Late Effects of Intensive Treatment for Acute Myeloid
Leukemia and Myelodysplasia in Childhood
By Raina J. Liesner, Alison D. Leiper, lan M. Hann, and Judith M. Chessells
Purpose: To perform a comprehensive assessment of
the ate effects of short-term intensive chemotherapy for
childhood acute myeloid leukemia (AML) and myelodys-
plasia, and compare the sequelae of intensive chemo-
therapy alone with those of total-body irradiation (TBI).
Patients and Methods: Of 33 survivors studied, 26
(group A) received intensive chemotherapy including an-
thracyclines, one also received busulfan, cyclophospha-
mide (Bu/Cy), and bone marrow transplantation (BMT).
Seven patients (group B) received chemotherapy, TBI,
and BMT. Hearing, sight, growth, and endocrine, renal,
and cardiac function were assessed.
Results: The mean height standard deviation score of
25 nontransplanted group A patients was +0.67 at diag-
nosis, -0.11 following treatment (P = .016), and +0.34
7 years later (P > .05), indicating no long-term growth
impairment. The patients had normal gonadal function
and the girls had normal uterine size and ovarian vol-
T HE LONG-TERM survival of children with acute
myeloid leukemia (AML) has dramatically im-
proved in the last 10 years with the use of more intensive
chemotherapy schedules and allogeneic bone marrow
transplantation (BMT).' Myelodysplastic syndromes
(MDS) in children remain more difficult to treat, but some
patients have achieved long-term remission with treat-
ment protocols designed for AML." 6 These intensive
schedules have been associated with more direct toxicity
and also with prolonged periods of pancytopenia and the
need for repeated courses of potentially toxic antibiotics.
Consequently, many children spend many months in the
hospital receiving treatment with antibiotics and the ma-
jority require intravenous feeding at some time.'
As the numbers of children who survive this intensive
treatment increase, it is becoming possible for the first
time, and increasingly important, to evaluate the signifi-
cant late effects and morbidity of the treatment, as this
will have an important bearing on the design of future
therapeutic schedules.7 It will also enable us to define the
important areas of surveillance in the long-term follow-
From The Hospitalsfor Sick Children, London, United Kingdom.
Submitted September 7, 1993; accepted January 24, 1994.
Supported by the Leukaemia Research Fund and the Medical
Research Council, London, United Kingdom.
Address reprint requests to Raina J. Liesner, MD, Department of
Haematology and Oncology, The Hospitalsfor Sick Children, Great
Ormond St, London WCIN 3JH, United Kingdom.
© 1994 by American Society of Clinical Oncology.
0732-183X/94/1205-0007$3.00/0
916 Journal of Clinical Oncology, Vol 12, No 5 (May), 1994: pp 916-924
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
ume. The Bu/Cy patient had primary ovarian failure.
Four group B children required growth hormone and four
sex steroids for growth or gonadal failure. The girls had
reduced uterine size and ovarian volume. Three had thy-
roid dysfunction and six had cataracts. Abnormalities of
renal function were found in both groups and hearing
loss in group A only. The mean cardiac shortening frac-
tion was significantly reduced at 29.2% in group A and
28.6%in group B compared with 36%in normal subjects.
Two group A patients have developed cardiac failure.
Conclusion: Chemotherapy and TBI before BMT for
AML has resulted in growth failure, gonadal and thyroid
damage, and cataracts in most children, whereas chemo-
therapy alone caused cardiac, renal, and hearing abnor-
malities only.
J Clin Oncol 12:916-924. © 1994 by American So-
ciety of Clinical Oncology.
up of these children and predict problems they may have
in adulthood.
In this study of our long-term survivors of AML and
MDS, we have attempted to define the significant late
effects of intensive chemotherapy alone and compare
them with those associated with chemotherapy, total-body
irradiation (TBI), and BMT.
PATIENTS AND METHODS
Patient Characteristics
Between 1981 and 1988, 103 newly diagnosed children were
treated on AML therapy protocols at the Hospital for Sick Children,
London, United Kingdom. Of these, 94 had de novo AML and
the other nine MDS (French-American-British category refractory
anemia with excess blasts [RAEB] or RAEB in transformation
[RAEB-t]). There were 40 survivors alive between 1.5 and 9 years
from the end of treatment, of whom 33 have been assessed for
late toxicity. The four survivors of MDS all had the cytogenetic
abnormality monosomy 7. The seven children not studied were un-
suitable for study: four had relapsed and been re-treated, two were
lost to follow-up, and in one there was absence of consent.
The 33 children studied have been divided into two groups on
the basis of whether they received TBI as part of treatment. Group
A consists of 26 patients who received intensive chemotherapy
alone, one of whom proceeded to allogeneic BMT from a human
leukocyte antigen (HLA)-compatible sibling donor following busul-
fan and cyclophosphamide (Bu/Cy) treatment (see following). Group
B consists of seven patients who were treated with chemotherapy,
TBI, and allogeneic BMT. Table I lists the patients' characteristics,
and Table 2 lists the systemic chemotherapy received by each group.
All but two group A patients received a minimum of 300 mg/m 2 of
anthracycline, whereas all group B patients received -! 300 mg/m2 .
All children had CNS-directed therapy in the form of five or more
intrathecal injections of either methotrexate alone, methotrexate with
cytarabine, or methotrexate with cytarabine and hydrocortisone. The
LATE EFFECTS OF INTENSIVE TREATMENT FOR AML 917
Table 1. Patient Characteristics the height for that age. 9 The mean height standard deviation score
Group A Group B
was then calculated for each of the two groups at diagnosis, at the
(chemotherapy) (chemotherapy + BMT) end of treatment, and then yearly thereafter. Bone age was estimated
by the Tanner Whitehouse (TW2) method.1 o
No. of patients 26 7
Gonadal function was assessed in a variety of ways. Pubertal
Sex
stage was documented clinically by Tanner staging" at all follow-
Male 10 3
up appointments. Children older than 9 years of age at the time of
Female 16 4
study had basal gonadotrophin (follicle-stimulating hormone [FSH]
Down syndrome 1 0
and luteinizing hormone [LH]) and sex steroid estimations. The girls
Age (years) at diagnosis
underwent ovarian ultrasound by a single experienced ultrasonogra-
Median 3.5 10.1
pher to document three parametersl214:
Range 0.3-13.2 4.9-14.3
(1) uterine size expressed as the cross-sectional area calculated
Diagnosis
from measurements of uterine length and depth in sagittal section
AML 24 5
(2) ovarian volume (V) calculated by measuring longitudinal (L),
Mon 7 MDS 2 2
anteroposterior (AP) and transverse (T) diameters and then using
WBC count > 100 x 10'/L 3 1
the formula for a prolate ellipsoid (V = L x AP x T x 0.5233);
CNS disease at diagnosis 3 0
and
Follow-up period (years) at study
(3) presence or absence of multicystic change within the ovaries.
Median 4.0 7.0
This is an expected finding on ultrasound in normal females just
Range 1.5-8.0 2.3-9.0
before external evidence of early puberty and during puberty.
Abbreviation: Mon 7 MDS, monosomy 7 myelodysplasia. Thyroid function was documented by measurement of serum thy-
roid-stimulating hormone (TSH) and thyroxine (T 4) concentrations.

three patients with CNS disease at presentation had more intensive

intrathecal chemotherapy and also had cranial irradiation at a dose Table 2. Treatment
of 18 Gy in 10 fractions in one child and 24 Gy in 15 fractions in
Group A Group B
the other two children. Treatment In = 26) In = 7)
Treatment before BMT in the group A patient was with busulfan
4 mg/kg x 4 and cyclophosphamide 50 mg/kg x 4, and she received Systemic chemotherapy
cyclosporine as graft-versus-host disease (GVHD) prophylaxis. The 1981-1983 (MRC AML 8)
group B patients received cyclophosphamide 60 mg/kg x 2, and six DAT (1 + 5) 1-8 courses 2 2
then received single-fraction TBI at a dose of 9 Gy and one received 1983-1987 (RATE 82/JOINT AML TRIAL6)
14 Gy fractionated into seven doses and administered over 3 days. DAT (3 + 8) x 2, MAZE, DAT, MAZE, DAT 11 0
Six patients received cyclosporine, three with methotrexate, as DAT (3 + 8) x 2, MAZE ± Melph 3 3
GVHD prophylaxis. One received methotrexate alone. Two had mild DAT (3 + 8) x 2, MAZE, Bu/Cy 1 0
acute GVHD controlled with corticosteroids. None developed
1987-1988 (MRC AML 10)
chronic GVHD.
ADE (3 + 10), ADE (3 + 8), MACE + MIDAC 8 1
The intensive chemotherapy schedules and preparative therapy
for BMT received by these children were followed by periods of Others
pancytopenia, which lasted 4 to 6 weeks. During this time, the CHOP x 5, MAZE x 5 1 1
children were kept in hospital and given blood product support and Anthracycline doses (mg/m2)
intravenous feeding as required, as well as prompt empirical courses < 300 2 3
of combination broad-spectrum antibiotics for febrile neutropenic 300-400 12 4
episodes.' This usually comprised an aminoglycoside and a ureido- 400-500 12 0
penicillin as a first choice. Amphotericin was introduced for persis- Antibiotics
tent culture-negative febrile episodes (Table 2). Aminoglycosides 26* 7
Amphotericin 17 3
Methods
Abbreviations: DR, daunorubicin; SC, subcutaneously; TG, thioguanine;
Growth, endocrine, renal, cardiac, ophthalmologic, and audiologic po, orally; IV, intravenously; VP16, etoposide; DAT (1 + 5), DR 50 mg/
2
function were assessed to define the important late effects of treat- m2 x 1, cytarabine SC, and TG po 200 mg/m x 5 days; DAT (3 + 8),
ment. DR 50 mg/m2 x 3, cytarabine 100 mg/m 2 continuous IV, and TG 150
Growth and endocrine function. Growth was assessed in all pa- mg/m2 po x 8 days; MAZE, M-AMSA, azacytidine, and VP16 100 mg/
2 2
tients at diagnosis, at the end of treatment, and at least yearly thereaf- m IV x 5; Melph, melphalan 80 mg/m x 1; Bu/Cy, busulfan 4 mg/kg
2
ter by standard anthropometric methods. These measurements were x 4, cyclophosphamide 50 mg/kg x 4; ADE (3 + 10), DR 50 mg/m x
2 2
then used to calculate yearly height standard deviation scores for 3, cytarabine 200 mg/m IV x 10, VP16 100 mg/m IV x 5; ADE (3 +
each child. Height standard deviation score is the height expressed 8), ADE (3 + 10) but cytarabine x 8; MACE, M-AMSA and VP16 100
2
as the Z score of the individual patient in relation to the height of mg/m x 5, cytarabine 200 mg/m2 continuous IV x 5; MidAC, mitozan-
2 2
normal children of the same age using the standards reported by trone 10 mg/m x 5, cytarabine 2 g/m x 3; CHOP, cyclophosphamide
2 2
Tanner et al.' It is calculated using the formula: standard deviation 750 mg/m , doxorubicin 45 mg/m2, vincristine 1.5 mg/m x 1 and pred-
2
score = (x - X)/S, where x is the height of the patient, X is the nisolone 50 mg/m x 8.
mean height for chronologic age, and S is the standard deviation of *Five of 26 toxic levels recorded.

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918
If there was evidence of either growth failure or delayed puberty,
pituitary function was assessed, which included measurement of the
growth hormone (GH) and cortisol response to intravenous insulin-
induced hypoglycemia combined with a luteinizing-hormone-re-
leasing hormone (LHRH) and thyrotrophin-releasing hormone
(TRH) stimulation test. In delayed puberty, GH stimulation tests
were primed with stilbestrol for 2 days before the test. Hormone
levels were measured by a double-antibody immunoassay.
Renalfunction. To assess renal function, the supine blood pres-
sure, plasma urea, electrolytes, and creatinine were measured. The
glomerular filtration rate (GFR) was estimated by analysis of the rate
of decrease of the plasma concentration of chromium-51 edathamil
following a single intravenous injection."
Cardiacfunction. Cardiac function was monitored in each child
by two-dimensional and M-mode echocardiography performed by
personnel experienced in pediatric echocardiography. The dimen-
sionless left ventricular fractional shortening, which has been found
to be independent of body-surface area and age in normal infants
and children,' 6 " was documented as an indicator of left ventricular
performance. This is calculated from the following formula: shorten-
ing fraction (SF) = ([left ventricular end diastolic diameter - end
systolic diameter]/end diastolic diameter) x 100.
Hearingand sight. Hearing was assessed by pure-tone audiome-
try and tympanometry performed by trained audiologic scientists.
All children had an ophthalmologic examination to check for the
presence of cataracts and other abnormalities.
StatisticalAnalysis
The mean height standard deviation scores of the group A children
were calculated and then the end-of-treatment and yearly scores were
compared with the score at diagnosis by paired t test.
The mean SF in each group was compared with that of normal
subjects using Student's t test. The possible correlation between
anthracycline dose received and SF in each patient was explored by
calculating the correlation coefficient and then applying the t test.
RESULTS
Growth
Group A. Growth was studied in detail in 21 of 26
group A patients. Of the five excluded from analysis, three
had CNS disease at presentation and had received cranial
irradiation, a well-documented cause of growth failure.
One patient with Down syndrome was excluded, as was
one child with inaccurate growth data at presentation.
The patient who received Bu/Cy and then BMT had
normal growth until ovarian failure supervened at the
age of 13 years, when sex steroid supplementation was
required for induction of puberty and initiation of a
growth spurt. None of the remaining 20 group A children
showed any evidence of growth failure during the follow-
up period, and the six who have entered puberty following
cessation of chemotherapy have all shown appropriate
pubertal growth spurts. The mean height standard devia-
tion scores at diagnosis, at the end of treatment, and at
yearly intervals are shown in Fig 1. The height standard
deviation score was only used once the children had
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LIESNER ET AL
4 C
I.D -
p = 0.016
1.0 -
u,
115
I3
a
0.5 -
I
0.0 -
-A-05 -
D //0 1 2 3 4 5 6 7
Years off Treatment
Fig 1. Mean height standard deviation scores (+ SEM) of group A
children at diagnosis (D), at the end of treatment, and then yearly.
Numbers in bars denote number of children over the age of 2 years
for whom data were analyzed.
reached the age of 2 years, hence, the difference in num-
bers between diagnosis and 1 year after cessation of treat-
ment. Because the children were predominantly very
young, seven had not reached the age of 2 years at the
end of the treatment period and one was not yet 2 years
old 1 year from the end of treatment. The mean height
standard deviation score of the group at diagnosis was
+0.67, and by the end of treatment had fallen to -0.11.
This difference was statistically significant, with a P value
of .016. The children then entered a period of catch-up
growth, after which they grew normally.
Group B. Six of seven patients in group B developed
some degree of growth failure (Table 3). The seventh
patient was already at final height at diagnosis. These six
patients underwent combined tests of pituitary function
and four had GH deficiency as defined by a peak GH
level of less than 20 mU/L following documented hypo-
glycemia. The other two had an adequate GH response,
but had growth failure. Three of the six were treated
with GH supplements, and in one other (patient no. 6),
treatment was refused by the parents. Two of the patients
(no. 1 and 2) had documented GH deficiency, but have
not required supplementation: one reached a satisfactory
final height soon after BMT, and the other is now growing
well despite being GH-deficient.
Gonadal Function
Data on pubertal status were complete in 25 group A
patients. Seventeen were appropriately prepubertal at the
time of study, aged 3.2 to 10.4 years. The patient who
received Bu/Cy and BMT had elevated gonadotrophin
LATE EFFECTS OF INTENSIVE TREATMENT FOR AML 919
Table 3. Growth and Endocrine Function in Group B
Age at
Patient Diagnosis
No./Sex (years) Conditioning Growth Gonadal Function Gonadotrophins Thyroid Function
1/M 14.3 Cyclo/TBI GHD; normal final Pubertal at diagnosis FSH increased; LH normal Normal
height
2/M 4.9 Cyclo/TBI GHD; growth velocity Spontaneous puberty FSH and LH increased Normal
normal
3/M 11.8 Cyclo/TBI Growth poor; on GH Arrested pubertal FSH and LH increased Hypothyroid; TA
development; on sex
steroids
4/F 8.4 Cyclo/TBI GHD; on GH Spontaneous puberty; FSH and LH normal Normal
late OF
5/F 6.1 Cyclo/TBI GHD; on GH Prepubertal, aged FSH and LH increased Euthyroid with increased
10.9 years TSH
6/F 10.1 Cyclo/TBI Growth poor; GH Primary OF; given sex FSH and LH increased Hypothyroid post-BMT; now
refused steroids; now euthyroid
normal gonadal
function
7/F 12.9 Cyclo/fTBI Final height at Primary OF; on sex FSH and LH increased Normal
diagnosis steroids
Abbreviations: M, male; F, female; Cyclo, cyclophosphamide; TBI, total-body irradiation (single fraction); fTBI, fractionated TBI; GH, growth hormone;
GHD, growth hormone-deficient; OF, ovarian failure; FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone; T4 ,
thyroxine; BMT, bone marrow transplant.

levels, developed primary ovarian failure, and required available from the ultrasounds performed in 14 group A
sex steroids for induction and progression through pu- and four group B girls (Fig 2). In the group A girls, the
berty. The other seven group A children entered and pro- uterine size was within normal limits in the 10 prepubertal
gressed through puberty normally, reaching Tanner stages patients, and had increased appropriately during and after
of puberty at the appropriate age (± 1.5 SD). Excluding puberty in the four pubertal patients. Ultrasound data on
the girl who received Bu/Cy, all 12 children over the age the girl who received Bu/Cy was not complete and was
of 9 years at the time of study had gonadotrophin and therefore not analyzed. Of the four Group B girls, one was
sex steroid concentrations that were within the normal prepubertal with an appropriately small uterine size. The
ranges for their age and pubertal status.
Endocrine status of the group B patients is documented
in Table 3. Of the six with elevated gonadotrophin con- "E
o
32 0 Prepubertal } Chemo
centrations, two boys (no. 1 and 2) have entered and Pubertal
28 •r
a Prepubertal } TBI
progressed through puberty normally, but may be sterile. Pubertal
0
One of the girls (no. 5) is prepubertal at the age of 10.9 24
years, but has abnormally high FSH and LH levels for 5- lb
20
her age and may have ovarian failure. The other three
children (one ioy, two girls) with high gonadotrophin 4.) 16
0
levels had gonadal failure and required sex steroids for
12
induction and progression through puberty. One of the 2
I,5 0
girls has since had a spontaneous menarche without sex 8a "*
* *

steroid therapy 8 years following TBI. The one group B (L 4

patient with normal gonadotrophin concentrations (no. 4) ..... . 00
...o .... ..
entered puberty spontaneously (Tanner stage B2, aged 0
0 2 4 6 8 10 12 14 16 18 20
12.55 years) with menarche 5 years after TBI, but then
entered a premature menopause 2 years later. Age (years)
Further information on gonadal function in the female
patients was obtained from pelvic ultrasound, although Fig 2. Uterine cross-sectional area in 14 group A girls and 4 group
B girls. (..... Range of uterine size in normal prepubertal girls."
numbers were too small to achieve any statistical signifi- Group A girls show a substantial increase with puberty, but group B
cance. Measurements of uterine cross-sectional area were children have poor uterine growth.

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920 LIESNER ET AL

other three were all fully estrogenized at the time of scan, Table 4. Renal Function and Hearing

either endogenously or exogenously with sex steroids, but Group A Group B

Findings (n - 23) (n = 7)
none has shown the rapid increase in uterine size that would
be expected for their hormonal and pubertal status. 12 Urea and creatinine above normal range 0 1
GFR*
Adequate information on ovarian size and cystic
Within normal range 21 5
change was available from scans in 10 group A and three Below normal range 2 2
group B girls and is shown in Fig 3. The majority of the Abnormal pure-tone audiogramt
group A patients have ovarian volumes within and around Total 6 1
the normal ranges before, as they enter, and as they prog- High-frequency loss post-Rx 4 0
Congenital sensorineural loss 1 1
ress through puberty. They also show appropriate devel-
Conductive loss and CSOM 1 0
opment of multicystic change. The three group B girls
Abbreviations: Rx, treatment; CSOM, chronic secretory otitis media.
all had ovarian volumes below the normal range, although
*GFR: normal range (± 2 SD), 89 to 165 mL/min/1.73 m' in 2- to 12-
one was prepubertal. The one girl who had a late menar- year age group, 88 to 174 in males greater than 12 years, 87 to 147 in
che 8 years following TBI has developed multicystic females greater than 12 years.
change in small-volume ovaries (group B patient at B5 tPure-tone audiogram abnormal if loss greater than 30 to 40 dB either
with multicystic change in Fig 3). unilaterally or bilaterally.

Thyroid Function
Thyroid function was normal in all group A patients.
Three of the eight patients in group B have had an abnor-
mality of thyroid function following treatment (Table 3).
Adrenal Function
Cortisol secretion was normal in all group B patients
following insulin-induced hypoglycemia.
Renal Function
Twenty-three of 26 patients in group A and all patients
in group B have had renal function investigated (Table
4). All patients in both groups had supine blood pressure
levels within the normal range for their age.
The group A patients all had normal urea and creatinine
values, but two had GFR values below the normal range
for their age. One was known to have a unilateral hydro-
nephrosis, which was detected on a pretreatment ultra-
sound scan. His renal function was stable during treatment
and has not deteriorated since the end of therapy. The
other had no structural renal abnormality, but had tran-
siently toxic levels of both gentamicin, with a peak level
of 14.5 mg/L, and vancomycin, with a peak level of 47.0
mg/L (acceptable gentamicin trough < 2.0 mg/L, peak
< 10 to 12 mg/L; vancomycin trough < 10 mg/L, peak

tIm)
< 30 mg/L). Neither had received amphotericin.
One group B child had a urea level just above and a
creatinine level just within the normal range. This patient
8 o Prepubertal, Chemo developed acute renal failure following BMT and has had
ubertal Chemo
E 7 * Prepubertal 1 TBI only partial recovery of his renal function, with a GFR value
* Pubertal TBI
6 (m) Multicystic J- of 44 mL/min/1.73 m2. The other group B patient had a
a
E 5
GFR that was only mildly reduced for her age at 75 mUL
0 C min/1.73 m2. She had had renal problems associated with
nr
4
o

0
3
2

1
-

o
]iiiii
a Im)m
......
L i?° . 0......
. m
..*
Henoch-Sch6nlein purpura 8 years before presentation with
AML and developed acute renal failure during the induction
treatment period. She underwent BMT with cyclophospha-
mide and TBI conditioning without any further renal prob-
p

o0 ,

lems. Both of these children received amphotericin and

0 1 2 3 4 5 6 7 8 9 101 cyclosporine, as well as aminoglycosides, during treatment,
Chronological Age (yrs)
81 B2 B4 B5
but no toxic levels were recorded in either case.
Pubertal Status (Tanner Stage) Cardiac Function
Fig 3. Ovarian volume and presence of multicystic change in 10 Twenty-three group A and all group B patients have
group A girls and 3 group B girls. Bars and dotted lines represent undergone echocardiography (Table 5). The mean SF of
range of ovarian volume in normal girls (mean ± 1 SD).8s', Most
group A girls are within but all group B girls are below the normal group A patients was 29.2% and of group B 28.6%. When
range. compared with the mean of normal infants and children,

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LATE EFFECTS OF INTENSIVE TREATMENT FOR AML 921

Table 5. Cardiac Function to have a congenital sensorineural hearing loss. The re-
Group A Group B maining five patients (all from group A) had not had
(n = 23) (n = 7) detectable hearing loss before treatment and had all un-
SF (%) dergone routine hearing screening in the community.
Range 19-40 25-31 However, on testing, one was found to have a conductive
Mean 29.2 28.6 loss secondary to chronic serous otitis media and the
Reduced SF < 28% (no. of patients) 8/23 2/7
remaining four have posttreatment bilateral high-fre-
A. DR dose (mg/m 2 )
Range 300-500 250 and 300 quency hearing loss with losses of > 50 dB at frequencies
Mean 390 275 - 2 kHz. This included the girl who had received Bu/
B. Time since treatment (years) Cy and then BMT. Three of the four had toxic antibiotic
Range 1.0-8.2 6.9 and 9.0
levels recorded: a gentamicin trough level of 4.0 mg/L
Median 4.0
Cardiac failure (no. of patients) 2/23 0 and a peak level of 14.0 mg/L, and a toxic vancomycin
level of 70 mg/mL. All four patients had received one or
NOTE. SF of normal infants: mean, 36%; 95%confidence interval, 28%
to 44%. more courses of amphotericin. Two of these four patients
Abbreviation: DR, daunorubicin. have a high-frequency loss severe enough to require am-
plification with losses of greater than 100 dB at frequen-
which is 36% with 95% confidence limits of 28% to cies of 2 to 8 kHz.
44%,"1 both groups have significantly reduced (P < .001)
left ventricular performance assessed by SF. The correla- Eyes
tion coefficient of the SF and the dose of anthracycline Ophthalmologic examination of group A patients did
received by either group in this series was not statistically not show any treatment-related abnormalities of the eye.
significant (r = .38, P = .05). However, six group B patients have cataracts, either uni-
Eight group A and two group B patients had a SF lateral or bilateral, and four have required surgery to
less than 28%, and therefore outside the 95% confidence maintain some useful vision. The seventh patient was
interval of normal subjects (Table 5). All had at least one only 2 years post-TBI at the time of study, and therefore
other echocardiographic abnormality in addition to the may develop cataracts in the future.
reduced SF, such as abnormally thin left ventricular pos-
terior wall, low ejection fraction, or abnormal left ventric- DISCUSSION
ular end diastolic or end systolic diameter. The group A In this study, we have attempted a comprehensive as-
subjects had received a mean daunorubicin dose of 390 sessment of the physical late effects of treatment in a
mg/m2, with the highest dose being 500 mg/m2. The me- group of children who received chemotherapy for AML
dian interval between the end of treatment and the time with or without TBI. We believe that this is the first such
of echocardiography was 4 years. Seven of eight patients systematic attempt at such a study, and it has demon-
had received other potentially cardiotoxic drugs, such as strated conclusively that with increasing survival from
amsacrine (M-AMSA), mitozantrone, or cyclophospha- childhood AML and MDS, there is significant associated
mide. Two of these patients have developed late severe morbidity from the long-term effects of treatment. Late
cardiac failure secondary to anthracycline cardiomyopa- sequelae following TBI and BMT in childhood have been
thy. One was at 3 years and the other 8 years after the reported in previous studies, 18' 19 but to date there has been
end of treatment during a pubertal growth spurt. The no published work on those apparently cured by intensive
latter patient failed to respond to conservative antifailure chemotherapy alone.
treatment and has undergone a heart transplant. In contrast to transplanted children, growth and endo-
The two group B patients with reduced left ventricular crine function were universally normal in the group A
performance received 250 and 300 mg/m2 of daunoru- children who received chemotherapy alone. However, as
bicin, high-dose cyclophosphamide, and TBI conditioning a group, they did suffer growth impairment during treat-
6.9 and 9 years before echocardiogram. To date, neither ment and showed catch-up growth thereafter. The major-
has developed clinical cardiac failure. ity (70%) were still in the prepubertal age group at the
time of study and it will be important to carefully reexam-
Hearing ine them over the next 5 to 10 years. These findings
The pure-tone audiogram was abnormal in six patients contrast with those of survivors of childhood acute
from group A and one from group B (Table 4). Two of lymphoblastic leukemia, in which a small but significant
these seven children, one from each group, were known number of children have impaired growth and/or early

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922
puberty.2 0-23 These effects are probably caused by cranial
irradiation and have brought about a change in current
treatment regimens, limiting irradiation to those children
with documented CNS disease or those at high risk of
CNS relapse. 24
The damage to growth and endocrine function in all
the children who received a BMT is dramatic, with none
of the eight children left unaffected. Growth failure after
BMT is known to be of multiple etiology, with GH defi-
ciency, gonadal and thyroid failure, and chronic GVHD
all being possible contributory factors.' 8 ' 19 In this series,
none of the patients had chronic GVHD and those who
were transplanted well into the second decade of life
reached final height without the need for hormonal sup-
plementation. However, the younger children who re-
ceived TBI all required GH treatment, whereas the girl
conditioned with Bu/Cy developed ovarian failure alone,
suggesting that, in this group, TBI is the main contributing
cause for growth failure.
The full effect on gonadal function of three group B
boys will only be recognized in the next decade or two,
when they may wish to father children. All have high
FSH levels and are likely to be sterile." Only one required
sex steroids to enter puberty, whereas the girls of pubertal
age have required sex steroids at some stage for ovarian
failure. These findings concur with those of other series
8 9
of transplanted children.' "
We were able to study gonadal function in the group
B girls in more detail with the help of pelvic ultrasound,
although the small numbers make the findings anecdotal.
Their reduced uterine size, despite full estrogenization, is
presumably an effect of irradiation. These findings concur
with those of other investigators who have documented
increased fetal loss and low-birth-weight babies in
women treated with abdominal irradiation in childhood
for Wilms' tumor.26 The pathogenesis of the uterine dam-
age is not fully understood, but extrapolating from what
is known about tissue response to radiation,2 7 reduced
distensibility of the uterine musculature and uterine vas-
cular insufficiency are probably important contributory
factors. Ovarian multicystic change heralds the onset of
puberty and was absent in two of three patients with
ovarian failure. However it was found in the small-vol-
ume ovaries of one girl who had puberty induced due to
gonadal failure, but eventually recovered function 8 years
after TBI.
We found impairment of renal function in both groups
and hearing deficits in group A only. Thyroid and oph-
thalmologic abnormalities were confined to post-TBI chil-
dren, as has been found in other series of posttransplant
children.18 ,19,28 -30 Presumably, the renal and hearing abnor-
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Copyright © 2019 American Society of Clinical Oncology. All rights reserved.
LIESNER ET AL
malities we found are attributable to the toxicity of the
chemotherapy, antibiotics, or immunosuppressive agents,
or to all three. They highlight the importance of frequent
monitoring during treatment of antibiotic levels and renal
function, as well as hearing by intermittent audiometry
during and after treatment. It is difficult to otherwise
envisage how these late effects could be minimized with-
out either compromising the treatment or undertreating
potentially life-threatening infections. However, the in-
creasing use of some of the newer broad-spectrum antibi-
otics and liposomal amphotericin will help to reduce renal
toxicity.
Anthracyclines are known to cause dose-dependent
cardiac toxicity. 3 ' 3 It is thought that cardiac muscle is
damaged at a cellular level by free-radical generation,34
which leads to damage to mitochondrial membranes and
myofibrillar lysis, as well as swelling of the sarcoplasmic
reticulum. 3 5 The affected myocytes degenerate, and inter-
stitial fibrosis develops with hypertrophy of remaining
myocytes.3 3 Irradiation is also known to be cardio-
toxic,36' 37 and M-AMSA,38 mitozantrone,3 9 and cyclo-
phosphamide 40 may contribute to and increase the risk of
cardiac damage. In our patients, echocardiographic abnor-
malities were found in 35% of group A and 28% of group
B children. We have used the dimensionless SF as an
indicator of left ventricular function. 41 However, there is
still considerable debate as to the most accurate and least
invasive way to assess anthracycline-induced cardiac
damage and how to predict those children who are likely
to develop problems and therefore need more frequent
surveillance and earlier intervention when an abnormality
is detected.42
To date, only two of our children, both in group A,
have become symptomatic from their cardiac dysfunction.
One of these has required a heart transplant for what was
shown histologically to be compatible with anthracycline-
induced cardiomyopathy. As she is one of the longest
survivors, her problems highlight a possible complication
that others could develop in the future. Her problems
developed when she was undergoing her pubertal growth
spurt, and this concurs with other studies that have docu-
mented the onset of problems in children at puberty when
it would appear that the remaining cardiac reserve is inad-
equate to support rapid somatic growth.33 She received
500 mg/m 2 of anthracycline, a dose that would now be
considered unacceptably high. The standard cut-off dose
has been 450 mg/m 2, but four other group A children
found to have a reduced SF had received only 300 mg/
m2. They also had received mitozantrone or cyclophos-
phamide, but nevertheless it is of great concern that we
are finding abnormalities at this dose. It may be difficult
LATE EFFECTS OF INTENSIVE TREATMENT FOR AML
to reduce the dose further without compromising the effi-
cacy of the treatment, unless alternative agents--such as
high-dose cytarabine--prove to be as effective. This is
one area that future trial protocols will have to address,
but for now the toxicity might be reduced by administer-
ing the anthracycline by infusion rather than bolus injec-
tion.43 "44Also in the future, there is the possibility that an
effective cardioprotective agent such as ICRF-187 may
4 possible late sequelae are illustrated well by the patient
be developed for clinical use."
These findings highlight the need for frequent surveil-
lance with cardiac assessment as a baseline before treat-
ment starts, after each course during treatment, and then
at frequent intervals after the end of intensive treatment.
If any significant deterioration is detected at any stage
during treatment, the remaining therapy may need to be
altered to limit further cardiotoxicity. If abnormalities are
detected later, they indicate the need for more frequent
surveillance, particularly at times of increasing cardiac out-
put such as puberty and during pregnancy and delivery.
Therefore, in conclusion, we have found significant
late sequelae in both groups of patients. Abnormalities of
growth and endocrine function and cataracts were con-
fined to the children who had undergone BMT; in view
of the severity of these abnormalities, the use of BMT
and TBI are questionable. However, to date, there has
not been a prospective pediatric assessment comparing
the use of TBI versus Bu/Cy, and TBI is therefore part
of the standard preparatory treatment for BMT in the
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