergency encountered by
physicians caring for children or adults with hematologic cancers
 When tumor cells release their contents into the bloodstream, either
spontaneously or in response to therapy-
leading to the characteristic findings of
hyperuricemia, hyperkalemia, hyperphosphatemia, and
hypocalcemia

3. Electrolyte and metabolic disturbances- progress to clinical
toxic effects- including
-renal insufficiency,
-cardiac arrhythmias,
-seizures, and
-death due to multiorgan failure
Several groups have advocated guidelines for risk stratification
and made recommendations for evaluating risk and for
prophylactic therapy for the tumor lysis syndrome.

4. DEFINITION
Laboratory tumor lysis syndrome : Requires that two or
more of the metabolic abnormalities occur within 3 days
before or up to 7 days after the initiation of therapy
Clinical tumor lysis syndrome: Laboratory tumor lysis
syndrome is accompanied by an increased creatinine level,
seizures, cardiac dysrhythmia, or death.

5. IN MALIGNANCIES
–high proliferative rate,
–large tumor burden,
–high sensitivity to treatment-
Initiation of cytotoxic chemotherapy,
Cytolytic antibody therapy,
Radiation therapy,
Sometimes glucocorticoid therapy alone
Rapid lysis of tumor cells!!!!!
Releases massive quantities of intracellular contents:
K+ , phosphate, and nucleic acids

7. Hyperuricemia
 Marked increase in uric acid excretion– Acute uric acid nephropathy
The precipitation of uric acid in the renal tubules
-Can induce renal vasoconstriction,
–Impaired autoregulation,
–decreased renal blood flow
-Inflammation
ACUTE KIDNEY INJURY!!!
 The presence of crystals of one solute can promote crystallization of the other
solutes.

8. Crystallization of uric acid and calcium
phosphate - Primary means of renal
damage in the TLS.
Large uric acid crystals (arrowhead)
Calcium oxalate crystals (arrows)
Autopsy of a 4-year-old boy who had high-grade
non-Hodgkin’s lymphoma and died of acute tumor
lysis syndrome.
Linear yellow streaks of precipitated uric acid in the
renal medulla are shown in the left panel (arrows);
-A single tubule containing a uric acid crystal
(arrowhead).

9. Hyperphosphatemia
 The phosphorus concentration in malignant cells is up to 4 times higher than in normal
cells.
Rapid tumor breakdown !!!
-Hyperphosphatemia cause secondary hypocalcemia.
-Hyperphosphatemia with calcium phosphate deposition in renal
tubules can also cause acute kidney injury.
-Precipitation in the heart may lead to cardiac arrhythmias.
-Since with the widespread use of hypouricemic agents, calcium
phosphate deposition (nephrocalcinosis), rather than hyperuricemia,
has become the major mechanism of acute kidney injury in TLS.

10. Xanthinuria
 Allopurinol blocks the catabolism of hypoxanthine and xanthine.
Massive TLS !!!
Those receiving allopurinol are at risk for xanthine precipitation in the
tubules, resulting in xanthine nephropathy or xanthine stone formation.
 Xanthine concentration is not increased by rasburicase (recombinant urate
oxidase)

11. Cairo MS, Bishop M. Tumour lysis syndrome: new therapeutic strategies and classification. Br J Haematol. 2004; 127:3–11.
[PubMed: 15384972]

12. CLINICAL MANIFESTATIONS
 Largely reflect the associated metabolic abnormalities
 -Nausea, vomiting, diarrhea, anorexia, lethargy
-Hematuria
-Heart failure, cardiac dysrhythmias
-Seizures, muscle cramps, tetany
-Syncope
-Flank pain can occur if there is renal pelvic or ureteral stone
formation
-Possible sudden death

14. ETIOLOGY AND RISK FACTORS
 The risk of TLS is greatest in patients treated for hematologic
malignancies
 Intrinsic tumor-related factors:-
High tumor cell proliferation rate
Chemosensitivity of the malignancy
Large tumor burden, as manifested by-
Bulky disease >10 cm in diameter
WBC >50,000/cmm
A pretreatment serum LDH >2 times UNL
Bone marrow involvement

15.  Conditions that predispose to development of TLS –
Pretreatment hyperuricemia and hyperphosphatemia
A pre-existing nephropathy or exposure to nephrotoxins
Oliguria and/or acidic urine
Dehydration, volume depletion, or inadequate hydration during
treatment

16. Cancer mass
Cell lysis potential
Features on patient presentation
Supportive care

17. Cancer mass
The greater the cancer mass, the greater the quantity
of cellular contents released after the administration
of effective anticancer therapy.
 Bulky tumor or extensive metastasis
 Organ infiltration by cancer cells
 Bone marrow involvement
 Renal infiltration or outflow-tract obstruction

18. Cell lysis potential
Cancers with a high potential for cell lysis include high-grade
lymphomas, acute leukemias, and other rapidly proliferating
tumors.
 High rate of proliferation of cancer cells- LDH
 Cancer-cell sensitivity to anticancer therapy
 Intensity of initial anticancer therapy

19. Patient presentation
 Dehydration or volume depletion
 Acidic urine
 Hypotension
 Exposure to nephrotoxins
 Nephropathy before diagnosis of
cancer

20. Supportive care
 Inadequate hydration
 Exogenous potassium
 Exogenous phosphate
 Delayed uric acid removal

21.  The tumor lysis syndrome increasingly has been reported in patients
with cancers that previously had been rarely associated with this
complication,
 such as endometrial cancer, hepatocellular carcinoma, chronic
lymphocytic leukemia*, and chronic myelogenous leukemia#
* Cheson BD. Etiology and management of tumor lysis syndrome in patients with chronic lymphocytic leukemia. Clin Adv Hematol Oncol. 2009; 7:263–71. [PubMed: 19521331]
# Keane C, Henden A, Bird R. Catastrophic tumour lysis syndrome following single dose of imatinib. Eur J Haematol. 2009; 82:244–5. [PubMed: 19067739]

23.  Disastrous cases of the tumor lysis syndrome occurred in patients with
nonhematologic cancer who received effective anticancer treatment but no
intravenous fluids or monitoring because the tumor lysis syndrome was not
anticipated.
 In contrast, patients with a bulky Burkitt’s lymphoma who have a high potential for
lysis have a low risk of clinical tumor lysis syndrome because they routinely receive
aggressive treatment with hydration and rasburicase, a recombinant urate oxidase
 Children with Burkitt’s lymphoma who received rasburicase were a fifth as likely to
undergo dialysis as those who received allopurinol,
-illustrating the dramatic difference that supportive care can make, even when other
risk factors for the tumor lysis syndrome are the same.*
* Cairo MS, Gerrard M, Sposto R, et al. Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia
in children and adolescents. Blood. 2007; 109:2736–43. [PubMed: 17138821]

24. Prevention and treatment
 Preventive measures include foremost hydration, allopurinol,
and oral phosphate binders
-Beginning preferably 24 hours before chemotherapy
administration
 Aggressive hydration- Begin immediately, administering at
least 3,000 mL/m2 per day, when possible delaying tumor
therapy so hydration can be administered.
 Urine alkalinization -controversial as it favors precipitation of
calcium/phosphate complexes in renal tubules— calcium
phosphate, unlike uric acid, becomes less soluble at an
alkaline pH.
 Metabolic alkalemia can worsen neurologic manifestations of
hypocalcemia.

25. Hyperkalemia
 Should be treated aggressively
 Cation exchange resins should be used, recognizing their value will be
delayed.
 Calcium giuconate antagonizes cardiac effects of hyperkalemia and can be
especially helpful if there is concomitant hypocalcemia.
 Sodium bicarbonate corrects acidemia and shifts potassium back into cells
 Administering hypertonic dextrose and insulin
 Loop diuretics- eliminate excess potassium in patients without renal failure
 Hemodialysis is indicated in renal impairment.

26. Hypocalcemia
 Symptomatic hypocalcemia should be treated with calcium at the lowest
doses required to relieve symptoms
 To avoid calcium-phosphate precipitation,
most symptomatic acutely hypocalcemic patients with hyperphosphatemia
due to TLS (particularly if the calcium phosphate product is >60 mg2 per dL2
should not be treated with calcium until hyperphosphatemia is corrected
 In most situations, use oral phosphate binders
 patients with severe symptoms of hypocalcemia (eg, tetany or cardiac
arrhythmia) should be considered for calcium replacement regardless of
the phosphate level
 Asymptomatic patients with hypocalcemia do not require treatment.

27. Hyperphosphatemia and its resultant
hypocalcemia
Require oral phosphate binders
Except to manage hyperkalemia avoid calcium
administration, because it can promote metastatic
calcifications.

28. Soft-tissue calcification of the
dorsum of the distal forearm
Occurred in a 15-year-old boy with acute lymphoblastic
leukemia and an initial white-cell count of 283,000 per
cubic millimeter in whom tumor lysis syndrome,
hyperphosphatemia, and symptomatic hypocalcemia
developed.
Several weeks after the treatment of hypocalcemia with
multiple doses of intravenous calcium carbonate
administered by means of a peripheral intravenous
catheter in the dorsum of the hand, ectopic calcification
was confirmed radiographically (arrows)

29. Hyperuricemia
 Hyperuricemia should be managed aggressively.
Allopurinol
-An analog of the purine base hypoxanthine, lowers uric acid by inhibiting
xanthine oxidase, the enzyme converting hypoxanthine to xanthine and
xanthine to uric acid
-Oral allopurinol – bioavailability 50%; alternately, intravenous allopurinol
may be administered
-Allopurinol should be discontinued if allergic reactions such as skin rashes
and urticaria occur (incidence increased in patients receiving amoxicillin,
ampicillin, or thiazides)

30. Allopurinol
 Dose in adults is 100 mg/m2
every 8 hours (maximum 800
mg/ day)
 In children, the dose is 50 -100
mg/m2 every 8 hrs (maximum
300 mg/m2 per day) or 10 mg/kg
per day in divided doses every 8
hours.
 Doses of allopurinol should be
adjusted for creatinine clearance

31. Febuxostat
 Alternative to allopurinol to prevent TLS in pts at intermediate
to high risk for TLS.
 Used in pts who cannot tolerate allopurinol
or
-in a setting where rasburicase is either not available or
contraindicated.
 Orally administered, potent, selective inhibitor of XO
 Dose adjustment is not needed in pts with mild to moderate
renal impairment
 There are fewer drug-drug interactions with febuxostat than
with allopurinol
 It is quite a bit more expensive than allopurinol

32. Rasburicase
 A recombinant urate oxidase
 Promotes the degradation of uric acid to the much more
water soluble compound allantoin.
 Because urate oxidase degrades uric acid rather than prevent
its synthesis (rapid fall to 0.5 to 1 mg/dL reduction in uric acid
within 4 hours of rasburicase injection)
 Despite normalization of uric acid levels with rasburicase, a
small % of cases may required dialysis.

33. Rasburicase
 Patients with G6PD deficiency, hydrogen peroxide, a breakdown product
of uric acid, can cause methemoglobinemia and, in severe cases,
hemolytic anemia
 For this reason, rasburicase is contraindicated in pts with G6PD
deficiency
 Dose of 0.2 mg/kg for up to 5 days
 However, except in rare patients with very high serum levels of uric acid,
much less is sufficient
A 5-day course of rasburicase is about 15,000 times more expensive than a
5-day course of allopurinol and 15 to 30 times more than intravenous
allopurinol !!!

36. Renal replacement therapy
 Renal replacement therapy includes dialysis (hemodialysis or peritoneal
dialysis), hemofiltration, and hemodiafiltration, which are various ways of
filtration of blood with or without machines.
 Among the indications for renal replacement therapy in patients with TLS are –
Severe oliguria or anuria
Intractable fluid overload
Persistent hyperkalemia
Hyperphosphatemia-induced symptomatic hypocalcemia
A calcium-phosphate product ≥70 mg2 /dL2
Ca–P product = (4 × serum calcium) × (3.1 × serum
phosphorus)

37. PREVENTION OF ACUTE KIDNEY INJURY
 All patients who are at risk for the TLS
-should receive intravenous hydration
-to rapidly improve renal perfusion and glomerular filtration and
to minimize acidosis and oliguria.
 Hydration is the preferred method of increasing urine output, but
diuretics may also be necessary.
 In patients whose urine output remains low after achieving an
optimal state of hydration –
-a loop diuretic agent (e.g., furosemide) to promote diuresis, with a
target urine output of at least 2 ml per kilogram per hour*.
* N Engl J Med. 2011 May 12; 364(19): 1844–1854. doi:10.1056/NEJMra0904569.

38.  REDUCING THE LEVEL OF URIC ACID
-Use of allopurinol and rasburicase, can preserve or improve renal function and reduce
serum phosphorus levels as a secondary beneficial effect.
 The level of uric acid may take 2 days or more to decrease,
-a delay that allows urate nephropathy to develop
 Moreover, despite treatment with allopurinol, xanthine may accumulate, resulting in
xanthine nephropathy
 By preventing xanthine accumulation and by directly breaking down uric acid, rasburicase

39.  Lab Precaution:
In patients treated with rasburicase, blood samples for the
measurement of the uric acid level must be placed on ice to prevent ex
vivo breakdown of uric acid by rasburicase and thus a spuriously low
level.
 Rasburicase is recommended as first-line treatment for patients who
are at high risk for clinical tumor lysis syndrome.*
 Patients Who Are At Low Risk can usually be treated with
fluids with or without allopurinol, but they should be monitored daily
for signs of the tumor lysis syndrome.
* Coiffier B, Altman A, Pui CH, Younes A, Cairo MS. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol. 2008; 26:2767–78. Erratum, J
Clin Oncol 2010;28:708. [PubMed: 18509186]

40. PREVENTION OF CARDIAC DYSARHYTHMIAS
AND NEUROMUSCULAR IRRITABILITY
 HYPERKALEMIA - can cause sudden death due to cardiac
dysrhythmia.
 Frequent measurement of potassium levels (every 4 to 6 hours),
continuous cardiac monitoring, and the administration of oral sodium
polystyrene sulfonate are recommended in patients with the tumor
lysis syndrome and acute kidney injury.
 Hemodialysis and hemofiltration effectively remove potassium.
 Glucose plus insulin or beta-agonists can be used as temporizing
measures, and calcium gluconate may be used cautiously to reduce
the risk of dysrhythmia while awaiting hemodialysis.

41.  Hypocalcemia- life-threatening dysrhythmias and neuromuscular
irritability
 Controlling the serum phosphorus level may prevent hypocalcemia.
 Symptomatic hypocalcemia should be treated with calcium at the
lowest dose required to relieve symptoms, since the administration of
excessive calcium increases the calcium–phosphate product and the
rate of calcium phosphate crystallization
 Hypocalcemia not accompanied by signs or symptoms does not
treatment.
 Despite the lack of studies that show the efficacy of phosphate binders
in patients with the tumor lysis syndrome, this treatment is typically
given.

42. MANAGEMENT OF SEVERE ACUTE KIDNEY
INJURY in TLS
 Develops in some patients and requires renal replacement therapy
 Hyperphosphatemia-induced symptomatic hypocalcemia may also
warrant dialysis.
 Advocating the use of continuous renal-replacement therapies in
patients with the tumor lysis syndrome, including continuous
venovenous hemofiltration, continuous venovenous hemodialysis, or
continuous venovenous hemodiafiltration.
 Once the tumor lysis syndrome was identified, treatment with
intravenous fluids, phosphate binders, and rasburicase prevents the
need for dialysis.

43. The normal kidney on the left, the medullary
pyramids are visible deep in the kidney
(arrowheads) and are surrounded by the renal
cortex (arrows), which is darker than the
collecting system and adjacent liver.
The ultrasonographic image on the right shows
a kidney from a patient with the tumor lysis
syndrome, in which there is loss of the normal
corticomedullary differentiation (arrowheads)
and poor visualization of the renal pyramids.
The brightness is similar to that of the adjacent
liver (arrows), and the kidney is abnormally
enlarged.

44. MONITORING of TLS
 Urine output is the key factor
 urine output and fluid balance- frequent assesment
 Patients at high risk
-continuous cardiac monitoring
-The measurement of electrolytes, creatinine, and uric acid every 4 to 6 hours
after the start of therapy.
 Those at intermediate risk
-Undergo laboratory monitoring every 8 to 12 hours, and those at
Those at low risk should undergo such monitoring daily.
 The laboratory parameters may change as per the chemo-sensitiveness of
tumour cells to a particular chemotherapeutic agent. *
* Pui CH, Campana D, Pei D, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009; 360:2730–41. [PubMed: 19553647]

45. DECREASING THE RATE OF TUMOR LYSIS
WITH A TREATMENT PREPHASE
 Patients at high risk for the tumor lysis syndrome may also receive low-
intensity initial therapy.
 Slower lysis of the cancer cells allows renal homeostatic mechanisms to clear
metabolites before they accumulate and cause organ damage.
Advanced B-cell NHL or Burkitt’s leukemia
-involved treatment with low-dose cyclophosphamide, vincristine,
and prednisone for a week before the start of intensive chemotherapy.
 A week of prednisone monotherapy for childhood acute lymphoblastic
leukemia.