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CLINICAL TRIALS AND OBSERVATIONS

Body mass index does not influence pharmacokinetics or outcome of treatment

in children with acute lymphoblastic leukemia
Nobuko Hijiya, John C. Panetta, Yinmei Zhou, Emily P. Kyzer, Scott C. Howard, Sima Jeha, Bassem I. Razzouk, Raul C. Ribeiro,
Jeffrey E. Rubnitz, Melissa M. Hudson, John T. Sandlund, Ching-Hon Pui, and Mary V. Relling

There is conflicting information about the
influence of body mass index (BMI) on
the pharmacokinetics, toxicity, and out-
come of chemotherapy. We compared
pharmacokinetics, outcome, and toxicity
data across 4 BMI groups (underweight,
BMI < 10th percentile; normal; at risk of
overweight, BMI > 85th and < 95th per-
centile; overweight, BMI > 95th per-
centile) in 621 children with acute lympho-
blastic leukemia (ALL) treated on 4
consecutive St Jude Total Therapy stud-
ies. Chemotherapy doses were not
adjusted to ideal BMI. Estimates of over-
all survival (86.1% ⴞ 3.4%, 86.0% ⴞ 1.7%,
85.9% ⴞ 4.3%, and 78.2% ⴞ 5.5%, respec-
tively; P ⴝ .533), event-free survival
(76.2% ⴞ 4.2%, 78.7% ⴞ 2.1%, 73.4% ⴞ 5.5%,
and 72.7% ⴞ 5.9%, respectively; P ⴝ .722),
and cumulative incidence of relapse
(16.0% ⴞ 3.7%, 14.4% ⴞ 1.8%, 20.6% ⴞ 5.1%,
and 16.7% ⴞ 5.1%, respectively; P ⴝ .862)
did not differ across the 4 groups. In
addition, the intracellular levels of thio-
guanine nucleotides and methotrexate
polyglutamates did not differ between the
4 BMI groups (P ⴝ .73 and P ⴝ .74, respec-
tively). The 4 groups also did not differ in
the overall incidence of grade 3 or 4
toxicity during the induction or postinduc-
tion periods. Further, the systemic clear-
ance of methotrexate, teniposide, etopo-
side, and cytarabine did not differ with
BMI (P > .3). We conclude that BMI does
not affect the outcome or toxicity of che-
motherapy in this patient population with
ALL. (Blood. 2006;108:3997-4002)
© 2006 by The American Society of Hematology

Introduction
The prevalence of obesity has increased substantially over the past
few decades and is now about 15% among children and adolescents
in the United States1; therefore, it is a factor frequently encountered
in pediatric oncology. Reports of the influence of adult obesity on
the outcome of cancer treatment2-6 and treatment-related toxic-
ity4,6,7 are contradictory, and there are few reports for pediatric
patients. The Children’s Cancer Group (CCG) found that over-
weight children with acute myeloid leukemia (AML) are at greater
risk of treatment-related complications8 and that overweight chil-
dren with acute lymphoblastic leukemia (ALL) aged 10 years or
older have a significantly greater risk of relapse and a lower
probability of event-free survival (EFS).9 There is little information
about the influence of underweight on the outcome of ALL,10-13 and
most available reports10-12 are from developing countries. In
children with AML, the CCG8 reported that underweight patients
have a lower chance of survival and a greater risk of toxicity.
Chemotherapy dosage for obese patients is often empirically
reduced on the basis of ideal body weight because of concerns
about excessive toxicity; however, dose reduction may compro-
mise the outcome of treatment.14 There are very few reports15,16
comparing the pharmacokinetics of various drugs in either adult or
pediatric obese patients and normal-weight controls, and these
studies were done in very small patient groups. None of the studies
found pharmacokinetic differences between overweight and non-
overweight patients to be associated with clinical effects. We
therefore retrospectively studied the influence of body mass index
(BMI) on the outcome, toxicity, and, when available, pharmacoki-
netics of chemotherapy agents in children with ALL treated on 4
consecutive studies at St Jude Children’s Research Hospital.
Patients, material, and methods
Patients
The Institutional Review Board of St Jude Children’s Research Hospital
approved this retrospective study. We reviewed the records of 653 patients
with newly diagnosed ALL treated on St Jude Total Therapy studies (Total
XII, XIIIA, XIIIB, and XIV) conducted from 1988 through 2000. Twenty-
six patients younger than 1 year of age at the time of diagnosis and 6
patients with Down syndrome were excluded from this analysis, leaving
621 patients. The details of these treatment regimens have been reported
elsewhere.17-20 The chemotherapy doses in the protocols were to be based
on actual body weight or body surface area in all protocols, and there were
no recommendations to adjust for abnormal body composition, although
half of the patients treated on the Total XII protocol had their dosage of
methotrexate, teniposide, and cytarabine adjusted on the basis of their drug
clearance.17 In addition, mercaptopurine doses were adjusted on the basis of
thiopurine methyltransferase (TPMT) activity and toxicity.21 Toxic effects
and their grades were defined by National Cancer Institute (NCI) toxicity
criteria (Version 2). BMI was calculated by using weight and height as
previously reported.22 For patients older than 2 years of age, underweight
was defined as a BMI-for-age at or below the 10th percentile; normal was
defined as a BMI-for-age above the 10th and below the 85th percentile; risk
of overweight was defined as a BMI-for-age at or above the 85th percentile
and less than the 95th percentile23; and overweight was defined as a
BMI-for-age at or above the 95th percentile. For patients aged 1 to 2 years,

From the Departments of Oncology, Pharmaceutical Sciences, and
Biostatistics, St Jude Children’s Research Hospital, Memphis, TN; and the
Departments of Pediatrics, Pharmaceutical Sciences, and Pharmacy and the
Center for Pediatric Pharmacokinetics and Therapeutics, College of Pharmacy,
University of Tennessee Health Science Center, Memphis, TN.
First Edition Paper, August 17, 2006; DOI 10.1182/blood-2006-05-024414.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.

Submitted May 22, 2006; accepted August 8, 2006. Prepublished online as Blood © 2006 by The American Society of Hematology

BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13 3997

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3998 HIJIYA et al
we used the weight-for-length percentile instead of the BMI-for-age
percentile. The SAS Program for the CDC Growth Charts (downloaded
from http://www.cdc.gov/nccdphp/dnpa/growthcharts/sas.htm) was used to
calculate the percentiles of BMI-for-age and weight-for-length; for children
2 years of age or older whose length was less than 77 cm or greater than 120
cm, the weight-for-length charts were used to determine the weight-for-
length percentile, as the above SAS program does not cover these 2 groups
of patients.
Pharmacokinetics
Pharmacokinetic data and confirmed actual administered doses were
available for high-dose methotrexate, etoposide, teniposide, cytarabine, and
oral mercaptopurine (dosing was available but concentration time data were
not). In addition, intracellular concentrations of thioguanine nucleotides
and methotrexate polyglutamates were available in the Total XII study. All
specimens were collected prospectively for pharmacokinetic analysis, and
some results have been reported previously.17,24-26 The population pharma-
cokinetics were determined by using the 2-stage approach.27 First, the
pharmacokinetic parameters for each individual were estimated for each of
the courses by using compartmental analysis. A 2-compartment model was
used for methotrexate, etoposide, and teniposide, and a 1-compartment
model was used for cytarabine. In all cases, the systemic clearance was
determined by the equation CL ⫽ ke/V, where ke is the elimination rate
constant and V is the systemic volume. Second, the population pharmacoki-
netics was analyzed by using linear mixed-effects modeling as implemented
in S-Plus (Version 7.0; Insightful Corporation, Seattle, WA) using the
following model:
ln(CLij)⫽␪1 ⫹ ␪2 䡠 (Obesity Group)
n
兺␪ 䡠 (Confounding Factor) ⫹ ␩ ⫹ ε
⫹ i i ij
i⫽3
where CLij is the clearance of the drug for patient i course j; ␪1 is the
logarithm of the population mean clearance; ␪2 is the coefficient that
describes the effects of the obesity grouping on the clearance; ␪i are the
coefficients that describe the effects of the confounding factors (study,
course, age); and ␩ and ⑀ represent the interpatient and intrapatient
(residual) variability, both of which values are assumed to have a mean of
zero. By taking the logarithm of the clearance, we assume that it is
log-normally distributed. The ability of the obesity group covariate to
significantly improve the model fit (as determined by a reduction of 3.84
[P ⬍ .05] in the negative 2 log likelihood, based on the F-test) was
investigated.
Statistical analysis
The distribution of presenting features and of the rate of remission at the
end of induction were compared across the groups by the chi-square test.
Multivariable logistic regression28 analysis was used to further compare
the rate of remission at the end of induction after adjusting for other
prognostic factors at diagnosis: age, white blood cell (WBC) count,
immunophenotype, presence of Philadelphia chromosome, DNA index,
and NCI risk category.
The main outcome measures were estimates of event-free survival (EFS),
overall survival (OS), and cumulative incidence of relapse (CIR). The duration of
EFS was measured from the date of complete remission to the date of first
treatment failure of any kind (relapse, death, ALL lineage switch, or second
malignancy) or to the date of most recent follow-up. Failure to induce remission
was considered an event at zero time. The duration of OS was calculated from the
date of diagnosis to the date of death due to any cause or the date of most recent
follow-up. Data for patients who were alive at the most recent contact date were
censored at the time of that contact. EFS and OS distributions were estimated by
the method of Kaplan and Meier29 and compared by using the log-rank test.30
Multivariable Cox proportional-hazards regression models31 adjusted for age at
diagnosis, sex, WBC count at diagnosis, immunophenotype, DNA index,
BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13
presence of the Philadelphia chromosome, the TEL-AML1 or MLL-AF4 fusion
genes, and NCI risk criteria were used to compare EFS and OS estimates among
the 4 groups.
Any leukemia relapse was included in the analysis of the CIR; second
cancer or death due to any cause were regarded as competing events.
Patients who did not enter remission were excluded, and patients who
remained alive and in remission were censored at the time of last follow-up.
The risk of relapse and competing risks were estimated as described by
Kalbfleisch and Prentice32 and compared by the method described by
Gray.33 Multiple-regression modeling of subdistribution functions34 in
competing risks, with adjustment for other prominent risk factors in
childhood ALL, was used to further assess the association between obesity
and leukemic relapse.
The chi-square test was used to compare the number of patients who
experienced grade 3 or 4 toxicity among the 4 BMI groups during and
after remission induction. Furthermore, for the toxicity after remission
induction, time at risk of toxicity and multiple episodes were taken into
account by weighted logistic regression. The weights were generated
according to the cumulative incidence of episodes of toxicity. More
specifically, each episode of toxicity was weighted according to the
following formula:
[ ]
1⫺tox
Zi
Wi ⫽ ,
max(Zi)
where Zi is the cumulative incidence of toxicity episodes at the time of the
ith toxicity episode or the time when a patient who had no toxicity was
censored; tox ⫽ 1 if Zi corresponds to a toxicity episode, and tox ⫽ 0
otherwise. Data were censored at the end of therapy for patients who did not
experience toxicity after induction (consolidation and continuation peri-
ods). Data for patients who went off therapy after induction before any
toxicity was observed were censored at the off-therapy time.
All analyses were stratified by protocol. A probability value of .05 or
less (P ⱕ .05) was prospectively selected as the criterion of statistical
significance. This analysis reflects the data as of January 31, 2006.
Results
Patients
Of 621 patients included in this analysis, 102 (16.4%) were
underweight at the time of diagnosis, 400 (64.4%) were of
normal weight, 64 (10.3%) were at risk of overweight, and 55
(8.9%) were overweight. There was no significant difference
among the 4 groups in the distribution of presenting features
(Table 1). Relative to the normal-weight group, there were
minimal differences (ⱕ 8%) in the administered drug dose (per
unit of body surface area) among the 3 other weight groups, with
the exception of the dose at day 5 in the targeted group for
cytarabine and teniposide (Table 2), but there were only 12
patients that received this dose.
Outcome of treatment according to BMI
As of January 31, 2006, the median duration of follow-up was 10.5
years (range, 2.4-16.9 years). The rate of complete remission (CR)
in the underweight (n ⫽ 102), normal weight (n ⫽ 400), at risk of
overweight (n ⫽ 64), and overweight (n ⫽ 55) groups was 99.0%,
97.0%, 98.4%, and 98.2%, respectively (P ⫽ .626). OS estimates
did not differ significantly across the 4 weight groups (P ⫽ .533;
Figure 1A). The 5-year OS estimates of these groups were
86.1% ⫾ 3.4%, 86.0% ⫾ 1.7%, 85.9% ⫾ 4.3%, and 78.2% ⫾ 5.5%,
respectively. The EFS curves (Figure 1B) showed the 5-year EFS
estimates to be 76.2% ⫾ 4.2%, 78.7% ⫾ 2.1%, 73.4% ⫾ 5.5%,
and 72.7% ⫾ 5.9%, respectively (P ⫽ .722). CIR did not differ
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BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13 EFFECT OF BMI IN CHILDHOOD ALL 3999

Table 1. Patient presenting features according to BMI

At risk of
Underweight Normal overweight Overweight P

No. patients 102 400 64 55

Median age, y (range) 4.87 (1.19-17.65) 5.85 (1.01-18.80) 6.40 (1.20-18.2) 8.76 (1.27-17.5) .168
1-9 y old, no. (%) 79 (77.5) 281 (70.3) 42 (65.6) 34 (61.8)
10 y old or older, no. (%) 23 (22.5) 119 (29.8) 22 (38.2) 21 (38.2)
Sex, no. (%) .358
Male 48 (47.1) 226 (56.5) 36 (56.3) 32 (58.2)
Female 54 (52.9) 174 (43.5) 28 (43.8) 23 (41.8)
Race, no. (%) .118
White 75 (73.5) 330 (82.5) 46 (71.9) 44 (80.0)
Black 17 (16.7) 51 (12.8) 13 (20.3) 10 (18.2)
Other 10 (9.8) 19 (4.8) 5 (7.8) 1 (1.8)
WBC count, no. (%) .870
Less than 50 ⫻ 109/L 80 (78.4) 298 (74.5) 48 (75.0) 42 (6.4)
At least 50 ⫻ 109/L 22 (21.6) 102 (25.5) 16 (25.0) 13 (23.6)
Immunophenotype, no. (%) .066
B lineage 93 (91.2) 324 (81.0) 51 (79.7) 48 (87.3)
T cell 9 (8.8) 76 (19.0) 13 (20.3) 7 (12.7)
DNA index, no. (%) .068
At least 1.16 30 (29.4) 94 (23.5) 17 (26.6) 6 (10.9)
Less than 1.16 72 (70.6) 306 (76.5) 47 (73.4) 49 (89.1)
CNS status, no. (%) .208
CNS-2 or -3* 31 (30.4) 137 (34.3) 26 (40.6) 25 (45.5)
CNS-1 71 (69.6) 263 (65.8) 38 (59.4) 30 (54.5)
Philadelphia chromosome, no. (%) .865†
Absent 98 (96.1) 382 (95.5) 62 (96.9) 52 (94.5)
Present 4 (3.9) 13 (3.3) 1 (1.6) 2 (3.6)
Unknown 0 (0) 5 (1.3) 1 (1.6) 1 (1.8)
TEL-AML1, no. (%) .496†
Absent 59 (57.8) 215 (53.8) 30 (46.9) 32 (58.2)
Present 23 (22.5) 76 (19.0) 12 (18.8) 6 (10.9)
Unknown 20 (19.6) 109 (27.3) 22 (34.4) 17 (30.9)
MLL-AF4, no. (%) .071†
Absent 100 (98.0) 389 (97.3) 63 (98.4) 51 (92.7)
Present 0 (0) 3 (0.8) 0 (0) 2 (3.6)
Unknown 2 (2.0) 8 (2.0) 1 (1.6) 2 (3.6)
Protocol, no. (%) .537
Total XII 32 (31.4) 120 (30.0) 18 (28.1) 10 (18.2)
Total XIIIA 23 (22.5) 104 (26.0) 19 (29.7) 14 (25.5)
Total XIIIB 41 (40.2) 147 (36.8) 20 (31.3) 24 (43.6)
Total XIV 6 (5.9) 29 (7.3) 7 (10.9) 7 (12.7)

*Includes traumatic tap with blasts.

†Unknown data were excluded from the analysis.

significantly between the 4 groups (P ⫽ .862; Figure 1C). The
5-year CIR was 16.0% ⫾ 3.7%, 14.4% ⫾ 1.8%, 20.6% ⫾ 5.1%,
and 16.7% ⫾ 5.1% for patients in the underweight, normal weight,
at risk of overweight, and overweight groups.
Because the CCG has reported an increased incidence of relapse in
obese patients 10 years of age or older,9 we compared OS, EFS, and CIR
in patients younger than 10 years old versus those 10 years of age or
older in each of the 4 BMI groups. We found no difference in any of
these parameters among the 4 BMI groups in patients younger than 10
years old (P ⫽ .628, P ⫽ .449, and P ⫽ .321 for OS, EFS, and CIR,
respectively) or in patients 10 years of age or older (P ⫽ .474, P ⫽ .103,
and P ⫽ .341 for OS, EFS, and CIR, respectively).
To assess whether the BMI thresholds used to define the BMI
groups had affected our results, we also compared the above
parameters across patient groups defined according to the follow-
ing thresholds: (1) 10th percentile or below, 11th to 94th percentile,
and 95th percentile or above; (2) 11th to 84th percentile and others
(10th percentile or below, or 85th percentile or above); (3) 10th
percentile or below, 11th to 84th percentile, and 85th percentile or
above; (4) 95th percentile or above, and below 95th percentile. No
significant difference in outcome was observed between the groups
as defined in any of these categories (data not shown).
Cox proportional-hazards regression models adjusted for pa-
tients’ characteristics at diagnosis (age, race, sex, WBC count,
immunophenotype, DNA index, Philadelphia chromosome, TEL-
AML1, MLL-AF4, and protocol) were used to separately assess the
effect of BMI on EFS, OS, and CIR. Age, sex, WBC count,
immunophenotype, DNA index, the Philadelphia chromosome,
TEL-AML1, and protocol were independent prognostic factors
(P ⬍ .05), as expected. BMI was not an independent predictor of
EFS, OS, or CIR in any analysis (data not shown).
Toxicity during the induction and postinduction periods
The frequency of grade 3 or 4 toxicity in the BMI groups during the
induction and postinduction periods is summarized in Table 3. The
4 groups did not differ significantly in the number of patients who
experienced grade 3 or 4 toxicity during the induction (P ⫽ .537)
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4000 HIJIYA et al BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13

Table 2. Population mean drug dose by BMI group

No. At risk of At risk of
patients/no. Normal, Underweight, Underweight, overweight, overweight, Overweight, Overweight,
Drug and study courses mg/m2 mg/m2 % change* mg/m2 % change* mg/m2 % change* P

High-dose methotrexate
TXII fixed dose 86/393 1501 1506 0 1489 ⫺1 1498 0 .47
TXII targeted 85/397 2041 2065 1 2215 9 2109 3 .53
TXIIIB 230/2174 1960 1979 1 1944 ⫺1 1929 ⫺2 .003
TXIV low 22/118 2427 2409 ⫺1 2406 ⫺1 2368 ⫺2 .007
TXIV high 26/138 4941 4773 ⫺3 4996 1 4944 0 .32
Etoposide
TXIIIB 113/184 299 291 ⫺3 299 0 301 1 .38
Cytarabine
TXII fixed dose
D1 86/394 299 298 0 299 0 293 ⫺2 .16
D3 67/274 299 296 ⫺1 296 ⫺1 291 ⫺3 .048
D5 11/16 307 NA NA 300 ⫺2 NA NA .15
TXII targeted
D1 83/396 428 399 ⫺7 418 ⫺2 412 ⫺4 .88
D3 65/253 419 415 ⫺1 418 0 435 4 .99
D5 12/19 285 299 5 317 11 347 22 .72
Teniposide
TXII fixed dose
D1 85/391 201 198 ⫺1 199 ⫺1 196 ⫺2 .048
D3 67/272 201 196 ⫺2 199 ⫺1 195 ⫺3 .032
D5 11/16 202 NA NA 201 0 NA NA .8
TXII targeted
D1 83/397 256 244 ⫺5 266 4 254 ⫺1 .89
D3 65/253 281 259 ⫺8 285 1 271 ⫺4 .89
D5 12/19 296 230 ⫺23 377 27 237 ⫺20 .51
Mercaptopurine
TXII 169/653 75.4 76.2 1 76.1 1 76.7 2 .74

NA indicates no data available for group.

*Relative to the normal-weight group.

or postinduction (P ⫽ .739) periods. When the incidence of
toxicity in the postinduction period was evaluated with adjustment
for the time at risk and multiple episodes, there was also no
significant difference (P ⫽ .887). The number of episodes of
toxicity during induction was not compared because of the brief
duration of induction. The frequency of the type of toxicity
(allergic, cardiovascular, endocrine, gastrointestinal, hematologic,
hepatic, metabolic, neurologic, pulmonary, renal, skin, infections,
coagulation, pain, syndromes, and constitutional symptoms) during
induction or the postinduction period was also compared among
the 4 BMI groups. No significant difference was observed with the
exception of a lower incidence of allergy in overweight patients
during the postinduction period (0% vs 1.0% in underweight, 20%
in normal-weight, and 7.8% in at-risk patients; P ⫽ .039), a finding
that may occur by chance due to multiple testing.
Pharmacokinetics according to BMI
Table 4 lists the population average systemic clearance of methotrexate,
teniposide, etoposide, and cytarabine in the 4 BMI groups. We adjusted
the analysis of each drug for known confounding factors, including age
(⬎ 10 vs ⱕ 10 years), course, and study. The mean systemic clearance
of the underweight, risk of overweight, and overweight groups differed
from that of the normal-weight group by less than 17% (P ⬎ .3). In
addition, the intracellular levels of thioguanine nucleotides and metho-
trexate polyglutamates did not differ between the 4 BMI groups
(P ⫽ .73 and P ⫽ .74, respectively).

Figure 1. Clinical outcomes of patients according to BMI category. BMI categories are as follows: underweight (BMI ⱕ 10th percentile, n ⫽ 102), normal weight
(BMI ⬎ 10th and ⬍ 85th percentile, n ⫽ 400), at risk of overweight (BMI ⱖ 85th and ⬍ 95th percentile, n ⫽ 64), or overweight (BMI ⱖ 95th percentile, n ⫽ 55). Shown are
Kaplan-Meier estimates of (A) overall survival; (B) event-free survival; and (C) cumulative incidence of relapse.
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BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13 EFFECT OF BMI IN CHILDHOOD ALL 4001

Table 3. Grade 3 or 4 toxicity during induction and the postinduction periods, according to BMI group
Occurrence of grade
3 or 4 toxicity Underweight Normal At risk for overweight Overweight P

No. patients, total 102 400 64 55

Induction phase*
Patients, no. 72 292 51 38 .537
Postinduction phase
Patients, no. 87 331 56 45 .739
Episodes, no.* 901 3129 511 421 .887

*The number of episodes was not analyzed for the induction period, which was brief and usually involved only 1 episode.

underweight status did not affect pharmacokinetics, outcome, or

Discussion
We observed no association between BMI and outcome or toxicity
in children with ALL. Our results should be interpreted with
caution because of the relatively small number of patients and the
use of different treatments, compared to those of the CCG study.9
Nonetheless, the major strength of this study is that we correlated
the BMI, clinical outcome, and pharmacokinetics in a large number
of patients. Previous studies had suggested that increased toxicity7,8
or decreased survival2,9 were associated with altered drug metabo-
lism in obese patients, but there were conflicting reports. Moreover,
most previously reported pharmacokinetic studies were single-
agent studies in relatively small patient groups.15 In our large
cohort, we found no difference in systemic clearance across the
BMI categories. This result is consistent with the absence of a
significant difference among these groups in outcome or toxicity.
Some studies have found an increased risk of relapse and a
reduced probability of survival in underweight patients with
ALL.10-12 Almost all such reports have come from developing
countries, where underweight patients are likely to be profoundly
malnourished and where malnutrition is usually accompanied by
low socioeconomic status, lack of education, and other factors that
contribute to poor outcome. In contrast, our patients were generally
not malnourished or mildly malnourished based on our observa-
tion, although nutritional status of our patients was not systemically
evaluated. Although malnutrition has been suggested to alter
pharmacokinetics, such an effect appears to apply only to severe
cases in which important parameters (eg, serum protein levels or
hepatic drug metabolism) are altered.35 Our results are consistent
with a prior report from a developed country13 indicating that
toxicity in children with ALL.
We found that drug clearance normalized to body surface
area of 4 drugs (high-dose methotrexate, etoposide, teniposide,
and cytarabine) did not differ among the weight groups. In
addition, the intracellular levels of thioguanine nucleotides and
methotrexate polyglutamates did not differ between the 4 BMI
groups (P ⫽ .73 and P ⫽ .74, respectively). This finding sug-
gests that these agents should be dosed based on actual body
surface area. We acknowledge that pharmacokinetic data were
available for only 4 drugs. Some studies in smaller groups of
patients have suggested that other chemotherapeutic agents
commonly used for ALL may have lower (cyclophosphamide,36
doxorubicin,16 methylprednisolone37) or higher (mercaptopu-
rine38) drug clearance in overweight patients.
We focused on the BMI at the time of diagnosis in our analysis.
When we examined the serial BMI data available for 279 patients, a
majority had an increase in BMI over the entire treatment period
(data not shown). Nonetheless, this change appears to be of little
importance in light of the lack of difference among the BMI groups
in pharmacokinetics or in outcome. BMI at diagnosis was not
associated with the CR rate, the drug clearance, or the risk of
toxicity during induction.
We conclude that the clearance of the chemotherapeutic agents
we tested was not affected by abnormal BMI. Furthermore, we
found no evidence that abnormal BMI adversely affected the
outcome or toxicity of treatment in children with ALL. Therefore,
we recommend that patients with ALL receive doses of methotrex-
ate, cytarabine, and epipodophyllotoxins calculated on the basis of
actual body surface area.

Table 4. Clearance of chemotherapeutic agents according to BMI category

Population average systemic clearance, mL/min/m2
Drug and study No. patients/no. courses Underweight Normal At risk for overweight Overweight P*

High-dose methotrexate
All studies 450/3266 111.1 114.1 115.3 114.9 .47
Total XII 171/790 100.0 99.7 102.3 96.0 .77
Total XIIIB 230/2174 125.2 129.1 129.5 129.3 .55
Total XIV 49/302 92.5 98.8 99.8 95.5 .75
Etoposide .41
Total XIIIB
D 29† 108/108 43.6 48.7 48.4 50.2
Wk 19† 27/27 38.6 43.2 42.9 44.5
Wk 54† 49/49 26.0 29.0 28.9 29.9
Cytarabine
Total XII 169/777 852.2 773.8 645.1 782.9 .56
Teniposide
Total XII 170/793 14.2 14.0 12.1 14.2 .35

*P value reflects comparison to model with other significant covariates (eg, course, study, and age) included.
†Day 29 of induction therapy, weeks 19 and 54 of continuation therapy.19
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4002 HIJIYA et al BLOOD, 15 DECEMBER 2006 䡠 VOLUME 108, NUMBER 13

Acknowledgments
This work was supported in part by grants CA-21765, CA-
51001, CA-36401, CA-78224, CA-71907, CA-60419, and GM-
61393 from the National Institutes of Health and by the
American Lebanese Syrian Associated Charities (ALSAC).
C.-H.P. is the American Cancer Society F. M. Kirby Clinical
Research Professor.
We thank Sharon Naron and Donald Samulack, PhD, for expert
editorial review; Tad McKeon, Elaine Entrekin, and Annette Stone
for data collection; Cheng Cheng, PhD, and Michael Hancock for
suggestions on statistical analysis; Terezie Mosby, MS, RD,
IBCLC, for discussion on nutrition; Julie Groff for assistance with
the figures; Jeana Cromer for administrative assistance; and Imella
Herrington for secretarial assistance.
Authorship
Contribution: N.H. provided the study concept; N.H., J.C.P., and
Y.Z. provided the study design and drafted the manuscript;
J.C.P. and Y.Z. provided statistical expertise; N.H., J.C.P., Y.Z.,
E.P.K., B.I.R., R.C.R., J.E.R., M.M.H., J.T.S., C.-H.P., S.C.H.,
S.J., and M.V.R. acquired the data; N.H., J.C.P., Y.Z., C.-H.P.,
and M.V.R. analyzed and interpreted data; all authors reviewed
the manuscript; C.-H.P. conducted the Total studies; and N.H.
and M.V.R. supervised the study.
Conflict-of-interest disclosure: The authors declare no compet-
ing financial interests.
Correspondence: Nobuko Hijiya, St Jude Children’s Research
Hospital, 332 North Lauderdale St, Memphis, TN 38105-2794;
e-mail: nobuko.hijiya@stjude.org.

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 From www.bloodjournal.org by guest on September 11, 2016. For personal use only.

2006 108: 3997-4002

doi:10.1182/blood-2006-05-024414 originally published
online August 17, 2006

Body mass index does not influence pharmacokinetics or outcome of

treatment in children with acute lymphoblastic leukemia
Nobuko Hijiya, John C. Panetta, Yinmei Zhou, Emily P. Kyzer, Scott C. Howard, Sima Jeha, Bassem
I. Razzouk, Raul C. Ribeiro, Jeffrey E. Rubnitz, Melissa M. Hudson, John T. Sandlund, Ching-Hon
Pui and Mary V. Relling

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