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white blood cell (WBC) count; evidence of large tu-

mor burden (bulky disease, hepatosplenomegaly);

high blood lactate dehydrogenase (LDH)10 or uric

acid levels; pre-existing dehydration, oliguria, or re-

nal failure9,11,12; and malignancies with high chemo-

sensitivity.13,14

However, the majority of children with newly

diagnosed ALL who are treated with standard TLS

prophylactic measures do not experience clinically

significant laboratory abnormalities either before or

shortly after chemotherapy.1 Yet patients without

high-risk features may be subjected to prophylactic

measures and monitoring similar to those used in

patients with high-risk features.

With the long-term aim of a risk-stratified

approach to the prevention of TLS, the objectives of

the current study were 1) to describe the prevalence

and predictors of TLS in childhood ALL and 2) to de-

velop a sensitive prediction rule to identify patientswho are at low risk for TLS.

MATERIALS AND METHODSMedical records from all children aged 18 years

who were diagnosed with ALL between 1998 and

2004 at the Hospital for Sick Children in Toronto,

Canada, were reviewed. We included all patients with

ALL but excluded those with 1) French-American-

British (FAB) classification L3 ALL, 2) patients who

were treated initially at another institution, 3) pa-

tients who were transferred to another institution

within the time frame of interest (from the date of

presentation to the seventh day after initiation of

chemotherapy), and 4) patients who did not receive

initial ALL therapy.

There were 342 children diagnosed with ALL dur-

ing the study period. Fourteen patients were

excluded for the following reasons: 6 patients had

FAB L3 morphology, 5 patients were diagnosed at

another center before arrival at our institution, 1

patient was transferred to another institution during

the time frame of interest, 1 patient received up-

front palliative care because of an unrelated underly-

ing medical condition, and medical records weremissing for 1 child. In total, 328 patients met inclu-

sion criteria and were reviewed. This study was

approved by the Research Ethics Board at the Hospi-

tal for Sick Children.

Outcomes Assessed

The primary outcome was the development of labo-

ratory TLS, which was defined as the occurrence of

any 2 or more of the following 5 laboratory abnorm-

alities during the time frame of interest: hyperkale-

mia (potassium !5.5 mmol/L), hyperphosphatemia

(phosphate !2.26 mmol/L), hypocalcemia (calcium

2.0 mmol/L), hyperuricemia (uric acid!475 lmol/L),

and azotemia (creatinine !1.5 times the age-defined

upper limit of normal). Our institutionally defined

upper limit of normal of creatinine for both sexes,by specific age groups, were: ages 7 to 60 days,

66 lmol/L; ages 2 months to 5 years, 44 lmol/L;

ages 6 to 9 years, 62 lmol/L; ages 10 to 13 years,

90 lmol/L; aged >14 years, 100 lmol/L. Laboratory

data were collected during the time frame of interest,

starting from the date of presentation, through to the

day of chemotherapy initiation (Day 0), and for each

of the following 7 days (Day17), a time frame that

previously defined a higher risk for TLS.3 This labora-

tory definition was modified from previously pub-

lished definitions of TLS3,11,15,16 to be more inclusive

for the purpose of the current study. Because our

focus was on identifying a low-risk subset, we purpo-sefully wanted to ensure that our definition maximized

sensitivity and minimized false-negative results. We

did not examine clinical TLS (seizures, arrhythmia,

dialysis, or death) as a separate endpoint.

If multiple measurements for a given electrolyte

were obtained on the same day, then the highest

daily value was recorded for serum potassium, phos-

phate, creatinine, and uric acid; whereas the lowest

daily value was recorded for serum calcium. To main-

tain consistency with previous studies, serum cal-

cium was not corrected for hypoalbuminemia.

Other outcomes of interest were measures used

in the prophylaxis or treatment of TLS, namely, the

initial intravenous fluid hydration rate on admission

to hospital; the duration of urine alkalinization; the

administration of allopurinol, urate oxidase, phos-

phate binders (aluminum hydroxide, sevelamer

hydrochloride), antihyperkalemic treatments (sodium

polystyrene sulfonate, insulin, salbutamol), and intra-

venous calcium; and the need for leukopheresis and/

or dialysis. The number of peripheral venipunctures

before the insertion of a central venous line was

recorded as a measure of the impact of TLS labora-

tory monitoring on each patient.

Potential Predictors Evaluated

The data collected at presentation on potential pre-

dictors of TLS included laboratory features, such as

WBC and LDH, and clinical indicators of bulk dis-

ease, such as the presence of a mediastinal mass on

chest radiographs, hepatomegaly (defined as a palpa-

ble liver !3 cm below the right costal margin), and

splenomegaly (defined as a palpable spleen !2 cm

below the left costal margin) as assessed by the phys-

ical examination on admission. These cutoff values

Predicting Low Risk of TLS in ALL/Truong et al. 1833


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were chosen a priori based on what were considered

clinically reasonable limits for deciding whether it

was clear that the liver or spleen was larger than nor-

mal. Other potential predictors examined were cen-

tral nervous system (CNS) status at diagnosis and

renal involvement by leukemia as inferred by renalenlargement on abdominal imaging studies, when

available. A cutoff value for LDH of !2000 U/L was

chosen, because that level represents an elevation at

least 2 times the upper limit of normal for any age

and sex and has been used in previous publications.3

The degrees of derangement of the initial serum po-

tassium, phosphate, creatinine, uric acid, and cal-

cium levels at presentation were not examined as

potential predictors, because such an analysis would

have been incorrect methodologically, in that those

values would contribute toward the definition of the

outcome (development of TLS).

The following induction chemotherapy protocolswere in use during the study period for patients with

precursor B-cell ALL: from 1998 to 1999, either Pedi-

atric Oncology Group (POG) Protocol 9201, or 9605,

or 9406 or our standard, institutional 3-drug (Proto-

col AB) or 4-drug (Protocol C) induction regimen17;

and, from 2000 to 2004, the POG 9900 protocol se-

ries, which is divided into a 3-drug induction and a

4-drug induction. Patients with T-cell ALL received

either Protocol C (4-drug induction) from 1998 to

1999 or Childrens Oncology Group (COG) Protocol

A5971, after August 2000. Patients with Infant ALL

were treated according to POG 9407 (19982004).

Protocols that contained a 3-drug induction during

the first week of chemotherapy included POG 9201

and POG 9605 (daily prednisone; vincristine on Days

0 and 7; and L-asparaginase on Days 1, 4, and 7),

Protocol AB (daily prednisone; vincristine on Days 0

and 7; and L-asparaginase on Days 1, 3, and 5), and

the POG 9900 3-drug induction (daily dexametha-

sone; vincristine on Days 0 and 7; and pegylated as-

paraginase on Day 4, 5, or 6). Protocols that

contained a 4-drug induction in the first week of

chemotherapy included POG 9406 (daily prednisone;

vincristine on Days 0 and 7; L-asparaginase on Days

1, 4, and 7; and daunomycin on Day 7), Protocol C(daily prednisone; vincristine on Days 0 and 7; dau-

nomycin on Days 0 and 7; and L-asparaginase on

Days 0, 3, 5, and 7), the POG 9900 4-drug induction

(daily prednisone; vincristine on Days 0 and 7; dau-

nomycin on Day 7; and L-asparaginase on Days 2, 4,

and 7), COG A5971 (Regimen B1: daily prednisone;

vincristine on Days 0 and 7; daunomycin on Days 0

and 7; and L-asparaginase on Days 3, 5, and 7), and

POG 9407 (daily prednisone; vincristine on Day 0;

daunomycin on Days 0 and 1; L-asparaginase on

Days 3, 5, and 7; and cyclophosphamide on Days 2

and 3).

Statistical Analysis

Baseline characteristic and demographic data were

described using frequencies and percentages for cat-

egorical variables and means standard deviation or

interquartile range (IQR) for continuous variables.Potential predictors of TLS were determined using

univariate logistic regression analyses. However, a

clinically useful prediction rule to identify those at

lower risk of TLS would incorporate factors available

at presentation. Therefore, only this subset of factors

was considered for the multiple logistic regression

model. Factors that were associated with TLS at P < .1

were entered into a forward selection model.

All statistical analyses were performed using the

SAS statistical program (SAS-PC, version 9.1; SAS

Institute Inc., Cary, NC). All tests of significance were

2-sided, and statistical significance was defined as

P< .05.

RESULTSIn total, 328 patients were included, and their demo-

graphics, clinical features, and induction chemother-

apy protocols are shown in Table 1. TLS, which was

defined as the presence of at least 2 laboratory

abnormalities during the time frame of interest,

occurred in 74 of 328 children (22.6%). The single

laboratory abnormality encountered most often was

TABLE 1Demographics of the Study Population

Characteristic

No. of patients (%),

N 5 328

Male sex 206 (62.8)Acute lymphoblastic leukemia immunophenotype

Precursor B-cell 285 (86.9)

T-cell 38 (11.6)

Other (biphenotypic) 5 (1.5)

CNS-positive disease status 21 (6.4)

Mediastinal mass 26 (7.9)

Ward of admission

Inpatient ward 307 (93.6)

Intensive care unit 21 (6.4)

Induction chemotherapy protocol

3-Drug induction 171 (52.1)

4-Drug induction 136 (41.5)

Chi ldrens Oncology Group protocol A5971* 16 (4.9)

Pediat ric Oncology Group Protocol 9407* 5 (1.5)

Prednisone cytoreductive prophase 9 (2.7)

CNS indicates central nervous system.

* Protocols that contained a 4-drug induction regimen.

1834 CANCER October 15, 2007 / Volume 110 / Number 8


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hypocalcemia (148 of 328 patients; 45.1%), whereas

the least frequent abnormality was azotemia (14 of

328 patients; 4.3%). The most common laboratory

abnormality pair for TLS was hypocalcemia and

hyperuricemia (40 of 328 patients; 12%), followed by

concurrent abnormalities of calcium and phosphate(11%) (Table 2). The peak laboratory values of potas-

sium, phosphate, uric acid, and creatinine as well as

the nadir of calcium are shown in Table 3, which

compares those laboratory values between patients

with and without TLS. The day on which these

peaks/nadirs occurred is shown relative to the day of

chemotherapy initiation (Day 0) for both groups.

Factors that were associated with TLS in univari-ate logistic regression analyses are shown in Table 4.

Mediastinal mass was the strongest predictor of TLS

(odds ratio [OR], 12.2; 95% confidence interval; [95%

CI], 4.930.4; P< .0001) and was identified in 58% of

children with T-cell ALL (22 of 38 patients) compared

with 1.4% of children with precursor B-cell ALL (4 of

290 patients). Of these potential predictors, only

those risk factors that were available immediately at

the time of presentation were entered into a multiple

regression analysis. Thus, CNS status and status of

leukemic renal involvement were not entered,

because these potential predictors generally are not

known until several hours or days after presentation.The initial LDH value was a strong predictor of TLS

(OR, 7.6; P < .0001); however, because only 33 LDH

samples were determined on the day of presentation

to hospital, this variable could not be included in the

multiple regression analysis. Of the remaining 7 vari-

ables (sex, age, WBC, mediastinal mass, hepatome-

galy, splenomegaly, and T-cell immunophenotype), 4

variables were identified in multiple regression as in-

dependent predictors of TLS: age !10 years (adjusted

OR, 5.1; 95% confidence interval, 2.610; P < .0001),

splenomegaly (adjusted OR, 2.5; 95% CI, 1.34.6;

P5 .005), mediastinal mass (adjusted OR, 6; 95% CI,

2.216.6; P5 .0005), and initial WBC !20 3 109/L

(adjusted OR, 3.7; 95% CI, 27.1; P < .0001). Two-

thirds of all patients (214 of 328 patients; 65%) had 1

TABLE 2Prevalence of Laboratory Abnormalities in Childhood AcuteLymphoblastic Leukemia From the Date of Presentation to 7 DaysAfter Treatment

Laboratory parameter*

No. of patients (%),

N 5 328

Hypocalcemia 148 (45.1)

Hyperuricemia 54 (16.5)Hyperphosphatemia 52 (15.9)

Hyperkalemia 33 (10.1)

Azotemia 14 (4.3)

Hypocalcemia and hyperuricemia 40 (12.2)

Hypocalcemia and hyperphosphatemia 35 (10.7)

Hyperphosphatemia and hyperuricemia 26 (7.9)

Hyperkalemia and hypocalcemia 22 (6.7)

Hyperkalemia and hyperuricemia 13 (4)

Hyperkalemia and hyperphosphatemia 12 (3.7)

Hypocalcemia and azotemia 10 (3)

Hyperphosphatemia and azotemia 8 (2.4)

Hyperuricemia and azotemia 5 (1.5)

Hyperkalemia and azotemia 2 (0.6)

* Abnormal laboratory parameters were defined as follows: hyperkalemia, serum potassium

!5.5 mmol/L; hypocalcemia, serum calcium 2.0 mmol/L; hyperphosphatemia, serum phosphate

!2.26 mmol/L; hyperuricemia, serum uric acid !475 lmol/L; azotemia, serum creatinine !1.5 times

the age-defined upper limit of normal.

TABLE 3Peak or Nadir of Laboratory Abnormality and Time Relative to Chemotherapy Initiation: Comparison ofPatients With and Without Tumor Lysis Syndrome

Laboratory parameter

TLS absent, N 5 254 TLS present, N 5 74

PMean 95% CI Mean 95% CI

Potassium peak, mmol/L 4.76 4.724.80 5.28 5.155.41


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or more of these 4 independent predictors of TLS at

presentation; and of these, 70 of 214 patients (33%)

developed TLS.

The absence of all 4 predictors of TLS was used

to define a group at low risk of developing TLS (the

low-risk TLS group). Of those who fulfilled low-risk

TLS criteria, 110 of 114 patients did not develop TLS,

resulting in a negative predictive value of 96.5% (95%

CI, 91.398.6%) and a sensitivity of 94.6% (95% CI,

8798%). However, within this low-risk group, 4 of114 patients (3.5%) also met our definition for TLS.

One of these 4 patients met criteria for TLS, because

this child presented with septic shock related to

streptococcal bacteremia and subsequently devel-

oped renal failure and required dialysis. The remaining

3 patients had only mild perturbations in potassium,

phosphate, and/or calcium that did not require sig-

nificant interventions beyond the prophylactic use of

phosphate lowering agents, increased hydration, and

increased laboratory monitoring.

A further analysis was done to refine our primary

definition of TLS to include only those patients who

had TLS laboratory abnormalities occurring withinany 48-hour time frame. In total, 54 patients (16.5%)

met this stricter definition of TLS. Multiple regression

analysis indicated that the same 4 factors remained

independent predictors of the stricter definition of

TLS: age !10 years (adjusted OR, 3.4; 95% CI, 1.6

7.2; P5 .002), splenomegaly (adjusted OR, 2.8; 95%

CI, 1.45.6; P5 .003), mediastinal mass (adjusted OR,

3.7; 95% CI, 1.49.7; P5 .0001), and initial WBC

!20 3 109/L (adjusted OR, 5.1; 95% CI, 2.410.8;

P< .0001). Of those who fulfilled the low risk of TLS

criteria, 112 of 114 patients did not develop TLS

according to the more strict definition, resulting in a

slightly improved negative predictive value of 98.2%

(95% CI, 93.899.5) and a sensitivity of 96.3% (95%

CI, 87.599).

The extremes of laboratory abnormalities and

the day of the extreme value relative to chemother-

apy initiation are shown in Table 5 according to

those at low risk (n 5 114 patients) and those not at

low risk (n5

214 patients) for TLS. Overall, mostlaboratory abnormalities occurred within 3 days after

the initiation of chemotherapy. Those in the low-risk

TLS group had milder laboratory abnormalities com-

pared with the nonlow-risk group. Generally, the lab-

oratory abnormalities occurred later in the low-risk

group compared with those in the nonlow-risk

group.

Hyperkalemia !6.0 mmol/L occurred in 11 of

328 patients (3.4%) during the time frame of interest,

all of whom also met both the conventional and

more strict definitions of TLS. Reassuringly, none of

these patients satisfied our prediction rule criteria for

the low-risk TLS group.Measures taken to prevent TLS are presented in

Table 6. Leukopheresis was used at diagnosis for an

extremely high initial WBC in 11 patients. Three

patients required renal dialysis; 2 for acute renal fail-

ure secondary to TLS and 1 because of overwhelming

sepsis.

The median number of times blood was drawn

on the first, second, and third full day of hospitaliza-

tion was 3 times (IQR, 23 times), 2 times (IQR, 13

times), and 2 times (IQR, 23 times), respectively.

TABLE 4Predictors of Tumor Lysis Syndrome by Univariate Analysis

Variable

No. of patients (%)

OR 95% CI P*TLS present (N 5 74) TLS absent (N 5 254)

Male sex 54 (73) 152 (59.8) 1.8 13.2 .041

Age !10 y 32 (43.2) 37 (14.6) 4.5 2.58


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Central venous lines were placed an average of

7.2 days (IQR, 49 days) from the date of presenta-

tion (data not shown).

DISCUSSIONBy using a very inclusive definition of TLS, we

observed that the prevalence of TLS in children with

ALL before and within 1 week of chemotherapy

initiation was 23%. We used the absence of 4 inde-

pendent risk factors at presentation (age !10 years,

splenomegaly, mediastinal mass, and initial WBC

!20 3 109/L) to develop a prediction rule for identi-

fying those at low risk of TLS. In the absence of all 4

factors, there was a 97% probability that TLS would

not occur; and, in our series, those cases that did

occur (n 5 4) were relatively mild, were identified

early, and did not require significant interventions.

Although many studies have attempted to iden-

tify a group of children at high risk for TLS, we

believe that the current study is important, because

TABLE 6Use of Prophylactic Measures and Interventions for Tumor Lysis Syndrome: Comparison of Patients at LowRisk Versus Patients Not at Low Risk for Tumor Lysis Syndrome

TLS prophylactic or interventional measure

No. of patients (%)

P

At low risk of tls,

N 5 114

Not at low risk of TLS,

N 5 214

Initial intravenous fluid hydration rate, cc/m2/h, mean SD 94 27.8 122.1 50.2


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it is the first attempt to our knowledge to delineate a

low-risk population. Our prediction rule is designed

to be applied at the time of initial hospital presenta-

tion, thus enabling the early identification of a group

of children at low risk for developing TLS who may

be candidates for less intensive TLS monitoring andprophylactic interventions.

Generally, peripheral venipuncture is the only

means of drawing blood until a central venous cathe-

ter can be inserted, which, at our institution, is

accomplished on average 1 week from the date of

presentation. Reducing the frequency of unnecessary

laboratory monitoring would minimize trauma to

young patients but should be considered only as

long as reduced monitoring would not compromise

the ability to detect TLS early enough to upgrade

prophylactic measures or institute treatments. The

use of urine alkalinization in an attempt to increase

uric acid solubility remains controversial. Titration ofsodium bicarbonate infusions to maintain a urine

pH between 6.5 and 7.5 is a burden to nursing staff,

whereas calcium-phosphate precipitation and subse-

quent nephrocalcinosis is more likely in alkali set-

tings.4,18 Furthermore, over-alkalinization may lead

to precipitation of uric acid precursors, such as hy-

poxanthine or xanthine.5,19,20 Although urine alkali-

zation still is considered the standard of care in

many institutions and treatment protocols,21 the

ability to stop this maneuver in a low-risk group of

children would be beneficial. In addition, although it

is demonstrably effective at lowering uric acid levels

and eliminating the need for alkalinization, urate oxi-

dase is very expensive; and the definition of a low-

risk group would be valuable to help avoid that

unnecessary expense and the rare but real risk of he-

molysis in glucose-6-phosphate dehydrogenase-defi-

cient patients. Our data indicate that clinicians

indeed are identifying correctly those children at low

risk of TLS, because none of these children received

urate oxidase (Table 6), and the intensity of their

prophylaxis/intervention was far less compared with

the intensity for the group that was not at low risk of

TLS. However, our findings may help to standardize

this clinical gestalt and further reduce TLS preventa-tive measures (such as alkalinization) and limit labo-

ratory monitoring in the low-risk population.

Although our prediction model had a 97% nega-

tive predictive value, further predictive capability by

the addition of the initial LDH value at presentation

is conceivable. In our study, a small minority of

patients had an LDH value obtained on the day of

presentation (n 5 33 patients); therefore, we could

not incorporate this factor into a model that was

intended for use at initial presentation. However,

results from 237 LDH samples collected over the first

3 days after presentation indicated that LDH eleva-

tion is a very significant risk factor for TLS (OR, 7.6).

Thus, future research may be focused on determin-

ing the additive value of this potential predictor of

TLS.The current study was limited, because the low-

risk factors that we identified were demonstrated in

the setting of standard TLS preventive measures.

Although there is no guarantee that these same chil-

dren would remain at low risk of TLS in the absence

of measures like urine alkalinization, it seems to be a

reasonable assumption, because some institutions

have ceased using this intervention for children with

ALL. Nonetheless, the current study provides a base-

line estimate for TLS in a low-risk cohort that may

be used as a comparison group in future research.

We conclude that a group of children with ALL at

who are at low risk for TLS can be identified at thetime of hospital presentation and may benefit from

reduced intensity of laboratory monitoring and lim-

ited TLS prophylactic measures.

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