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4th Asia Pacific Oncology Pharmacy Congress (APOPC)
Jakarta, Indonesia 1st - 3rd November 2012
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4.3cm x 5.5cm
Dr Vivianne Shih Pharm.D., BCPS, BCOP
Principal Clinical Pharmacist National Cancer Centre Singapore
Lymphoma & Tumour Lysis Syndrome (TLS)
Learning Objectives
At the end of this session, attendees should be able to
Define tumour lysis syndrome (TLS)
List the risk factors for TLS
Describe preventive strategies, monitoring
parameters & treatment for TLS
2
Overview Definition & Risk Factors
Classification of TLS
Pathogenesis & Clinical Manifestations of TLS
Prevention & Management of TLS
Case
ARZ, a 59 yr old male, is currently admitted to hospital on
5th Sept with abdominal distension.
HPI: has abdominal distension for 1 mth, denies pain.
a/w LOA & LOW & has a change in bowel habit. No PR
bleed / melena.
PMHx: Nil of note
SHx:
Works as a taxi driver
Ex-smoker (stopped in 1997, 20 pack yr history)
4
Case
O/E:
Afebrile, BP 145/70mmHg, HR 90/min, Sp02 90% RA
H: S1S2
L: reduced air entry over (R) lung base
A: soft, non-tender, distended
PR: brown stool, no melena / PR bleed
Calves supple, no pedal edema
5
Case: Investigations
CT (T/A/P): 7th Sept Peritoneal carcinomatosis with extensive omental caking. Short segment
thickening of distal ileum could represent the primary tumour. Bilateral pleural effusions
Exploratory laparotomy & bx of omental mass (11th Sept) 3cm x 3cm small bowel mass in loop of ileum, ascites and scattered
tumour nodules along entire small bowel wall
Histopathology report (11th Sept) Burkitt’s lymphoma
Hep B, Hep C & HIV screen (12th Sept): Negative
2D echo (13th Sept): LVEF = 61%
Bone marrow (14th Sept): No evidence of lymphomatous involvement
6
Introduction
What is Tumour Lysis Syndrome (TLS?)
Introduction
Tumour Lysis Syndrome (TLS)
First described in adult chronic leukemia patients who
had undergone RT1
Potentially life-threatening oncology emergency
Incidence is highly variable 2 (3 to 22%) Dependent on type of cancer, chemotherapeutic agents use
& other risk factors
8
1. Bedrna J & Polcak J. Med Klin 1929;25:1700-1.2. Solh M & Appel J. Hospital Physician 2008;25-9.
Tumour Lysis Syndrome (TLS)
Massive & abrupt release of cellular components into the
blood after rapid lysis of malignant cells
→ resulting in metabolic derangements
May occur spontaneously or, more frequently,
consequence of chemotherapy, RT or immunotherapy
Most frequently observed in hematologic malignancies
9
Risk Factors for
10
TLS Risk Factors
Tumourtype
Tumour burden / extent of disease
Renalimpairment Effective &
rapid cytoreductive
therapy High baseline
uric acid Eg > 450umol/L
Coiffier B et al. J Clin Oncol 2008;26:2767-78.
Risk Stratification
11
Type of cancer Risk
High Intermediate Low NHL Burkitt’s,
lymphoblastic, B-ALL
DLBCL Indolent NHL
ALL WBC > 100K WBC 50 to 100K WBC < 50 K
AML WBC > 50K, monoblastic
WBC 10K to 50K WBC < 10K
CLL - WBC 10K to 100K therapy with fludarabine
Other hematologicmalignancies (including CML & MM) & solid tumours
- Rapid proliferation with expected rapid response to therapy
Remainder of pts
Coiffier B et al. J Clin Oncol 2008;26:2767-78.
TLS Risk Assessment for Lymphomas
Cairo MS et al. Br J Haematol 2010;149:578-86.
LRD = Low risk disease IRD = Intermediate risk disease HRD = High risk disease
TLS Risk Assessment for Lymphomas
Cairo MS et al. Br J Haematol 2010;149:578-86.
LRD = Low risk disease IRD = Intermediate risk disease HRD = High risk disease
TLS Risk Assessment for Lymphomas
Cairo MS et al. Br J Haematol 2010;149:578-86.
LRD = Low risk disease IRD = Intermediate risk disease HRD = High risk disease
Case
Baseline Labs (12th Sept)
15
Lab Values Normal Range WBC (x 109/L) 20.5 4 – 10 LDH (U/L) 3635 180 – 380 K+ (mmol/L) 4.5 3.3 – 4.9Cr (umol/L) 91 63 – 110 Calculated CrCl (ml/min) 71Albumin (g/L) 29 37 – 51 Total Ca (mmol/L) 2.05 2.1 – 2.6 Ca, corrected (mmol/L) 2.27Phosphate (mmol/L) 1.3 0.77 – 1.38Uric acid (umol/L) 988 232 – 494
Classification of TLS
Classification
Classification for TLS
Hande & Garrow classification (1993)
Limitations
Does not account for pre-existing abnormal
laboratory values
Changes in lab values must occur within 4 days of
initiation of therapy
17Hande KR, Garrow GC. Am J Med 1993;94:133-9.
Classification for TLS
18
Element Value Change from baseline
Uric acid > 476 umol/l or 8mg/dl 25% ↑
Potassium > 6 mmol/L or 6mg/dl
Phosphorus > 1.45 mmol/L (adults)
Calcium < 1.75mmol/L 25% ↓
Note: 2 or more laboratory changes within 3 days before or 7 days after chemotherapy
Cairo MS, Bishop M. Br J Haematol 2004;127:3-11.
Cairo-Bishop Definition of Laboratory TLS
Classification for TLS
Cairo–Bishop Definition of CLINICAL TLS (CTLS)
Presence of LTLS AND
One or more of the following significant clinical
complications
Renal insufficiency
Cardiac arrhythmias
Seizures
19Cairo MS, Bishop M. Br J Haematol 2004;127:3-11.
Cairo-Bishop CTLS Definition & Grading
20
Complication Grade
0 1 2 3 4
Creatinine * < 1.5 X ULN
1.5 X ULN > 1.5 to 3 x ULN > 3 to 6 x ULN > 6 x ULN
Cardiacarrhythmia *
None Interventionnot indicated
Nonurgent medical intervention indicated
Symptomatic & incompletely controlled medically or controlled with device (egdefibrillator)
Life-threatening (eg arrhythmia associated with CHF, hypotension, syncope, shock)
Seizures* None - One brief, generalized seizures; seizure(s) well controlled by anticonvulsants or infrequent focal motor seizures not interfering with ADL
Seizure in whichconsciousness is altered; poorly controlled seizure disorder; with breakthrough generalized seizures despite medical intervention
Seizure of any kind which are prolonged, repetitive or difficult to control (eg status epilepticus, intractable epilepsy)
* Not directly or probably attributable to therapeutic agent
Pathogenesis & Clinical Manifestations of TLS
Clinical M
anifestations
Pathogenesis of TLS
22Howard SC et al. N Engl J Med 2011;364:1844-54.
Hyperkalemia
May present as early as 6 hrs after start of tx to 72 hrs
Remains the most serious manifestation
Can be exacerbated by
Renal failure / dysfunction OR
Due to excess admin of K+
23
Hyperphosphatemia / Hypocalcemia
Hyperphosphatemia usu develop in first 24 to 48 hrs
after treatment
Cancer cells, has 4x more intracellular phosphates
compared to normal cells1-2
Risk of ppt of calcium phosphate crystals ↑ when
plasma Ca-PO4 product > 4.6mmol/L3
Binding of excess phosphate to ionized Ca when Ca
PO4 solubility pdt is exceeded → hypocalcemia
24
1. Zusman J et al. N Engl J Med 1973;289:1335-40.2. Flombaum CD. Semin Oncol 2000;27:322-34. 3. Locatelli F & Rossi F. Contrib Nephrol 2005;147:61-8.
Hyperuricemia
25
Most often develops 48 to 72 hrs after start of
chemotherapy
Under normal conditions, uric acid is cleared via kidneys
As concentration of uric acid ↑, the risk of crystal
formation & deposition ↑
Clinical Manifestations
Usu observed within 12 to 72 hr after initiation of chemo
Anorexia
Congestive heart failure / cardiac dysrhythmias
Diarrhoea
Edema / Fluid Overload
Hematuria
Lethargy
Nausea, Vomiting
Seizures, Muscle cramps, tetany
26
Complications of TLS
Acute renal dysfunction
Multifactorial causes
Uric acid crystal obstructive uropathy
Calcium phosphate nephrocalcinosis
Renal tumour infiltration
Xanthinuria
Urethral obstruction
Nephrotoxic drugs
Intravascular volume depletion
27
Prevention & Management of TLS
Managem
ent
Prevention & Management of TLS
Hydration
Alkalinization?
Correct electrolyte abnormalities (if any)
Allopurinol
Rasburicase (Recombinant urate oxidase)
Hemodialysis (as appropriate)
29
Hydration
Hyper-hydrate with 2.5 to 3L/m2/day
Rationale
Increases intravascular volume, renal blood flow &
glomerular filtration1-3
↑ excretion of uric acid & phosphate
Use of diuretics
Maintain adequate urine output (at least 2ml/kg/hr)
30
1. Jones DP et al. Pediatr Nephrol 1995;9:206-12.2. Andreoli SP et al. J Pediatr 1986;109:292-8. 3. Silverman P, Distelhorst CW. Semin Oncol 1989:16:504-15.
Alkalinization?
31
Rationale
↑ solubility of uric acid1
15mg/dl @ pH 5
200mg/dl @ pH 7
Limitations
Does not increase solubility of xanthine & hypoxanthine 2-5
Xanthine crystals can ppt in renal tubules due to Low solubility of xanthine 6
↑ levels post allopurinol therapy
1. Wossmann W et al. Ann Hematol 2003;82:160-5. 2. Jones DP et al. Pediatr Nephrol 1995;9:206-12. 3. Andreoli SP et al. J Pediatr 1986;109:292-8. 4. Ten Harkel AD et al. Med Pediatr Oncol 1998;31:27-8. 5. Tsokes GC et al. Medicine (Baltimore) 1981:60:218-29.6. Cairo MS, Bishop M. Br J Hematol 2004;127:3-11.
Management of Electrolyte Abnormalities
32
Electrolyte Abnormalities RecommendationHyperphosphatemia(1) Moderate > 2.1mmol/L
(2) Severe
Avoid IV Phosphate administration Administer Phosphate binder
Dialysis, CAVH, CVVH, CAVHD or CVVHD
Hypocalcemia < 1.75mmol/L (1) Asymptomatic (2) Symptomatic
No therapy IV Calcium gluconate 50 to 100mg/kg
Hyperkalemia(1) Moderate & asymptomatic > 6 mmol/L
(2) Severe (> 7 mmol/L) &/or symptomatic
Avoid IV & PO potassium ECG & cardiac rhythm monitoring Sodium polystyrene sulphonate
Same as above + Calcium gluconate 100 to 200 mg/kg by slow IV
infusion (life threatening arrthythmias) Regular insulin (0.1U/kg IV) + D25 (2ml/kg) IV NaHCO3 (1-2mEq/kg IV push) to induce influx of K+
into cells Dialysis
Cairo MS, Bishop M. Br J Haematol 2004;127:3-11.
Allopurinol
33
Purine Catabolism
Hypoxanthine
Xanthine
Uric Acid (Low solubility)
Allantoin(Highly Soluble)
(Urinary Excretion)
Allopurinol Xanthine Oxidase
UrateOxidase / Rasburicase
Urate(insoluble)
pH 5-6
pH ~7.3
Allopurinol Usage
Dose
PO
100mg/m2/dose q 8hr
Max 800mg/day
IV
200 to 400mg/m2/day in 1-3 divided doses
Max 600mg/day
34
Limitations of Allopurinol Usage
Ineffective in ↓ levels of uric acid pre-treatment
Onset of drug effect takes several days
↑ levels of xanthine & hypoxanthine
→ leads to ppt of xanthine crystals in renal tubules
→ may result in acute obstructive uropathy
Reduce clearance of other purine-based chemotherapy
agents eg mercaptopurine (dose reduction req’d)
Hypersensitivity reactions
35
Rasburicase (Recombinant urate oxidase)
Catalyses the enzymatic oxidation of uric acid to allantoin
Recommended as 1st line treatment
HIGH risk patients with tumours prone to rapid lysis or
Presence of pre-existing kidney injury
Elevated uric acid levels 1-2
Uric acid levels ↓ within 4 hrs of initial administration
36
1. Cairo MS et al. Br J Hematol 2010;149:578-86. 2. Coiffier B et al. J Clin Oncol 2008;26:2767-78.
Rasburicase (Recombinant urate oxidase)
Dose
0.15 to 0.2mg/kg once daily over 30 mins for 5 days
Contraindication
G6PD deficiency
Precaution
Place blood sample IMMEDIATELY on ice to avoid
continual enzymatic degradation of uric acid
→ falsely low uric acid levels
37
Allopurinol vs Rasburicase
38
Allopurinol Rasburicase
Formulation PO & IV IV
Mechanism of Action Inhibits xanthine oxidase Converts uric acid to allantoin
Effects on uric acid Reduces uric acid levels post initiation
No effect on preexisting hyperuricemia
Reduces pre-existinghyperuricemia
Onset of action Slow (days) Rapid (hrs)Plasma half-life 1 – 2 hrs for allopurinol
15 hrs for oxypurinol(active metabolite)
16 hr for 0.15mg/kg dose 21 hr for 0.2mg/kg dose
Dose adjustments for organ impairment
Dose adjustment required for renal impairment No dose adjustment required for hepatic impairment
No dosage adjustments required in renal or hepatic impairment
Potential drug-drug interactions
6-mercaptopurine, azathioprine No cytochrome P450 inhibition or induction
Treatment Algorithm for Prevention & Mx of Hyperuricemia
39
• Clinical judgement & monitoring Low risk
• Hydration + initial Mx with allopurinol (rasburicase may be considered in paed pts)
• If hyperuricemia develops, initiate rasburicase therapy
Intermediate risk
• Hydration + initial management with rasburicaseHigh risk
Coiffier B et al. J Clin Oncol 2008;26:2767-78.
Case – Labs
40
12/9 (AM) 12/9 (PM)
12/9 (late PM)
13/9(AM)
13/9 (PM)
13/9 (late PM)
LDH (U/L) 3635 3954 3771 4517 3680 3949
K+ (mmol/L) 4.9 4.5 4.3 4.2 3.9 4.8
Cr (umol/L) 91 101 95 95 84 77
Cal CrCl(ml/min)
71 64 68 68 77 84
Albumin(g/L)
31 32 30 34
Total Ca(mmol/L)
2.05 2.16 2.05 2.04 2.09 2.12
Ca, corrected (mmol/L)
2.23 2.32 2.25 2.16
Phosphate(mmol/L)
1.3 1.17 1.05 1.18 0.88 1.05
Uric acid (umol/L)
988 1064 1023 1014 965
Case – Labs
41
13/9(AM)
13/9 (PM)
13/9 (late PM)
14/9 (AM)
14/9 (PM)
15/9 (AM)
15/9(PM)
LDH (U/L) 4517 3680 3949 3490 2846 3076 2382
K+ (mmol/L) 4.2 3.9 4.8 4 4 3.8 3.6
Cr (umol/L) 95 84 77 86 60 58 56
Cal CrCl(ml/min)
68 77 84 75 108 112 116
Albumin(g/L)
34 32
Total Ca(mmol/L)
2.04 2.09 2.12 2.15 2.05 2.15 2.11
Ca, corrected (mmol/L)
2.16 2.31
Phosphate(mmol/L)
1.18 0.88 1.05 1.04 0.89 1.23 0.93
Uric acid (umol/L)
1014 965 314 235 222 213
Rasburicase 6mg
Rasburicase – Optimal dosing?
42
Darmon M & Guichard I. J Clin Oncol 2011;29(3):e67-8.
Single Fixed Dose Rasburicase: NCCS Data
Aim: To assess efficacy of single dose rasburicase in
preventing TLS in lymphoma patients
Method: From June 2007 to Nov 2010
Case series of lymphoma patients at high risk of TLSwho received single fixed dose of rasburicase
Uric acid, serum Cr, LDH & electrolytes weremonitored at least 24 to 48 hrs post administration
43Chiang J et al. Asia-Pac J Clin Oncol 2011;7:351-6.
Single Fixed Dose Rasburicase: NCCS Data
Results Majority were Chinese (91%) Males (64%) Median age 61 yrs (range 41 – 84) All had > 2 risk factors for TLS 10 pts received 6mg rasburicase, 1 pt received 4.5mg
44
PRE-rasburicase mean uric acid level (umol/L)
POST-rasburicase (24hr) mean uric acid level (umol/L)
P value
835 (318 – 1237) 186 (30 -653) p < 0.001
Improvement of renal fn (72 hrs post-rasburicase):73% Normalization of serum electrolytes achieved within 96 hrs
Chiang J et al. Asia-Pac J Clin Oncol 2011;7:351-6.
Hemodialysis
Indications
Significant AKI
Poor response to medical management
Symptomatic life-threatening metabolic derangements
Reverses biochemical abnormalities & addresses fluid
overload1
45
1. Jones DP et al. Pediatr Nephrol 1995;9:206-12.
Case – Labs
46
23/9 24/9
LDH (U/L) 1282 1798
K+ (mmol/L) 4.6 3.9
Cr (umol/L) 67 63
Cal CrCl(ml/min)
97
Albumin(g/L)
33 33
Total Ca(mmol/L)
2.29 2.21
Ca, corrected (mmol/L)
2.43
Phosphate(mmol/L)
1.27 1.22
Uric acid (umol/L)
311 439
Day 1 REPOCH
REPOCH: IV Rituximab 375mg/m2 (Day 1), CI Etoposide 50mg/m2/day , CI Doxorubicin 10mg/m2/day, CI Vincristine 0.4mg/m2/day (Day 1 to 4)PO Prednisolone 60mg/m2/day (Day 1 to 5) IV Cyclophosphamide 750mg/m2/day (Day 5)
Is patient at risk for TLS?
What preventive strategieswould you recommend?
What recommendations would you make with regardsto monitoring parameters?
Monitoring Parameters
Urine output / Fluid balance
Check K+, PO4, Ca, Cr & uric acid levels
Should continue monitoring for entire period when pt is at
risk for TLS
47
Case – Labs
48
23/9 24/9 25/9 (AM)
25/9(PM)
26/9 27/9 28/9
LDH (U/L) 1282 1798 2324 2243 1457 1255 1135
K+ (mmol/L) 4.6 3.9 4.8 5.4 4.1 4.3 4.1
Cr (umol/L) 67 63 52 57 55 57 43
Cal CrCl(ml/min)
97
Albumin(g/L)
33 33 34 35 34 35
Total Ca(mmol/L)
2.29 2.21 2.28 2.22 2.3 2.44 2.46
Ca, corrected (mmol/L)
2.43
Phosphate(mmol/L)
1.27 1.22 1.66 1.58 1.46 1.32
Uric acid (umol/L)
311 439 546 603 334 211
Day 1 REPOCH
REPOCH: IV Rituximab 375mg/m2 (Day 1), CI Etoposide 50mg/m2/day , CI Doxorubicin 10mg/m2/day, CI Vincristine 0.4mg/m2/day (Day 1 to 4)PO Prednisolone 60mg/m2/day (Day 1 to 5) IV Cyclophosphamide 750mg/m2/day (Day 5)
Take home message…
Prevention is KEY!
Most impt is to ensure adequate hydration
Practitioners need to be able to
Identify risk factors for TLS in patients &
Recommend appropriate preventive strategies and
monitoring parameters
Prompt intervention is required as TLS is considered an
oncology emergency!
49
Stay vigilant!
Thank you
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4.3cm x 5.5cm
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