Tumor lysis syndrome and hyperphosphatemia · St. Jude Leukemia/Lymphoma Board: 13 November 2007?...

Tumor Tumor LysisLysis Syndrome Focusing Syndrome Focusing on on HyperphosphatemiaHyperphosphatemia

St. Jude Leukemia/Lymphoma Board:St. Jude Leukemia/Lymphoma Board:13 November 200713 November 2007

Scott Howard, MD, MSScott Howard, MD, MS Wren Kennedy, PNP/OWren Kennedy, PNP/O

Scott Howard, MD, Scott Howard, MD, MScMScAssociate Member, OncologyAssociate Member, OncologyDirector of Clinical Trials, International Outreach ProgramDirector of Clinical Trials, International Outreach ProgramSt. Jude Children’s Research HospitalSt. Jude Children’s Research Hospital



Tumor lysis syndrome Tumor lysis syndrome and hyperphosphatemiaand hyperphosphatemia

November 13, 2007November 13, 2007

•• Understand the pathophysiology of Understand the pathophysiology of tumor lysis syndrome (TLS)tumor lysis syndrome (TLS)

•• Review risk factors to develop TLS Review risk factors to develop TLS •• Manage hyperphosphatemia and Manage hyperphosphatemia and

hyperuricemiahyperuricemia•• Be aware of ongoing TLS researchBe aware of ongoing TLS research

Wren Kennedy, PNP Scott Howard, MDWren Kennedy, PNP Scott Howard, MDMecneide Lins, MD Francisco Pedrosa, MDMecneide Lins, MD Francisco Pedrosa, MD

Wren Kennedy, PNP/OWren Kennedy, PNP/OMember HematologyMember Hematology--OncologyOncologyCertified Nurse Practitioner in Pediatric OncologyCertified Nurse Practitioner in Pediatric OncologySt. Jude Children’s Research HospitalSt. Jude Children’s Research Hospital



Case PresentationCase Presentation•• 33--year old girl with newly diagnosed year old girl with newly diagnosed

acute lymphoblastic leukemia (ALL)acute lymphoblastic leukemia (ALL)•• Admitted to IMIP (Recife) with Admitted to IMIP (Recife) with

anemia and abdominal distensionanemia and abdominal distension•• Hemoglobin 8.2 g/dLHemoglobin 8.2 g/dL•• WBC 85,490 x 10WBC 85,490 x 1099/L (blasts 80%)/L (blasts 80%)•• Platelets 39,000 x 10Platelets 39,000 x 1099/L /L •• Serum Chemistries: Potassium 4.2; Serum Chemistries: Potassium 4.2;

Uric acid 16.4Uric acid 16.4; ; Calcium 9.8; Calcium 9.8; Phosphorus 3.5Phosphorus 3.5; Creatinine 1.0; Creatinine 1.0

Physical ExamPhysical Exam

•• Weight 13 Kg; height 89 cm; surface area, Weight 13 Kg; height 89 cm; surface area, 0.57 m0.57 m22;Temp 37C; HR 112; RR 25; BP ;Temp 37C; HR 112; RR 25; BP 100/60 100/60

•• Irritable and pale. Facial and lower extremity Irritable and pale. Facial and lower extremity edema. Afebrile. edema. Afebrile.

•• The abdomen was distended (abdominal The abdomen was distended (abdominal circumference 54 cm). Splenomegaly (9 cm circumference 54 cm). Splenomegaly (9 cm below the LCM) and hepatomegaly (10 cm below the LCM) and hepatomegaly (10 cm below the RCM) below the RCM)

•• Generalized adenopathy, (largest node 2 cm Generalized adenopathy, (largest node 2 cm in diameter in the inguinal region bilaterally)in diameter in the inguinal region bilaterally)

Laboratory InvestigationsLaboratory Investigations

•• Abdomen US showed bilateral Abdomen US showed bilateral nephromegaly nephromegaly

•• Bone marrow aspirate revealed that Bone marrow aspirate revealed that ssmall to intermediatemall to intermediate--sized blasts (L1) sized blasts (L1) comprised ~92% of nucleated bone comprised ~92% of nucleated bone marrow cells marrow cells

•• DNA index = 1.0 DNA index = 1.0 •• Molecular studies for ALL Molecular studies for ALL

translocations were negativetranslocations were negative•• CSF was negative for leukemiaCSF was negative for leukemia

Immunophenotype FindingsImmunophenotype Findings

26%26%LambdaLambda2.4%2.4%KappaKappa87%87%CD22CD220.9%0.9%CD34CD3472%72%CD10CD108.8%8.8%CD33CD334.0%4.0%CD13CD131.4%1.4%CD7CD70.03%0.03%CD3CD389%89%CD19CD1988%88%CD45CD45

ResultsResultsSurface Surface MarkersMarkers

46%46%TdTTdT

90%90%cyIgMcyIgM

3.7%3.7%cyCD3cyCD3

04%04%MPOMPO

96%96%cyCD79acyCD79a

ResultsResultsCytoplasmicCytoplasmicMarkersMarkers

Management and clinical courseManagement and clinical course•• DayDay 1:1: AdmittedAdmitted toto ICUICU onon allopurinol,allopurinol,

hyperhydrationhyperhydration (3L/m(3L/m22),), LasixLasix (2(2 mg/kg/day).mg/kg/day).•• UrineUrine outputoutput ofof 3.53.5 mL/kg/hrmL/kg/hr (1,005(1,005 mL/24mL/24 hr)hr)•• UrineUrine pHpH 66 toto 77•• DayDay 2:2: startedstarted prednisone.prednisone.•• UrineUrine outputoutput decreaseddecreased toto 1.91.9 mL/kg/day,mL/kg/day, (fluid(fluid

balancebalance +2L,+2L, generalizedgeneralized edema).edema).•• HydrationHydration increasedincreased toto 44 L/mL/m22/day/day (no(no

alkalinization)alkalinization) andand LasixLasix toto 44 mg/kg/day.mg/kg/day.•• SerumSerum Chemistries:Chemistries: PotassiumPotassium 4.2;4.2; UricUric acidacid

7.87.8;; CalciumCalcium 5.1;5.1; PhosphorusPhosphorus 15.915.9;; CaCa xx P=81;P=81;CreatinineCreatinine 1.1;1.1; BUNBUN 95.95.

Management and course (2)Management and course (2)

•• Day 3: Hydration increased to 5L/mDay 3: Hydration increased to 5L/m22/day, /day, and Lasix to 5mg/kg/day q4 hr. and Lasix to 5mg/kg/day q4 hr.

•• Phosphate binder was started. Phosphate binder was started. •• Patient developed generalized tetany. Patient developed generalized tetany.

Calcium was given (100 mg/kg x1 dose). Calcium was given (100 mg/kg x1 dose). •• Serum Chemistries: Potassium 4.6; Serum Chemistries: Potassium 4.6; Uric Uric

acid 5.8acid 5.8; ; Calcium 5.2; Phosphorus Calcium 5.2; Phosphorus 20.820.8; Ca x P=108; Creatinine 1.0; BUN ; Ca x P=108; Creatinine 1.0; BUN 114.114.

Management and course (3)Management and course (3)

•• Day 4: WBC 2,400 and platelet count Day 4: WBC 2,400 and platelet count 44,000. 44,000.

•• Serum chemistries: Potassium 3.1; Serum chemistries: Potassium 3.1; Uric Uric acid 3.8acid 3.8; ; Calcium 3.5; Phosphorus Calcium 3.5; Phosphorus 1919; Ca x P=66; Creatinine 0.8; BUN 131. ; Ca x P=66; Creatinine 0.8; BUN 131.

•• DiuresisDiuresis of 10.4 mL/kg/hr. of 10.4 mL/kg/hr. •• Day 5: continued to improve clinically Day 5: continued to improve clinically

and developed polyuria (12 mL/kg/hr).and developed polyuria (12 mL/kg/hr).

FluidFluid balancebalance DuringDuring thethe InitialInitial TherapyTherapy

665544332211DayDay

28512851388838883240324061661671371311341134OutputOutput

-- 2222-- 11701170-- 996996+2143+2143+2143+2143+810+810BalanceBalance

282928292718271822442244275927592856285619441944IntakeIntake

09.1209.1209.1109.1109.1009.1009.0909.0909.0809.0809.0709.07DateDate

Fluid Balance During Initial TherapyFluid Balance During Initial Therapy

0

500

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4500

1 2 3 4 5 6

intakediuresis

Changes in Selected Laboratory Changes in Selected Laboratory Parameters During Initial TreatmentParameters During Initial Treatment

66554433221100DayDay136136--141141136136131131--135135126126--130130122122130130138138NaNa

1.7801.7802.0202.0202.2902.29017.90017.90084.00084.00085.49085.49063.50063.500WBCWBC

8.5358.53513.3813.382213.50013.500NANA22.90022.90014.50014.50024.30024.300LDHLDH

6.46.4--6.36.34.64.63.53.5--4.04.05.15.1--5.25.27.97.9NANA9.89.8CaCa4.24.2--3.73.710.210.21919--13.913.91616--20203.53.52.72.73.53.5PhosPhos

0.70.70.90.90.80.81.11.11.11.11.11.11.01.0CreatCreat3.93.9--2.82.86.36.33.83.8--6.26.27.87.8--5.85.87.67.614.714.716.416.4UAUA

1.91.9--3.13.12.02.03.13.1--2.32.34.24.2--4.64.63.43.43.93.94.24.2KK

09/1209/1209/1109/1109/1009/1009/0909/0909/0809/0809/0709/0709/0609/06

White Blood Cell (x10White Blood Cell (x1099/L) Count /L) Count Changes During Initial TherapyChanges During Initial Therapy

0

10000

20000

30000

40000

50000

60000

70000

80000

90000

9/2006

9/2006

9/200

6

9/2006

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9/200

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9/200

6Days from diagnosis

Phosphorus and Blast Count Changes Phosphorus and Blast Count Changes During Initial TreatmentDuring Initial Treatment

0

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/2006

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/2006

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/2006

09/09

/2006

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/2006

11/09

/2006

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/2006

Fósforo Blastos

Phosphate (mg/dL)

Percent Blasts

Scott Howard, MD, Scott Howard, MD, MScMScAssociate Member, OncologyAssociate Member, OncologyDirector of Clinical Trials, International Outreach ProgramDirector of Clinical Trials, International Outreach ProgramSt. Jude Children’s Research HospitalSt. Jude Children’s Research Hospital



??

Questions and AnswersQuestions and Answers

Phosphate and uric acid during Phosphate and uric acid during the week after diagnosisthe week after diagnosis

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Tumor lysis syndrome and Tumor lysis syndrome and hyperphosphatemiahyperphosphatemia

Learning objectivesLearning objectives







••• Review risk factors to develop TLS Review risk factors to develop TLS Review risk factors to develop TLS ••• Manage hyperphosphatemia and Manage hyperphosphatemia and Manage hyperphosphatemia and

hyperuricemiahyperuricemiahyperuricemia••• Be aware of ongoing TLS researchBe aware of ongoing TLS researchBe aware of ongoing TLS research

Howard and Pui, Childhood Leukemias, 2nd ed. 2006

Arrambide K, Arrambide K, Semin Semin NephrolNephrol 19931993

Chasty RC, Chasty RC, Br J Hosp Br J Hosp MedMed 19931993

Goldman SC, Goldman SC, Blood Blood 20012001Howard and Pui, Childhood Leukemias, 2nd ed. 2006Howard and Pui, Childhood Leukemias, 2nd ed. 2006

0

2

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1

Days

mg/

dL

CalciumPhosphorusUric acid

00 11 22 33 44Days from diagnosisDays from diagnosis

Arrambide K, Arrambide K, Semin Semin NephrolNephrol 19931993

Chasty RC, Chasty RC, Br J Hosp Br J Hosp MedMed 19931993

Goldman SC, Goldman SC, Blood Blood 20012001Howard and Pui, Childhood Leukemias, 2nd ed. 2006Howard and Pui, Childhood Leukemias, 2nd ed. 2006 Howard and Pui, Childhood Leukemias, 2nd ed. 2006Howard and Pui, Childhood Leukemias, 2nd ed. 2006

Uric Acid Crystals in Renal Tubules

Effect of pH on solubility of uric acidEffect of pH on solubility of uric acid

Howard SC, et al. Childhood Leukemias, 2nd ed: 2006.

1

10

100

1000

4.5 5 5.5 6 6.5 7 7.5Urine pH

Solu

bilit

y (m

g/dL

) Uric acidXanthineCalcium phosphateAllantoinHypoxanthine




•• Review risk factors to develop TLS Review risk factors to develop TLS ••• Manage hyperphosphatemia and Manage hyperphosphatemia and Manage hyperphosphatemia and

hyperuricemiahyperuricemiahyperuricemia••• Be aware of ongoing TLS researchBe aware of ongoing TLS researchBe aware of ongoing TLS research

Howard and Pui, Leuk Lymph 2006

Na polystyrene sulfate

Na polystyrene sulfonate



Laboratory tumor lysis syndromeLaboratory tumor lysis syndrome

Clinical tumor lysis syndromeClinical tumor lysis syndrome





Cancer Cancer factorsfactors

Patient Patient factorsfactors

Risk for TLS Risk for TLS –– Cancer FactorsCancer Factors

Leuk Lymph 2006

•• Bulky tumors Bulky tumors –– Large tumor massLarge tumor mass–– Organ infiltrationOrgan infiltration–– Bone marrow involvement Bone marrow involvement

(leukemias are bulky)(leukemias are bulky)

•• Highly proliferative Highly proliferative tumors tumors -- LDH is a markerLDH is a marker

•• Chemosensitive tumorsChemosensitive tumors–– Burkitt lymphomaBurkitt lymphoma–– Lymphoblastic lymphomaLymphoblastic lymphoma–– Acute leukemiasAcute leukemias

Leukemic blasts removed by pheresisLeukemic blasts removed by pheresis Risk for TLS Risk for TLS –– Cancer FactorsCancer Factors

• Burkitt lymphoma• Lymphoblastic lymphoma• Acute leukemia• Low-grade lymphoma • Breast carcinoma, SCLC• Seminoma• Medulloblastoma, neuroblastoma,

colorectal carcinoma

Common

Uncommon

Case reports







•• Patient factorsPatient factors– Gout– Chronic renal insufficiency– Hypertension

•• PresentationPresentation– Hyperuricemia– Dehydration – Diminished urine output – Acute renal insufficiency– Acidic urine

Howard and Pui. Leuk Lymph 2006

Risk for TLS Risk for TLS –– Patient FactorsPatient Factors

Assess risk for Assess risk for clinicalclinical TLSTLS•• Very low riskVery low risk –– nonnon--bulky lowbulky low--risk cancers risk cancers •• Low riskLow risk –– lymphoma, lymphoma, seminomaseminoma, ,

neuroblastoma but low tumor burden, neuroblastoma but low tumor burden, normal LDH, no laboratory TLS, good urine normal LDH, no laboratory TLS, good urine outputoutput

•• Intermediate riskIntermediate risk –– acute leukemia without acute leukemia without leukocytosis, lymphoma without large leukocytosis, lymphoma without large tumor burden, moderately high LDHtumor burden, moderately high LDH

•• High riskHigh risk –– Burkitt or other highBurkitt or other high--grade grade lymphomas with large tumor burden, high lymphomas with large tumor burden, high LDH, existing laboratory TLSLDH, existing laboratory TLS






Patient Patient factorsfactorsProphylaxisProphylaxis

TreatmentTreatment




•• Review risk factors to develop TLSReview risk factors to develop TLS•• Manage hyperphosphatemia and Manage hyperphosphatemia and

hyperuricemiahyperuricemia••• Be aware of ongoing TLS researchBe aware of ongoing TLS researchBe aware of ongoing TLS research

Tumor Lysis Syndrome ManagementTumor Lysis Syndrome Management

Howard, unpublished

HydrationClose monitoring

No potassiumReduce phosphorus

Nothing for uric acid

Daily oral allopurinol

Rasburicase x 1 dose

Hemodialysis

Very low Very low riskrisk

Low Low riskrisk

Moderate or Moderate or high riskhigh risk

LifeLife--threatening threatening TLS (high KTLS (high K++))

Textbook of Medical Physiology. AC Guyton, HE Hall. Elsevier Saunders 2006. Figure 25-1 pg 292 Textbook of Medical Physiology. AC Guyton, HE Hall. Elsevier Saunders 2006. Figure 25-2 pg 294

Textbook of Medical Physiology. AC Guyton, HE Hall. Elsevier Saunders 2006. Table 25-2 pg 294

Phosphorus in and out of cells (Phosphorus in and out of cells (mOsmmOsm/L)/L)

SomeSome0000Cell membranesCell membranesA lotA lot000 0 DNA and RNADNA and RNA

3.73.7HexoseHexosemonophosphatemonophosphate

4545PhosphoPhospho--creatinecreatine

55ATPATP11112222HPOHPO44 and Hand H22POPO44

IntracellularIntracellularInterstitialInterstitialPlasmaPlasmaSubstanceSubstance

Phosphorus metabolism in humansPhosphorus metabolism in humans

Brenner, BM. The Kidney, 7th Ed. Vol. 1 p. 552

Renal phosphate excretionRenal phosphate excretion

•• 9090--100% filtered100% filtered•• 80% to 97% reabsorbed80% to 97% reabsorbed•• Net excretion = 3% to 20% of filtered Net excretion = 3% to 20% of filtered

loadload•• Amount depends on PTH, Amount depends on PTH,

1,25(OH)1,25(OH)22Vitamin D, and Vitamin D, and phosphatoninsphosphatonins•• 100,000 100,000 lymphoblasts/microLlymphoblasts/microL contain contain

enough phosphate to raise serum enough phosphate to raise serum phosphate about 25 mg/phosphate about 25 mg/dLdL

AC Guyton, HE Hall. Textbook of Medical Physiology. Elsevier Saunders 2006. Figure 79-11 pg 988

Textbook of Medical Physiology. AC Guyton, HE Hall. Elsevier Saunders 2006. Figure 79-10 pg 986

Regulation of calcium and Regulation of calcium and phosphate by parathyroid hormonephosphate by parathyroid hormone

AC Guyton, HE Hall. Textbook of Medical Physiology. Elsevier Saunders 2006.

White Blood Cell (x10White Blood Cell (x1099/L) Count /L) Count Changes During Initial TherapyChanges During Initial Therapy

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Uric acidPhosphate

Correction of Electrolyte Abnormalities Correction of Electrolyte Abnormalities Hyperphosphatemia, HypocalcemiaHyperphosphatemia, Hypocalcemia

•• Oral phosphate binderOral phosphate binder– Aluminum hydroxide (Amphojel),

sevelamer (Renajel), lanthanum•• Dietary phosphate restrictionDietary phosphate restriction•• Avoid calcium (unless tetany or Avoid calcium (unless tetany or

arrhythmia)arrhythmia)•• DiuresisDiuresis (furosemide, mannitol)(furosemide, mannitol)•• Protect the kidney so it can filterProtect the kidney so it can filter•• HemofiltrationHemofiltration/dialysis/dialysis

Jeha S. Semin Hematol 2001

Why do people alkalinize the urine in Why do people alkalinize the urine in newly diagnosed patients with newly diagnosed patients with

leukemia/lymphoma?leukemia/lymphoma?



1.1. ImprovesImproves renalrenal bloodblood flowflow2.2. StabilizesStabilizes thethe myocardiummyocardium3.3. MakesMakes uricuric acidacid moremore solublesoluble4.4. DrivesDrives potassiumpotassium intointo cellscells



1.1. ImprovesImproves renalrenal bloodblood flowflow2.2. StabilizesStabilizes thethe myocardiummyocardium3.3. MakesMakes uricuric acidacid moremore solublesoluble4.4. DrivesDrives potassiumpotassium intointo cellscells 1

10

100

1000

4.5 5 5.5 6 6.5 7 7.5

Urine pH

Solu

bilit

y (m

g/dL

)

Uric acid

Xanthine

CalciumphosphateAllantoin

Hypoxanthine


Howard and Pui, Childhood Leukemias, 2nd ed. 2006Howard and Pui, Childhood Leukemias, 2nd ed. 2006

1

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1000

4.5 5 5.5 6 6.5 7 7.5

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Solu

bilit

y (m

g/dL

)

Uric acid

Xanthine


Hypoxanthine


Solubility by pHSolubility by pH



1

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1000

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Solu

bilit

y (m

g/dL

)

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Xanthine


Hypoxanthine


Allantoin is highly soluble at any pHAllantoin is highly soluble at any pH

Rasburicase Clinical Trials Rasburicase Clinical Trials Children and AdultsChildren and Adults

Normal UA,Normal UA,TLS, ARFTLS, ARFRasburicaseRasburicase107107LascombesLascombes

19981998

UA, UA, SCrSCr, safety, safetyRasburicaseRasburicase100100CoiffierCoiffier 20032003

UA control in 1st UA control in 1st 96 hours, 96 hours, SCrSCr

Rasburicase vs Rasburicase vs allopurinolallopurinol5252Goldman Goldman

20012001

UA, ARF, safetyUA, ARF, safetyRasburicaseRasburicase10691069Jeha 2005Jeha 2005

UA, ARF, safetyUA, ARF, safetyRasburicaseRasburicase278278BoslyBosly 20032003

UA, UA, SCrSCr, safety, safetyRasburicaseRasburicase131131Pui 2001Pui 2001

OutcomesOutcomesInterventionInterventionNN

4.1

9.2

0.50.50

2

4

6

8

10

Nonhyperuricemic(n = 260)

Hyperuricemic(n = 398)

Uric

Aci

d (m

g/dL

BaselinePost-treatment

Jeha S, et al. Leukemia 2005.

Rasburicase in children with Rasburicase in children with hematologic malignancieshematologic malignancies

P <.001 P <.001

Jeha S. Leukemia 2005

How many doses of rasburicase How many doses of rasburicase do most children need?do most children need?

•• Number of doses needed (of Number of doses needed (of 682 patients)682 patients)– 1 dose for 657 (96%)– 2 doses for 22 (3%)– 3 doses for 2 (0.3%)– 4 doses for 1 (0.1%)

•• Response rateResponse rate– Prevention 260/260 = 100%– Treatment 392/398 = 98.5% 0

2

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dL

00 11 22 33 44

RasburicaseRasburicase

Days From Diagnosis Days From Diagnosis

VincristineVincristinePrednisonePrednisone CyclophosphamideCyclophosphamide

Rasburicase dosing as needed in a 9Rasburicase dosing as needed in a 9--yearyear--old with Burkitt Lymphomaold with Burkitt Lymphoma

Renal Complications Renal Complications Pediatric Stage IV BPediatric Stage IV B--NHLNHL

0%0%0%0%8%8%5%5%Death Death from TLSfrom TLS

P iP i JCOJCO 20012001P ttP ttAtAt

0%0%2.6%2.6%16%16%23%23%DialysisDialysis

Recombinant Recombinant urate oxidaseurate oxidase

NR orate NR orate oxidaseoxidaseAllopurinolAllopurinolAllopurinoAllopurino

ll

HypouricemiHypouricemic c

agentagent

LightLightLightLightLightLightIntenseIntenseCytoreductioCytoreductio

n n intensityintensity

COPCOPCOPCOPCOPCOPCHOPCHOPCytoreductioCytoreductionn

20201521526363123123NN

CCGCCG--5911/ 5911/ LMB TherapyLMB TherapyLMBLMB--8989

UKCCSG UKCCSG 90029002POGPOG--86178617Clinical TrialClinical Trial

TLS, renal insufficiency, TLS, renal insufficiency, and dialysis for Burkitt and dialysis for Burkitt

Group C on LMB 96Group C on LMB 96

0.0040.00415%15%3%3%DialysisDialysis0.0020.00226%26%9%9%Renal Renal insufficinsuffic0.0050.00527%27%11%11%TLSTLS

PP--ValueValueCCG (CCG (AlloAllo--purinolpurinol))

SFOP (Urate SFOP (Urate Oxidase)Oxidase)

Blood 109: 2736-43, 2007

Time From First Dose (hours)

Plas

ma

Uric

Aci

d (m

g/dL

)

0 24 48 72 96 120 24 HR POST

0123456789

1011

Rasburicase: MeanAUC = 128 +/- 70

Rasburicase vs AllopurinolRasburicase vs AllopurinolEffect on Uric Acid ExposureEffect on Uric Acid Exposure

Goldman SC, et al. Blood 2001; 97:2998-3003

Allopurinol: Mean AUC = 329 +/- 129

P < .0001

8

Time (hours)

Uric

Aci

d m

g/dL

01234567

0 4 12 24 36 48 60 72 84 96

Allopurinol = 329 ± 129Rasburicase = 128 ± 70

P < 0.0001

Uric acid levels by treatment armUric acid levels by treatment arm

Cairo MS, Br J Haematol. 2004;127(1):3-11Goldman SC, Blood. 2001;97(10):2998-03

Howard and Pui, Childhood Leukemias, 2nd ed. 2006Howard and Pui, Childhood Leukemias, 2nd ed. 2006


Phosphorus Creatinine Uric Acid

0.5

1.0

Allopurinol Rasburicase

0.5

1.0

0

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36 14413210884600.0

Uric

Aci

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spho

rus

Leve

l (m

g/dL

)

0

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36 14413210884600.0

Creatinine Level (m

g/dL)

Changes in serum phosphorus, calcium, Changes in serum phosphorus, calcium, and uric acid by treatment groupand uric acid by treatment group

Goldman SC, et al. Blood. 2001;97(10):2998-3003

Rasburicase vs Allopurinol Rasburicase vs Allopurinol Effect on Serum CreatinineEffect on Serum Creatinine

Goldman SC, et al. Blood 2001Days After First Dose

Seru

m C

reat

inin

e (%

of N

orm

al)

180

170

160

150

140

130

120

110

100

90

80

Baseline 1 2 3 4

Allopurinol

Rasburicase


Textbook of Medical Physiology. AC Guyton, HE Hall. Elsevier Saunders 2006. Figure 27-18 pg 345 Textbook of Medical Physiology. AC Guyton, HE Hall. Elsevier Saunders 2006. Table 25-2 pg 294

Total kidney and per nephron Total kidney and per nephron excretion in renal failureexcretion in renal failure

3.03.00.750.75Volume excreted per Volume excreted per nephron (nephron (nlnl/min)/min)

1.51.51.51.5Volume excreted for Volume excreted for all nephrons (ml/min)all nephrons (ml/min)

3030125125Total GFR (ml/min)Total GFR (ml/min)500,000500,0002,000,0002,000,000Number of nephronsNumber of nephrons

75% loss of 75% loss of nephronsnephrons

NormalNormal



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Uric acidPhosphate







TreatmentTreatment

1

10

100

1000

4.5 5 5.5 6 6.5 7 7.5

Urine pH

Sol

ubili

ty (m

g/dL

) Uric acid

Xanthine


Hypoxanthine

Urine alkalinization increases uric acid Urine alkalinization increases uric acid solubility but solubility but decreasesdecreases CaPOCaPO44 solubilitysolubility

Howard SC, et al. Childhood Leukemias, 2nd ed: 2006.

NephrocalcinosisNephrocalcinosis

Howard SC, et al. Childhood Leukemias, 2nd ed: 2006.Howard and Pui, Childhood Leukemias, 2nd ed. 2006

Ectopic CalcificationEctopic Calcification

Howard SC, et al. Childhood Leukemias, 2nd ed: 2006.Howard and Pui, Childhood Leukemias, 2nd ed. 2006 Howard and Pui, Childhood Leukemias, 2nd ed. 2006Howard and Pui, Childhood Leukemias, 2nd ed. 2006


Tumor Lysis Syndrome ManagementTumor Lysis Syndrome Management

Howard, unpublished

HydrationClose monitoring

No potassiumReduce phosphorus

Nothing for uric acid

Daily oral allopurinol

Rasburicase x 1 dose

Hemodialysis

Very low Very low riskrisk

Low Low riskrisk

Moderate or Moderate or high riskhigh risk

LifeLife--threatening threatening TLS (high KTLS (high K++))

Why rasburicase x 1 dose?Why rasburicase x 1 dose?•• Low threshold for the first dose Low threshold for the first dose

– Lowers uric acid to < 0.5– Uric acid usually stays low for 24 hr– Minimizes additional uric acid

crystallization in renal tubules•• Higher threshold for 2Higher threshold for 2ndnd, 3, 3rdrd, 4, 4thth, and 5, and 5thth

doses (e.g. when uric acid rises to > 5)doses (e.g. when uric acid rises to > 5)– If uric acid starts to rise within 24 hours

after rasburicase, the patient has a very high production rate






•• Randomized trial of uric acid vs Randomized trial of uric acid vs rasburicase in adults at risk for rasburicase in adults at risk for clinical TLSclinical TLS– Primary outcome: renal damage

(i.e. incidence of clinical TLS)

TLS research in progressTLS research in progress

Jeha S, et al. Leukemia 2005.

Compassionate Use of Compassionate Use of Rasburicase: Adverse EventsRasburicase: Adverse Events

12 (1.1)12 (1.1)5 (1.3)5 (1.3)7 (1.0)7 (1.0)Grade 2Grade 2

9 (0.8)9 (0.8)0 (0.0)0 (0.0)9 (1.3)9 (1.3)Grade 4Grade 44 (0.4)4 (0.4)2 (0.5)2 (0.5)2 (0.3)2 (0.3)Grade 3

19 (1.8)19 (1.8)11 (2.8)11 (2.8)8 (1.2)8 (1.2)Grade 1Grade 1Worst grade of AEWorst grade of AE

44/6944/6918/2118/2126/4826/48Patients/no. of AEPatients/no. of AE

Total Total (n = 1,069)(n = 1,069)

Adult Adult (n = 387)(n = 387)

Pediatric Pediatric (n = 682)(n = 682)

Adverse Events (AE)*Adverse Events (AE)*No. of Patients (%)No. of Patients (%)

*Events occurring during the first course of treatment.

•• Randomized trial of uric acid vs Randomized trial of uric acid vs rasburicase in adults at risk for rasburicase in adults at risk for clinical TLSclinical TLS– Primary outcome: renal damage

(i.e. incidence of clinical TLS)•• RASALL studyRASALL study

– Documenting the incidence of rasburicase side effects in patients with allergy, asthma, or eczema

TLS research in progressTLS research in progress

ConclusionsConclusions•• TLS can cause death, kidney damage, TLS can cause death, kidney damage,

seizure, and increased hospital staysseizure, and increased hospital stays•• General management for everyone:General management for everyone:

–– Close monitoringClose monitoring–– Hydration, avoid alkalinizationHydration, avoid alkalinization–– Avoid KAvoid K++

•• Reduce phosphorus early in everyoneReduce phosphorus early in everyone•• Uric acid management tailored to risk:Uric acid management tailored to risk:

–– Oral allopurinol for low risk Oral allopurinol for low risk –– Rasburicase x1 for moderate/high riskRasburicase x1 for moderate/high risk

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Scott Howard, MD, Scott Howard, MD, MScMScWren Kennedy, PNP/OWren Kennedy, PNP/O

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Tumor lysis syndrome and hyperphosphatemia · St. Jude Leukemia/Lymphoma Board: 13 November 2007?...

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