Received for publication Oct 12, 1987; accepted May 13, 1988. Reprint requests to (T.A.K.) Division of Pediatric Neurology, MDCC 22-464, UCLA School of Medicine, Los Angeles, CA
90024.
Normal
Neurodevelopment
in Four Young
Children
Treated
With
Bone
Marrow
Transplantation
for Acute
Leukemia
or
Aplastic
Anemia
Thomas
A. Kaleita,
PhD,
W. Donald
Shields,
MD, Alan
Tesler,
MD,
and Stephen
A. Feig,
MD
From the Departments of Pediatrics, Neurology, and Radiation Oncology, the Gwynne
Hazen Cherry Memorial Lahoratories, Jonsson Cancer Center, University of California,
Los Angeles, School of Medicine, Los Angeles
ABSTRACT. Longitudinal neurodevelopmental studies of
four consecutive young children treated by bone marrow
transplantation for acute leukemia or aplastic anemia are presented. The children, the only four children less than
2years of age who have received bone marrow transplants
for these diseases at UCLA Medical Center, ranged in
age from 36 weeks to 24 months at the time of transplan-tation. Conditioning involved high-dose
cyclophospha-mide treatment; three also had total body irradiation
prior to bone marrow transplantation. Their respective
outcomes after follow-up times of 28 months to 71 months posttransplantation are remarkable for normal somatic growth and normal development of intelligence, language, perception, and motor coordination. These findings
in-dicate that future therapeutic studies of infants and young children with acute leukemia or aplastic anemia using total body irradiation, cyclophosphamide, and bone
marrow transplantation are not contraindicated by risks
of debilitating neurodevelopmental sequelae. Pediatrics
1989;83:753-757; bone marrow transplantation, acute leu-hernia, aplastic anemia, total body irradiation.
Bone marrow transplantation is being used in-creasingly for the treatment of pediatric malignan-cies, aplastic anemia, and inherited disorders in
children.’ Prior to 1980, bone marrow
transplanta-tion was viewed more as an experimental procedure, used in adolescents and adults with advanced dis-ease that had failed to respond to conventional therapy.2 Steadily improving results have made bone marrow transplantation accepted as a pre-ferred therapeutic option, and it is now being
con-sidered increasingly in the treatment of young
chil-then. Potential complications, especially
neurotox-icity caused by conditioning regimens, are an
important consideration when infants and toddlers are prepared for bone marrow transplantation, be-cause chemotherapy and irradiation given to young children have been generally associated with neu-rologic sequelae. In this report, the results of serial
neurodevelopmental assessments in four
consecu-tive infants and young children receiving trans-plants because of acute leukemia or aplastic anemia
are presented.
PATIENTS AND METHODS
Patients
Four consecutively studied children, all 24 months of age or less at the time of bone marrow transplantation from HLA-matched siblings, were
serially assessed with standardized tests of
devel-opment, intelligence, language, perception,
mem-ory, and motor coordination. These children,
iden-tified by disease type, sex, disease duration prior to
bone marrow transplantation, age at the time of bone marrow transplantation, and duration of fol-low-up are presented in Table 1.
Bone Marrow
Transplantation
Conditioning
Regimens
The conditioning regimens used were: (1) cyclo-phosphamide (120 mg/kg in two equal daily doses) followed by single-dose total body irradiation with
TABLE 1. Patie nt Characteristics
Patient Sex Disease Disease Duration Age (mo) When Follow-up
No. (mo) Prior to
Bone Marrow Transplantation
Transplantation Done
(mo)
1 M Acute
undifferen-tiated leukemia
2 12 63
2 F Acute myelogenous
leukemia
2 13 60
3 M Aplastic anemia 5 24 71
4 F Aplastic anemia 2 8 28
received total body irradiation with 300 cGy,
be-cause he had received multiple transfusions prior
to transplantation.
Neurodevelopmental Assessment
The Gesell Development Assessment Schedules3
were administered to all four children immediately
prior to and/or following bone marrow
transpian-tation. Later examinations of each child have
in-cluded the Stanford-Binet Intelligence Scale, form L-M4; the Wechsler Intelligence Scale for Chil-then-Revised5; the Beery Development Test of
Visual-Motor Integration6; Token Test for
Children7; and Peabody Picture Vocabulary Test Revised.8
CASE REPORTS
Case I
Acute undifferentiated leukemia was diagnosed in this 9-month-old boy. Developmental milestones prior to di-agnosis were normal. Initial therapy with vincristine, prednisone, and L-asparaginase failed to induce remis-sion. A single course of combination therapy consisting of vincristine, prednisone, adriamycin, and cytosine ara-binoside successfully induced remission; no intrathecal prophylaxis was given. A conditioning regimen as de-scribed previously was performed and then bone marrow transplantation was performed when the baby was 12 months of age. Graft v host disease did not develop.
Subsequent to bone marrow transplantation, develop-ment was normal except for decreased vocalization and
delayed attainment of speech milestones (Table 2). At
the time of the second examination at age 14#{189}months, the child was not using words at all. At 26#{189}months, he
had not discarded jargon and seldom used two words
together. Language therapy was given from 3#{189}to 5 years of age. The last two examinations showed superior per-formances on all standardized tests of language, memory,
and visual-motor coordination. During the last
exami-nation, he had clearly articulated speech, was able to print his name, the alphabet, and numbers from 1 through
20, and sustained attention easily. No behavioral diffi-culties have been reported by parents or teachers. He is socially spontaneous, without evidence of mood disturb-ance. He has small, nonprogressive cataracts but no
difficulties with either close or far vision. His height was below the fifth percentile at the time of the last exami-nation. He was then treated for thyroid insufficiency and now is growing normally.
Case 2
Acute myelogenous leukemia was diagnosed when this
girl was 11 months of age. Early developmental
mile-stones were normal. Remission was achieved after one
course of vincristine, prednisone, adriamycin, and cyto-sine arabinoside. No intrathecal chemotherapy was ad-ministered. Bone marrow transplantation was performed
during the first remission when she was 13 months of age. No graft v host disease was seen.
An intention tremor was noted, and expressive
lan-guage was delayed at the the time ofthe first examination
which was performed prior to bone marrow transplanta-tion (Table 2). The child had acquired two new words and showed stable fine and gross motor abilities during
her hospitalization for the transplantation. During the
examination performed 44 months after transplantation, she scored within the first standard deviation above the
mean on all standarized tests of intelligence, language,
memory, and visual-motor coordination. During the last
examination performed at 6 years 1 month of age, she
demonstrated clearly articulated speech, and she was able to print her name, the alphabet, and numbers from 1 to 20. Parents and kindergarten teachers reported no diffi-culties with sustained attention, behavior, or
tempera-ment, and none were observed during the last two
ex-aminations. She has nonprogressive cataracts but no
difficulties with visual acuity. Somatic growth has been normal since bone marrow transplantation.
Case 3
This infant boy was noted to have petechiae during
the first day of life. Initial CBC count showed a platelet count of 30,000/dL. Gestation, labor, and delivery had been normal. He weighed 2,924 kg (6 lb 8 oz) at birth.
The petechiae disappeared rapidly after birth, but he
remained persistently thrombocytopenic; bone marrow
aspirates were hypocellular with markedly diminished
megakaryocytes. Results of hemoglobin and WBC counts
during the first year of life were normal. Progressive
pancytopenia and aplasia were noted during the second
year of life.
Developmental milestones during the first year were
TABLE 2. Neurodevelopmental Testing
Patient No. and Chronologic Age
Test Results
Gesell Develo pmental As (mo)
sessment Schedules DIQ Stanford-Binet
MA IQ
(mo)
Token Test (Age-SS)
PPVT-R
55 %ile Bee
VMI
55 %ile WISCR
IQ
Gross Fine Motor Motor
Adaptive Language Personal! Social
1
12 mo (-7 d) 12.0 18.5 15.7 16 15.2 107
14.5 mo (+2 mo) 14.0 16.0 14.6 16 15.0 100
26.5 mo (+14 mo) 30.0 36.0 32.0 23 25.0 108
64.0 mo (+51 mo) 89 135 503 13 93
76.0 mo (+63 mo) 108 138 506 126 96 14 91
2
13 mo (-7 d) 13.2 15.2 13.0 13 14.0 103
22 mo (+9 mo) 24.0 22.5 23.5 23 24.0 108
57 mo (+44 mo) 64 102 507 105 63 11 66
73 mo (+60 mo) 82 107 504 113 80 10 67
3
24 mo (-1 d) 24.0 30.0 26.5 22 28.5 108
95 mo (+71 mo) 504 107 68 10 60 128
4
9.5 mo (+1 mo) 9.8 9.5 10.0 9.5 10.0
36 mo (+28 mo) 46 121 119 90 3-11
* Abbreviations: PPVT-R, Peabody Picture Vocabulary Test-Revised; VMI, Visual Motor Integration; DIQ,
Develop-mental Quotient; MA, Mental Age; 55, Standard Score. Numbers in parentheses indicate time relative to transpian-tation.
had normal acquisition of expressive vocabulary and
syn-tax. Both gross and fine motor skills developed
appropri-ately prior to bone marrow transplantation.
He was conditioned with total body irradiation and
cyclophosphamide as described previously and underwent a bone marrow transplantation at 24 months of age. Skin manifestations of chronic graft v host disease developed after the procedure, which were treated successfully with prednisone. Somatic growth has been consistently within
normal limits for chronologic age. He has a small
non-progressive cataract in his left eye, and his eyes do not tear and are light sensitive.
At the time of the follow-up examination performed
71 months after bone marrow transplantation, the child was about to begin the third grade. He is enrolled in an accelerated curriculum, and there are no concerns about development in cognition, motor coordination, or behav-ior (Table 2).
Case 4
During the first 8 months of life, this child’s platelet counts ranged from 1,000 to 80,000/dL, and easy bruising was noted. At 6 months of age, anemia was noted. Bone
marrow biopsy findings were consistent with those of
aplastic anemia; the cause could not be identified. Early developmental milestones were normal.
The patient was conditioned with cyclophosphamide,
and bone marrow transplantation was performed when
she was 8 months of age. Since transplantion, there has
been no evidence of graft v host disease, and her parents report normal somatic growth.
The results oftwo examinations are presented in Table
2. At the time of the first examination, this child showed
an excellent attention span, although a mild hesitancy and unsteadiness of grasp was noted. During the
follow-up examination, she articulated words clearly, showed an
excellent attention span, and demonstrated appropriate fine motor skills without abnormal movements. Gross motor coordination was considered completely normal.
DISCUSSION
Prognosis for patients with acute leukemia and
aplastic anemia is often poor, especially when the diagnosis is made during infancy.9”0 Our four pa-tients are remarkable because of their excellent neurodevelopmental outcome following bone mar-row transplantation at a young age. The outcomes of these four patients are encouraging for other
young patients with disorders potentially amenable
to bone marrow transplantation, especially
consid-ering the lack of neurodevelopmental sequelae.
Re-cent studies of infants treated for leukemia indicate that survivors often have significant long-term complications including severe neurologic Se-quelae.9” A recent report of survivors of aplastic anemia treated by bone marrow transplantation does not contain specific data about young children and neurodevelopmental outcome.’2
The scientific literature indicates a high
proba-bility of nervous system toxicity when children are
treated with cranial irradiation and chemotherapy
disa-bility associated with this treatment.’3”4 Reports in
which the effects of chemotherapy on the nervous
system are described suggest that young children
are more likely to have neurodevelopmental
toxic-ity,’5’16 as do many of the major studies specifically
involving patients with acute lymphoblastic
leuke-mia.17’9 Studies addressing the neurologic outcome
of children treated by bone marrow transplantation indicate no evidence of graft v host disease in the
CNS2#{176}but do show substantial percentages of
pa-tients with nervous system-related abnormali-ties.2”22
The potential effects of total body irradiation on
the immature nervous system are poorly
under-stood. There have been studies conducted only in
children who were in utero during the atomic
bomb-ings of Japan or during diagnostic pelvic x-ray
procedures. Studies of the human population of Hiroshima found that small head size and mental retardation were associated with proximity to the
“hypocenter” and to a gestational age of less than
15 weeks at the time of exposure.23 Microcephaly
and reduced intellectual abilities are sufficiently common in both circumstances to be singled out as
the most reliable indicators of total body
irradia-tion-induced injury. The four children presented here all have normal head growth, and their most
recent performances on standardized tests show
normal development of intelligence, language, per-ception, and motor coordination.
An extensive review of the literature suggests
that hereditary factors in individuals and between
species play an important role in the response to
irradiation.24 Studies of the neonatal rat have
in-dicated that myelinogenesis is affected so that hypo- or amyelination and a decreased number of neuroglia are predictable.25 Lesions were found
most frequently in the subcortical white matter,
basal ganglia, hypothalamus, cerebellum, and
me-dulla, particularly in younger age groups.26 Basic
mechanisms underlying these lesions are still not
precisely known, but capillary endothelial cells are
thought to be the main targets of irradiation.27
These changes in brain development are thought to be relevant to the human species but, like the atomic bomb studies, have involved levels of irra-diation at high levels or at dose rates not likely to be used in the treatment of young children.
More-over, disadvantages of using animal models, even
studies of the Macaca mulatta,28 involve interpre-tation of experimental results derived from normal
brains that are not potentially affected by
hema-topoietic disease or chemotherapeutic agents. The
children presented in this series must all be
consid-ered highly vulnerable to neurotoxic effects of
irra-diation and chemotherapy, nevertheless, because of
age and disease. All four demonstrate
neurodevel-opmental courses that are contrary to predictions of higher risk of toxicity based upon the studies cited previously.
The question then arises as to the tolerance of the young brain to chemotherapy and total body irradiation prior to bone marrow transplantation. The use of 300 cGy for conditioning of patients with aplastic anemia greatly reduced the graft
re-jection rate.29 The two patients with aplastic
ane-mia presented here are a part of a larger series of eight children and adolescents with this disease given 300 rads of total body irradiation,
cyclophos-phamide, and bone marrow transplantation, who have been studied longitudinally (T. Kaleita, un-published observations) The lack, in that series, of the neurodevelopmental sequelae often associated with cranial irradiation of leukemic children sup-ports findings presented here from two young pa-tients with aplastic anemia in whom 300 rads of
total body irradiation did not by itself produce
significant neurologic sequelae. Unpublished obser-vations from Seattle (J. Sanders), where 1,000 cGy
in a single fraction is used prior to bone marrow
transplantation, indicate that young children may be susceptible to neurodevelopmental sequelae at
that dose.
The most surprising aspect of this report is the lack of neurodevelopmental abnormalities in the two leukemic patients who received 750 rads of
total body irradiation. With only two young
pa-tients studied after this dose, it is of course difficult to draw any conclusions. It may be speculated, however, that certain factors support the favorable outcome. Notably, neither of these children re-ceived any methotrexate, either systemically or in-trathecally, at any time in their course, in contra-distinction to leukemic children treated with more conventional CNS prophylaxis. The radiation was also delivered at a low-dose rate (3.7 cGy/min and
6.8 cGy/min compared with 100 to 300 cGy/min
for conventional cranial irradiation), which allows repair of sublethal damage to occur as treatment is given. This low-dose rate (4 to 10 cGy/min) was
also used for the patients with aplastic anemia
mentioned before and may have contributed to their apparent freedom from late sequelae as well. The rationale and details of these procedures are pre-sented in an earlier report.3#{176}
In summary, the long-term outcomes of these four children are encouraging for future infants and young children with acute leukemia or aplastic ane-mia. These experiences suggest that intensive con-ditioning with chemoradiotherapy may be associ-ated with a good neurologic outcome when admin-istered during early brain development. They further suggest that future therapeutic studies of
us-ing total body irradiation, cyclophosphamide, and bone marrow transplantation are not contraindi-cated by risk of debilitating neurodevelopmental sequelae.
ACKNOWLEDGMENTS
This work was supported by grants from the US
De-partment of Health and Human Services, Public Health
Service (CA16042, CA23175, and RR865) and the Cali-fornia Institute for Cancer Research (G80125).We are
grateful to the UCLA housestaff and nursing staff for
their assistance in the care of these patients and to
Marygrace Literatus and Shirley Knisley for preparation
of this manuscript.
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