Tumor Lysis Syndrome and Hyperphosphatemia

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

Tumor Lysis Syndrome Focusing Tumor Lysis Syndrome Focusing on Hyperphosphatemia on Hyperphosphatemia

Scott Howard, MD, MSc Scott Howard, MD, MS Wren Kennedy, PNP/O Associate Member, Oncology Director of Clinical Trials, International Outreach Program St. Jude Children’s Research Hospital

Tumor lysis syndrome and hyperphosphatemia November 13, 2007 • Understand the pathophysiology of tumor lysis syndrome (TLS) • Review risk factors to develop TLS • Manage hyperphosphatemia and hyperuricemia • Be aware of ongoing TLS research

Mecneide Lins, MD Francisco Pedrosa, MD Wren Kennedy, PNP Scott Howard, MD

St. Jude Leukemia/Lymphoma Board: 13 November 2007

Tumor Lysis Syndrome Focusing on Hyperphosphatemia

Wren Kennedy, PNP/O Member Hematology-Oncology Certified Nurse Practitioner in Pediatric Oncology St. Jude Children’s Research Hospital Case Presentation Physical Exam

• 3-year old girl with newly diagnosed • Weight 13 Kg; height 89 cm; surface area, acute lymphoblastic leukemia (ALL) 0.57 m2;Temp 37C; HR 112; RR 25; BP • Admitted to IMIP (Recife) with 100/60 anemia and abdominal distension • Irritable and pale. Facial and lower extremity edema. Afebrile. • Hemoglobin 8.2 g/dL • The abdomen was distended (abdominal 9 • WBC 85,490 x 10 /L (blasts 80%) circumference 54 cm). Splenomegaly (9 cm • Platelets 39,000 x 109/L below the LCM) and hepatomegaly (10 cm • Serum Chemistries: Potassium 4.2; below the RCM) Uric acid 16.4; Calcium 9.8; • Generalized adenopathy, (largest node 2 cm Phosphorus 3.5; Creatinine 1.0 in diameter in the inguinal region bilaterally)

Immunophenotype Findings Laboratory Investigations Surface Results • Abdomen US showed bilateral Markers nephromegaly CD45 88% Cytoplasmic Results • Bone marrow aspirate revealed that CD19 89% Markers CD3 0.03% small to intermediate-sized blasts (L1) cyCD79a 96% comprised ~92% of nucleated bone CD7 1.4% marrow cells CD13 4.0% MPO 04% CD33 8.8% • DNA index = 1.0 cyCD3 3.7% CD10 72% • Molecular studies for ALL CD34 0.9% cyIgM 90% translocations were negative CD22 87% TdT 46% • CSF was negative for leukemia Kappa 2.4% Lambda 26%

Management and clinical course Management and course (2) • Day 1: Admitted to ICU on allopurinol, hyperhydration (3L/m2), Lasix (2 mg/kg/day). • Day 3: Hydration increased to 5L/m2/day, • Urine output of 3.5 mL/kg/hr (1,005 mL/24 hr) and Lasix to 5mg/kg/day q4 hr. • Urine pH 6 to 7 • Phosphate binder was started. • Day 2: started prednisone. • Patient developed generalized tetany. • Urine output decreased to 1.9 mL/kg/day, (fluid Calcium was given (100 mg/kg x1 dose). balance +2L, generalized edema). • Serum Chemistries: Potassium 4.6; Uric 2 • Hydration increased to 4 L/m /day (no acid 5.8; Calcium 5.2; Phosphorus alkalinization) and Lasix to 4 mg/kg/day. 20.8; Ca x P=108; Creatinine 1.0; BUN • Serum Chemistries: Potassium 4.2; Uric acid 114. 7.8; Calcium 5.1; Phosphorus 15.9; Ca x P=81; Creatinine 1.1; BUN 95. Management and course (3) Fluid balance During the Initial Therapy • Day 4: WBC 2,400 and platelet count 44,000. • Serum chemistries: Potassium 3.1; Uric Date 09.07 09.08 09.09 09.10 09.11 09.12 acid 3.8; Calcium 3.5; Phosphorus Day 1 2 3 4 5 6 19; Ca x P=66; Creatinine 0.8; BUN 131. Intake 1944 2856 2759 2244 2718 2829 • Diuresis of 10.4 mL/kg/hr. Output 1134 713 616 3240 3888 2851 • Day 5: continued to improve clinically and developed polyuria (12 mL/kg/hr). Balance +810 +2143 +2143 - 996 - 1170 - 22

Changes in Selected Laboratory Fluid Balance During Initial Therapy Parameters During Initial Treatment

09/06 09/07 09/08 09/09 09/10 09/11 09/12 4500 Day 0 1 2 3 4 5 6 4000 136- 3500 Na 138 130 122 126-130 131-135 136 141 3000 K 4.2 3.9 3.4 4.2-4.6 3.1-2.3 2.0 1.9-3.1 2500 intake UA 16.4 14.7 7.6 7.8-5.8 3.8-6.2 6.3 3.9-2.8 2000 diuresis Creat 1.0 1.1 1.1 1.1 0.8 0.9 0.7 1500 Phos 3.5 2.7 3.5 16-20 19-13.9 10.2 4.2-3.7 1000 Ca 9.8 NA 7.9 5.1-5.2 3.5-4.0 4.6 6.4-6.3 500 13.38 LDH 24.300 14.500 22.900 NA 13.500 8.535 0 2 123456 WBC 63.500 85.490 84.000 17.900 2.290 2.020 1.780

White Blood Cell (x109/L) Count Phosphorus and Blast Count Changes Changes During Initial Therapy During Initial Treatment

90000 90 80000 80 70000 70 Percent Blasts 60000 60 50000 50 Fósforo 40 Blastos 40000 30 30000 20 20000 10 10000 0Phosphate (mg/dL) 0 6 6 6 6 06 06 00 00 0 0 /2 /2 /200 /2 /2 6 6 6 9/200 9/2006 9 9 9 9 9 0 0 0 /0 /0 /0 /0 /0 /0 /0 006 Days from diagnosis 6 7 8 9 0 1 2 2 2006 /20 2006 /2006 /20 /20 0 0 0 0 1 1 1 9/ 9/ 9 9/ 9 9 9 St. Jude Leukemia/Lymphoma Board: 13 November 2007 ?

Tumor Lysis Syndrome Focusing on Hyperphosphatemia Questions and Answers

Scott Howard, MD, MSc Associate Member, Oncology Director of Clinical Trials, International Outreach Program St. Jude Children’s Research Hospital

Phosphate and uric acid during the week after diagnosis Tumor lysis syndrome and 20 hyperphosphatemia 18 Learning objectives Uric acid 16 Phosphate 14 • Understand the pathophysiology of 12 tumor lysis syndrome (TLS) 10 • Review risk factors to develop TLS 8 • Manage hyperphosphatemia and 6 • Manage hyperphosphatemia and 4 hyperuricemia 2 • Be aware of ongoing TLS research 0 0.0 1.0 2.0 3.0 3.5 4.0 4.5 5.0 6.0 6.5

Tumor lysis syndrome and hyperphosphatemia Learning objectives

• Understand the pathophysiology of tumor lysis syndrome (TLS) • Review risk factors to develop TLS • Manage hyperphosphatemia and hyperuricemia • Be aware of ongoing TLS research

Howard and Pui, Childhood Leukemias, 2nd ed. 2006 16 Calcium 14 Phosphorus 12 Uric acid

8 mg/dL 6

Arrambide K, Semin 0 Nephrol 1993 Chasty RC, Br J Hosp 01 1 2 3 4 Med 1993 Goldman SC, Blood 2001 Days from Daysdiagnosis Howard and Pui, Childhood Leukemias, 2nd ed. 2006

Uric Acid Crystals in Renal Tubules

Arrambide K, Semin Nephrol 1993 Chasty RC, Br J Hosp Med 1993 Goldman SC, Blood 2001 Howard and Pui, Childhood Leukemias, 2nd ed. 2006 Howard and Pui, Childhood Leukemias, 2nd ed. 2006

Effect of pH on solubility of uric acid Tumor lysis syndrome and hyperphosphatemia 1000 Learning objectives

Uric acid • Understand the pathophysiology of 100 Xanthine tumor lysis syndrome (TLS) Calcium phosphate • Review risk factors to develop TLS Allantoin 10

Solubility (mg/dL) Hypoxanthine • Manage hyperphosphatemia and hyperuricemia 1 • Be aware of ongoing TLS research 4.5 5 5.5 6 6.5 7 7.5 Urine pH Howard SC, et al. Childhood Leukemias, 2nd ed: 2006. Na polystyrene Na polystyrene sulfonate sulfonate

Laboratory tumor lysis syndrome

Na polystyrene sulfate

Clinical tumor lysis syndrome

Howard and Pui, Leuk Lymph 2006 Howard and Pui, Leuk Lymph 2006

Risk for TLS – Cancer Factors

Cancer Patient • Bulky tumors – Large tumor mass factors factorsNa polystyrene sulfonate – Organ infiltration – Bone marrow involvement Laboratory tumor lysis syndrome (leukemias are bulky) • Highly proliferative tumors - LDH is a marker • Chemosensitive tumors Clinical tumor lysis syndrome – Burkitt lymphoma – Lymphoblastic lymphoma

Howard and Pui, Leuk Lymph 2006 – Acute leukemias Leuk Lymph 2006

Leukemic blasts removed by pheresis Risk for TLS – Cancer Factors

• Burkitt lymphoma • Lymphoblastic lymphoma Common • Acute leukemia • Low-grade lymphoma • Breast carcinoma, SCLC Uncommon • Seminoma • Medulloblastoma, neuroblastoma, Case reports colorectal carcinoma Risk for TLS – Patient Factors Cancer Patient • Patient factors – Gout factors factorsNa polystyrene sulfonate – Chronic renal insufficiency – Hypertension Laboratory tumor lysis syndrome • Presentation – Hyperuricemia – Dehydration – Diminished urine output Clinical tumor lysis syndrome – Acute renal insufficiency – Acidic urine Howard and Pui, Leuk Lymph 2006 Howard and Pui. Leuk Lymph 2006

Assess risk for clinical TLS • Very low risk – non-bulky low-risk cancers Cancer Patient • Low risk – lymphoma, seminoma, Prophylaxis factors factorsNa polystyrene neuroblastoma but low tumor burden, sulfonate normal LDH, no laboratory TLS, good urine output Laboratory tumor lysis syndrome • Intermediate risk – acute leukemia without leukocytosis, lymphoma without large Treatment tumor burden, moderately high LDH • High risk – Burkitt or other high-grade Clinical tumor lysis syndrome lymphomas with large tumor burden, high LDH, existing laboratory TLS Howard and Pui, Leuk Lymph 2006

Tumor Lysis Syndrome Management Tumor lysis syndrome and Hydration hyperphosphatemia Close monitoring Learning objectives No potassium • Understand the pathophysiology of Reduce phosphorus tumor lysis syndrome (TLS) Very low Low Moderate or risk risk high risk • Review risk factors to develop TLS • Manage hyperphosphatemia and hyperuricemia Nothing for Daily oral Rasburicase • Be aware of ongoing TLS research uric acid allopurinol x 1 dose Life-threatening + Howard, unpublished TLS (high K ) Hemodialysis 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

Phosphorus metabolism in humans Phosphorus in and out of cells (mOsm/L)

Substance Plasma Interstitial Intracellular

HPO4 and H2PO4 2 2 11 ATP 5 Phospho- 45 creatine Hexose 3.7 monophosphate DNA and RNA 0 0 A lot Cell membranes 0 0 Some

th Textbook of Medical Physiology. AC Guyton, HE Hall. Elsevier Saunders 2006. Table 25-2 pg 294 Brenner, BM. The Kidney, 7 Ed. Vol. 1 p. 552

Renal phosphate excretion

• 90-100% filtered • 80% to 97% reabsorbed • Net excretion = 3% to 20% of filtered load • Amount depends on PTH,

1,25(OH)2Vitamin D, and phosphatonins • 100,000 lymphoblasts/microL contain enough phosphate to raise serum phosphate about 25 mg/dL

AC Guyton, HE Hall. Textbook of Medical Physiology. Elsevier Saunders 2006. Figure 79-11 pg 988 White Blood Cell (x109/L) Count Regulation of calcium and Changes During Initial Therapy phosphate by parathyroid hormone 90000

80000

70000 60000

50000

40000

30000

20000

10000 0

Textbook of Medical Physiology. AC Guyton, HE Hall. Elsevier Saunders 2006. Figure 79-10 pg 986 06 06 06 AC Guyton, HE Hall. Textbook of Medical Physiology. Elsevier Saunders 2006. 006 Days from diagnosis 2 2006 /20 2006 /2006 /20 /20 9/ 9/ 9 9/ 9 9 9

Phosphate and uric acid during Correction of Electrolyte Abnormalities the week after diagnosis Hyperphosphatemia, Hypocalcemia 20 • Oral phosphate binder 18 Uric acid – Aluminum hydroxide (Amphojel), 16 Phosphate sevelamer (Renajel), lanthanum 14 12 • Dietary phosphate restriction 10 • Avoid calcium (unless tetany or 8 arrhythmia) 6 4 • Diuresis (furosemide, mannitol) 2 • Protect the kidney so it can filter 0 • Hemofiltration/dialysis 0.0 1.0 2.0 3.0 3.5 4.0 4.5 5.0 6.0 6.5 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. Improves renal blood flow 2. Stabilizes the myocardium 3. Makes uric acid more soluble 4. Drives potassium into cells Why do people alkalinize the urine in newly diagnosed patients with 1000 Uric acid leukemia/lymphoma? Xanthine 100 1. Improves renal blood flow Calcium phosphate 2. Stabilizes the myocardium 10 Allantoin Solubility (mg/dL) Solubility 3. Makes uric acid more soluble Hypoxanthine 4. Drives potassium into cells 1 4.5 5 5.5 6 6.5 7 7.5 Urine pH

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

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

Solubility by pH

1000 Uric acid

Xanthine 100 Calcium phosphate 10 Allantoin Solubility (mg/dL) Solubility Hypoxanthine

1 4.5 5 5.5 6 6.5 7 7.5 Urine pH

Howard and Pui, Childhood Leukemias, 2nd ed. 2006 Howard and Pui, Childhood Leukemias, 2nd ed. 2006 Allantoin is highly soluble at any pH

1000 Uric acid

Xanthine 100 Calcium phosphate 10 Allantoin Solubility (mg/dL) Solubility Hypoxanthine

1 4.5 5 5.5 6 6.5 7 7.5 Urine pH

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

Rasburicase Clinical Trials Rasburicase in children with Children and Adults hematologic malignancies N Intervention Outcomes 10 9.2 Lascombes Normal UA, Baseline 107 Rasburicase L Post-treatment 1998 TLS, ARF 8 Pui 2001 131 Rasburicase UA, SCr, safety 6 4.1 P <.001 P <.001 4 Bosly 2003 278 Rasburicase UA, ARF, safety

Uric Acid (mg/dUric 2 0.5 0.5 Jeha 2005 1069 Rasburicase UA, ARF, safety 0 Goldman Rasburicase vs UA control in 1st Nonhyperuricemic Hyperuricemic 52 2001 allopurinol 96 hours, SCr (n = 260) (n = 398) Coiffier 2003 100 Rasburicase UA, SCr, safety Jeha S, et al. Leukemia 2005.

How many doses of rasburicase Rasburicase dosing as needed in a 9-year- old with Burkitt Lymphoma do most children need? 16 Rasburicase Prednisone Vincristine Cyclophosphamide • Number of doses needed (of 14 682 patients) 682 patients) 12 – 1 dose for 657 (96%) 10 – 2 doses for 22 (3%) 8

– 3 doses for 2 (0.3%) mg/dL – 4 doses for 1 (0.1%) 6 • Response rate 4 – Prevention 260/260 = 100% 2 0 – Treatment 392/398 = 98.5% 0 1 2 3 4 Jeha S. Leukemia 2005 1 Days From Diagnosis Renal Complications Pediatric Stage IV B-NHL UKCCSG CCG-5911/ Blood 109: 2736-43, 2007 Clinical Trial POG-8617 9002 LMB-89 LMB Therapy N 123 63 152 20 Cytoreductio TLS, renal insufficiency, CHOP COP COP COP n and dialysis for Burkitt Cytoreductio n Intense Light Light Light Group C on LMB 96 intensity Hypouricemi Allopurino NR orate Recombinant SFOP (Urate CCG (Allo- P-Value c Allopurinol l oxidase urate oxidase agent Oxidase) purinol) TLS 11% 27% 0.005 Dialysis 23% 16% 2.6% 0% Renal insuffic 9% 26% 0.002 Death Dialysis 3% 15% 0.004 from TLS 5% 8% 0% 0% At Ptt PiJCO 2001

Rasburicase vs Allopurinol Uric acid levels by treatment arm Effect on Uric Acid Exposure 11 8 10 7 Allopurinol = 329 ± 129 9 8 6 Rasburicase = 128 ± 70 P < .0001 7 5 6 5 4 4 Allopurinol: Mean 3 AUC = 329 +/- 129 P < 0.0001 3 2 2 Rasburicase: Mean Plasma Uric (mg/dL)Acid 1 AUC = 128 +/- 70 mg/dL Uric Acid 1 0 0 0 24 48 72 96 120 24 HR POST 0 4 12 24 36 48 60 72 84 96 Time From First Dose (hours) Time (hours)

Goldman SC, et al. Blood 2001; 97:2998-3003 Goldman SC, Blood. 2001;97(10):2998-03 Cairo MS, Br J Haematol. 2004;127(1):3-11

Uric Acid Crystals in Renal Tubules Changes in serum phosphorus, calcium, and uric acid by treatment group

Phosphorus Creatinine Uric Acid Creatinine Level(mg/dL) 10 10

8 1.0 8 1.0

6 6

4 0.5 4 0.5

2 2

0 0.0 0 0.0 84 144 Uric Acid or Phosphorus Level (mg/dL) Level or Phosphorus Uric Acid 0 12 36 60 108 132 0 12 36 60 84 108 132 144 Allopurinol Rasburicase

Howard and Pui,Pui, Childhood Leukemias,Leukemias, 2nd ed. 2006 Goldman SC, et al. Blood. 2001;97(10):2998-3003 Rasburicase vs Allopurinol Effect on Serum Creatinine 180

170

160

150 Allopurinol 140

130

120

110

100 Rasburicase

Serum Creatinine (% of Normal)Serum Creatinine (% 90

80 Baseline 1 2 3 4 Days After First Dose Goldman SC, et al. Blood 2001

Textbook of Medical Physiology. AC Guyton, HE Hall. Elsevier Saunders 2006. Figure 27-19 pg 346

Total kidney and per nephron excretion in renal failure

Normal 75% loss of nephrons Number of nephrons 2,000,000 500,000 Total GFR (ml/min) 125 30 Volume excreted for 1.5 1.5 all nephrons (ml/min) Volume excreted per 0.75 3.0 nephron (nl/min)

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

Phosphate and uric acid during the week after diagnosis 20 18 Uric acid 16 Phosphate 14 12 10 8 6 4 2 0

Textbook of Medical Physiology. AC Guyton, HE Hall. Elsevier Saunders 2006. Figure 31-6 pg 411 0.0 1.0 2.0 3.0 3.5 4.0 4.5 5.0 6.0 6.5 Phosphate and uric acid during the week after diagnosis 20 Cancer Patient 18 factors factors Uric acid factors factorsNa polystyrene sulfonate 16 Phosphate 14 12 Laboratory tumor lysis syndrome 10 8 Treatment 6 4 2 Clinical tumor lysis syndrome 0 0.0 1.0 2.0 3.0 3.5 4.0 4.5 5.0 6.0 6.5 Howard and Pui, Leuk Lymph 2006

Urine alkalinization increases uric acid solubility but decreases CaPO4 solubility Nephrocalcinosis

1000

Uric acid

100 Xanthine

Calcium 10 phosphate

Solubility (mg/dL) Allantoin

1 Hypoxanthine 4.555.566.577.5 Urine pH

Howard SC, et al. Childhood Leukemias, 2nd ed: 2006. Howard and Pui, ChildhoodHoward SC, et Leukemias,al. Childhood Leukemias, 2nd 2nded. ed: 20062006.

Uric Acid Crystals in Renal Tubules Ectopic Calcification

Howard and Pui, ChildhoodHoward SC, et Leukemias,al. Childhood Leukemias, 2nd 2nded. ed: 20062006. Howard and Pui,Pui, Childhood Leukemias,Leukemias, 2nd ed. 2006 Tumor Lysis Syndrome Management Why rasburicase x 1 dose? Hydration • Low threshold for the first dose Close monitoring • Low threshold for the first dose – Lowers uric acid to < 0.5 No potassium – Uric acid usually stays low for 24 hr Reduce phosphorus – Minimizes additional uric acid Very low Low Moderate or risk risk high risk crystallization in renal tubules • Higher threshold for 2nd, 3rd, 4th, and 5th doses (e.g. when uric acid rises to > 5) Nothing for Daily oral Rasburicase – If uric acid starts to rise within 24 hours uric acid allopurinol x 1 dose after rasburicase, the patient has a very Life-threatening high production rate + Howard, unpublished TLS (high K ) Hemodialysis

Tumor lysis syndrome and TLS research in progress hyperphosphatemia • Randomized trial of uric acid vs Learning objectives • Randomized trial of uric acid vs rasburicase in adults at risk for • Understand the pathophysiology of clinical TLS tumor lysis syndrome (TLS) – Primary outcome: renal damage • Review risk factors to develop TLS (i.e. incidence of clinical TLS) • Manage hyperphosphatemia and hyperuricemia • Be aware of ongoing TLS research

Compassionate Use of TLS research in progress Rasburicase: Adverse Events No. of Patients (%) • Randomized trial of uric acid vs Adverse Events (AE)* Pediatric Adult Total rasburicase in adults at risk for (n = 682) (n = 387) (n = 1,069) (n = 682) (n = 387) (n = 1,069) clinical TLS Patients/no. of AE 26/48 18/21 44/69 Worst grade of AE – Primary outcome: renal damage Grade 1 8 (1.2) 11 (2.8) 19 (1.8) (i.e. incidence of clinical TLS) Grade 2 7 (1.0) 5 (1.3) 12 (1.1) • RASALL study Grade 3 2 (0.3) 2 (0.5) 4 (0.4) – Documenting the incidence of Grade 4 9 (1.3) 0 (0.0) 9 (0.8) rasburicase side effects in patients with allergy, asthma, or eczema *Events occurring during the first course of treatment. Jeha S, et al. Leukemia 2005. Conclusions • TLS can cause death, kidney damage, ? seizure, and increased hospital stays • General management for everyone: – Close monitoring – Hydration, avoid alkalinization Questions and Answers – Avoid K+ • Reduce phosphorus early in everyone • Uric acid management tailored to risk: – Oral allopurinol for low risk – Rasburicase x1 for moderate/high risk

End ?

Scott Howard, MD, MSc Wren Kennedy, PNP/O Questions and Answers

More medical education materials are available at:

You may print and download content for personal educational use only. All material is copyrighted by the author of the content or St. Jude Children’s Research Hospital. See legal terms and conditions at http://www.Cure4Kids.org