Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: Howard SC, Jones DP, Pui C-H. The tumor lysis syndrome. N Engl J Med 2011;364:1844-54.
 Table 1 (Online supplement). Incidence of tumor lysis syndrome in selected studies with 100
patients or more
Reference Cancers included Patients TLS prevention Incidence of TLS* Incidence Death
used in addition of dialysis from
to intravenous TLS
fluids
Cohorts treated with allopurinol
Montesinos Acute myeloid leukemia 772 adults Allopurinol 17% 0.9% 2.5%
et al. 20081
Mato et al. Acute myeloid leukemia 194 adults Allopurinol 9.8% 0.5% 0%
20062
Truong et Acute lymphoblastic 326 children Allopurinol 23% Not Not
al. 20073 leukemia (rasburicase in reported reported
6% of patients)
Bowman et Advanced-stage B-cell 133 children Allopurinol Not reported 21% 2.2%
al. 19964 non-Hodgkin lymphoma
Clinical trials in which rasburicase was used in some patients and allopurinol in others
Cairo et al. Advanced-stage B-cell 101 children Allopurinol 26% 15% 0%
20075 non-Hodgkin lymphoma (USA)
98 children Rasburicase 9% 3% 0%
(France)
Cortes et al. Hematologic 91 adults Allopurinol 41% (4% clinical) Not 0%
20106 malignancies 92 adults Rasburicase 21% (3% clinical) reported 0%
92 adults Rasburicase 27% (3% clinical) 0%
plus allopurinol
Cohorts treated with rasburicase (or a non-recombinant urate oxidase)
Patte et al. Advanced-stage B-cell 410 children Non- Not reported (8.3% 1.7% 0%
20027 non-Hodgkin lymphoma recombinant had metabolic
urate oxidase problems)
Jeha et al. Mostly hematologic 1069 adults Rasburicase Not reported (4.2% 2.8% 0%
20058 malignancies and children had renal
insufficiency)
Coiffier et Diffuse or bulky 100 adults Rasburicase Not reported 0% 0%
al. 20039 lymphoma (mostly
diffuse large B-cell
histology)
Pui et al. Leukemia or lymphoma 131 children Rasburicase Not reported 0% 0%
200110
Bosly et al. Mostly hematologic 278 adults Rasburicase Not reported 1.8% 0.4%
200311 malignancies and children
Pui et al. Mostly hematologic 245 adults Rasburicase Not reported 4.1% 0.4%
200112 malignancies and children
Pui et al. Hematologic 134 children Rasburicase Not reported 0% 0%
199713 malignancies
*Includes both laboratory and clinical TLS. Note that the definition of TLS and clinical TLS differed
somewhat in different studies. TLS, tumor lysis syndrome.

1
 Table 2 (Online supplement). Sample cohorts of patients with different risk features for
clinical TLS

Cohort Disease Cancer mass Cell lysis Patient Hypothetical Risk group
potential characteristics incidence of (assigned by
clinical TLS* definition)§
1 AML, WBC >50,000 Moderate (if Adults, no 6% Intermediate
newly Organomegaly initially treated chronic kidney
diagnosed present without injury or major
clofarabine or comorbidity
other new
agents)
2 AML, WBC >50,000 High (if Adults, no 12% High
newly Organomegaly initially treated chronic kidney
diagnosed present with injury or major
clofarabine) comorbidity
3 AML, first WBC >50,000 Low to Adults, no 4% Intermediate
relapse Organomegaly moderate chronic kidney
present injury or major
comorbidity
4 AML, WBC >50,000 Low Adults, no 3% Intermediate
second or Organomegaly chronic kidney
subsequen present injury or major
t relapse comorbidity
5 AML, WBC <10,000, High (if Adults, no 6% Intermediate
newly Organomegaly initially treated chronic kidney
diagnosed absent with injury or major
clofarabine) comorbidity
6 Burkitt Stage I, non- Very high Children, no 1% Low
lymphoma bulky chronic kidney
injury or major
comorbidity
7 Burkitt Stage III or IV Very high Children, no 27% High
lymphoma chronic kidney
5
injury or major
comorbidity
8 Colorectal Stage I, II Low Adults, no 0.02% Negligible
carcinoma chronic kidney
injury or major
comorbidity

* The incidences listed in this table are for purposes of illustration only, and refer to the
hypothetical incidence of clinical TLS in patients managed without rasburicase. The true
incidence in each cohort of patients must be determined empirically. One must clearly
distinguish laboratory TLS from clinical TLS when determining the incidence, since not all

2
patients who develop laboratory TLS develop clinical TLS. Unfortunately, most publications to
date have not reported the incidence of clinical TLS (see Supplementary Appendix Table 1).

§ Once the incidence is determined (or estimated, based on similar patient cohorts or risk
models), the risk category is predetermined based on the definition. The cut-off values proposed
to define risk groups are based on clinical utility.14 High-risk patients (>5% incidence of clinical
TLS) require high rates of intravenous fluids, monitoring in the hospital, frequent assessment of
urine output and electrolytes, and rasburicase; intermediate-risk patients (1% to 5% incidence of
clinical TLS) require intravenous fluids, close monitoring, daily assessment of urine output and
electrolytes, and usually one dose of rasburicase; low-risk patients (<1% incidence of clinical
TLS) require fluids, daily monitoring, and allopurinol; and negligible-risk patients (almost no
risk of clinical TLS) require no interventions for TLS prevention. However, these management
strategies are not evidence-based, since no clinical trials to date have specified the clinical TLS
incidence that defines each risk group.

3
Table 3 (Online supplement). Comparison of renal replacement methods

Hemodialysis Continuous veno- Continuous veno-

venous venous
hemofiltration hemodialysis
Clearance mechanism
Convection + ++++ +
Diffusion ++++ - ++++
Hemodynamic stability ++ +++ +++
Blood flow rate (mL/min) ≥ 200 < 200 < 200
Dialysate flow rate+ (mL/min) ≥ 500 - 20-80
Fluid replacement rate† - 20-80 -
(mL/min)
Ultrafiltration rate* (net, mL/hr) 0-1000 0-200 0-200
Solute clearance Efficient Less efficient Less efficient
Typical duration 3-4 hours 24 hours 24 hours
Membrane size exclusion 5,000 50,000 50,000
(Daltons)
Drug and nutrient clearance + ++++ ++++
Anticoagulant Heparin or Citrate or heparin Citrate or heparin
none
+
The dialysate flow rate is the rate of delivery of biocompatible electrolyte solutions (dialysate)
through the hemofilter countercurrent to blood flow; solute clearance occurs by diffusion.
†
The fluid replacement rate is prescribed by the clinician. Fluid replacement occurs
simultaneously with ultrafiltration across the hemofilter; replacement solutions containing
electrolytes are infused as plasma ultrafiltrate enters the waste collection bag. This process
accomplishes solute clearance via convection.

*The ultrafiltration rate refers to the volume of fluid removed per unit of time. Net ultrafiltration
is the ultimate volume removed from the patient after total intake is subtracted from total output.

Information for this table was adapted from: Mehta RL, Supportive Therapies: Intermittent
Hemodialysis, Continuous Renal Replacement Therapies, and Peritoneal Dialysis. From Atlas of
Diseases of the Kidney, Ed. Robert Schrier, Volume One, Editors: T. Berl and J.V. Bonventre.
Section II. Chapter 19, pages 19.0-19.16. http://www.kidneyatlas.org/toc.htm.

4
Supplemental Figure 1a. Solubility of metabolites important in tumor lysis syndrome over a range of physiologic urine pH values

Uric acid solubility is highly pH-dependent. As urine pH rises from 5 to 7, the solubility increases 25-fold, from 8 mg/dL to 200 mg/dL.
This increased uric acid solubility and consequent decreased risk of crystal formation and acute kidney injury is the reason urine
alkalinization was standard for patients at risk for tumor lysis syndrome prior to the advent of rasburicase. In contrast to uric acid,
calcium phosphate becomes less soluble and more likely to crystallize as urine pH increases. Xanthine has low solubility and
hypoxanthine relatively high solubility, regardless of urine pH. Note that the scale is logarithmic. Used with kind permission of
Cambridge University Press, from Figure 29.4 of Chapter 29.15

5
Supplemental Figure 1b. Uric acid levels during the first four days of treatment in patients at risk for tumor lysis syndrome
randomized to receive rasburicase versus allopurinol

In patients at risk for tumor lysis syndrome, rasburicase was associated with a rapid decrease in uric acid and a corresponding lower area-
under-the-concentration-time curve for uric acid, as measured over the first four days of therapy (128 ± 70 versus 329 ± 129 mg/dL*hour,
p <0.0001). Adapted from Goldman SC et al.16

6
References
1 Montesinos P, Lorenzo I, Martin G et al. Tumor lysis syndrome in patients with acute
myeloid leukemia: identification of risk factors and development of a predictive model.
Haematologica 2008; 93:67-74

2 Mato AR, Riccio BE, Qin L et al. A predictive model for the detection of tumor lysis
syndrome during AML induction therapy. Leuk Lymphoma 2006; 47:877-883

3 Truong TH, Beyene J, Hitzler J et al. Features at presentation predict children with acute
lymphoblastic leukemia at low risk for tumor lysis syndrome. Cancer 2007; 110:1832-1839

4 Bowman WP, Shuster JJ, Cook B et al. Improved survival for children with B-cell acute
lymphoblastic leukemia and stage IV small noncleaved-cell lymphoma: a pediatric
oncology group study. J Clin Oncol 1996; 14:1252-1261

5 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; 109:2736-2743

6 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; 28:4207-4213

7 Patte C, Sakiroglu C, Ansoborlo S et al. Urate-oxidase in the prevention and treatment of

metabolic complications in patients with B-cell lymphoma and leukemia, treated in the
Societe Francaise d'Oncologie Pediatrique LMB89 protocol. Ann Oncol 2002; 13:789-795

8 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

9 Coiffier B, Mounier N, Bologna S et al. Efficacy and safety of rasburicase (recombinant

urate oxidase) for the prevention and treatment of hyperuricemia during induction
chemotherapy of aggressive non-Hodgkin's lymphoma: results of the GRAAL1 (Groupe
d'Etude des Lymphomes de l'Adulte Trial on Rasburicase Activity in Adult Lymphoma)
study. J Clin Oncol 2003; 21:4402-4406

10 Pui CH, Mahmoud HH, Wiley JM et al. Recombinant urate oxidase for the prophylaxis or
treatment of hyperuricemia in patients with leukemia or lymphoma. J Clin Oncol 2001;
19:697-704

11 Bosly A, Sonet A, Pinkerton CR et al. Rasburicase (recombinant urate oxidase) for the
management of hyperuricemia in patients with cancer: report of an international
compassionate use study. Cancer 2003; 98:1048-1054

7
12 Pui CH, Jeha S, Irwin D, Camitta B. Recombinant urate oxidase (rasburicase) in the
prevention and treatment of malignancy-associated hyperuricemia in pediatric and adult
patients: results of a compassionate-use trial. Leukemia 2001; 15:1505-1509

13 Pui CH, Relling MV, Lascombes F et al. Urate oxidase in prevention and treatment of
hyperuricemia associated with lymphoid malignancies. Leukemia 1997; 11:1813-1816

14 Cairo MS, Coiffier B, Reiter A, Younes A. 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; 149:578-586

15 Howard SC, Ribeiro RC, Pui C-H. Acute complications. In: Pui C-H, editor. Childhood
Leukemias. Cambridge: 2006: 709-749.

16 Goldman SC, Holcenberg JS, Finklestein JZ et al. A randomized comparison between

rasburicase and allopurinol in children with lymphoma or leukemia at high risk for tumor
lysis. Blood 2001; 97:2998-3003